PGD

تشخیص ژنتیکی قبل از لانه گزینی جنین

 (PGD)

اغلب بیماران سوال میکنند در مواقعی که احتمال خطر ابتلا به

بیماری خاصی بدلیل ازدواج فامیلی و.... بالا می باشد آیا راهی

وجود دارد تا بتوان در ابتدای حاملگی عدم ابتلا جنین را ثابت کرد؟

برای پاسخ به این سوال و نیز برای آشنایی با روش

PGD:Preimplantation Genetic Diagnosis

شما میتوانید به ادامه همین مطلب رجوع نمایید

پرده بکارت

 توضیحاتی در مورد پرده بکارت

ادامه مطلب 

واکسن HPV

 

 پرسش و پاسخ پیرامون برنامه مایه کوبی با واکسن H PV

در سال 2008 در بسایری از کشورها

تدبیری برای پیشگیری از سرطان دهانه رحم

پرسش HPV یعنی چه :

 Human papillomavirus: HPV پاپیلو وایروس انسانی نامی است که به

یک گروه از ویروس هائی داده شده که باعث زگیل های پوستی و زگیل های ناحیه تناسلی و برخی از سرطان ها می شوند .عفونت با HPV معمولا بدون علائم است.

برای اطلاع بیشتر از تارنمای www.ncirs.usyd.edu.au دیدن نمائید

پرسش: رابطه بینHPVو سرطان دهانه رحم چیست؟

دو نوع خاص از HPV عامل ایجاد حدود % 80  از سرطانهای دهانه رحم در استرالیا می باشند.

 برآورد ها حاکی از  آنست که ویروسHPV  در زنان از راه تماس جنسی منتقل میشود.

79 در صد از زنان استرالیا در زمانی از عمر خود دچار ویروس HPVمی شوند.

البته بطور طبیعی   بیشتر کسانی که دچار ویروسHPV می شوند  به سرطان دهانه رحم مبتلا نمی گردند ولی در این افرا د احتمال ابتلا بالاتر میرود و همانطور که گفته شد در ۸۰ در صد از سرطانهای دهانه رحم آلودگی قبلی با این ویروس دیده میشود.

پرسش: ویروس HPV  چگونه  پخش می شود؟

پاسخ: ویروس از راه تماس جنسی یا تماس بدن در ناحیه تناسلی از شخص  آلوده به ویروس  HPV  به شخص سالم سرایت می کند.این ویروس از راه خراش های بسیار

ظریف وارد پوست بدن می شود. این ویروس از راه خون یا سایر مایعات بدن پخش نمی شود. استفاده از کاندوم حفاظ محدودی می باشد چون کلیه پوست های ناحیه تناسلی را نمی پوشاند.

پرسش: چرا دختر ان بایستی واکسینه شوند ؟

پاسخ: این واکسن در پیشگیری از انواع عفونت هایHPV بسیار کارا می باشد.و از آنجاییکه برای این بیماری معالجه ای وجود ندارد و لی عوارض این  عفونتHPV  نظیر عفونت های زگیل های ناحیه تناسلی و غیر عادی شدن یاخته های دهانه رحم را می توان درمان کرد. البته واکسیناسیون نیز وقتی بیشترین کارائی را دارد که دختر یا زن هنوز به ویروس HPV آلوده نشده باشد.

حتی اکر زنان جوان فعالیت های مقاربتی خود را آغاز کرده باشند هم مایه کوبی

با این واکسن فوایدی دارد. چون اغلب آنان با تعداد اندکی از مردان همبستری

 دارند بدین معنی که احتمال ابتلای آنان به انواعی از ویروس های HPV هنوز هم کمتر است و ممکنست استفاده از این واکسن برای انها نیز مفید باشد

پرسش: چه کسی واجد شرایط دریافت واکسن HPV  به طور رایگان می باشد؟

پاسخ: برنامه مایه کوبی  به همه دختران دانش آموز با واکسنHPV

در سال  2007و 2008 به رسم رایگان در مدارس نیوساوت ولز انجام می شود.

پرسش: آیا دانش آموزان پسر هم در مدارس با واکسن HPV

مایه   کوبی می شوند؟

پاسخ: نه. تحقیق در مورد کارائی واکسنHPVدر پیشگیری از عفونت HPV

مردان هنوز پایان نیافته است.

 پرسش: واکسن HPV دارای چه مواد و اجزائی است؟

پاسخ: واکسن H pVحاوی دارو های کمکی، نمک طعام، آلومی نیوم ،yeast دارای مخمر .پُلی سُربات، و برات سدیم است. ،L-histidine اِل هیستیدین

اجزاء بالا تنها به مقدار نا چیزی در این واکسن موجود می باشند تا در کارائی

واکسن اثر مثبت داشته باشد یا اینکه کار نگهدارنده را به عهده دارند. این واکسن

دارای ویروس زنده نیست.

پرسش: چند نوبت واکسن لازم است و اثر واکسن تا چند وقت می

باشد؟

 پاسخ: واکسنHPV به صورت سه نوبت تزریق به عضله فوقانی بازو انجام می 

شود. معمولا این کار به فاصله شش ماه صورت می گیرد. زمان این برنامه ممکن

است بسته به اینکه چه وقت نهاد خدماتی بتواند از دخترتان در مدرسه اش دیدار

نماید، اندکی تغییر داشته باشد.

برای بهترین محافظت در برابر ویروس، لازم است که هر سه نوبت واکسن ظرف

مدت 12 ماه تزریق شود. پس از پایان مایه کوبی با سه نوبت واکسن اثر واکسن

به مدت 5 سال دوام خواهد یافت. در حال حاضر معلوم نیست که نوبت HPV

های یادآور هم ضرورت دارد یا نه.

 پرسش: عوارض جانبی واکسن HPV کدامند؟

پاسخ: واکسنHPV معمولا خیلی راحت تحمل می شود. اثرات جنبی مایه کوبی

خفیف بوده و معمولا شامل درد، ورم، و سرخی ناحیه تزریق می باشد. اثرات جنبی شدید معمولا بسیار نادر است. اطلاعات بیشتر در باره انواع رویدادهای مضری در رابطه با واکسن موجود است که در وب سایت http://www.csl.com.au/Gardasil.asp  آورده شده است

برای رفع ناراحتی بعد از زدن واکسن میشود یک پارچه مرطوب سرد را در محل

تزریق گذاشت و پاراستامول داد. پاراستامول را میشود برای پایین آوردن تب و رفع

ناراحتی داد. در صورتیکه تب ادامه پیدا کند یا واکنشی رخ دهد که به نظرتان

جدی یا غیر منتظره میآید، از یک پزشک راهنمایی بگیرید.

 پرسش: حساسیت بیش از حد Anaphylaxis یعنی چه؟

 پاسخ: حساسیت بیش از حد (Anaphylaxis )یک آلرژی بسیار شدید است که ممکن

است باعث از هوش رفتن و در صورتی که به سرعت درمان نشود، موجب مرگ شود.

این پدیده در موارد بسیار نادر پس از مایه کوبی رُخ می دهد. پرستاران به خوبی

در مورد درمان حساسیت بیش از حد آموزش دیده اند.

س. آیا زن جوانی که حامله است یا فکر میکند ممکن است حامله باشد باید واکسن بزند؟

ج. نه. هر زن جوانی که حامله است یا فکر میکند ممکن است حامله باشد نباید

این واکسن را بزند.

در روز کلینیک، پرستاری که واکسن را میزند از دختر شما خواهد پرسید که آیا

حامله است یا فکر میکند ممکن است حامله باشد. اگر دخترتان به این سوال جواب

مثبت بدهد واکسن به او زده نخواهد شد.

دخترتان تشویق خواهد شد که بلافاصله در این باره با پدر، مادر یا قیمش صحبت

کند و کمک پزشکی بگیرد. جزئیات تماس با یک سرویس ارجاع بهداشتی که به او

مشورت، پشتیبانی و راهنمایی عرضه خواهد کرد نیز به وی داده خواهد شد.

پرسش: آیا پس از واکسیناسیون باز هم آزمایش پاپ اسمیر

ضرورت دارد؟

پاسخ: بله. انجام آزمایشات پاپ اسمیر به طور مرتب باز هم اهمیت دارد چون HPV  یکی از عواملی است که  باعث ایجاد سرطان دهانه رحم HPVمیشود و همه انواع ویروس های HPV  نیز با واکسن مایه کوبی نشده اند لذا لازم . تمام زنانی که واکسینه شده اند نیز  از سن 18 سالگی یا 2 سال پس اولین مقاربت جنسی هرکدام که دیر تر بود

آزمایشات پاپ اسمیر را به طور مرتب همچنان انجام دهند.

این واکسن ۳ بار در یک دوره شش ماهه به دختر خانمهای ۹تا ۲۶ سال تجویز میشود

دستگاه تولید مثل در مردان

Print   Close Window

Note: Large images and tables on this page may necessitate printing in landscape mode. Copyright © The McGraw-Hill Companies.  All rights reserved. Harrison's Internal Medicine > Chapter 340. Disorders of the Testes and Male Reproductive System > Disorders of the Testes and Male Reproductive System: Introduction The male reproductive system regulates sex differentiation, virilization, and the hormonal changes that accompany puberty, ultimately leading to spermatogenesis and fertility. Under the control of the pituitary hormones—luteinizing hormone (LH) and follicle-stimulating hormone (FSH)—the Leydig cells of the testes produce testosterone and germ cells are nurtured by Sertoli cells to divide, differentiate, and mature into sperm. During embryonic development, testosterone and dihydrotestosterone (DHT) induce the wolffian duct and virilization of the external genitalia. During puberty, testosterone promotes somatic growth and the development of secondary sex characteristics. In the adult, testosterone is necessary for spermatogenesis and stimulation of libido and normal sexual function. This chapter focuses on the physiology of the testes and disorders associated with decreased androgen production, which may be caused by gonadotropin deficiency or by primary testis dysfunction. A variety of testosterone formulations now allow more physiologic androgen replacement. Infertility occurs in ~5% of men and is increasingly amenable to treatment by hormone replacement or by using sperm transfer techniques. For further discussion of sexual dysfunction, disorders of the prostate, and testicular cancer, see Chaps. 49, 91, 92, respectively. Development and Structure of the Testis The fetal testis develops from the undifferentiated gonad after expression of a genetic cascade that is initiated by the SRY (sex-related gene on the Y chromosome) (Chap. 343). SRY induces differentiation of Sertoli cells, which surround germ cells and, together with peritubular myoid cells, form testis cords that will later develop into seminiferous tubules. Fetal Leydig cells and endothelial cells migrate into the gonad from the adjacent mesonephros but may also arise from interstitial cells that reside between testis cords. Leydig cells produce testosterone, which supports the growth and differentiation of wolffian duct structures that develop into the epididymis, vas deferens, and seminal vesicles. Testosterone is also converted to DHT (see below), which induces formation of the prostate and the external male genitalia, including the penis, urethra, and scrotum. Testicular descent through the inguinal canal is controlled in part by Leydig cell production of insulin-like factor 3 (INSL3), which acts via a receptor termed Great (G protein–coupled receptor affecting testis descent). Sertoli cells produce müllerian inhibiting substance (MIS), which causes regression of the müllerian structures, including the fallopian tube, uterus, and upper segment of the vagina. Normal Male Pubertal Development Although puberty commonly refers to the maturation of the reproductive axis and the development of secondary sex characteristics, it involves a coordinated response of multiple hormonal systems including the adrenal gland and the growth hormone (GH) axis (Fig. 340-1). The development of secondary sex characteristics is initiated by adrenarche, which usually occurs between 6 and 8 years of age when the adrenal gland begins to produce greater amounts of androgens from the zona reticularis, the principal site of dehydroepiandrosterone (DHEA) production. The sex maturation process is greatly accelerated by the activation of the hypothalamic-pituitary axis and the production of gonadotropin-releasing hormone (GnRH). The GnRH pulse generator in the hypothalamus is active during fetal life and early infancy but is quiescent until the early stages of puberty, when the sensitivity to steroid inhibition is gradually lost, causing reactivation of GnRH secretion. Although the pathways that initiate reactivation of the GnRH pulse generator have been elusive, mounting evidence supports involvement of GPR54, a G protein–coupled receptor that binds an endogenous ligand, metastin. Individuals with mutations of GPR54 fail to enter puberty, and experiments in primates demonstrate that infusion of the ligand is sufficient to induce premature puberty. Leptin, a hormone produced by adipose cells, may play a permissive role in the onset of puberty, as leptin-deficient individuals also fail to enter puberty (Chap. 74). Figure 340-1 Pubertal events in males. Sexual maturity ratings for genitalia and pubic hair and divided into five stages. (From WA Marshall, JM Tanner: Variations in the pattern of pubertal changes in boys. Arch Dis Child 45:13, 1970.) The early stages of puberty are characterized by nocturnal surges of LH and FSH. Growth of the testes is usually the first sign of puberty, reflecting an increase in seminiferous tubule volume. Increasing levels of testosterone deepen the voice and increase muscle growth. Conversion of testosterone to DHT leads to growth of the external genitalia and pubic hair. DHT also stimulates prostate and facial hair growth and initiates recession of the temporal hairline. The growth spurt occurs at a testicular volume of about 10–12 mL. GH increases early in puberty and is stimulated in part by the rise in gonadal steroids. GH increases the level of insulin-like growth factor 1 (IGF-1), which enhances linear bone growth. The prolonged pubertal exposure to gonadal steroids (mainly estradiol) ultimately causes epiphyseal closure and limits further bone growth. Regulation of Testicular Function Regulation of the Hypothalamic-Pituitary-Testis Axis in Adult Man Hypothalamic GnRH regulates the production of the pituitary gonadotropins, LH and FSH (Fig. 340-2). GnRH is released in discrete pulses approximately every 2 h, resulting in corresponding pulses of LH and FSH. These dynamic hormone pulses account in part for the wide variations in LH and testosterone, even within the same individual. LH acts primarily on the Leydig cell to stimulate testosterone synthesis. The regulatory control of androgen synthesis is mediated by testosterone and estrogen feedback on both the hypothalamus and the pituitary. FSH acts on the Sertoli cell to regulate spermatogenesis and the production of Sertoli products such as inhibin B, which acts to selectively suppress pituitary FSH. Despite these somewhat distinct Leydig and Sertoli cell–regulated pathways, testis function is integrated at several levels: GnRH regulates both gonadotropins; spermatogenesis requires high levels of testosterone; numerous paracrine interactions between Leydig and Sertoli cells are necessary for normal testis function. Figure 340-2 Human pituitary gonadotropin axis, structure of testis, seminiferous tubule. E2, 17 estradiol; DHT, dihydrotestosterone. The Leydig Cell: Androgen Synthesis LH binds to its seven transmembrane, G protein–coupled receptor to activate the cyclic AMP pathway. Stimulation of the LH receptor induces steroid acute regulatory (StAR) protein, along with several steroidogenic enzymes involved in androgen synthesis. LH receptor mutations cause Leydig cell hypoplasia or agenesis, underscoring the importance of this pathway for Leydig cell development and function. The rate-limiting process in testosterone synthesis is the delivery of cholesterol by the StAR protein to the inner mitochondrial membrane. Peripheral benzodiazepine receptor, a mitochondrial cholesterol-binding protein, is also an acute regulator of Leydig cell steroidogenesis. The five major enzymatic steps involved in testosterone synthesis are summarized in Fig. 340-3. After cholesterol transport into the mitochondrion, the formation of pregnenolone by CYP11A1 (side chain cleavage enzyme) is a limiting enzymatic step. The 17-hydroxylase and the 17,20-lyase reactions are catalyzed by a single enzyme, CYP17; posttranslational modification (phosphorylation) of this enzyme and the presence of specific enzyme cofactors confer 17,20-lyase activity selectively in the testis and zona reticularis of the adrenal gland. Testosterone can be converted to the more potent DHT by 5-reductase, or it can be aromatized to estradiol by CYP19 (aromatase). Figure 340-3 The biochemical pathway in the conversion of 27-carbon sterol cholesterol to androgens and estrogens. Testosterone Transport and Metabolism In males, 95% of circulating testosterone is derived from testicular production (3–10 mg/d). Direct secretion of testosterone by the adrenal and the peripheral conversion of androstenedione to testosterone collectively account for another 0.5 mg/d of testosterone. Only a small amount of DHT (70 g/d) is secreted directly by the testis; most circulating DHT is derived from peripheral conversion of testosterone. Most of the daily production of estradiol (approximately 45 g/d) in men is derived from aromatase-mediated peripheral conversion of testosterone and androstenedione. Circulating testosterone is bound to two plasma proteins: sex hormone–binding globulin (SHBG) and albumin (Fig. 340-4). SHBG binds testosterone with much greater affinity than albumin. Only 0.5–3% of testosterone is unbound. According to the "free hormone" hypothesis, only the unbound fraction is biologically active; however, albumin-bound hormone dissociates readily in the capillaries and may be bioavailable. The finding that SHBG-bound testosterone may be internalized through endocytic pits by binding to a protein called megalin have challenged the "free hormone" hypothesis. SHBG concentrations are decreased by androgens, obesity, insulin, and nephrotic syndrome. Conversely, estrogen administration, hyperthyroidism, many chronic inflammatory illnesses, and aging are associated with high SHBG concentrations. Figure 340-4 Androgen metabolism and actions. SHBG, sex hormone–binding globulin. Testosterone is metabolized predominantly in the liver, although some degradation occurs in peripheral tissues, particularly the prostate and the skin. In the liver, testosterone is converted by a series of enzymatic steps that involve 5- and 5-reductases, 3- and 3-hydroxysteroid dehydrogenases, and 17-hydroxysteroid dehydrogenase into androsterone, etiocholanolone, DHT, and 3--androstanediol. These compounds undergo glucuronidation or sulfation before being excreted by the kidneys. Mechanism of Androgen Action The androgen receptor (AR) is structurally related to the nuclear receptors for estrogen, glucocorticoids, and progesterone (Chap. 332). The AR is encoded by a gene on the long arm of the X chromosome and has a molecular mass of about 110 kDa. A polymorphic region in the amino terminus of the receptor, which contains a variable number of glutamine repeats, modifies the transcriptional activity of the receptor. The AR protein is distributed in both the cytoplasm and the nucleus. Androgen binding to the AR causes it to translocate into the nucleus, where it binds to DNA or other transcription factors already bound to DNA. The ligand also induces conformational changes that allow the recruitment and assembly of tissue-specific cofactors. Thus, the AR is a ligand-regulated transcription factor. Some androgen effects may be mediated by nongenomic AR signal transduction pathways. Testosterone binds to AR with half the affinity of DHT. The DHT-AR complex also has greater thermostability and a slower dissociation rate than the testosterone-AR complex. However, the molecular basis for selective testosterone versus DHT actions remains incompletely explained. The Seminiferous Tubules: Spermatogenesis The seminiferous tubules are convoluted, closed loops with both ends emptying into the rete testis, a network of progressively larger efferent ducts that ultimately form the epididymis (Fig. 340-2). The seminiferous tubules total about 600 m in length and comprise about two-thirds of testis volume. The walls of the tubules are formed by polarized Sertoli cells that are apposed to peritubular myoid cells. Tight junctions between Sertoli cells create a blood-testis barrier. Germ cells comprise the majority of the seminiferous epithelium (~60%) and are intimately embedded within the cytoplasmic extensions of the Sertoli cells, which function as "nurse cells." Germ cells progress through characteristic stages of mitotic and meiotic divisions. A pool of type A spermatogonia serve as stem cells capable of self-renewal. Primary spermatocytes are derived from type B spermatogonia and undergo meiosis before progressing to spermatids that undergo spermiogenesis (a differentiation process involving chromatin condensation, acquisition of an acrosome, elongation of cytoplasm, and formation of a tail) and are released from Sertoli cells as mature spermatozoa. The complete differentiation process into mature sperm requires 74 days. Peristaltic-type action by peritubular myoid cells transports sperm into the efferent ducts. The spermatozoa spend an additional 21 days in the epididymis, where they undergo further maturation and capacitation. The normal adult testes produce >100 million sperm per day. Naturally occurring mutations in the FSH gene and in the FSH receptor confirm an important, but not essential, role for this pathway in spermatogenesis. Females with these mutations are hypogonadal and infertile because ovarian follicles do not mature; males exhibit variable degrees of reduced spermatogenesis, presumably because of impaired Sertoli cell function. Because Sertoli cells produce inhibin B, an inhibitor of FSH, seminiferous tubule damage (e.g., by radiation) causes a selective increase of FSH. Testosterone reaches very high concentrations locally in the testis and is essential for spermatogenesis. Several cytokines and growth factors are also involved in the regulation of spermatogenesis by paracrine and autocrine mechanisms. A number of knockout mouse models exhibit impaired germ cell development or spermatogenesis, presaging possible mutations associated with male infertility. The human Y chromosome contains a small pseudoautosomal region that can recombine with homologous regions of the X chromosome. Most of the Y chromosome does not recombine with the X chromosome and is referred to as the male-specific region of the Y (MSY). The MSY contains 156 transcription units that encode for 26 proteins, including nine families of Y-specific multicopy genes; many of these Y-specific genes are also testis-specific and necessary for spermatogenesis. Microdeletions of several Y chromosome azoospermia factor (AZF) genes (e.g., RNA-binding motif, RBM; deleted in azoospermia, DAZ) are associated with oligospermia or azoospermia. Male Factor Infertility: Treatment Treatment options for male factor infertility have expanded greatly in recent years. Secondary hypogonadism is highly amenable to treatment with pulsatile GnRH or gonadotropins (see below). In vitro techniques have provided new opportunities for patients with primary testicular failure and disorders of sperm transport. Choice of initial treatment options depends on sperm concentration and motility. Expectant management should be attempted initially in men with mild male factor infertility (sperm count of 15–20 x 106/mL and normal motility). Moderate male factor infertility (10–15 x 106/mL and 20–40% motility) should begin with intrauterine insemination alone or in combination with treatment of the female partner with clomiphene or gonadotropins, but it may require in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI). For men with a severe defect (sperm count of <10 x 106/mL, 10% motility), IVF with ICSI or donor sperm should be used. Clinical and Laboratory Evaluation of Male Reproductive Function History and Physical Examination The history should focus on developmental stages such as puberty and growth spurts, as well as androgen-dependent events such as early morning erections, frequency and intensity of sexual thoughts, and frequency of masturbation or intercourse. Although libido and the overall frequency of sexual acts are decreased in androgen-deficient men, young hypogonadal men may achieve erections in response to visual erotic stimuli. Men with acquired androgen deficiency often report decreased energy and increased irritability. The physical examination should focus on secondary sex characteristics such as hair growth, gynecomastia, testicular volume, prostate, and height and body proportions. Eunuchoid proportions are defined as an arm span >2 cm greater than height and suggest that androgen deficiency occurred before epiphyseal fusion. Hair growth in the face, axilla, chest, and pubic regions is androgen-dependent; however, changes may not be noticeable unless androgen deficiency is severe and prolonged. Ethnicity also influences the intensity of hair growth (Chap. 50). Testicular volume is best assessed by using a Prader orchidometer. Testes range from 3.5 to 5.5 cm in length, which corresponds to a volume of 12–25 mL. Advanced age does not influence testicular size, although the consistency becomes less firm. Asian men generally have smaller testes than western Europeans, independent of differences in body size. Because of its possible role in infertility, the presence of varicocele should be sought by palpation while the patient is standing; it is more common on the left side. Patients with Klinefelter syndrome have markedly reduced testicular volumes (1–2 mL). In congenital hypogonadotropic hypogonadism, testicular volumes provide a good index for the degree of gonadotropin deficiency and the likelihood of response to therapy. Gonadotropin and Inhibin Measurements LH and FSH are measured using two-site immunoradiometric, immunofluorometric, or chemiluminescent assays, which have very low cross-reactivity with other pituitary glycoprotein hormones and human chorionic gonadotropin (hCG) and have sufficient sensitivity to measure the low levels present in patients with hypogonadotropic hypogonadism. In men with a low testosterone level, an LH level can distinguish primary (high LH) versus secondary (low or inappropriately normal LH) hypogonadism. An elevated LH level indicates a primary defect at the testicular level, whereas a low or inappropriately normal LH level suggests a defect at the hypothalamic-pituitary level. LH pulses occur about every 1–3 h in normal men. Thus, gonadotropin levels fluctuate, and samples should be pooled or repeated when results are equivocal. FSH is less pulsatile than LH because it has a longer half-life. Increased FSH suggests damage to the seminiferous tubules. Inhibin B, a Sertoli cell product that suppresses FSH, is reduced with seminiferous tubule damage. Inhibin B is a dimer with -B subunits and is measured by two-site immunoassays. GnRH Stimulation Testing The GnRH test is performed by measuring LH and FSH concentrations at baseline and at 30 and 60 min after intravenous administration of 100 g of GnRH. A minimally acceptable response is a twofold LH increase and a 50% FSH increase. In the prepubertal period or with severe GnRH deficiency, the gonadotrope may not respond to a single bolus of GnRH because it has not been primed by endogenous hypothalamic GnRH; in these patients, GnRH responsiveness may be restored by chronic, pulsatile GnRH administration. With the availability of sensitive and specific LH assays, GnRH stimulation testing is used rarely except to evaluate gonadotrope function in patients who have undergone pituitary surgery or have a space-occupying lesion in the hypothalamic-pituitary region. Testosterone Assays Total Testosterone Total testosterone includes both unbound and protein-bound testosterone and is measured by radioimmunoassays, immunometric assays, or liquid chromatography tandem mass spectrometry (LC-MS/MS). LC-MS/MS involves extraction of serum by organic solvents, separation of testosterone from other steroids by high-performance liquid chromatography and mass spectrometry, and quantitation of unique testosterone fragments by mass spectrometry. LC-MS/MS provides accurate and sensitive measurements of testosterone levels even in the low range and is emerging as the method of choice for testosterone measurement. A single random sample provides a good approximation of the average testosterone concentration with the realization that testosterone levels fluctuate in response to pulsatile LH. Testosterone is generally lower in the late afternoon and is reduced by acute illness. The testosterone concentration in healthy young men ranges from 300 to 1000 ng/dL in most laboratories, although these reference ranges are not derived from population-based random samples. Alterations in SHBG levels due to aging, obesity, some types of medications, or chronic illness, or on a congenital basis, can affect total testosterone levels. Measurement of Unbound Testosterone Levels Most circulating testosterone is bound to SHBG and to albumin; only 0.5–3% of circulating testosterone is unbound, or "free." The unbound testosterone concentration can be measured by equilibrium dialysis or calculated from total testosterone, SHBG, and albumin concentrations by using published mass-action equations. Tracer analogue methods are relatively inexpensive and convenient, but they are inaccurate. Bioavailable testosterone refers to unbound testosterone plus testosterone that is loosely bound to albumin; it can be estimated by the ammonium sulfate precipitation method. hCG Stimulation Test The hCG stimulation test is performed by administering a single injection of 1500–4000 IU of hCG intramuscularly and measuring testosterone levels at baseline and 24, 48, 72, and 120 h after hCG injection. An alternative regimen involves three injections of 1500 units of hCG on successive days and measuring testosterone levels 24 h after the last dose. An acceptable response to hCG is a doubling of the testosterone concentration in adult men. In prepubertal boys, an increase in testosterone to >150 ng/dL indicates the presence of testicular tissue. No response may indicate an absence of testicular tissue or marked impairment of Leydig cell function. Measurement of MIS, a Sertoli cell product, is also used to detect the presence of testes in prepubertal boys with cryptorchidism. Semen Analysis Semen analysis is the most important step in the evaluation of male infertility. Samples are collected by masturbation following a period of abstinence for 2–3 days. Semen volumes and sperm concentrations vary considerably among fertile men, and several samples may be needed before concluding that the results are abnormal. Analysis should be performed within an hour of collection. The normal ejaculate volume is 2–6 mL and contains sperm counts of >20 million/mL, with a motility of >50% and >15% normal morphology. Some men with low sperm counts are nevertheless fertile. A variety of tests for sperm function can be performed in specialized laboratories, but these add relatively little to the treatment options. Testicular Biopsy Testicular biopsy is useful in some patients with oligospermia or azoospermia as an aid in diagnosis and indication for the feasibility of treatment. Using local anesthesia, fine-needle aspiration biopsy is performed to aspirate tissue for histology. Alternatively, open biopsies can be performed under local or general anesthesia when more tissue is required. A normal biopsy in an azoospermic man with a normal FSH level suggests obstruction of the vas deferens, which may be correctable surgically. Biopsies are also used to harvest sperm for ICSI and to classify disorders such as hypospermatogenesis (all stages present but in reduced numbers), germ cell arrest (usually at primary spermatocyte stage), and Sertoli cell–only syndrome (absent germ cells) or hyalinization (sclerosis with absent cellular elements). Disorders of Puberty Precocious Puberty Puberty in boys before age 9 is considered precocious. Isosexual precocity refers to premature sexual development consistent with phenotypic sex and includes features such as the development of facial hair and phallic growth. Isosexual precocity is divided into gonadotropin-dependent and gonadotropin-independent causes of androgen excess (Table 340-1). Heterosexual precocity refers to the premature development of estrogenic features in boys, such as breast development. Table 340-1 Causes of Precocious or Delayed Puberty in Boys I. Precocious puberty A. Gonadotropin-dependent 1. Idiopathic 2. Hypothalamic hamartoma or other lesions 3. CNS tumor or inflammatory state B. Gonadotropin-independent 1. Congenital adrenal hyperplasia 2. hCG -secreting tumor 3. McCune-Albright syndrome 4. Activating LH receptor mutation 5. Exogenous androgens II. Delayed puberty A. Constitutional delay of growth and puberty B. Systemic disorders 1. Chronic disease 2. Malnutrition 3. Anorexia nervosa C. CNS tumors and their treatment (radiotherapy and surgery) D. Hypothalamic-pituitary causes of pubertal failure (low gonadotropins) 1. Congenital disorders (Table 340-2) a. Hypothalamic syndromes (e.g., Prader-Willi) b. Idiopathic hypogonadotropic hypogonadism c. Kallmann syndrome d. GnRH receptor mutations e. Adrenal hypoplasia congenita f. PROP1 mutations g. Other mutations affecting pituitary development/function 2. Acquired disorders a. Pituitary tumors b. Hyperprolactinemia E. Gonadal causes of pubertal failure (elevated gonadotropins) 1. Klinefelter syndrome 2. Bilateral undescended testes or anorchia 3. Orchitis 4. Chemotherapy or radiotherapy F. Androgen insensitivity Note: CNS, central nervous system; hCG, human chronic gonadotropin; LH, luteinizing hormone; GnRH, gonadotropin-releasing hormone. Gonadotropin-Dependent Precocious Puberty This disorder, called central precocious puberty (CPP), is less common in boys than in girls. It is caused by premature activation of the GnRH pulse generator, sometimes because of central nervous system (CNS) lesions such as hypothalamic hamartomas, but it is often idiopathic. CPP is characterized by gonadotropin levels that are inappropriately elevated for age. Because pituitary priming has occurred, GnRH elicits LH and FSH responses typical of those seen in puberty or in adults. MRI should be performed to exclude a mass, structural defect, infection, or inflammatory process. Gonadotropin-Independent Precocious Puberty Androgens from the testis or the adrenal are increased but gonadotropins are low. This group of disorders includes hCG-secreting tumors; congenital adrenal hyperplasia; sex steroid–producing tumors of the testis, adrenal, and ovary; accidental or deliberate exogenous sex steroid administration; hypothyroidism; and activating mutations of the LH receptor or Gs subunit. Familial Male-Limited Precocious Puberty Also called testotoxicosis, familial male-limited precocious puberty is an autosomal dominant disorder caused by activating mutations in the LH receptor, leading to constitutive stimulation of the cyclic AMP pathway and testosterone production. Clinical features include premature androgenization in boys, growth acceleration in early childhood, and advanced bone age followed by premature epiphyseal fusion. Testosterone is elevated, and LH is suppressed. Treatment options include inhibitors of testosterone synthesis (e.g., ketoconazole), androgen receptor antagonists (e.g., flutamide), and aromatase inhibitors (e.g., anastrazole). Mccune-Albright Syndrome This is a sporadic disorder caused by somatic (postzygotic) activating mutations in the Gs subunit that links G protein–coupled receptors to intracellular signaling pathways (Chap. 349). The mutations impair the guanosine triphosphatase activity of the Gs protein, leading to constitutive activation of adenylyl cyclase. Like activating LH receptor mutations, this stimulates testosterone production and causes gonadotropin-independent precocious puberty. In addition to sexual precocity, affected individuals may have autonomy in the adrenals, pituitary, and thyroid glands. Café au lait spots are characteristic skin lesions that reflect the onset of the somatic mutations in melanocytes during embryonic development. Polyostotic fibrous dysplasia is caused by activation of the parathyroid hormone receptor pathway in bone. Treatment is similar to that in patients with activating LH receptor mutations. Bisphosphonates have been used to treat bone lesions. Congenital Adrenal Hyperplasia Boys with congenital adrenal hyperplasia (CAH) who are not well controlled with glucocorticoid suppression of adrenocorticotropic hormone (ACTH) can develop premature virilization because of excessive androgen production by the adrenal gland (Chaps. 336 and 343). LH is low, and the testes are small. Rarely, adrenal rests may develop within the testis because of chronic ACTH stimulation. Heterosexual Sexual Precocity Breast enlargement in prepubertal boys can result from familial aromatase excess, estrogen-producing tumors in the adrenal gland, Sertoli cell tumors in the testis, marijuana smoking, or exogenous estrogens or androgens. Occasionally, germ cell tumors that secrete hCG can be associated with breast enlargement due to excessive stimulation of estrogen production (see "Gynecomastia," below). Approach to the Patient: Precocious Puberty After verification of precocious development, serum LH and FSH levels should be measured to determine whether gonadotropins are increased in relation to chronologic age (gonadotropin-dependent) or whether sex steroid secretion is occurring independent of LH and FSH (gonadotropin-independent). In children with gonadotropin-dependent precocious puberty, CNS lesions should be excluded by history, neurologic examination, and MRI scan of the head. If organic causes are not found, one is left with the diagnosis of idiopathic central precocity. Patients with high testosterone but suppressed LH concentrations have gonadotropin-independent sexual precocity; in these patients, DHEA sulfate (DHEAS) and 17-hydroxyprogesterone should be measured. High levels of testosterone and 17-hydroxyprogesterone suggest the possibility of CAH due to 21-hydroxylase or 11-hydroxylase deficiency. If testosterone and DHEAS are elevated, adrenal tumors should be excluded by obtaining a CT scan of the adrenal glands. Patients with elevated testosterone but without increased 17-hydroxyprogesterone or DHEAS should undergo careful evaluation of the testis by palpation and ultrasound to exclude a Leydig cell neoplasm. Activating mutations of the LH receptor should be considered in children with gonadotropin-independent precocious puberty in whom CAH, androgen abuse, and adrenal and testicular neoplasms have been excluded. Precocious Puberty: Treatment In patients with a known cause (e.g., a CNS lesion or a testicular tumor), therapy should be directed towards the underlying disorder. In patients with idiopathic CPP, long-acting GnRH analogues can be used to suppress gonadotropins and decrease testosterone, halt early pubertal development, delay accelerated bone maturation, and prevent early epiphyseal closure, without causing osteoporosis. The treatment is most effective for increasing final adult height if it is initiated before age 6. Puberty resumes after discontinuation of the GnRH analogue. Counseling is an important aspect of the overall treatment strategy. In children with gonadotropin-independent precocious puberty, inhibitors of steroidogenesis, such as ketoconazole, and AR antagonists have been used empirically. Long-term treatment with spironolactone (a weak androgen antagonist), testolactone (aromatase inhibitor), and ketoconazole has been reported to normalize growth rate and bone maturation and to improve predicted height in small, nonrandomized trials in boys with familial male-limited precocious puberty. Delayed Puberty Puberty is delayed in boys if it has not ensued by age 14, an age that is 2–2.5 standard deviations above the mean for healthy children. Delayed puberty is more common in boys than in girls. There are four main categories of delayed puberty: (1) constitutional delay of growth and puberty (~60% of cases); (2) functional hypogonadotropic hypogonadism caused by systemic illness or malnutrition (~20% of cases); (3) hypogonadotropic hypogonadism caused by genetic or acquired defects in the hypothalamic-pituitary region (~10% of cases); and (4) hypergonadotropic hypogonadism secondary to primary gonadal failure (~15% of cases) (Table 340-1). Functional hypogonadotropic hypogonadism is more common in girls than in boys. Permanent causes of hypogonadotropic or hypergonadotropic hypogonadism are identified in <25% of boys with delayed puberty. Approach to the Patient: Delayed Puberty Any history of systemic illness, eating disorders, excessive exercise, social and psychological problems, and abnormal patterns of linear growth during childhood should be verified. Boys with pubertal delay may have accompanying emotional and physical immaturity relative to their peers, which can be a source of anxiety. Physical examination should focus on height; arm span; weight; visual fields; and secondary sex characteristics, including hair growth, testicular volume, phallic size, and scrotal reddening and thinning. Testicular size >2.5 cm generally indicates that the child has entered puberty. The main diagnostic challenge is to distinguish those with constitutional delay, who will progress through puberty at a later age, from those with an underlying pathologic process. Constitutional delay should be suspected when there is a family history and when there are delayed bone age and short stature. Pituitary priming by pulsatile GnRH is required before LH and FSH are synthesized and secreted normally. Thus, blunted responses to exogenous GnRH can be seen in patients with constitutional delay, GnRH deficiency, or pituitary disorders (see "GnRH Stimulation Testing," above). On the other hand, low-normal basal gonadotropin levels or a normal response to exogenous GnRH is consistent with an early stage of puberty, which is often heralded by nocturnal GnRH secretion. Thus, constitutional delay is a diagnosis of exclusion that requires ongoing evaluation until the onset of puberty and the growth spurt. Delayed Puberty: Treatment If therapy is considered appropriate, it can begin with 25–50 mg testosterone enanthate or testosterone cypionate every 2 weeks, or by using a 2.5-mg testosterone patch or 25-mg testosterone gel. Because aromatization of testosterone to estrogen is obligatory for mediating androgen effects on epiphyseal fusion, concomitant treatment with aromatase inhibitors may allow attainment of greater final adult height. Testosterone treatment should be interrupted after 6 months to determine if endogenous LH and FSH secretion have ensued. Other causes of delayed puberty should be considered when there are associated clinical features or when boys do not enter puberty spontaneously after a year of observation or treatment. Reassurance without hormonal treatment is appropriate for many individuals with presumed constitutional delay of puberty. However, the impact of delayed growth and pubertal progression on a child's social relationships and school performance should be weighed. Also, boys with constitutional delay of puberty are less likely to achieve their full genetic height potential and have reduced total body bone mass as adults, mainly due to narrow limb bones and vertebrae as a result of impaired periosteal expansion during puberty. Administration of androgen therapy to boys with constitutional delay does not affect final height, and when administered with an aromatase inhibitor, it may improve final height. Disorders of the Male Reproductive Axis during Adulthood Hypogonadotropic Hypogonadism Because LH and FSH are trophic hormones for the testes, impaired secretion of these pituitary gonadotropins results in secondary hypogonadism, which is characterized by low testosterone in the setting of low LH and FSH. Those with the most severe deficiency have complete absence of pubertal development, sexual infantilism, and, in some cases, hypospadias and undescended testes. Patients with partial gonadotropin deficiency have delayed or arrested sex development. The 24-h LH secretory profiles are heterogeneous in patients with hypogonadotropic hypogonadism, reflecting variable abnormalities of LH pulse frequency or amplitude. In severe cases, basal LH is low and there are no LH pulses. A smaller subset of patients has low-amplitude LH pulses or markedly reduced pulse frequency. Occasionally, only sleep-entrained LH pulses occur, reminiscent of the pattern seen in the early stages of puberty. Hypogonadotropic hypogonadism can be classified into congenital and acquired disorders. Congenital disorders most commonly involve GnRH deficiency, which leads to gonadotropin deficiency. Acquired disorders are much more common than congenital disorders and may result from a variety of sellar mass lesions or infiltrative diseases of the hypothalamus or pituitary. Congenital Disorders Associated with Gonadotropin Deficiency Most cases of congenital hypogonadotropic hypogonadism are idiopathic, despite extensive endocrine testing and imaging studies of the sellar region. Among known causes, familial hypogonadotropic hypogonadism can be transmitted as an X-linked (20%), autosomal recessive (30%), or autosomal dominant (50%) trait. Some individuals with idiopathic hypogonadotropic hypogonadism (IHH) have sporadic mutations in the same genes that cause inherited forms of the disorder. Kallmann syndrome is an X-linked disorder caused by mutations in the KAL1 gene, which encodes anosmin, a protein that mediates the migration of neural progenitors of the olfactory bulb and GnRH-producing neurons. These individuals have GnRH deficiency and variable combinations of anosmia or hyposmia, renal defects, and neurologic abnormalities including mirror movements. Gonadotropin secretion and fertility can be restored by administration of pulsatile GnRH or by gonadotropin replacement. Mutations in the FGFR1 gene cause an autosomal dominant form of hypogonadotropic hypogonadism that clinically resembles Kallmann syndrome. Prokineticin 2 (PROK2) also encodes a protein involved in migration and development of olfactory and GnRH neurons. Recessive mutations in PROK2 cause anosmia and hypogonadotropic hypogonadism. The FGFR1 gene product may be the receptor for the KAL1 gene product, anosmin, thereby explaining the similarity in clinical features. Other autosomal dominant causes remain unexplained. X-linked hypogonadotropic hypogonadism also occurs in adrenal hypoplasia congenita, a disorder caused by mutations in the DAX1 gene, which encodes a nuclear receptor in the adrenal gland and reproductive axis. Adrenal hypoplasia congenita is characterized by absent development of the adult zone of the adrenal cortex, leading to neonatal adrenal insufficiency. Puberty usually does not occur or is arrested, reflecting variable degrees of gonadotropin deficiency. Although sexual differentiation is normal, some patients have testicular dysgenesis and impaired spermatogenesis despite gonadotropin replacement. Less commonly, adrenal hypoplasia congenita, sex reversal, and hypogonadotropic hypogonadism can be caused by mutations of steroidogenic factor 1 (SF1). GnRH receptor mutations account for ~40% of autosomal recessive and 10% of sporadic cases of hypogonadotropic hypogonadism. These patients have decreased LH response to exogenous GnRH. Some receptor mutations alter GnRH binding affinity, allowing apparently normal responses to pharmacologic doses of exogenous GnRH, whereas other mutations may alter signal transduction downstream of hormone binding. Recessive mutations in the G protein–coupled receptor GPR54 cause gonadotropin deficiency without anosmia. Patients retain responsiveness to exogenous GnRH, suggesting an abnormality in the neural pathways controlling GnRH release. Rarely, recessive mutations in the LH or FSH genes have been described in patients with selective deficiencies of these gonadotropins. Deletions or mutations of the GnRH gene have not been found in patients with hypogonadotropic hypogonadism. A number of homeodomain transcription factors are involved in the development and differentiation of the specialized hormone-producing cells within the pituitary gland (Table 340-2). Patients with mutations of PROP1 have combined pituitary hormone deficiency that includes GH, prolactin (PRL) thyroid-stimulating hormone (TSH), LH, and FSH, but not ACTH. LHX3 mutations cause combined pituitary hormone deficiency in association with cervical spine rigidity. HESX1 mutations cause septooptic dysplasia and combined pituitary hormone deficiency. Table 340-2 Causes of Congenital Hypogonadotropic Hypogonadism Gene Locus Inheritance Associated Features KAL1  Xp22 X-linked Anosmia, renal agenesis, synkinesia, cleft lip/palate, oculomotor/visuospatial defects, gut malrotations NELF  9q34.3 AR Anosmia, hypogonadotropic hypogonadism FGFR1  8p11-p12 AD Anosmia, cleft lip/palate, synkinesia, syndactyly PROK2  20p13 AR Anosmia, hypogonadotropic hypogonadism LEP  7q31 AR Obesity LEPR  1p31 AR Obesity PC1  5q15-21 AR Obesity, diabetes mellitus, ACTH deficiency HESX1  3p21 AR AD Septooptic dysplasia, CPHD Isolated GH insufficiency LHX3  9q34 AR CPHD (ACTH spared), cervical spine rigidity PROP1  5q35 AR CPHD (ACTH usually spared) GPR54  19p13 AR None GNRHR  4q21 AR None FSHb  11p13 AR LH LHb  19q13 AR FSH SF1 (NR5A1)  9p33 AD/AR Primary adrenal failure, XY sex reversal DAX1 (NR0B1)  Xp21 X-linked Primary adrenal failure, impaired spermatogenesis Abbreviations: ACTH, adrenocorticotropic hormone; AD, autosomal dominant; AR, autosomal recessive; CPHD, combined pituitary hormone deficiency; KAL1, Interval-1 gene; NELF, nasal embryonic LHRH factor; FGFR1, fibroblast growth factor receptor 1; PROK2, prokineticin 2; LEP, leptin; LEPR, leptin receptor; PC1, prohormone convertase 1; HESX1, homeo box gene expressed in embryonic stem cells 1; LHX3, LIM homeobox gene 3; PROP1, Prophet of Pit 1; GPR54, G protein–coupled receptor 54; GNRHR, gonadotropin-releasing hormone receptor; FSHb, follicle-stimulating hormone b-subunit; LHb, luteinizing hormone b-subunit; SF1, steroidogenic factor 1; DAX1, dosage-sensitive sex-reversal, adrenal hypoplasia congenita, X-chromosome. Prader-Willi syndrome is characterized by obesity, hypotonic musculature, mental retardation, hypogonadism, short stature, and small hands and feet. Prader-Willi syndrome is a genomic imprinting disorder caused by deletions of the proximal portion of paternally derived chromosome 15q, uniparental disomy of the maternal alleles, or mutations of the genes/loci involved in imprinting (Chap. 63). Laurence-Moon syndrome is an autosomal recessive disorder characterized by obesity, hypogonadism, mental retardation, polydactyly, and retinitis pigmentosa. Recessive mutations of leptin, or its receptor, cause severe obesity and pubertal arrest, apparently because of hypothalamic GnRH deficiency (Chap. 74). Acquired Hypogonadotropic Disorders Severe Illness, Stress, Malnutrition, and Exercise These may cause reversible gonadotropin deficiency. Although gonadotropin deficiency and reproductive dysfunction are well documented in these conditions in women, men exhibit similar but less-pronounced responses. Unlike women, most male runners and other endurance athletes have normal gonadotropin and sex steroid levels, despite low body fat and frequent intensive exercise. Testosterone levels fall at the onset of illness and recover during recuperation. The magnitude of gonadotropin suppression generally correlates with the severity of illness. Although hypogonadotropic hypogonadism is the most common cause of androgen deficiency in patients with acute illness, some have elevated levels of LH and FSH, which suggest primary gonadal dysfunction. The pathophysiology of reproductive dysfunction during acute illness is unknown but likely involves a combination of cytokine and/or glucocorticoid effects. There is a high frequency of low testosterone levels in patients with chronic illnesses such as HIV infection, end-stage renal disease, chronic obstructive lung disease, and many types of cancer and in patients receiving glucocorticoids. About 20% of HIV-infected men with low testosterone levels have elevated LH and FSH levels; these patients presumably have primary testicular dysfunction. The remaining 80% have either normal or low LH and FSH levels; these men have a central hypothalamic-pituitary defect or a dual defect involving both the testis and the hypothalamic-pituitary centers. Muscle wasting is common in chronic diseases associated with hypogonadism, which also leads to debility, poor quality of life, and adverse outcome of disease. There is great interest in exploring strategies that can reverse androgen deficiency or attenuate the sarcopenia associated with chronic illness. Men using opioids for relief of cancer or noncancerous pain or because of addiction often have suppressed testosterone and LH levels; the degree of suppression is dose-related. Opioids suppress GnRH secretion and alter the sensitivity to feedback inhibition by gonadal steroids. Men who are heavy users of marijuana have decreased testosterone secretion and sperm production. The mechanism of marijuana-induced hypogonadism is decreased GnRH secretion. Gynecomastia observed in marijuana users can also be caused by plant estrogens in crude preparations. Obesity In men with mild to moderate obesity, SHBG levels decrease in proportion to the degree of obesity, resulting in lower total testosterone levels. However, free testosterone levels usually remain within the normal range. The decrease in SHBG levels is caused by increased circulating insulin, which inhibits SHBG production. Estradiol levels are higher in obese men compared to healthy, nonobese controls, because of aromatization of testosterone to estradiol in adipose tissue. Weight loss is associated with reversal of these abnormalities including an increase in total and free testosterone levels and a decrease in estradiol levels. A subset of massively obese men may have a defect in the hypothalamic-pituitary axis as suggested by low free testosterone in the absence of elevated gonadotropins. Weight gain in adult men can accelerate the rate of age-related decline in testosterone levels. Hyperprolactinemia (See also Chap. 333.) Elevated PRL levels are associated with hypogonadotropic hypogonadism. PRL inhibits hypothalamic GnRH secretion either directly or through modulation of tuberoinfundibular dopaminergic pathways. A PRL-secreting tumor may also destroy the surrounding gonadotropes by invasion or compression of the pituitary stalk. Treatment with dopamine agonists reverses gonadotropin deficiency, although there may be a delay relative to PRL suppression. Sellar Mass Lesions Neoplastic and nonneoplastic lesions in the hypothalamus or pituitary can directly or indirectly affect gonadotrope function. In adults, pituitary adenomas constitute the largest category of space-occupying lesions affecting gonadotropin and other pituitary hormone production. Pituitary adenomas that extend into the suprasellar region can impair GnRH secretion and mildly increase PRL secretion (usually <50 g/L) because of impaired tonic inhibition by dopaminergic pathways. These tumors should be distinguished from prolactinomas, which typically secrete higher PRL levels. The presence of diabetes insipidus suggests the possibility of a craniopharyngioma, infiltrative disorder, or other hypothalamic lesions (Chap. 334). Hemochromatosis (See also Chap. 351.) Both the pituitary and testis can be affected by excessive iron deposition. However, the pituitary defect is the predominant lesion in most patients with hemochromatosis and hypogonadism. The diagnosis of hemochromatosis is suggested by the association of characteristic skin discoloration, hepatic enlargement or dysfunction, diabetes mellitus, arthritis, cardiac conduction defects, and hypogonadism. Primary Testicular Causes of Hypogonadism Common causes of primary testicular dysfunction include Klinefelter syndrome, uncorrected cryptorchidism, cancer chemotherapy, radiation to the testes, trauma, torsion, infectious orchitis, HIV infection, anorchia syndrome, and myotonic dystrophy. Primary testicular disorders may be associated with impaired spermatogenesis, decreased androgen production, or both. See Chap. 343 for disorders of testis development, androgen synthesis, and androgen action. Klinefelter Syndrome (See also Chap. 343.) Klinefelter syndrome is the most common chromosomal disorder associated with testicular dysfunction and male infertility. It occurs in about 1 in 1000 live-born males. Azoospermia is the rule in men with Klinefelter syndrome who have the 47,XXY karyotype; however, men with mosaicism may have germ cells, especially at a younger age. Testicular histology shows hyalinization of seminiferous tubules and absence of spermatogenesis. Although their function is impaired, the number of Leydig cells appears to increase. Testosterone is decreased and estradiol is increased, leading to clinical features of undervirilization and gynecomastia. Men with Klinefelter syndrome are at increased risk of breast cancer, non-Hodgkin's lymphoma, and lung cancer, and reduced risk of prostate cancer. Periodic mammography for breast cancer surveillance is recommended for men with Klinefelter syndrome. Cryptorchidism Cryptorchidism occurs when there is incomplete descent of the testis from the abdominal cavity into the scrotum. About 3% of full-term and 30% of premature male infants have at least one cryptorchid testis at birth, but descent is usually complete by the first few weeks of life. The incidence of cryptorchidism is <1% by 9 months of age. Cryptorchidism is associated with increased risk of malignancy and infertility. Unilateral cryptorchidism, even when corrected before puberty, is associated with decreased sperm count, possibly reflecting unrecognized damage to the fully descended testis or other genetic factors. Epidemiologic, clinical, and molecular evidence supports the idea that cryptorchidism, hypospadias, impaired spermatogenesis, and testicular cancer may be causally related to common genetic and environment perturbations, and are components of the testicular dysgenesis syndrome. Acquired Testicular Defects Viral orchitis may be caused by the mumps virus, echovirus, lymphocytic choriomeningitis virus, and group B arboviruses. Orchitis occurs in as many as one-fourth of adult men with mumps; the orchitis is unilateral in about two-thirds and bilateral in the remainder. Orchitis usually develops a few days after the onset of parotitis but may precede it. The testis may return to normal size and function or undergo atrophy. Semen analysis returns to normal for three-fourths of men with unilateral involvement but normal for only one-third of men with bilateral orchitis. Trauma, including testicular torsion, can also cause secondary atrophy of the testes. The exposed position of the testes in the scrotum renders them susceptible to both thermal and physical trauma, particularly in men with hazardous occupations. The testes are sensitive to radiation damage. Doses >200 mGy (20 rad) are associated with increased FSH and LH levels and damage to the spermatogonia. After ~800 mGy (80 rad), oligospermia or azoospermia develops, and higher doses may obliterate the germinal epithelium. Permanent androgen deficiency in adult men is uncommon after therapeutic radiation; however, most boys given direct testicular radiation therapy for acute lymphoblastic leukemia have permanently low testosterone levels. Sperm banking should be considered before patients undergo radiation treatment or chemotherapy. Drugs interfere with testicular function by several mechanisms, including inhibition of testosterone synthesis (e.g., ketoconazole), blockade of androgen action (e.g., spironolactone), increased estrogen (e.g., marijuana), or direct inhibition of spermatogenesis (e.g., chemotherapy). Combination chemotherapy for acute leukemia, Hodgkin's disease, and testicular and other cancers may impair Leydig cell function and cause infertility. The degree of gonadal dysfunction depends on the type of chemotherapeutic agent and the dose and duration of therapy. Because of high response rates and the young age of these men, infertility and androgen deficiency have emerged as important long-term complications of cancer chemotherapy. Cyclophosphamide and combination regimens containing procarbazine are particularly toxic to germ cells. Thus, 90% of men with Hodgkin's lymphoma receiving MOPP (mechlorethamine, oncovin, procarbazine, prednisone) therapy develop azoospermia or extreme oligozoospermia; newer regimens that do not include procarbazine, such as ABVD (adriamycin, bleomycin, vinblastine, dacarbazine), are less toxic to germ cells. Alcohol, when consumed in excess for prolonged periods, decreases testosterone, independent of liver disease or malnutrition. Elevated estradiol and decreased testosterone levels may occur in men taking digitalis. The occupational and recreational history should be carefully evaluated in all men with infertility because of the toxic effects of many chemical agents on spermatogenesis. Known environmental hazards include microwaves and ultrasound and chemicals such as nematocide dibromochloropropane, cadmium, phthalates, and lead. In some populations, sperm density is said to have declined by as much as 40% in the past 50 years. Environmental estrogens or antiandrogens may be partly responsible. Testicular failure also occurs as a part of polyglandular autoimmune insufficiency (Chap. 345). Sperm antibodies can cause isolated male infertility. In some instances, these antibodies are secondary phenomena resulting from duct obstruction or vasectomy. Granulomatous diseases can affect the testes, and testicular atrophy occurs in 10–20% of men with lepromatous leprosy because of direct tissue invasion by the mycobacteria. The tubules are involved initially, followed by endarteritis and destruction of Leydig cells. Systemic disease can cause primary testis dysfunction in addition to suppressing gonadotropin production. In cirrhosis, a combined testicular and pituitary abnormality leads to decreased testosterone production independent of the direct toxic effects of ethanol. Impaired hepatic extraction of adrenal androstenedione leads to extraglandular conversion to estrone and estradiol, which partially suppresses LH. Testicular atrophy and gynecomastia are present in approximately one-half of men with cirrhosis. In chronic renal failure, androgen synthesis and sperm production decrease despite elevated gonadotropins. The elevated LH level is due to reduced clearance, but it does not restore normal testosterone production. About one-fourth of men with renal failure have hyperprolactinemia. Improvement in testosterone production with hemodialysis is incomplete, but successful renal transplantation may return testicular function to normal. Testicular atrophy is present in one-third of men with sickle cell anemia. The defect may be at either the testicular or the hypothalamic-pituitary level. Sperm density can decrease temporarily after acute febrile illness in the absence of a change in testosterone production. Infertility in men with celiac disease is associated with a hormonal pattern typical of androgen resistance, namely elevated testosterone and LH levels. Neurologic diseases associated with altered testicular function include myotonic dystrophy, spinobulbar muscular atrophy, and paraplegia. In myotonic dystrophy, small testes may be associated with impairment of both spermatogenesis and Leydig cell function. Spinobulbar muscular atrophy is caused by an expansion of the glutamine repeat sequences in the amino-terminal region of the AR; this expansion impairs function of the AR, but it is unclear how the alteration is related to the neurologic manifestations. Men with spinobulbar muscular atrophy often have undervirilization and infertility as a late manifestation. Spinal cord lesions that cause paraplegia can lead to a temporary decrease in testosterone levels and may cause persistent defects in spermatogenesis; some patients retain the capacity for penile erection and ejaculation. Androgen Insensitivity Syndromes Mutations in the AR cause resistance to the action of testosterone and DHT. These X-linked mutations are associated with variable degrees of defective male phenotypic development and undervirilization (Chap. 343). Although not technically hormone-insensitivity syndromes, two genetic disorders impair testosterone conversion to active sex steroids. Mutations in the SRD5A2 gene, which encodes 5-reductase type 2, prevent the conversion of testosterone to DHT, which is necessary for the normal development of the male external genitalia. Mutations in the CYP19 gene, which encodes aromatase, prevent testosterone conversion to estradiol. Males with CYP19 mutations have delayed epiphyseal fusion, tall stature, eunuchoid proportions, and osteoporosis, consistent with evidence from an estrogen receptor–deficient individual that these testosterone actions are mediated indirectly via estrogen. Gynecomastia Gynecomastia refers to enlargement of the male breast. It is caused by excess estrogen action and is usually the result of an increased estrogen/androgen ratio. True gynecomastia is associated with glandular breast tissue that is >4 cm in diameter and often tender. Glandular tissue enlargement should be distinguished from excess adipose tissue: glandular tissue is firmer and contains fibrous-like cords. Gynecomastia occurs as a normal physiologic phenomenon in the newborn (due to transplacental transfer of maternal and placental estrogens), during puberty (high estrogen to androgen ratio in early stages of puberty), and with aging (increased fat tissue and increased aromatase activity), but it can also result from pathologic conditions associated with androgen deficiency or estrogen excess. The prevalence of gynecomastia increases with age and body mass index (BMI), likely because of increased aromatase activity in adipose tissue. Medications that alter androgen metabolism or action may also cause gynecomastia. The relative risk of breast cancer is increased in men with gynecomastia, although the absolute risk is relatively small. Pathologic Gynecomastia Any cause of androgen deficiency can lead to gynecomastia, reflecting an increased estrogen/androgen ratio, as estrogen synthesis still occurs by aromatization of residual adrenal and gonadal androgens. Gynecomastia is a characteristic feature of Klinefelter syndrome (Chap. 343). Androgen insensitivity disorders also cause gynecomastia. Excess estrogen production may be caused by tumors, including Sertoli cell tumors in isolation or in association with Peutz-Jegher syndrome or Carney complex. Tumors that produce hCG, including some testicular tumors, stimulate Leydig cell estrogen synthesis. Increased conversion of androgens to estrogens can be a result of increased availability of substrate (androstenedione) for extraglandular estrogen formation (CAH, hyperthyroidism, and most feminizing adrenal tumors) or to diminished catabolism of androstenedione (liver disease) so that estrogen precursors are shunted to aromatase in peripheral sites. Obesity is associated with increased aromatization of androgen precursors to estrogens. Extraglandular aromatase activity can also be increased in tumors of the liver or adrenal gland or rarely as an inherited disorder. Several families with increased peripheral aromatase activity inherited as an autosomal dominant or as an X-linked disorder have been described. In some families with this disorder, an inversion in chromosome 15q21.2-3 causes the CYP19 gene to be activated by the regulatory elements of contiguous genes resulting in excessive estrogen production in the fat and other extragonadal tissues. Drugs can cause gynecomastia by acting directly as estrogenic substances (e.g., oral contraceptives, phytoestrogens, digitalis), inhibiting androgen synthesis (e.g., ketoconazole), or action (e.g., spironolactone). Because up to two-thirds of pubertal boys and half of hospitalized men have palpable glandular tissue that is benign, detailed investigation or intervention is not indicated in all men presenting with gynecomastia (Fig. 340-5). In addition to the extent of gynecomastia, recent onset, rapid growth, tender tissue, and occurrence in a lean subject should prompt more extensive evaluation. This should include a careful drug history, measurement and examination of the testes, assessment of virilization, evaluation of liver function, and hormonal measurements including testosterone, estradiol, and androstenedione, LH, and hCG. A karyotype should be obtained in men with very small testes to exclude Klinefelter syndrome. In spite of extensive evaluation, the etiology is established in fewer than one-half of patients. Figure 340-5 Evaluation of gynecomastia. T, testosterone; LH, luteinizing hormone; FSH, follicle-stimulating hormones; hCG, human chorionic gonadotropin ; E2, 17-estradiol. Gynecomastia: Treatment When the primary cause can be identified and corrected, breast enlargement usually subsides over several months. However, if gynecomastia is of long duration, surgery is the most effective therapy. Indications for surgery include severe psychological and/or cosmetic problems, continued growth or tenderness, or suspected malignancy. In patients who have painful gynecomastia and in whom surgery cannot be performed, treatment with antiestrogens such as tamoxifen (20 mg/d) can reduce pain and breast tissue size in over half the patients. Aromatase inhibitors can be effective in the early proliferative phase of the disorder, although the experience is largely based on the use of testolactone, a relatively weak aromatase inhibitor; placebo-controlled trials with more potent aromatase inhibitors such as anastrozole, fadrozole, letrozole, or formestane are needed. In a randomized trial in men with established gynecomastia, anastrozole proved no more effective than placebo in reducing breast size. Aging-Related Changes in Male Reproductive Function A number of cross-sectional and longitudinal studies (e.g., The Baltimore Longitudinal Study of Aging and the Massachusetts Male Aging Study) have established that testosterone concentrations decrease with advancing age. This age-related decline starts in the third decade of life and progresses slowly; the rate of decline in testosterone concentrations is greater for men with chronic illness and for those taking medications than in healthy older men. Because SHBG concentrations are higher in older men than in younger men, free or bioavailable testosterone concentrations decline with aging to a greater extent than total testosterone concentrations. The age-related decline in testosterone is due to defects at all levels of the hypothalamic-pituitary-testicular axis: pulsatile GnRH secretion is attenuated, LH response to GnRH is reduced, and testicular response to LH is impaired. However, the gradual rise of LH with aging suggests that testis dysfunction is the main cause of declining androgen levels. The term andropause has been used to denote age-related decline in testosterone concentrations; this term is a misnomer because there is no discrete time when testosterone concentrations decline abruptly. In epidemiologic surveys, low total and bioavailable testosterone concentrations have been associated with decreased appendicular skeletal muscle mass and strength, decreased self-reported physical function, higher visceral fat mass, insulin resistance, and increased risk of coronary artery disease and mortality. In systematic reviews of randomized controlled trials, testosterone therapy of healthy older men with low or low-normal testosterone levels was associated with greater increments in lean body mass, grip strength, and self-reported physical function than that associated with placebo. Testosterone therapy also induced greater improvement in vertebral but not femoral bone mineral density. Testosterone therapy of older men with sexual dysfunction and unequivocally low testosterone levels improves libido, but testosterone effects on erectile function and response to selective phosphodiesterase inhibitors have been inconsistent. Testosterone therapy has not been shown to improve depression scores, fracture risk, cognitive function, or clinical outcomes in older men. Furthermore, the long-term risks of testosterone supplementation in older men remain largely unknown. In particular, physiologic testosterone replacement might increase the risk of prostate cancer or exacerbate cardiovascular disease. Population screening of all older men for low testosterone levels is not recommended, and testing should be restricted to men who have symptoms or physical features attributable to androgen deficiency. Testosterone therapy is not recommended for all older men with low testosterone levels. In older men with significant symptoms of androgen deficiency who have testosterone levels below 200 ng/dL, testosterone therapy may be considered on an individualized basis and should be instituted after careful discussion of the risks and benefits (see "Testosterone Replacement," below). Testicular morphology, semen production, and fertility are maintained up to a very old age in men. Although concern has been expressed about age-related increases in germ cell mutations and impairment of DNA repair mechanisms, the frequency of chromosomal aneuploidy or structural abnormalities does not increase in the sperm of older men. However, the incidence of autosomal dominant diseases, such as achondroplasia, polyposis coli, Marfan syndrome, and Apert's syndrome, increases in the offspring of men who are advanced in age, consistent with transmission of sporadic missense mutations. Approach to the Patient: Androgen Deficiency Hypogonadism is often heralded by decreased sex drive, reduced frequency of sexual intercourse or inability to maintain erections, reduced beard growth, loss of muscle mass, decreased testicular size, and gynecomastia. Less than 10% of patients with erectile dysfunction alone have testosterone deficiency. Thus, it is useful to look for a constellation of symptoms and signs suggestive of androgen deficiency. Except when extreme, these clinical features may be difficult to distinguish from changes that occur with normal aging. Moreover, androgen deficiency may develop gradually. Population studies, such as the Massachusetts Male Aging Study, suggest that about 4% of men between the ages of 40 and 70 have testosterone levels <150 ng/dL. Thus, androgen deficiency is not uncommon. When symptoms or clinical features suggest possible androgen deficiency, the laboratory evaluation is initiated by the measurement of total testosterone, preferably in the morning (Fig. 340-6). A total testosterone level <200 ng/dL measured by a reliable assay, in association with symptoms, is evidence of testosterone deficiency. An early-morning testosterone level >350 ng/dL makes the diagnosis of androgen deficiency unlikely. In men with testosterone levels between 200 and 350 ng/dL, the total testosterone level should be repeated and a free testosterone level should be measured. In older men and in patients with other clinical states that are associated with alterations in SHBG levels, a direct measurement of free testosterone level by equilibrium dialysis can be useful in unmasking testosterone deficiency. Figure 340-6 Evaluation of hypogonadism. T, testosterone; LH, luteinizing hormone; GnRH, gonadotropin-releasing hormone. When androgen deficiency has been confirmed by low testosterone concentrations, LH should be measured to classify the patient as having primary (high LH) or secondary (low or inappropriately normal LH) hypogonadism. An elevated LH level indicates that the defect is at the testicular level. Common causes of primary testicular failure include Klinefelter syndrome, HIV infection, uncorrected cryptorchidism, cancer chemotherapeutic agents, radiation, surgical orchiectomy, or prior infectious orchitis. Unless causes of primary testicular failure are known, a karyotype should be performed in men with low testosterone and elevated LH to exclude Klinefelter syndrome. Men who have a low testosterone but "inappropriately normal" or low LH levels have secondary hypogonadism; their defect resides at the hypothalamic-pituitary level. Common causes of acquired secondary hypogonadism include space-occupying lesions of the sella, hyperprolactinemia, chronic illness, hemochromatosis, excessive exercise, and substance abuse. Measurement of PRL and MRI scan of the hypothalamic-pituitary region can help exclude the presence of a space-occupying lesion. Patients in whom known causes of hypogonadotropic hypogonadism have been excluded are classified as having IHH. It is not unusual for congenital causes of hypogonadotropic hypogonadism, such as Kallmann syndrome, to be diagnosed in young adults. Age-Related Reproductive Dysfunction: Treatment Gonadotropins Gonadotropin therapy is used to establish or restore fertility in patients with gonadotropin deficiency of any cause. Several gonadotropin preparations are available. Human menopausal gonadotropin (hMG; purified from the urine of postmenopausal women) contains 75 IU FSH and 75 IU LH per vial. hCG (purified from the urine of pregnant women) has little FSH activity and resembles LH in its ability to stimulate testosterone production by Leydig cells. Recombinant hCG is now available. Because of the expense of hMG, treatment is usually begun with hCG alone, and hMG is added later to promote the FSH-dependent stages of spermatid development. Recombinant human FSH (hFSH) is now available and is indistinguishable from purified urinary hFSH in its biologic activity and pharmacokinetics in vitro and in vivo, although the mature subunit of recombinant hFSH has seven fewer amino acids. Recombinant hFSH is available in ampoules containing 75 IU (~7.5 g FSH), which accounts for >99% of protein content. Once spermatogenesis is restored using combined FSH and LH therapy, hCG alone is often sufficient to maintain spermatogenesis. Although a variety of treatment regimens are used, 1500–2000 IU of hCG or recombinant human LH (rhLH) administered intramuscularly three times weekly is a reasonable starting dose. Testosterone levels should be measured 6–8 weeks later and 48–72 h after the hCG or rhLH injection; the hCG/rhLH dose should be adjusted to achieve testosterone levels in the mid-normal range. Sperm counts should be monitored on a monthly basis. It may take several months for spermatogenesis to be restored; therefore, it is important to forewarn patients about the potential length and expense of the treatment and to provide conservative estimates of success rates. If testosterone levels are in the mid-normal range but the sperm concentrations are low after 6 months of therapy with hCG alone, FSH should be added. This can be done by using hMG, highly purified urinary hFSH, or recombinant hFSH. The selection of FSH dose is empirical. A common practice is to start with the addition of 75 IU FSH three times each week in conjunction with the hCG/rhLH injections. If sperm densities are still low after 3 months of combined treatment, the FSH dose should be increased to 150 IU. Occasionally, it may take 18–24 months for spermatogenesis to be restored. The two best predictors of success using gonadotropin therapy in hypogonadotropic men are testicular volume at presentation and time of onset. In general, men with testicular volumes >8 mL have better response rates than those who have testicular volumes <4 mL. Patients who became hypogonadotropic after puberty experience higher success rates than those who have never undergone pubertal changes. Spermatogenesis can usually be reinitiated by hCG alone, with high rates of success for men with postpubertal onset of hypogonadotropism. The presence of a primary testicular abnormality, such as cryptorchidism, will attenuate testicular response to gonadotropin therapy. Prior androgen therapy does not affect subsequent response to gonadotropin therapy. GnRH In patients with documented GnRH deficiency, both pubertal development and spermatogenesis can be successfully induced by pulsatile administration of low doses of GnRH. This response requires normal pituitary and testicular function. Therapy usually begins with an initial dose of 25 ng/kg per pulse administered subcutaneously every 2 h by a portable infusion pump. Testosterone, LH, and FSH levels should be monitored. The dose of GnRH is increased until testosterone levels reach the mid-normal range. Doses ranging from 25 to 200 ng/kg may be required to induce virilization. Once pubertal changes have been initiated, the dose of GnRH can often be reduced. Increased sperm counts and testicular volume have been reported in >70% of treated men, and improvements in sexual function and virilization can be induced in >90% of patients. Cutaneous infections occur but are infrequent and minor. Carrying a portable infusion device can be cumbersome, and follow-up of these patients requires physician supervision and laboratory monitoring. Some patients with IHH have cryptorchidism; men with this additional testicular defect may not respond to GnRH or gonadotropin therapy. Comparative studies of gonadotropin therapy and pulsatile GnRH administration demonstrate that these two therapies are similar in terms of the time to first appearance of sperm or pregnancy rates; both approaches are equally effective in inducing spermatogenesis in men with hypogonadotropic hypogonadism caused by GnRH deficiency. However, most patients find intermittent gonadotropin injections preferable to wearing a continuous infusion pump. Testosterone Replacement Androgen therapy is indicated to restore testosterone levels to normal to correct features of androgen deficiency. Testosterone replacement improves libido and overall sexual activity; increases energy, lean muscle mass, and bone density; and gives the patient a better sense of well-being. The benefits of testosterone replacement therapy have only been proven in men who have documented androgen deficiency, as demonstrated by testosterone levels that are well below the lower limit of normal (<250 ng/dL). Testosterone is available in a variety of formulations with distinct pharmacokinetics (Table 340-3). Testosterone serves as a prohormone and is converted to 17-estradiol by aromatase and to 5-dihydrotestosterone by 5-reductase. Therefore, when evaluating testosterone formulations, it is important to consider whether the formulation being used can achieve physiologic estradiol and DHT concentrations, in addition to normal testosterone concentrations. Although testosterone concentrations at the lower end of the normal male range can restore sexual function, it is not clear whether low-normal testosterone levels can maintain bone mineral density and muscle mass. The current recommendation is to restore testosterone levels to the mid-normal range. Table 340-3 Clinical Pharmacology of Some Testosterone Formulations Formulation Regimen Pharmacokinetic Profile DHT and Estradiol Advantages Disadvantages Testosterone enanthate or cypionate 100 mg IM weekly or 200 mg IM every 2 weeks After a single IM injection, serum testosterone levels rise into the supraphysiologic range and then decline gradually into the hypogonadal range by the end of the dosing interval DHT and estradiol levels rise in proportion to the increase in testosterone levels; T:DHT and T:E2 ratios do not change   Corrects symptoms of androgen deficiency Relatively inexpensive, if self-administered Flexibility of dosing Requires IM injection Peaks and troughs in serum testosterone levels Scrotal testosterone patcha   One scrotal patch designed to nominally deliver 6 mg over 24 h applied daily Normalizes serum testosterone levels in many but not all androgen-deficient men Serum estradiol levels are in the physiologic male range, but DHT levels rise into the supraphysiologic range; T:DHT ratio is significantly lower than in healthy men Corrects symptoms of androgen deficiency To promote optimum adherence of the patch, scrotal skin needs to be shaved High DHT levels Nongenital transdermal system 1 or 2 patches, designed to nominally deliver 5–10 mg testosterone over 24 h applied daily on nonpressure areas Restores serum testosterone, DHT, and estradiol levels into the physiologic male range T:DHT and T:estradiol levels are in the physiologic male range Ease of application, corrects symptoms of androgen deficiency, and mimics the normal diurnal rhythm of testosterone secretion Lesser increase in hemoglobin than injectable esters Serum testosterone levels in some androgen-deficient men maybe in the low-normal range; these men may need application of 2 patches daily Skin irritation at the application site may be a problem for some patients Testosterone gel 5–10 g testosterone gel containing 50–100 mg testosterone applied daily Restores serum testosterone and estradiol levels into the physiologic male range Serum DHT levels are higher and T:DHT ratios are lower in hypogonadal men treated with the testosterone gel than in healthy eugonadal men Corrects symptoms of androgen deficiency, provides flexibility of dosing, ease of application, good skin tolerability Potential of transfer to a female partner or child by direct skin-to-skin contact; moderately high DHT levels 17- methyl testosterone 17- alkylated compound that should not be used because of potential for liver toxicity Orally active     Clinical responses are variable; potential for liver toxicity; should not be used for treatment of androgen deficiency Buccal, bioadhesive, testosterone tablets 30 mg controlled release, bioadhesive tablets used twice daily Absorbed from the buccal mucosa Normalizes serum testosterone and DHT levels in hypogonadal men Corrects symptoms of androgen deficiency in healthy, hypogonadal men Gum-related adverse events in 16% of treated men Oral testosterone undecanoateb   40–80 mg orally 2 or 3 times daily with meals When administered in oleic acid, testosterone undecanoate is absorbed through the lymphatics, bypassing the portal system; considerable variability in the same individual on different days and among individuals High DHT:T ratio Convenience of oral administration Not approved in the USA Variable clinical responses, variable serum testosterone levels, high DHT:T ratio Injectable long-acting testosterone undecanoate in oilb  1000 mg injected IM followed by 1000 mg at 6 weeks, then 1000 mg every 12 weeks When administered at a dose of 1000 mg IM, serum testosterone levels are maintained in the normal range in a majority of treated men DHT and estradiol levels rise in proportion to the increase in testosterone levels; T:DHT and T:E2 ratios do not change   Corrects symptoms of androgen deficiency Requires infrequent administration Requires IM injection of a large volume (4 mL) Testosterone pellets 4–6 200-mg pellets implanted SC Serum testosterone peaks at 1 month and then sustained in normal range for 4–6 months T:DHT and T:E2 ratios do not change   Corrects symptoms of androgen deficiency Requires surgical incision for insertions; pellets may extrude spontaneously aNot currently available in the United States. bFormulation available outside the United States but not currently approved by the U.S. Food and Drug Administration. Abbreviations: IM, intramuscular; DHT, dihydrotestosterone; T, testosterone; E2, 17-estradiol; SC, subcutaneously. Source: Reproduced from the Endocrine Society Guideline for Testosterone Therapy of Androgen Deficiency Syndromes in Adult Men (Bhasin et al). Oral Derivatives of Testosterone Testosterone is well-absorbed after oral administration but quickly degrades during the first pass through the liver. Therefore, it is not possible to achieve sustained blood levels of testosterone after oral administration of crystalline testosterone. 17-Alkylated derivatives of testosterone (e.g., 17-methyl testosterone, oxandrolone, fluoxymesterone) are relatively resistant to hepatic degradation and can be administered orally; however, because of the potential for hepatotoxicity, including cholestatic jaundice, peliosis, and hepatoma, these formulations should not be used for testosterone replacement. Hereditary angioedema due to C1 esterase deficiency is the only exception to this general recommendation; in this condition, oral 17-alkylated androgens are useful because they stimulate hepatic synthesis of the C1 esterase inhibitor. Injectable Forms of Testosterone The esterification of testosterone at the 17-hydroxy position makes the molecule hydrophobic and extends its duration of action. The slow release of testosterone ester from an oily depot in the muscle accounts for its extended duration of action. The longer the side chain, the greater the hydrophobicity of the ester and longer the duration of action. Thus, testosterone enanthate and cypionate with longer side chains have longer duration of action than testosterone propionate. Within 24 h after intramuscular administration of 200 mg testosterone enanthate or cypionate, testosterone levels rise into the high-normal or supraphysiologic range and then gradually decline into the hypogonadal range over the next 2 weeks. A bimonthly regimen of testosterone enanthate or cypionate therefore results in peaks and troughs in testosterone levels that are accompanied by changes in a patient's mood, sexual desire, and energy level. The kinetics of testosterone enanthate and cypionate are similar. Estradiol and DHT levels are normal if testosterone replacement is physiologic. Transdermal Testosterone Patch The nongenital testosterone patch, when applied in an appropriate dose, can normalize testosterone, DHT, and estradiol levels 4–12 h after application. Sexual function and a sense of well-being are restored in androgen-deficient men treated with the nongenital patch. One 5-mg patch may not be sufficient to increase testosterone into the mid-normal male range in all hypogonadal men; some patients may need daily administration of two 5-mg patches to achieve the targeted testosterone concentrations. The transdermal patches are more expensive than testosterone esters. The use of testosterone patches may be associated with skin irritation in some individuals. Testosterone Gel Two testosterone gels, Androgel and Testim, are available in 2.5- and 5-g unit doses that nominally deliver 25 and 50 mg of testosterone to the application site. Initial pharmacokinetic studies have demonstrated that 5-, 7.5-, and 10-g doses applied daily to the skin can maintain total and free testosterone concentrations in the mid- to high-normal range in hypogonadal men. Total and free testosterone concentrations are uniform throughout the 24-h period. The current recommendations are to begin with a 50-mg dose and adjust the dose based on testosterone levels. The advantages of the testosterone gel include the ease of application, its invisibility after application, and its flexibility of dosing. A major concern is the potential for inadvertent transfer of the gel to a sexual partner or to children who may come in close contact with the patient. The ratio of DHT to testosterone concentrations is higher in men treated with the testosterone gel. A buccal adhesive testosterone tablet, which adheres to the buccal mucosa and releases testosterone as it is slowly dissolved, has been approved. After twice-daily application of 30-mg tablets, serum testosterone levels are maintained within the normal male range in a majority of treated hypogonadal men. The adverse effects include buccal ulceration and gum problems in a few subjects. The clinical experience with this formulation is limited, and the effects of food and brushing on absorption have not been studied in detail. Testosterone Formulations Not Available in the United States Testosterone undecanoate, when administered orally in oleic acid, is absorbed preferentially through the lymphatics into the systemic circulation and is spared the first-pass degradation in the liver. Doses of 40–80 mg orally, two or three times daily, are typically used. However, the clinical responses are variable and suboptimal. DHT-to-testosterone ratios are higher in hypogonadal men treated with oral testosterone undecanoate, as compared to eugonadal men. Implants of crystalline testosterone can be inserted in the subcutaneous tissue by means of a trocar through a small skin incision. Testosterone is released by surface erosion of the implant and absorbed into the systemic circulation. Four to six 200-mg implants can maintain testosterone in the mid- to high-normal range for up to 6 months. Potential drawbacks include incising the skin for insertion and removal, and spontaneous extrusions and fibrosis at the site of the implant. After initial priming, long-acting testosterone undecanoate in oil, when administered intramuscularly every 12 weeks, maintains serum testosterone, estradiol, and DHT in the normal male range and corrects symptoms of androgen deficiency in a majority of treated men. However, large injection volume (4 mL) is its relative drawback. Novel Androgen Formulations A number of androgen formulations with better pharmacokinetics or more selective activity profiles are under development. A biodegradable testosterone microsphere formulation provides physiologic testosterone levels for 10–11 weeks. Two long-acting esters, testosterone buciclate and testosterone undecanoate, when injected intramuscularly, can maintain circulating testosterone concentrations in the male range for 7–12 weeks. Initial clinical trials have demonstrated the feasibility of administering testosterone by the sublingual or buccal routes. 7-Methyl-19-nortestosterone is an androgen that cannot be 5-reduced; therefore, compared to testosterone, it has relatively greater agonist activity in muscle and gonadotropin suppression but lesser activity on the prostate. Analogous to the selective estrogen receptor modulators, such as raloxifene, it may be possible to develop selective androgen receptor modulators (SARMs) that exert the desired physiologic effects on muscle, bone, or sexual function but without adversely affecting the prostate and the cardiovascular system. Pharmacologic Uses of Androgens Androgens and selective androgen receptor modulators are being evaluated as anabolic therapies for functional limitations associated with aging and chronic illness. Testosterone supplementation increases skeletal muscle mass, maximal voluntary strength, and muscle power in healthy men, hypogonadal men, older men with low testosterone levels, HIV-infected men with weight loss, and men receiving glucocorticoids. These anabolic effects of testosterone are related to testosterone dose and circulating concentrations. Systematic reviews have confirmed that testosterone therapy of HIV-infected men with weight loss promotes improvements in body weight, lean body mass, muscle strength, and depression indices, leading to recommendations that testosterone be considered as an adjunctive therapy in HIV-infected men who are experiencing unexplained weight loss and who have low testosterone levels. Similarly, in glucocorticoid-treated men, testosterone therapy should be considered to maintain muscle mass and strength, and vertebral bone mineral density. It is unknown whether testosterone therapy of older men with functional limitations can improve physical function, reduce disability, and improve health-related quality of life. Concerns about potential adverse effects of testosterone on prostate and cardiovascular event rates have encouraged the development of selective androgen receptor modulators that are preferentially anabolic and spare the prostate. Testosterone administration induces hypertrophy of both type 1 and 2 fibers and increases satellite cell (muscle progenitor cells) and myonuclear number. Androgens promote the differentiation of mesenchymal, multipotent progenitor cells into the myogenic lineage and inhibit their differentiation into the adipogenic lineage. Testosterone may have additional effects on satellite cell replication and muscle protein synthesis, which may contribute to an increase in muscle mass. Other indications for androgen therapy are in selected patients with anemia due to bone marrow failure (an indication largely supplanted by erythropoietin) or for hereditary angioedema. Male Hormonal Contraception Based on Combined Administration of Testosterone and Gonadotropin Inhibitors Supraphysiologic doses of testosterone (200 mg testosterone enanthate weekly) act by suppressing LH and FSH secretion and induce azoospermia in 50% of Caucasian men and >95% of Chinese men. Because of concern about long-term adverse effects of supraphysiologic testosterone doses, regimens that combine other gonadotropin inhibitors, such as GnRH antagonists and progestins with replacement doses of testosterone, are being investigated. Oral etonogestrel daily in combination with intramuscular testosterone decanoate every 4–6 weeks induced azoospermia or severe oligozoospermia (sperm density <1 million/mL) in 99% of treated men over a 1-year period. This regimen was associated with weight gain, deceased testicular volume, and decreased plasma high-density lipoprotein (HDL) cholesterol; the long-term safety has not been demonstrated. Selective androgen receptor modulators that are more potent inhibitors of gonadotropins than testosterone and spare the prostate hold promise for their contraceptive potential. Recommended Regimens for Androgen Replacement Testosterone esters are administered weekly at doses of 75–100 mg intramuscularly, or 150–200 mg every 2 weeks. One or two 5-mg nongenital testosterone patches can be applied daily over the skin of the back, thigh, or upper arm away from pressure areas. Testosterone gel is typically applied over a covered area of skin at a dose of 5–10 g daily; patients should wash their hands after gel application. Bioadhesive buccal testosterone tablets at a dose of 30 mg are typically applied twice daily on the buccal mucosa. Establishing Efficacy of Testosterone Replacement Therapy Because a clinically useful marker of androgen action is not available, restoration of testosterone levels into the mid-normal range remains the goal of therapy. Measurements of LH and FSH are not useful in assessing the adequacy of testosterone replacement. Testosterone should be measured 3 months after initiating therapy to assess adequacy of therapy. In patients who are treated with testosterone enanthate or cypionate, testosterone levels should be 350–600 ng/dL 1 week after the injection. If testosterone levels are outside this range, adjustments should be made to either the dose or the interval between injections. In men on transdermal patch or gel, or buccal testosterone therapy, testosterone levels should be in the mid-normal range (500–700 ng/dL) 4–12 h after application. If testosterone levels are outside this range, the dose should be adjusted. Restoration of sexual function, secondary sex characteristics, and energy level and sense of well-being are important objectives of testosterone replacement therapy. The patient should also be asked about sexual desire and activity, the presence of early morning erections, and the ability to achieve and maintain erections adequate for sexual intercourse. Some hypogonadal men continue to complain about sexual dysfunction even after testosterone replacement has been instituted; these patients may benefit from counseling. The hair growth in response to androgen replacement is variable and depends on ethnicity. Hypogonadal men with prepubertal onset of androgen deficiency who begin testosterone therapy in their late 20s or 30s may find it difficult to adjust to their newly found sexuality and may benefit from counseling. If the patient has a sexual partner, the partner should be included in counseling because of the dramatic physical and sexual changes that occur with androgen treatment. Contraindications for Androgen Administration Testosterone administration is contraindicated in men with a history of prostate or breast cancer (Table 340-4). Testosterone should not be prescribed to men with severe symptoms of benign prostatic hypertrophy (American Urological Association symptom score >19) or with baseline prostate-specific antigen (PSA) >3 ng/mL without a urologic evaluation. Testosterone replacement should not be administered to men with baseline hematocrit 50%. Testosterone can induce and exacerbate sleep apnea because of its neuromuscular effects on the upper airway. Testosterone should not be administered to men with congestive heart failure with class III or IV symptoms. Table 340-4 Conditions in Which Testosterone Administration Is Associated with a Risk of Adverse Outcome Conditions in which testosterone administration is associated with very high risk of serious adverse outcomes:   Metastatic prostate cancer   Breast cancer Conditions in which testosterone administration is associated with moderate to high risk of adverse outcomes   Undiagnosed prostate nodule or induration   Unexplained PSA elevation   Erythrocytosis (hematocrit >50%)   Severe lower urinary tract symptoms associated with benign prostatic hypertrophy as indicated by American Urological Association/International prostate symptom score >19   Unstable severe congestive heart failure (class III or IV) Note: PSA, prostate-specific antigen. Source: Reproduced from the Endocrine Society Guideline for Testosterone Therapy of Androgen Deficiency Syndromes in Adult Men (Bhasin et al). Monitoring Potential Adverse Experiences The clinical effectiveness and safety of testosterone replacement therapy should be performed 3 and 6 months after initiating testosterone therapy and annually thereafter (Table 340-5). Potential adverse effects include acne, oiliness of skin, erythrocytosis, breast tenderness and enlargement, leg edema, induction and exacerbation of obstructive sleep apnea, and increased risk of prostate cancer, though it may increase the incidence of detection rather than the actual occurrence rate. In addition, there may be formulation-specific adverse effects such as skin irritation with transdermal patch, risk of gel transfer to a sexual partner with testosterone gels, buccal ulceration and gum problems with buccal testosterone, and pain and mood fluctuation with injectable testosterone esters. Table 340-5 Monitoring of Men Receiving Testosterone Therapy 1. Evaluate the patient 3 months after treatment starts and then annually to assess whether symptoms have responded to treatment and whether the patient is suffering from any adverse effects. 2. Monitor testosterone levels 2 or 3 months after initiation of testosterone therapy.   The therapy should aim to raise serum testosterone levels into the mid-normal range.   Injectable testosterone enanthate or cypionate: Measure serum testosterone levels midway between injections. If testosterone is >700 ng/dL (24.5 nmol/L) or <350 ng/dL (12.3 nmol/L), adjust dose or frequency.    Transdermal patch: Assess testosterone levels 3–12 hours after application of the patch; adjust dose to achieve testosterone levels in the mid-normal range.     Buccal testosterone bioadhesive tablet: Assess levels immediately before or after application of fresh system.     Transdermal gel: Assess testosterone level any time after patient has been on treatment for at least 1 week; adjust dose to achieve serum testosterone levels in the mid-normal range.    Oral testosterone undecanoatea: Monitor serum testosterone levels 3–5 h after ingestion.    Injectable testosterone undecanoatea: Measure serum testosterone level just prior to each subsequent injection and adjust the dosing interval to maintain serum testosterone in mid-normal range.   3. Check hematocrit at baseline, at 3 months, and then annually. If hematocrit is >54%, stop therapy until hematocrit decreases to a safe level; evaluate the patient for hypoxia and sleep apnea; reinitiate therapy with a reduced dose. 4. Measure bone mineral density of lumbar spine and/or femoral neck after 1–2 years of testosterone therapy in hypogonadal men with osteoporosis or low trauma fracture, consistent with regional standard of care. 5. Perform digital rectal examination and check PSA level before initiating treatment, at 3 months, and then in accordance with guidelines for prostate cancer screening depending on the age and race of the patient. 6. Obtain urological consultation if there is:   Verified serum PSA concentration >4.0 ng/mL   An increase in serum PSA concentration >1.4 ng/mL within any 12-month period of testosterone treatment   A PSA velocity of >0.4 ng/mL/year using the PSA level after 6 months of testosterone administration as the reference (only applicable if PSA data are available for a period exceeding 2 years)   Detection of a prostatic abnormality on digital rectal examination   An AUA/IPSS of >19 7. Evaluate formulation-specific adverse effects at each visit.   Buccal testosterone tablets: Inquire about alterations in taste and examine the gums and oral mucosa for irritation.     Injectable testosterone esters (enanthate and cypionate): Ask about fluctuations in mood or libido.     Testosterone patches: Look for skin reaction at the application site.    Testosterone gels: Advise patients to cover the application sites with a shirt and to wash the skin with soap and water before having skin-to-skin contact, as testosterone gels leave a testosterone residue on the skin that can be transferred to a woman or child who might come in close contact. Serum testosterone levels are maintained when the application site is washed 4–6 hours after application of the testosterone gel.  aNot approved for clinical use in the United States. Note: PSA, prostate-specific antigen; AUA, American Urological Association; IPSS, international prostate symptom score. Source: Reproduced from the Endocrine Society Guideline for Testosterone Therapy of Androgen Deficiency Syndromes in Adult Men (Bhasin et al). Hemoglobin Levels Administration of testosterone to androgen-deficient men is typically associated with a 3–5% increase in hemoglobin levels, but the magnitude of hemoglobin increase may be greater in men who have sleep apnea, a significant smoking history, or chronic obstructive lung disease. Erythrocytosis is the most frequent adverse event reported in testosterone trials in middle-aged and older men and is also the most frequent cause of treatment discontinuation in these trials. The frequency of erythrocytosis is higher in older men than younger men and higher in hypogonadal men treated with injectable testosterone esters than in those treated with transdermal formulations, presumably due to the higher testosterone dose delivered by the typical regimens of testosterone esters. If hematocrit rises above 54%, testosterone therapy should be stopped until hematocrit has fallen to <50%. After evaluation of the patient for hypoxia and sleep apnea, testosterone therapy may be reinitiated at a lower dose. Digital Examination of the Prostate and Serum PSA Levels Testosterone replacement therapy increases prostate volume to the size seen in age-matched controls but should not increase prostate volume beyond that expected for age. There is no evidence that testosterone replacement causes prostate cancer. However, androgen administration can exacerbate preexisting prostate cancer. Many older men harbor microscopic foci of cancer in their prostates. It is not known whether long-term testosterone administration will induce these microscopic foci to grow into clinically significant cancers. PSA levels are lower in testosterone-deficient men and are restored to normal after testosterone replacement. There is considerable test-retest variability in PSA measurements; the average interassay coefficient of variation of PSA assays is 15%. The 95% confidence interval for the change in PSA values, measured 3–6 months apart, is 1.4 ng/mL. Increments in PSA levels after testosterone supplementation in androgen-deficient men are generally <0.5 ng/mL, and increments >1.0 ng/mL over a 3–6-month period are unusual. Nevertheless, administration of testosterone to men with baseline PSA levels between 2.5 and 4.0 ng/mL will cause PSA levels to exceed 4.0 ng/mL for some, and many of these men may undergo prostate biopsies. PSA velocity criterion can be used for patients who have sequential PSA measurements for >2 years; a change of >0.40 ng/mL per year merits closer urologic follow-up. Cardiovascular Risk Assessment The long-term effects of testosterone supplementation on cardiovascular risk are unknown. Testosterone effects on lipids depend on the dose (physiologic or supraphysiologic), the route of administration (oral or parenteral), and the formulation (whether aromatizable or not). Physiologic testosterone replacement by an aromatizable androgen has a modest effect on HDL or no effect at all. In middle-aged men with low testosterone levels, physiologic testosterone replacement has been shown to improve insulin sensitivity and reduce visceral obesity. In epidemiologic studies, testosterone concentrations are inversely related to waist-to-hip ratio and directly correlated with HDL cholesterol levels. These data suggest that physiologic testosterone concentration is correlated with factors associated with reduced cardiovascular risk. However, no prospective studies have examined the effect on testosterone replacement on cardiovascular risk. Androgen Abuse by Athletes and Recreational Bodybuilders The illicit use of androgenic steroids to enhance athletic performance is widespread among professional and high school athletes and recreational bodybuilders. Although androgen supplementation increases skeletal muscle mass and strength, whether and how androgens improve athletic performance is unknown. The most commonly used androgenic steroids include testosterone esters, nandrolone, stanozolol, methandienone, and methenolol. Athletes generally use increasing doses of multiple steroids in a practice known as stacking. A majority of athletes who abuse androgenic steroids also use other drugs that are perceived to be muscle-building or performance-enhancing, such as growth hormone; IGF-1; insulin; stimulants such as amphetamine, clenbuterol, ephedrine, and thyroxine; and drugs perceived to reduce adverse effects such as hCG, aromatase inhibitors, or estrogen antagonists. The adverse effects of androgen abuse include a marked decrease in plasma HDL cholesterol and an increase in LDL cholesterol, changes in clotting factors, suppression of spermatogenesis resulting in reduced fertility, and increase in liver enzymes. Elevations of liver enzymes, hepatic neoplasms, and peliosis hepatis have been reported, mostly with the use of oral, 17- alkylated androgenic steroids but not with parenterally administered testosterone or its esters. There are anecdotal reports of the association of androgenic steroid use with "rage reactions." Breast tenderness and enlargement are not uncommon among athletes abusing aromatizable androgens. Oral 17- alkylated androgens also can induce insulin resistance and glucose intolerance. A serious, underappreciated adverse effect of androgen use is the suppression of the hypothalamic-pituitary-testicular axis. Upon discontinuation of exogenous androgen use, the suppressed hypothalamic-pituitary axis may take weeks to months to recover. During this period when testosterone levels are low, the athletes may experience sexual dysfunction, hot flushes, fatigue, and depressed mood, causing some athletes to resume androgen use and thus perpetuating the cycle of abuse, withdrawal symptoms, and dependence. Also, the use of nonsterile needles confers the risk of local infection, sepsis, hepatitis, and HIV infection. Disproportionate gains in muscle mass and strength without commensurate adaptations in tendons and other connective tissues may predispose to the risk of tendon injuries. Accredited laboratories use gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry to detect anabolic steroid abuse. In recent years, the availability of high-resolution mass spectrometry and tandem mass spectrometry has further improved the sensitivity of detecting androgen abuse. Illicit testosterone use is detected generally by the application of the measurement of urinary testosterone to epitestosterone ratio and further confirmed by the use of the 13C:12C ratio in testosterone by the use of isotope ratio combustion mass spectrometry. Exogenous testosterone administration increases urinary testosterone glucuronide excretion and consequently the testosterone to epitestosterone ratio. Ratios above 6 suggest exogenous testosterone use but can also reflect genetic variation. Synthetic testosterone has a lower 13C:12C ratio than endogenously produced testosterone and these differences in 13C:12C ratio can be detected by isotope ratio combustion mass spectrometry, which is used to confirm exogenous testosterone use in individuals with a high testosterone to epitestosterone ratio. Further Readings Achermann JC et al: Inherited disorders of the gonadotropin hormones. Mol Cell Endocrinol 179:89, 2001 [PMID: 11420133] Bhasin S: An approach to infertile men. J Clin Endocrinol Metab 92:1995, 2007 [PMID: 17554051] ——— et al: Testosterone therapy in adult men with androgen deficiency syndromes: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 91:1995, 2006 Bolona ER et al: Testosterone use in men with sexual dysfunction: A systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc 82:20, 2007 [PMID: 17285782] Feldman HA et al: Age trends in the level of serum testosterone and other hormones in middle-aged men: Longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 87:589, 2002 [PMID: 11836290] Ferlin A et al: Molecular and clinical characterizations of Y chromosome microdeletions in infertile men: A 10-year experience in Italy. J Clin Endocrinol Metab 92:762, 2007 [PMID: 17213277] Sedlmeyer IL, Palmert MR: Delayed puberty: Analysis of a large case series from an academic center. J Clin Endocrinol Metab 87:1613, 2002 [PMID: 11932291] Bibliography Bay K et al: Testicular dysgenesis syndrome: Possible role of endocrine disrupters. Best Pract Res Clin Endocrinol Metab 20:77, 2006 [PMID: 16522521] Beranova M et al: Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 86:1580, 2001 [PMID: 11297587] Bhasin S, Wu F: Making a diagnosis of androgen deficiency in adult men: What to do until all the facts are in? Nat Clin Pract Endocrinol Metab 2:529, 2006 [PMID: 17024145] ——— et al: Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab 90:678, 2005 ——— et al: Testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Pract Endocrinol Metab 2:146, 2006 Calof OM et al: Adverse events associated with testosterone replacement in middle-aged and older men: A meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 60:1451, 2005 [PMID: 16339333] Carani C et al: Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 337:91, 1997 [PMID: 9211678] Harman SM et al: Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 86:724, 2001 [PMID: 11158037] Klein KO et al: Increased final height in precocious puberty after long-term treatment with LHRH agonists: The NIH experience. J Clin Endocrinol Metab 86:4711, 2001 [PMID: 11600530] Seminara SB et al: The GPR54 gene as a regulator of puberty. N Engl J Med 349:1614, 2003 [PMID: 14573733] Shozu M et al: Estrogen excess associated with novel gain-of-function mutations affecting the aromatase gene. N Engl J Med 348:19, 2003  Skaletsky H et al: The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 423:825, 2003 [PMID: 12815422] Snyder PJ et al: Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 84:2647, 1999 [PMID: 10443654] Swerdlow AJ et al: Cancer incidence and mortality in men with Klinefelter syndrome: A cohort study. J Natl Cancer Inst 97:1204, 2005 [PMID: 16106025] WHO Task Force for Male Fertility Regulation: Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for the regulation of male fertility. Lancet 336:955, 1990  Wickman S: A specific aromatase inhibitor and potential increase in adult height in boys with delayed puberty: A randomised controlled trial. Lancet 357:1743, 2001 [PMID: 11403810]

دستگاه تولید مثل در زنان

Harrison's Internal Medicine > Chapter 341. The Female Reproductive System: Infertility and Contraceptin > The Female Reproductive System: Infertility and Contraception: Introduction The female reproductive system regulates the hormonal changes responsible for puberty and adult reproductive function. Normal reproductive function in women requires the dynamic integration of hormonal signals from the hypothalamus, pituitary, and ovary, resulting in repetitive cycles of follicle development, ovulation, and preparation of the endometrial lining of the uterus for implantation should conception occur. For further discussion of related topics, see the following chapters: menstrual cycle disorders (Chap. 51), hyperandrogenic disorders (Chap. 50), sexually transmitted diseases (Chap. 124), sexual differentiation (Chap. 343), menopause (Chap. 342), gynecologic malignancies (Chap. 93), and male hormonal contraception (Chap. 340). Development of the Ovary and Early Follicular Growth The ovary orchestrates the development and release of a mature oocyte and also elaborates hormones (e.g., estrogen, progesterone, inhibin) that are critical for pubertal development and preparation of the uterus for conception, implantation, and the early stages of pregnancy. To achieve these functions in repeated monthly cycles, the ovary undergoes some of the most dynamic changes of any organ in the body. Primordial germ cells can be identified by the third week of gestation and their migration to the genital ridge is complete by 6 weeks' gestation. Germ cells can only persist within the genital ridge and are then referred to as oogonia. In contrast to testis development, germ cells are essential for induction of normal ovarian development, reflecting a key role of oogonia in the formation of primordial follicles. Although one X chromosome undergoes X inactivation in somatic cells, it is reactivated in oogonia and genes on both X chromosomes are required for normal ovarian development. A streak ovary containing only stromal cells is found in patients with 45, X Turner syndrome (Chap. 343). Starting at ~8 weeks' gestation, oogonia begin to enter prophase of the first meiotic division and become primary oocytes. This allows the oocyte to be surrounded by a single layer of flattened granulosa cells to form a primordial follicle. Granulosa cells are derived from mesonephric cells that invade the ovary early in its development, pushing the germ cells to the periphery or ovarian cortex. Although recent studies have reopened the debate, the weight of evidence supports the concept that the ovary contains a nonrenewable pool of germ cells. Through the combined processes of mitosis, meiosis, and atresia, the population of oogonia reaches its maximum of 6–7 million by 20 weeks' gestation after which there is inexorable loss of both oogonia and primordial follicles through the process of atresia. At birth, oogonia are no longer present in the ovary, and only 1–2 million germ cells remain (Fig. 341-1). Figure 341-1 Ovarian germ cell number is maximal at mid-gestation, then decreases precipitously. The oocyte persists in prophase of the first meiotic division until just before ovulation, when meiosis resumes. The quiescent primordial follicles are recruited to further growth and differentiation through a highly regulated process that limits the size of the developing cohort to ensure that folliculogenesis can continue throughout the reproductive life span. This initial recruitment of primordial follicles to form primary follicles is characterized by growth of the oocyte and the transition from squamous to cuboidal granulosa cells (Fig. 341-2). The theca interna cells that surround the developing follicle begin to form as the primary follicle grows. Acquisition of a zona pellucida by the oocyte and the presence of several layers of surrounding cuboidal granulosa cells mark the development of secondary follicles. It is at this stage that granulosa cells develop follicle-stimulating hormone (FSH), estradiol, and androgen receptors and communicate with one another through the development of gap junctions. Figure 341-2 The primordial to primary follicle transition involves somatic cell differentiation to cuboidal granulosa cells and the formation of a theca cell layer from the surrounding stromal cells. These steps require the cooperative interaction of signals from the oocyte and the somatic cells. AMH, anti-müllerian hormone; bFGF, basic fibroblast growth factor; KL, kit ligand; BMP, bone morphogenic protein. (From Knight and Glister, 2006; with permission.) In murine models, genes that regulate ovarian development and follicle formation have been identified (Fig. 341-3). Bidirectional signals between the oocyte and its surrounding somatic cells are essential for normal follicular development. For example, the oocyte-derived factor in the germline (FIG) is required for initial follicle formation. Anti-müllerian hormone (AMH) and activins derived from somatic cells induce the development of primary follicles from primordial follicles. Oocyte-derived growth differentiation factor 9 (GDF-9) is required for migration of pre-theca cells to the outer surface of the developing follicle (Fig. 341-2). GDF-9 is also required for formation of secondary follicles, as are granulosa cell–derived KIT ligand (KITL) and the forkhead transcription factor (Foxl2). All of these genes are potential candidates for premature ovarian failure in women, and mutations in the human FOXL2 gene have already been shown to cause the syndrome of blepharophimosis/ptosis/epicanthus inversus, which is associated with ovarian failure. Figure 341-3 Specific genes control the orderly development of ovarian development and follicle formation. (From MM Matzuk, DJ Lamb: Nat Cell Biol 4:Suppl S41–9, 2002; with permission.) Development of a Mature Follicle The early stages of follicle growth are primarily driven by intraovarian factors, whereas maturation to the state required for ovulation, including the resumption of meiosis in the oocyte, requires the combined stimulus of FSH and luteinizing hormone (LH). Recruitment of secondary follicles from the resting follicle pool requires the direct action of FSH. Accumulation of follicular fluid between the layers of granulosa cells creates an antrum that divides the granulosa cells into two functionally distinct groups: mural cells that line the follicle wall and cumulus cells that surround the oocyte (Fig. 341-4). A single dominant follicle emerges from the growing follicle pool within the first 5–7 days after the onset of menses, and the majority of follicles fall off their growth trajectory and become atretic. Autocrine actions of activin and bone morphogenic protein 6 (BMP-6), derived from the granulosa cells, and paracrine actions of GDF-9, BMP-15, and BMP-6, derived from the oocyte, are involved in granulosa cell proliferation and modulation of FSH responsiveness. Differential exposure to these factors may explain why one follicle is selected for continued growth to the preovulatory stage. The dominant follicle can be distinguished by its size, evidence of granulosa cell proliferation, large number of FSH receptors, high aromatase activity, and elevated concentrations of estradiol and inhibin A in follicular fluid. Figure 341-4 Development of ovarian follicles. (Courtesy of JH Eichhorn and D Roberts, Massachusetts General Hospital; with permission.) The dominant follicle undergoes rapid expansion during the 5–6 days prior to ovulation, reflecting granulosa cell proliferation and accumulation of follicular fluid. FSH induces LH receptors on the granulosa cells, and the preovulatory, or Graffian, follicle moves to the outer ovarian surface in preparation for ovulation. The LH surge triggers the resumption of meiosis, the suppression of granulosa cell proliferation, and the induction of cyclooxygenase 2 (COX-2), prostaglandins, and the progesterone receptor, each of which are required for ovulation, which involves cumulus expansion and the controlled expulsion of the egg and follicular fluid. The process of luteinization is induced by LH in conjunction with the loss of oocyte-derived luteinization inhibitors including GDF-9, BMP-15, and BMP-6. Regulation of Ovarian Function Hypothalamic and Pituitary Secretion Gonadotropin-releasing hormone (GnRH) neurons develop from epithelial cells outside the central nervous system and migrate, initially alongside the olfactory neurons, to the medial basal hypothalamus. Approximately 7000 GnRH neurons, scattered throughout the medial basal hypothalamus, establish contacts with capillaries of the pituitary portal system in the median eminence. GnRH is secreted into the pituitary portal system in discrete pulses to stimulate synthesis and secretion of LH and FSH from pituitary gonadotropes, which comprise ~10% of cells in the pituitary (Chap. 333). Functional connections of GnRH neurons with the portal system are established by the end of the first trimester, coinciding with the production of pituitary gonadotropins. Thus, like the ovary, the hypothalamic and pituitary components of the reproductive system are present before birth. However, the high levels of estradiol and progesterone produced by the placenta suppress hormonal secretion in the fetus. After birth, and the removal of placental steroids, gonadotropin levels rise. FSH levels are much higher in girls than in boys. This rise in FSH is associated with ovarian activation (evident on ultrasound) and increased inhibin B and estradiol levels. By 12–20 months of age, the reproductive axis is again suppressed, and a period of relative quiescence persists until puberty (Fig. 341-5). At the onset of puberty, pulsatile GnRH secretion induces pituitary gonadotropin production. In the early stages of puberty, LH and FSH secretion are apparent only during sleep, but as puberty develops, pulsatile gonadotropin secretion occurs throughout the day and night. Figure 341-5 Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are increased during the neonatal years but go through a period of childhood quiescence before increasing again during puberty. Gonadotropin levels are cyclic during the reproductive years and increase dramatically with the loss of negative feedback that accompanies menopause. The mechanisms responsible for the childhood quiescence and pubertal reactivation of the reproductive axis remain incompletely understood. GnRH neurons in the hypothalamus respond to both excitatory and inhibitory factors. Increased sensitivity to the inhibitory influence of gonadal steroids has long been implicated in the inhibition of GnRH secretion during childhood. Metabolic signals, such as adipocyte-derived leptin, also play a permissive role in reproductive function (Chap. 74). Studies of patients with isolated GnRH deficiency reveal that mutations in the G protein–coupled receptor 54 (GPR54) gene preclude the onset of puberty. The ligand for this receptor, metastin, is derived from the parent peptide, kisspeptin-1 (KISS1), and is a powerful stimulant for GnRH release. A potential role for metastin in the onset of puberty has been suggested by upregulation of KISS1 and GPR54 transcripts in the hypothalamus at the time of puberty. The KISS/GPR54 system may also be involved in estrogen feedback regulation of GnRH secretion. Ovarian Steroids Ovarian steroid–producing cells do not store hormones but produce them in response to LH and FSH during the normal menstrual cycle. The sequence of steps and the enzymes involved in the synthesis of steroid hormones are similar in the ovary, adrenal, and testes. However, the specific enzymes required to catalyze specific steps are compartmentalized and may not be abundant or even present in all cell types. Within the developing ovarian follicle, estrogen synthesis from cholesterol requires close integration between theca and granulosa cells—sometimes called the two-cell model for steroidogenesis (Fig. 341-6). FSH receptors are confined to the granulosa cells, whereas LH receptors are restricted to the theca cells until the late stages of follicular development, when they are also found on granulosa cells. The theca cells surrounding the follicle are highly vascularized and use cholesterol, derived primarily from circulating lipoproteins, as the starting point for the synthesis of androstenedione and testosterone under the control of LH. Androstenedione and testosterone are transferred across the basal lamina to the granulosa cells, which receive no direct blood supply. The mural granulosa cells are particularly rich in aromatase and, under the control of FSH, produce estradiol, the primary steroid secreted from the follicular phase ovary and the most potent estrogen. Theca cell–produced androstenedione and, to a lesser extent, testosterone are also secreted into peripheral blood, where they can be converted to dihydrotestosterone in skin and to estrogens in adipose tissue. The hilar interstitial cells of the ovary are functionally similar to Leydig cells and are also capable of secreting androgens. Although stromal cells proliferate in response to androgens [as in polycystic ovarian syndrome (PCOS)], they do not secrete androgens. Figure 341-6 Estrogen production in the ovary requires the cooperative function of the theca and granulosa cells under the control of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). HSD, hydroxysteroid dehydrogenase; OHP, hydroxyprogesterone. Rupture of the follicle at the time of ovulation is accompanied by the development of a rich capillary network induced by angiogenic factors such as granulosa-cell derived vascular endothelial growth factor (VEGF), making it possible for large molecules such as low-density lipoprotein (LDL) to reach the luteinized granulosa and theca lutein cells. Luteinized granulosa cells express genes involved in progestin synthesis. Theca lutein cells produce 17-hydroxyprogesterone, a substrate for aromatization by the luteinized granulosa cells. While the major secretory product of the corpus luteum is progesterone, estradiol and 17-hydroxyprogesterone are also produced. LH is critical for normal structure and function of the corpus luteum. Because LH and human chorionic gonadotropin (hCG) bind to a common receptor, the role of LH in support of the corpus luteum can be replaced by hCG in the first 10 weeks after conception, and hCG is commonly used for luteal phase support in the treatment of infertility. Steroid Hormone Actions (See Chap. 332) Both estrogen and progesterone play critical roles in the expression of secondary sexual characteristics in women. Estrogen promotes development of the ductule system in the breast, whereas progesterone is responsible for glandular development. In the reproductive tract, estrogens create a receptive environment for fertilization and support pregnancy and parturition through carefully coordinated changes in the endometrium, thickening of the vaginal mucosa, thinning of the cervical mucus, and uterine growth and contractions. Progesterone induces secretory activity in the estrogen-primed endometrium, increases the viscosity of cervical mucus, and inhibits uterine contractions. Both gonadal steroids play critical roles in the negative and positive feedback controls of gonadotropin secretion. Progesterone also increases basal body temperature and has therefore been used clinically as a marker of ovulation. The vast majority of circulating estrogens and androgens are carried in the blood bound to carrier proteins, which restrain their free diffusion into cells and prolong their clearance, serving as a reservoir. High-affinity binding proteins include sex hormone–binding globulin (SHBG), which binds androgens with somewhat greater affinity than estrogens, and corticosteroid-binding globulin (CBG), which also binds progesterone. Modulations in binding protein levels by insulin, androgens, and estrogens contribute to high bioavailable testosterone levels in PCOS and to high circulating estrogen and progesterone levels during pregnancy. Estrogens act primarily through binding to the nuclear receptors, estrogen receptor (ER) and . Transcriptional coactivators and co-repressors modulate ER action (Chap. 332). Both ER subtypes are present in the hypothalamus, pituitary, ovary, and reproductive tract. Although ER and - exhibit some functional redundancy, there is also a high degree of specificity, particularly in cell type expression. For example, ER functions in the ovarian theca cells, whereas ER is critical for granulosa cell function. There is also evidence for membrane-initiated signaling by estrogen. Similar signaling mechanisms pertain for progesterone with evidence of transcriptional regulation through progesterone receptor (PR) and protein isoforms, as well as rapid membrane signaling. Ovarian Peptides Inhibin was initially isolated from gonadal fluids based on its ability to selectively inhibit FSH secretion from pituitary cells. Inhibin is a heterodimer composed of an -subunit and a A- or B-subunit to form inhibin A or inhibin B, both of which are secreted from the ovary. Activin is a homodimer of inhibin subunits with the capacity to stimulate the synthesis and secretion of FSH. Inhibins and activins are members of the transforming growth factor (TGF-) superfamily of growth and differentiation factors. During the purification of inhibin, follistatin, an unrelated monomeric protein that inhibits FSH secretion, was discovered. Follistatin inhibits FSH secretion indirectly through binding and neutralizing activin. Inhibin B is secreted from the granulosa cells of small antral follicles, whereas inhibin A is present in both granulosa and theca cells and is secreted by dominant follicles. Inhibin A is also present in luteinized granulosa cells and is a major secretory product of the corpus luteum. Inhibin B increases in serum in response to FSH and is used clinically as a marker of ovarian reserve. Inhibin B also plays an important negative feedback role on FSH, independent of estradiol, during the menstrual cycle. Although activin is also secreted from the ovary, the excess of follistatin in serum, combined with its nearly irreversible binding of activin, make it unlikely that ovarian activin plays an endocrine role in FSH regulation. However, as indicated above, there is evidence that activin plays an autocrine/paracrine role in the ovary, and it may also act locally in the pituitary to modulate FSH production. Müllerian-inhibiting substance (MIS) (also known as anti-müllerian hormone, AMH) plays an important role in ovarian biology in addition to its traditional role in the degeneration of the müllerian ducts in the male. MIS is produced by granulosa cells and, like inhibin B, is a marker of ovarian reserve. MIS may also inhibit the recruitment of primordial follicles into the follicle pool by inhibiting aromatase expression. Hormonal Integration of the Normal Menstrual Cycle The sequence of changes responsible for mature reproductive function is coordinated through a series of negative and positive feedback loops that alter pulsatile GnRH secretion, the pituitary response to GnRH, and the relative secretion of LH and FSH from the gonadotrope. The frequency and amplitude of pulsatile GnRH secretion influence the differential synthesis and secretion of LH and FSH, with slow frequencies favoring FSH synthesis and increased amplitudes favoring LH synthesis. Activin is produced in both pituitary gonadotropes and folliculostellate cells and stimulates the synthesis and secretion of FSH. Inhibins function as potent antagonists of activins through sequestration of the activin receptors. Although inhibin is expressed in the pituitary, gonadal inhibin is the principal source of feedback inhibition of FSH. For the majority of the cycle, the reproductive system functions in a classic endocrine negative feedback mode. Estradiol and progesterone inhibit GnRH secretion, and the inhibins act at the pituitary to selectively inhibit FSH synthesis and secretion (Fig. 341-7). This negative feedback control of FSH is critical to development of the single mature oocyte that characterizes normal reproductive function in women. In addition to these negative feedback controls, the menstrual cycle is uniquely dependent on estrogen-induced positive feedback to produce an LH surge that is essential for ovulation of a mature follicle. The neural signaling pathways that distinguish estrogen negative versus positive feedback are incompletely understood. Figure 341-7 The reproductive system in women is critically dependent on both negative feedback of gonadal steroids and inhibin to modulate follicle-stimulating hormone (FSH) secretion and on estrogen positive feedback to generate the preovulatory luteinizing hormone (LH) surge. GnRH, gonadotropin-releasing hormone. The Follicular Phase This phase is characterized by recruitment of a cohort of secondary follicles and the ultimate selection of a dominant preovulatory follicle (Fig. 341-8). The follicular phase begins, by convention, on the first day of menses. However, follicular recruitment is initiated by the rise in FSH that begins in the late luteal phase in conjunction with the loss of negative feedback of gonadal steroids and likely inhibin A. The fact that a 20–30% increase in FSH is adequate for follicular recruitment speaks to the marked sensitivity of the resting follicle pool to FSH. The resultant granulosa cell proliferation is responsible for stimulating early follicular phase levels of inhibin B. Inhibin B in conjunction with rising levels of estradiol, and probably inhibin A, restrain FSH secretion during this critical period such that only a single follicle matures in the vast majority of cycles. The increased risk of multiple gestation associated with the increased levels of FSH characteristic of advanced maternal age, or with exogenous gonadotropin administration in the treatment of infertility, attest to the importance of the negative feedback regulation of FSH. With further growth of the dominant follicle, estradiol and inhibin A increase exponentially and the follicle acquires LH receptors. Increasing levels of estradiol are responsible for proliferative changes in the endometrium. The exponential rise in estradiol results in positive feedback on the pituitary, leading to the generation of an LH surge (and a smaller FSH surge), thereby triggering ovulation and luteinization of the granulosa cells. Figure 341-8 Relationship between gonadotropins, follicle development, gonadal secretion, and endometrial changes during the normal menstrual cycle. FSH, follicle-stimulating hormone; LH, luteinizing hormone; E2, estradiol; Prog, progesterone; Endo, endometrium. The Luteal Phase This phase begins with the formation of the corpus luteum from the ruptured follicle in response to ovulation signals. Progesterone and inhibin A are produced from the luteinized granulosa cells, which continue to aromatize theca-derived androgen precursors, producing estradiol. The combined actions of estrogen and progesterone are responsible for the secretory changes in the endometrium that are necessary for implantation. The corpus luteum is supported by LH but has a finite life span because of diminished sensitivity to LH. The demise of the corpus luteum results in a progressive decline in hormonal support of the endometrium. Inflammation or local hypoxia and ischemia result in vascular changes in the endometrium leading to the release of cytokines, cell death, and shedding of the endometrium. If conception occurs, hCG produced by the trophoblast binds to LH receptors on the corpus luteum, maintaining steroid hormone production and preventing involution of the corpus luteum. The corpus luteum is essential for the hormonal maintenance of the endometrium during the first 6–10 weeks of pregnancy until this function is taken over by the placenta. Clinical Assessment of Ovarian Function Menstrual bleeding should become regular within 2 to 4 years of menarche, although anovulatory and irregular cycles are common before that. For the remainder of adult reproductive life, the cycle length counted from the first day of menses to the first day of subsequent menses, is ~28 days, with a range of 25–35 days. However, cycle-to-cycle variability for an individual woman is ± 2 days. Luteal phase length is relatively constant between 12 and 14 days in normal cycles; thus, the major variability in cycle length is due to variations in the follicular phase. The duration of menstrual bleeding in ovulatory cycles varies between 4 and 6 days. There is a gradual shortening of cycle length with age such that women over the age of 35 have cycles that are shorter than during their younger reproductive years. Anovulatory cycles increase as women approach the menopause, and bleeding patterns may be erratic. Women who report regular monthly bleeding with cycles that do not vary by >4 days generally have ovulatory cycles, but several other clinical signs can be used to assess the likelihood of ovulation. Some women experience mittelschmerz, described as mid-cycle pelvic discomfort that is thought to be caused by the rapid expansion of the dominant follicle at the time of ovulation. A constellation of premenstrual moliminal symptoms such as bloating, breast tenderness, and food cravings often occur several days before menses in ovulatory cycles, but their absence cannot be used as evidence of anovulation. Methods that can be used to determine whether ovulation is likely include a serum progesterone level >5 ng/mL ~7 days before expected menses, an increase in basal body temperature of >0.5°F (0.24°C) in the second half of the cycle due to the thermoregulatory effect of progesterone, or the detection of the urinary LH surge using ovulation predictor kits. Because ovulation occurs ~36 h after the LH surge, urinary LH can be helpful in timing intercourse to coincide with ovulation. Ultrasound can be used to detect the growth of the fluid-filled antrum of the developing follicle and to assess endometrial proliferation in response to increasing estradiol levels in the follicular phase, as well as the characteristic echogenicity of the secretory endometrium of the luteal phase. Puberty Normal Pubertal Development in Girls The first menstrual period (menarche) occurs relatively late in the series of developmental milestones that characterize normal pubertal development (Table 341-1). Menarche is preceded by the appearance of pubic and then axillary hair as a result of maturation of the zona reticularis in the adrenal gland and increased adrenal androgen secretion, particularly dehydroepiandrosterone (DHEA). The triggers for adrenarche remain unknown but may involve increases in body mass index as well as in utero and neonatal factors. Menarche is also preceded by breast development (thelarche), which is exquisitely sensitive to the very low levels of estrogens that result from peripheral conversion of adrenal androgens and the low levels of estrogen secreted from the ovary early in pubertal maturation. Breast development precedes the appearance of pubic and axillary hair in ~60% of girls. The interval between the onset of breast development and menarche is ~2 years. There has been a gradual decline in the age of menarche over the past century, attributed in large part to improvement in nutrition, and there is a relationship between adiposity and earlier sexual maturation in girls. In the United States, menarche occurs at an average age of 12.5 years (Table 341-1). Much of the variation in the timing of puberty is due to genetic factors, with heritability estimates of 50–80%. Both adrenarche and breast development occur ~1 year earlier in African-American compared with Caucasian girls, although the timing of menarche differs by only 6 months between these ethnic groups. Table 341-1 Mean Age (Years) of Pubertal Milestones in Girls, with 95% Confidence Intervals   Onset of Breast/Pubic Hair Development Age of Peak Height Velocity Menarche Final Breast/Pubic Hair Development Adult Height Caucasian 10.2 11.9 12.6 14.3 17.1 African Amercan 9.6 11.5 12 13.6 16.5 Source: From FM Biro et al: J Pediatr 148:234, 2006. Other important hormonal changes also occur in conjunction with puberty. Growth hormone (GH) levels increase early in puberty, stimulated in part by the pubertal increases in estrogen secretion. GH increases IGF-I, which enhances linear growth. The growth spurt is generally less pronounced in girls than in boys, with a peak growth velocity of ~7 cm/year. Linear growth is ultimately limited by closure of epiphyses in the long bones as a result of prolonged exposure to estrogen. Puberty is also associated with mild insulin resistance. Disorders of Puberty The differential diagnosis of precocious and delayed puberty is similar in boys and girls. However, there are differences in the timing of normal puberty and differences in the relative frequency of specific disorders in girls compared with boys. Precocious Puberty Traditionally, precocious puberty has been defined as the development of secondary sexual characteristics before the age of 8 in girls based on data from Marshall and Tanner in British girls studied in the 1960s. More recent studies led to recommendations that girls be evaluated for precocious puberty if breast development or pubic hair were present at <7 years of age for Caucasian girls or <6 years for African-American girls. Precocious puberty is most often centrally mediated (Table 341-2), resulting from early activation of the hypothalamic-pituitary-ovarian axis. It is characterized by pulsatile LH secretion and an enhanced LH and FSH response to exogenous GnRH (two- to threefold stimulation) (Table 341-3). True precocity is marked by advancement in bone age of >2 SD, a recent history of growth acceleration, and progression of secondary sexual characteristics. In girls, centrally mediated precocious puberty is idiopathic in ~85% of cases; however, neurogenic causes must also be considered. GnRH agonists that induce pituitary desensitization are the mainstay of treatment to prevent premature epiphyseal closure and preserve adult height, as well to manage psychosocial repercussions of precocious puberty. Table 341-2 Differential Diagnosis of Precocious Puberty Central (GnRH dependent)  Peripheral (GnRH independent)    Idiopathic   Congenital adrenal hyperplasia   CNS tumors   Estrogen-producing tumors     Hamartomas     Adrenal tumors     Astrocytomas     Ovarian tumors     Adenomyomas   Gonadotropin/hCG-producing tumors     Gliomas   Exogenous exposure to estrogen or androgen     Germinomas   McCune-Albright syndrome   CNS infection   Aromatase excess syndrome   Head trauma     Iatrogenic       Radiation       Chemotherapy       Surgical     CNS malformation       Arachnoid or suprasellar cysts       Septo-optic dysplasia       Hydrocephalus   Note: GnRH, gonadotropin-releasing hormone; CNS, central nervous system; hCG, human chorionic gonadotropin. Table 341-3 Evaluation of Precocious and Delayed Puberty   Precocious Delayed Initial screening tests        History and physical x x   Assessment of growth velocity x x   Bone age x x   LH, FSH x x   Estradiol, testosterone x x   DHEAS x x   17-Hydroxyprogesterone x     TSH, T4   x x   Complete blood count   x   Sedimentation rate, C-reactive protein   x   Electrolytes, renal function   x   Liver enzymes   x   IGF-I, IGFBP-3   x   Urinalysis   x Secondary tests        Pelvic ultrasound x x   Cranial MRI x x   -hCG x     GnRH/agonist stimulation test x x   ACTH stimulation test x     Inflammatory bowel disease panel x x   Celiac disease panel   x   Prolactin   x   Karyotype   x Note: LH, luteinizing hormone; FSH, follicle-stimulating hormone; DHEAS, dehydroepiandrosterone sulfate; TSH, thyroid-stimulating hormone; T4, thyroxine; IGF, insulin-like growth factor; IGFBP-3, IGF-binding protein 3; hCG, human chorionic gonadotropin; ACTH, adrenocorticotropic hormone. Peripherally mediated precocious puberty does not involve activation of the hypothalamic-pituitary-ovarian axis and is characterized by suppressed gonadotropins in the presence of elevated estradiol. Management of peripheral precocious puberty involves treating the underlying disorder (Table 341-2) and limiting the effects of gonadal steroids using aromatase inhibitors, inhibitors of steroidogenesis, and estrogen receptor blockers. It is important to be aware that central precocious puberty can also develop in girls whose precocity was initially peripherally mediated, as in McCune-Albright syndrome and congenital adrenal hyperplasia. Incomplete and intermittent forms of precocious puberty may also occur. For example, premature breast development may occur in girls before the age of 2 years, with no further progression and without significant advancement in bone age, androgen production, or compromised height. Premature adrenarche can also occur in the absence of progressive pubertal development, but it must be distinguished from late-onset congenital adrenal hyperplasia and androgen-secreting tumors, in which case it may be termed heterosexual precocity. Premature adrenarche may be associated with obesity, hyperinsulinemia, and subsequent predisposition to PCOS. Delayed Puberty Delayed puberty (Table 341-4) is defined as the absence of secondary sexual characteristics by age 13 in girls. The diagnostic considerations are very similar to those for primary amenorrhea (Chap. 51). Between 25 and 40% of delayed puberty in girls is of ovarian origin, with Turner syndrome constituting a majority of such patients. Functional hypogonadotropic hypogonadism encompasses diverse etiologies such as systemic illnesses, including celiac disease and chronic renal disease, and endocrinopathies, such as diabetes and hypothyroidism. In addition, girls appear to be particularly susceptible to the adverse effects of abnormalities in energy balance that result from exercise, dieting, and/or eating disorders. Together these reversible conditions account for ~25% of delayed puberty in girls. Congenital hypogonadotropic hypogonadism in girls or boys can be caused by mutations in several different genes or combinations of genes (Chap. 340, Table 340-2). Family studies suggest that genes identified in association with absent puberty may cause delayed puberty and that there may be a genetic susceptibility to environmental stresses such as diet and exercise. Although neuroanatomic causes of delayed puberty are considerably less common in girls than in boys, it is always important to rule these out in the setting of hypogonadotropic hypogonadism. Table 341-4 Differential Diagnosis of Delayed Puberty Hypergonadotropic   Ovarian     Turner syndrome     Gonadal dysgenesis     Chemotherapy/radiation therapy     Galactosemia     Autoimmune oophoritis     Congenital lipoid hyperplasia   Steroidogenic enzyme abnormalities     17-hydroxylase deficiency     Aromatase deficiency   Gonadotropin/receptor mutations     FSH, LHR, FSHR   Androgen resistance syndrome Hypogonadotropic   Genetic     Hypothalamic syndromes        Letpin/leptin receptor        HESX1 (septooptic dysplasia)        PC1 (prohormone convertase)     IHH and Kallmann syndrome        KAL, FGFR1        GnRHR, GPR54     Abnormalities of pituitary development/function        PROP1   CNS tumors/infiltrative disorders     Craniopharyngioma     Astrocytoma, germinoma, glioma     Prolactinomas, other pituitary tumors     Histiocytosis X   Chemotherapy/radiation   Functional     Chronic diseases     Malnutrition     Excessive exercise     Eating disorders Note: FSH, follicle-stimulating hormone chain; FSHR, FSH receptor; LHR, luteinizing hormone receptor; HESX1, homeobox, embryonic stem cell expressed 1; IHH, idiopathic hypogonadotropic hypogonadism; KAL, Kallmann; FGFR1, fibroblast growth factor 1; GnRHR, gonadotropin-releasing hormone receptor; GPR54, G protein-coupled receptor 54; PROP1, prophet of Pit1, paired-like homeodomain transcription factor; CNS, central nervous system. Infertility Definition and Prevalence Infertility is defined as the inability to conceive after 12 months of unprotected sexual intercourse. In a study of 5574 English and American women who ultimately conceived, pregnancy occurred in 50% within 3 months, 72% within 6 months, and 85% within 12 months. These findings are consistent with predictions based on fecundability, the probability of achieving pregnancy in one menstrual cycle (approximately 20–25% in healthy young couples). Assuming a fecundability of 0.25, 98% of couples should conceive within 13 months. Based on this definition, the National Survey of Family Growth reports a 14% rate of infertility in the United States in married women aged 15–44. The infertility rate has remained relatively stable over the past 30 years, although the proportion of couples without children has risen, reflecting a trend to delay childbearing. This trend has important implications because of an age-related decrease in fecundability, which begins at age 35 and decreases markedly after age 40. Causes of Infertility The spectrum of infertility ranges from reduced conception rates or the need for medical intervention to irreversible causes of infertility. Infertility can be attributed primarily to male factors in 25%, female factors in 58%, and is unexplained in about 17% of couples (Fig. 341-9). Not uncommonly, both male and female factors contribute to infertility. Figure 341-9 Causes of infertility. FSH, follicle-stimulating hormone; LH, luteinizing hormone. Approach to the Patient: Infertility Initial Evaluation In all couples presenting with infertility, the initial evaluation includes discussion of the appropriate timing of intercourse and discussion of modifiable risk factors such as smoking, alcohol, caffeine, and obesity. A description of the range of investigations that may be required and a brief description of infertility treatment options, including adoption, should be reviewed. Initial investigations are focused on determining whether the primary cause of the infertility is male, female, or both. These investigations include a semen analysis in the male, confirmation of ovulation in the female, and, in the majority of situations, documentation of tubal patency in the female. In some cases, after an extensive workup excluding all male and female factors, a specific cause cannot be identified and infertility may ultimately be classified as unexplained. Psychological Aspects of Infertility Infertility is invariably associated with psychological stress related not only to the diagnostic and therapeutic procedures themselves but also to repeated cycles of hope and loss associated with each new procedure or cycle of treatment that does not result in the birth of a child. These feelings are often combined with a sense of isolation from friends and family. Counseling and stress-management techniques should be introduced early in the evaluation of infertility. Infertility and its treatment do not appear to be associated with long-term psychological sequelae. Female Causes Abnormalities in menstrual function constitute the most common cause of female infertility. These disorders, which include ovulatory dysfunction and abnormalities of the uterus or outflow tract, may present as amenorrhea or as irregular or short menstrual cycles. A careful history and physical examination and a limited number of laboratory tests will help to determine whether the abnormality is: (1) hypothalamic or pituitary (low FSH, LH, and estradiol with or without an increase in prolactin), (2) PCOS (irregular cycles and hyperandrogenism in the absence of other causes of androgen excess), (3) ovarian (low estradiol with increased FSH), or (4) uterine or outflow tract abnormality. The frequency of these diagnoses depends on whether the amenorrhea is primary or occurs after normal puberty and menarche (see Fig. 51-2). The approach to further evaluation of these disorders is described in detail in Chap. 51. Ovulatory Dysfunction In women with a history of regular menstrual cycles, evidence of ovulation should be sought as described above. An endometrial biopsy to exclude luteal phase insufficiency is no longer considered an essential part of the infertility workup for most patients. Even in the presence of ovulatory cycles, evaluation of ovarian reserve is recommended for women over 35 by measurement of FSH on day 3 of the cycle or in response to clomiphene, an estrogen antagonist (see below). An FSH level < 10 IU/mL on cycle day 3 predicts adequate ovarian oocyte reserve. Antral follicle count, inhibin B, and MIS are also being investigated as indicators of ovarian reserve. Tubal Disease This may result from pelvic inflammatory disease (PID), appendicitis, endometriosis, pelvic adhesions, tubal surgery, and previous use of an intrauterine device (IUD). However, a cause is not identified in up to 50% of patients with documented tubal factor infertility. Because of the high prevalence of tubal disease, evaluation of tubal patency by hysterosalpingogram (HSG) or laparoscopy should occur early in the majority of couples with infertility. Subclinical infections with Chlamydia trachomatis may be an underdiagnosed cause of tubal infertility and requires the treatment of both partners. Endometriosis Endometriosis is defined as the presence of endometrial glands or stroma outside the endometrial cavity and uterine musculature. Its presence is suggested by a history of dyspareunia (painful intercourse), worsening dysmenorrhea that often begins before menses, or by a thickened rectovaginal septum or deviation of the cervix on pelvic examination. The pathogenesis of the infertility associated with endometriosis is unclear but may involve effects on the normal endometrium as well as adhesions. Endometriosis is often clinically silent, however, and can only be excluded definitively by laparoscopy. Male Causes (See also Chap. 340) Known causes of male infertility include primary testicular disease, disorders of sperm transport, and hypothalamic-pituitary disease resulting in secondary hypogonadism. However, the etiology is not ascertained in up to half of men with suspected male factor infertility. The key initial diagnostic test is a semen analysis. Testosterone levels should be measured if the sperm count is low on repeated examination or if there is clinical evidence of hypogonadism. Infertility: Treatment The treatment of infertility should be tailored to the problems unique to each couple. In many situations, including unexplained infertility, mild to moderate endometriosis, and/or borderline semen parameters, a stepwise approach to infertility is optimal, beginning with low-risk interventions and moving to more invasive, higher risk interventions only if necessary. After determination of all infertility factors and their correction, if possible, this approach might include, in increasing order of complexity: (1) expectant management, (2) clomiphene citrate (see below) with or without intrauterine insemination (IUI), (3) gonadotropins with or without IUI, and (4) in vitro fertilization (IVF). The time used to complete the evaluation, correction, and expectant management can be longer in women <30 years of age, but this process should be advanced rapidly in women >35. In some situations expectant management will not be appropriate. Ovulatory Dysfunction Treatment of ovulatory dysfunction should first be directed at identification of the etiology of the disorder to allow specific management when possible. Dopamine agonists, for example, may be indicated in patients with hyperprolactinemia (Chap. 333); lifestyle modification may be successful in women with low body weight or a history of intensive exercise (Chap. 76). Medications used for ovulation induction include clomiphene citrate, gonadotropins, and pulsatile GnRH. Clomiphene citrate is a nonsteroidal estrogen antagonist that increases FSH and LH levels by blocking estrogen negative feedback at the hypothalamus. The efficacy of clomiphene for ovulation induction is highly dependent on patient selection. It induces ovulation in ~60% of women with PCOS and is the initial treatment of choice. It may be combined with agents that modify insulin levels, such as metformin. Clomiphene citrate is less successful in patients with hypogonadotropic hypogonadism. Aromatase inhibitors have also been investigated for the treatment of infertility. Initial studies are promising, but these medications have not been approved for this indication. Gonadotropins are highly effective for ovulation induction in women with hypogonadotropic hypogonadism and PCOS and are used to induce multiple follicular recruitment in unexplained infertility and in older reproductive-aged women. Disadvantages include a significant risk of multiple gestation and the risk of ovarian hyperstimulation, but careful monitoring and a conservative approach to ovarian stimulation reduce these risks. Currently available gonadotropins include urinary preparations of LH and FSH, highly purified FSH, and recombinant FSH. Though FSH is the key component, there is growing data that the addition of some LH (or hCG) may improve results, particularly in hypogonadotropic patients. Pulsatile GnRH is highly effective for restoring ovulation in patients with hypothalamic amenorrhea. Pregnancy rates are similar to those following the use of gonadotropins, but rates of multiple gestation are lower and there is virtually no risk of ovarian hyperstimulation. Unfortunately, pulsatile GnRH is not widely available in the United States. None of these methods are effective in women with premature ovarian failure in whom donor oocyte or adoption are the methods of choice. Tubal Disease If hysterosalpingography suggests a tubal or uterine cavity abnormality, or if a patient is 35 at the time of initial evaluation, laparoscopy with tubal lavage is recommended, often with a hysteroscopy. Although tubal reconstruction may be attempted if tubal disease is identified, it is generally being replaced by the use of IVF. These patients are at increased risk of developing an ectopic pregnancy. Endometriosis Though 60% of women with minimal or mild endometriosis may conceive within 1 year without treatment, laparoscopic resection or ablation appears to improve conception rates. Medical management of advanced stages of endometriosis is widely used for symptom control but has not been shown to enhance fertility. In moderate to severe endometriosis, conservative surgery is associated with pregnancy rates of 50 and 39%, respectively, compared with rates of 25 and 5% with expectant management alone. In some patients, IVF may be the treatment of choice. Male Factor Infertility The treatment options for male factor infertility have expanded greatly in recent years (Chap. 340). Secondary hypogonadism is highly amenable to treatment with pulsatile GnRH or gonadotropins. In vitro techniques have provided new opportunities for patients with primary testicular failure and disorders of sperm transport. Choice of initial treatment options depends on sperm concentration and motility. Expectant management should be attempted initially in men with mild male factor infertility (sperm count of 15 to 20 x 106/mL and normal motility). Moderate male factor infertility (10 to 15 x 106/mL and 20–40% motility) should begin with IUI alone or in combination with treatment of the female partner with clomiphene or gonadotropins, but it may require IVF with or without intracytoplasmic sperm injection (ICSI). For men with a severe defect (sperm count of <10 x 106/mL, 10% motility), IVF with ICSI or donor sperm should be used. If ICSI is performed because of azoospermia due to congenital bilateral absence of the vas deferens, genetic testing and counseling should be provided because of the risk of cystic fibrosis. Assisted Reproductive Technologies The development of assisted reproductive technologies (ART) has dramatically altered the treatment of male and female infertility. IVF is indicated for patients with many causes of infertility that have not been successfully managed with more conservative approaches. IVF or ICSI is often the treatment of choice in couples with a significant male factor or tubal disease, whereas IVF using donor oocytes is used in patients with premature ovarian failure and in women of advanced reproductive age. Success rates depend on the age of the woman and the cause of the infertility and are generally 18–24% per cycle when initiated in women <40. In women >40, there is a marked decrease in both the number of oocytes retrieved and their ability to be fertilized. Though often effective, IVF is expensive and requires careful monitoring of ovulation induction and invasive techniques including the aspiration of multiple follicles. IVF is associated with a significant risk of multiple gestation (31% twins, 6% triplets, and 0.2% higher order multiples). Contraception Though various forms of contraception are widely available, ~30% of births in the United States are the result of unintended pregnancy. Teenage pregnancies continue to represent a serious public health problem in the United States, with >1 million unintended pregnancies each year—a significantly greater incidence than in other industrialized nations. Contraceptive methods are widely used (Table 341-5). Only 15% of couples report having unprotected sexual intercourse in the past 3 months. A reversible form of contraception is used by >50% of couples, while sterilization (in either the male or female) has been employed as a permanent form of contraception by over a third of couples. Pregnancy termination is relatively safe when directed by health care professionals but is rarely the option of choice. Table 341-5 Effectiveness of Different Forms of Contraception Method of Contraception Theoreticala Effectiveness, %   Actuala Effectiveness, %   Percent Continuing Use at 1 Yearb   Contraceptive Methods Used by U.S. Womenc   Barrier methods           Condoms 98 88 63 20   Diaphragm 94 82 58 2   Cervical cap 94 82 50 <1 Spermicides 97 79 43 1 Sterilization           Male 99.9 99.9 100 11   Female 99.8 99.6 100 28 Intrauterine device       1   Copper T380 99 97 78     Progestasert 98 97 81     Mirena 99.9 99.8     Oral contraceptive pill     72 27   Combination 99.9 97       Progestin only 99.5 97     Long-acting progestins           Depo-Provera 99.7 99.7 70 <1 aAdapted from J Trussel et al: Obstet Gynecol 76:558, 1990. bAdapted from Contraceptive Technology Update. Contraceptive Technology, Feb. 1996, Vol 17, No 1, pp 13–24. cAdapted from LJ Piccinino and WD Mosher: Fam Plan Perspective 30:4, 1998. No single contraceptive method is ideal, although all are safer than carrying a pregnancy to term. The effectiveness of a given method of contraception depends not only on the efficacy of the method itself. Discrepancies between theoretical and actual effectiveness emphasize the importance of patient education and compliance when considering various forms of contraception (Table 341-5). Knowledge of the advantages and disadvantages of each contraceptive is essential for counseling an individual about the methods that are safest and most consistent with his or her lifestyle. The World Health Organization (WHO) has extensive family planning resources for the physician and patient that can be accessed on line. Barrier Methods Barrier contraceptives (such as condoms, diaphragms, and cervical caps) and spermicides are easily available, reversible, and have fewer side effects than hormonal methods. However, their effectiveness is highly dependent on adherence and proper use (Table 341-5). A major advantage of barrier contraceptives is the protection provided against sexually transmitted diseases (STIs) (Chap. 124). Consistent use is associated with a decreased risk of HIV, gonorrhea, nongonococcal urethritis, and genital herpes, probably due in part to the concomitant use of spermicides. Natural membrane condoms may be less effective than latex condoms, and petroleum-based lubricants can degrade condoms and decrease their efficacy for preventing HIV infection. A highly effective female condom, which also provides protection against STIs, was approved in 1994 but has not achieved widespread use. Sterilization Sterilization is the method of birth control most frequently chosen by fertile men and multiparous women >30 (Table 341-5). Sterilization refers to a procedure that prevents fertilization by surgical interruption of the fallopian tubes in women or the vas deferens in men. Although tubal ligation and vasectomy are potentially reversible, these procedures should be considered permanent and should not be undertaken without patient counseling. Several methods of tubal ligation have been developed, all of which are highly effective with a 10-year cumulative pregnancy rate of 1.85 per 100 women. However, when pregnancy does occur, the risk of ectopic pregnancy may be as high as 30%. The success rate of tubal reanastomosis depends on the method used, but even after successful reversal, the risk of ectopic pregnancy remains high. In addition to prevention of pregnancy, tubal ligation reduces the risk of ovarian cancer, possibly by limiting the upward migration of potential carcinogens. Vasectomy is a highly effective outpatient surgical procedure that has little risk. The development of azoospermia may be delayed for 2–6 months, and other forms of contraception must be used until two sperm-free ejaculations provide proof of sterility. Reanastomosis may restore fertility in 30–50% of men, but the success rate declines with time after vasectomy and may be influenced by factors such as the development of anti-sperm antibodies. Intrauterine Devices IUDs inhibit pregnancy primarily through a spermicidal effect caused by a sterile inflammatory reaction produced by the presence of a foreign body in the uterine cavity (copper IUDs) or by the release of progestins (Progestasert, Mirena). IUDs provide a high level of efficacy in the absence of systemic metabolic effects, and ongoing motivation is not required to ensure efficacy once the device has been placed. However, only 1% of women in the United States use this method compared to a utilization rate of 15–30% in much of Europe and Canada, despite evidence that the newer devices are not associated with increased rates of pelvic infection and infertility, as occurred with earlier devices. An IUD should not be used in women at high risk for development of STI or in women at high risk for bacterial endocarditis. The IUD may not be effective in women with uterine leiomyomas because they alter the size or shape of the uterine cavity. IUD use is associated with increased menstrual blood flow, although this is less pronounced with the progesterone-releasing IUD than the copper-containing device. Hormonal Methods Oral Contraceptive Pills Because of their ease of use and efficacy, oral contraceptive pills are the most widely used form of hormonal contraception. They act by suppressing ovulation, changing cervical mucus, and altering the endometrium. The current formulations are made from synthetic estrogens and progestins. The estrogen component of the pill consists of ethinyl estradiol or mestranol, which is metabolized to ethinyl estradiol. Multiple synthetic progestins are used. Norethindrone and its derivatives are used in many formulations. Low-dose norgestimate and the more recently developed progestins (desogestrel, gestodene, drospirenone) have a less androgenic profile; levonorgestrel appears to be the most androgenic of the progestins and should be avoided in patients with hyperandrogenic symptoms. The three major formulations of oral contraceptives are (1) fixed-dose estrogen-progestin combination, (2) phasic estrogen-progestin combination, and (3) progestin only. Each of these formulations is administered daily for 3 weeks followed by a week of no medication during which menstrual bleeding generally occurs. Two extended oral contraceptives have recently been approved for use in the United States; Seasonalle is a 3-month preparation with 84 days of active drug and 7 day of placebo, Lybrel is a continuous preparation containing 90 g of levonorgestrel and 20 g of ethinyl estradiol. Current doses of ethinyl estradiol range from 20–50 g. However, indications for the 50-g dose are rare, and the majority of formulations contain 35 g of ethinyl estradiol. The reduced estrogen and progesterone content in the second- and third-generation pills has decreased both side effects and risks associated with oral contraceptive use (Table 341-6). At the currently used doses, patients must be cautioned not to miss pills due to the potential for ovulation. Side effects, including break-through bleeding, amenorrhea, breast tenderness, and weight gain, are often responsive to a change in formulation. Table 341-6 Oral Contraceptives: Contraindications and Disease Risk Contraindications    Absolute     Previous thromboembolic event or stroke     History of an estrogen-dependent tumor     Active liver disease     Pregnancy     Undiagnosed abnormal uterine bleeding     Hypertriglyceridemia     Women over age 35 who smoke heavily (>15 cigarettes per day)   Relative     Hypertension     Women receiving anticonvulsant drug therapy Disease Risks    Increased     Coronary heart disease—increased only in smokers > 35; no relation to progestin type     Hypertension—relative risk 1.8 (current users) and 1.2 (previous users)     Venous thrombosis—relative risk ~4; markedly increased with factor V Leiden or prothrombin-gene mutations (see Chap. 110)     Stroke—increased only in combination with hypertension; unclear relation to migraine headache     Cerebral vein thrombosis—relative risk ~13–15; synergistic with prothrombin-gene mutation     Cervical cancer—relative risk 2–4   Decreased     Ovarian cancer—50% reduction in risk     Endometrial cancer—40% reduction in risk The microdose progestin-only minipill is less effective as a contraceptive, having a pregnancy rate of 2–7 per 100 women-years. However, it may be appropriate for women with cardiovascular disease or for women who cannot tolerate synthetic estrogens. New Methods A weekly contraceptive patch (Ortho Evra) is available and has similar efficacy to oral contraceptives but may be associated with less breakthrough bleeding. Approximately 2% of patches fail to adhere, and a similar percentage of women have skin reactions. Efficacy is lower in women >90 kg. The amount of estrogen delivered may be comparable to that of a 40-g ethinyl estradiol oral contraceptive, raising the possibility of increased risk of venous thromboembolism, which must be balanced against potential benefits for women not able to successfully use other methods. A monthly contraceptive estrogen/progestin injection (Lunelle) is highly effective, with a first-year failure rate of <0.2%, but it may be less effective in obese women. Its use is associated with bleeding irregularities that diminish over time. Fertility returns rapidly after discontinuation. A monthly vaginal ring (NuvaRing) that is intended to be left in place during intercourse is also available for contraceptive use. It is highly effective, with a 12-month failure rate of 0.7%. Ovulation returns within the first recovery cycle after discontinuation. Long-Term Contraceptives Long-term progestin administration in the form of Depo-Provera acts primarily by inhibiting ovulation and causing changes in the endometrium and cervical mucus that result in decreased implantation and sperm transport. Depo-Provera requires an IM injection and is effective for 3 months, but return of fertility after discontinuation may be delayed for up to 12–18 months. Although highly effective, Norplant is no longer being manufactured. Amenorrhea, irregular bleeding, and weight gain are the most common adverse effects associated with both injectable forms of contraception. A major advantage of the injectable progestin-based contraceptives is the apparent lack of increased arterial and venous thromboembolic events, but increased gallbladder disease and decreased bone density may result. Postcoital Contraception Postcoital contraceptive methods prevent implantation or cause regression of the corpus luteum and are highly efficacious if used appropriately. Unprotected intercourse without regard to the time of the month carries an 8% incidence of pregnancy, an incidence that can be reduced to 2% by the use of emergency contraceptives within 72 h of unprotected intercourse. A notice published in 1997 by the U.S. Food and Drug Administration indicated that certain oral contraceptive pills could be used within 72 h of unprotected intercourse [Ovral (2 tablets, 12 h apart) and Lo/Ovral (4 tablets, 12 h apart)]. Preven (50 mg ethinyl estradiol and 0.25 mg levonorgestrel) and Plan B (0.75 mg Levonorgestrel) are now approved for postcoital contraception. Side effects are common with these high doses of hormones and include nausea, vomiting, and breast soreness. Recent studies suggest that 600 mg mifepristone (RU486), a progesterone receptor antagonist, may be equally as effective as or more effective than hormonal regimens, with fewer side effects. Mifepristone is now available in the United States as Mifeprex, to be used with or with out misoprostol (synthetic prostaglandin E1, an off-label indication for this use of misoprostol). Further Readings

سندرم تخمدان پلی کیستیک

تخمدان پلی کیستیک ( تنبلی تخمدانها ) این بیماری به صورت معمول با قاعدگی کاملاً نامنظم ، نازایی ، پرمویی بدن ، چاقی و بزرگی دو طرفه تخمدان پر از کیست است . حدود ۳٪ افراد در سنین باروری به این بیماری مبتلا بوده و علت بیماری به طور کامل شناخته نشده است ولی شاخص ترین اختلال مربوط به غدد درون ریز بوده که در آن افزایش هورمون های مردانه یا آندروژنها دیده می شود .  علائم ، نشانه ها و ارزیابی نشانه های عدم تخمک گذاری این حالت با خونریزی های نامنظم ( حدود ۱۵٪ بیماران ) ، عدم قاعدگی ( حدود ۵۰٪ بیماران ) و نازایی ( ۷۵٪ بیماران ) تظاهر می کند . افزایش آندروژن افزایش آندروژن های تخمدان و غده فوق کلیوی باعث بروز پرمویی ، چرب شدن پوست و آکنه به درجات مختلف می شود . شیوع پرمویی حدود ۹۰-۷۰ درصد موارد بوده و اغلب سرعت پیشرفت و شدت آن کم می باشد . افزایش آندروژن غالباً به قدری زیاد است که موجب عضلانی شدن اندام ، کلفت شدن صدا و ریزش موهای شقیقه می شود ، لذا در صورت پیشرفت سریع و شدید علائم فوق باید به فکر بیماری های دیگری مثل بدخیمی و مشکلات غده فوق کلیه بود . چاقی در حدود ۵۰ -۴۰ درصد مبتلایان به این بیماری چاق هستند . چاقی خود موجب افزایش هورمون تستوسترون آزاد و نیز تولید دائمی استروژن از آندروژن می شود . همچنین ضایعات پررنگ پوستی که قهوه ای ، مایل به سبز و قرینه هستند و در لمس ظریف به صورت مخمل حس می شوند و بیشتر مناطق گردن ، زیربغل و کشاله ران را گرفتار می کنند و در حدود ۵۰-۳۰ درصد بیماران مبتلا و در افراد  چاق  دیده می شود . تدابیر درمانی درمان بیماران مبتلا به بیماری تنبلی تخمدان وابسته به نیاز و شکایت بیمار بوده و دارای ۳ جنبه اصلی است که هریک درمان خاص خود را می طلبد و شامل پرمویی ، آکنه ، عدم تخمک گذاری مزمن و در نتیجه وجود ممتد استروژن و ضخیم شدن لایه درونی رحم ( آندومتر ) است . در درمان پرموئی باید نکات زیر را مد نظر قرار داد و به بیمار نیز انتقال داده شود : موهایی در بدن وابسته به آندروژن هستند و اینها به درمان طبی پاسخ میدهند . این موها عبارتند از : موهای صورت ، سینه ، شکم و کشاله ران ، موهای سایر نقاط بدن نظیر اطراف سینه ، بازوها ، پشت و ساق پاها پاسخ مناسبی به درمان طبی نمی دهند . به غیر از قرص ضدبارداری در استفاده از سایر داروها باید یک روش مطمئن جلوگیری از حاملگی در طول درمان بکار برده شود . حداقل مدت زمان لازم برای مشاهده اثرات درمانی دارو  حدود ۶ ماه است . در بیش از نیمی از بیمارانی که معالجه شده اند ، پس از قطع دارو موها مجدداً رشد می کنند . تا حصول نتیجه مطلوب ، بهتر است از روش مکانیکی ( بی رنگ کردن ، تراشیدن و کندن مو ) نیز استفاده شود . آن گروه از موهایی که مدتهای مدیدی است رشد کرده و دارای ضخامت زیادی هستند ، به درمان طبی پاسخ مناسب نداده و باید به روش فیزیکی آنها را از بین برد . در افراد چاق کاهش وزن می تواند در هر ۳ جنبه درمان کمک کننده باشد http://www2.irib.ir/health/html/ovary-polycystic%20.htm

وازینیت

واژینیت ( التهاب مهبل ) اغلب خانمها حداقل یک بار در طول عمر خود عفونت مهبل را تجربه می کنند . واژینیت یک بیماری بسیار شایع می باشد ولی نه همیشه به فرم بسیار جدی نمی باشد . علل و به تبع آن درمانهای متفاوتی برای این بیماری وجود دارد . * واژینیت چیست ؟ واژینیت یک التهاب داخل مهبل ( vagina ) بوده که علائم آن شامل خارش - و سوزش مجرا است . یک مهبل طبیعی به طور دائم دارای ترشحاتی روشن و حتی کدر و دارای بوی خاص می باشد که خارش و سوزش ندارد . در مهبل طبیعی تعادلی از ارگانیسمهای متفاوت وجود دارد مثل باکتری ها و قارچها . هنگامیکه شخص دارای مهبل سالم می باشد این باکتریهای غیربیماریزا و جریان ترشحات طبیعی مهبل را در مقابل عفونتها محافظت می کنند ، اگر این محیط مناسب به هم بخورد یا باکتریهای بیماریزا وارد مهبل شوند ممکن است مهبل طبیعی به سمت عفونی شدن و التهاب پیش رود . هنگامیکه مهبل عفونی شود افزایش ترشحات غلیظ به همراه بوی نامطبوع و خارش و سوزش و تورم مشاهده می شود . علل زیر می توانند محیط طبیعی دفاعی مهبل را تغییردهند : ۱ - آنتی بیوتیکها ۲ - تغییر در سطوح طبیعی هورمونهای بدن که در حاملگی ، شیردهی و یائسگی رخ می دهد . ۳ - شستشوی مهبل ، دئودورانتهای مهبل و صابونها ۴ - مواد اسپرم کش ۵ - نزدیکی جنسی ۶ - بیماریهای منتقله از طریق جنسی ۷ - تحریک ۸ - مواد خارجی مثل نوارهای بهداشتی * علائم : هر خانمی نمای خاصی از ترشح طبیعی مهبل برای خودش دارد و تغییر در آن بایستی شخص را متوجه واژینیت کند . ولی نبایستی شخصاً تشخیص واژینیت را بگذارید چون ممکن است علامتی از یک بیماری بسیار جدی و خطرناک مثل سوزاک باشد . تستها و تشخیص : در هنگام معاینه پزشک شرح حال شما را بررسی می کند . سپس نیاز به معاینه مهبل و اندامهای تناسلی شما بوده و پس از آن از ترشحات مهبل شما نمونه جمع آوری کرده و جهت بررسی میکروسکوپی به آزمایشگاه می فرستند . به خاطر داشته باشید ۲ روز قبل از معاینه دوش واژن یا اسپری مهبل و هر درمان مهبلی بایستی قطع شده و هیچگونه دستکاری طی دو روز نبایستی انجام پذیرد . * انواع واژینیت سه نوع واژینیت خانمها را درگیر می کند : ۱ - قارچی : افزایش رشد قارجها در مهبل به علت تغییرات هورمونی یا قند خون بالا یا کاهش مقاومت در مقابل بیماری اتفاق می افتد که علائم آن شامل : الف - سوزش و خارش حتی هنگام ادرار کردن یا مقاربت ب - ترشحات سفید متراکم ج - بوی خفیف بوده و درمان آن شامل کرمها یا شیافهای مهبلی ضدقارج می باشد . ۲ - تریکوموناسی : تریکومونا نوعی انگل تک یاخته ای که از طریق مقاربت جنسی از شخصی به شخص دیگر منتقل می شود علائم آن شامل : الف - خارش و سوزش و تورم شدید مهبل ب - ترشحات کف آلود خاکستری یا زرد - سبز ج - بوی نامطبوع ماهی د - درد حین ادرار کردن یا مقاربت جنسی بوده و برای درمان آن نیاز به تجویز آنتی بیوتیک خوراکی وجود دارد . اغلب بیماران با یک دوز دارو درمان می شوند . همسر شخص مبتلا هم بایستی درمان شود و تا درمان وی بایستی از مقاربت اجتناب شود چون باعث آلودگی مجدد می شود . ۳- باکتریایی : که باعث واژینوز باکتریایی می شوند که ناشی از رشد شدید باکتریها در مهبل می باشد که می تواند با علت ناشناخته باشد یا از طریق مقاربت جنسی انتقال یابد . علائم آن شامل : ۱ - خارش ، سوزش و تورم مهبل ۲ - ترشحات آبکی خاکستری ۳ - بوی نامطبوع ماهی ۴ - درد حین ادرار کردن یا مقاربت درمان آن شامل آنتی بیوتیک خوراکی یا روشهای دیگر می باشد. همسر بیمار هم بایستی همزمان درمان شود . تا پایان درمان از مقاربت اجتناب شود . * پیشگیری : بستگی به تغییر در عادات و پوشش و سبک زندگی دارد : ۱ - از صابونهای ملایم استفاده کنید و هنگام حمام کردن از تحریک مهبل اجتناب نمائید . ۲ - سطح خارجی مهبل را روزانه شستشو داده و خشک نمائید . ۳ - هنگام شستشو پس از اجابت مزاج سطح خارجی مهبل را از سمت جلو به طرف عقب شستشو نمائید تا میکروبهای مدفوع به سمت مهبل رانده نشوند . ۴ - از دوش مهبلی و اسپری مهبلی و مواد مانند آنها اجتناب نمائید . ۵ - در طی دوره قاعدگی مرتباً نوارهای بهداشتی خود را عوض نمائید . ۶ - هنگام استفاده از مواد یا سواپهای اسپرم کش دقت لازم را مبذول دارید تا عفونتی را به مهبل انتقال ندهید . ۷ - از لباس زیر مرطوب استفاده نکنید . ۸ - از لباسهای زیر غیرکتانی استفاده نکنید . ۹ - رعایت مسائل اخلاقی واجتناب از ارتباطهای نامشروع ۱۰- اگر چاق هستید وزن خود را کاهش دهید ۱۱ - خواب و استراحت کافی داشته باشید . ۱۲ - به اندازه کافی ورزش نموده و از استرسها پرهیز کنید .

کیست تخمدان

                       کیست تخمدان   

آماس حاوی مایع که درون یا روی یک یا هر دو تخمدان رشد مینماید را کیست تخمدان گویند .

سن : بیشتر در سنین بین 45-30 سال شایع است .

جنس و نحوۀ زندگی : عوامل قابل توجهی به شمار نمی روند . کیستهای تخمدان ساکهای حاوی مایعی هستند که درون یا روی تخمدان رشد می نمایند . اغلب کیستهای تخمدان غیر سرطانی می باشند و زیان آور نیستند اما یک کیست گاهی ممکن است سرطانی شود . کیستهای سرطانی بیشتر در خانمها ی بالای 40 سال بروز می نمایند .

انواع کیست

انواع بسیاری کیست تخمدان وجود دارد . شایعترین نوع آنها کیست فولیکولی می باشد که در یکی از فولیکولیها که تخمک در آن رشد می کند ، نمو نموده و پراز مایع می شود . این نوع از کیست تخمدان ممکن است تا قطر 5 سانتیمتر ( 2 اینچ ) رشد نموده و معمولاً یک کیست می باشد . تصور می شود کیستهای متعدد کوچک که در تخمدان رشد می نمایند به علت اختلالات هورمونی ایجاد می شوند و به این حالت سندرم تخمدان پلی کیستیک گویند .

با شیوع کمتری ، کیستها ممکن است در کورپوس لوتئوم Corpus Luteum تشکیل شود . کورپوس لوتئوم بافت زردی است که از یک فولیکول پس از رها سازی تخمک رشد می نماید . این کیستها حاوی خون می باشند و می توانند تا 3 سانتیمتر ( یک و یک چهارم اینچ ) رشد نمایند .

یک کیست درموئید Dermoid  ، کیستی می باشد که حاوی سلولهایی است که بطور طبیعی در هر قسمت بدن نظیر سلولهای پوست و مو یافت می شوند . یک کیست آدنوما Cystadenoma  ، کیستی است که از یک نوع سلول تخمدان رشد می نماید . در موارد نادر ، یک کیست آدنوما به تنهایی می تواند طور کامل حفره شکم را پر نماید .

علائم بیماری

اغلب کیستهای تخمدان منجر به علائمی نمی شوند ، اما در صورت وجود علائم ، آنها عبارتند از :

• احساس ناراحتی در شکم
• درد به هنگام مقاربت
• بی نظمی قاعدگی که گاهی همراه با خونریزی شدید می باشد
• خونریزی بعد از یائسگی

کیستهای بزرگ می توانند موجب فشار روی مثتانه گردیده و منجر به احتباس ادرار شوند و یا ممکن است منجر به تکرار ادرار گردند .

عوارض کیستها

اگر کیستی پاره شده و یا دچار پیچ خوردگی شود موجب درد شدید شکم ، تهوع و تب خواهد شد . کیستها ممکن است آنقدر بزرگ شوند که موجب بزرگ شدن شکم گردند . در موارد نادر کیست هورمون استروژن قبل از بلوغ تولید می نماید که منجر به رشد جنسی زود رس می شود . بعضی کیستهای تخمدان هورمونهای جنسی مردانه تولید می نمایند که منجر به بروز صفات مردانه نظیر رشد مو در صورت می شود .

اقدامات درمانی

گاهی کیستهای تخمدان فقط در هنگام معاینات لگنی که در طی یک چکاب روتین انجام می شود ، کشف می گردند . در صورت وجود علائم کیست ، پزشک معاینه لگنی انجام خواهد داد . ممکن است همچنین سونوگرافی یا لاپراسکوپی جهت تأیید و تعیین اندازه و محل کیست انجام شود . همچنین شما آزمایشات خونی جهت احتمال بررسی کیست سرطانی خواهید داشت . کیستهای تخمدان ممکن است بدون درمان از بین بروند ، هر چند که اندازه کیست ممکن است با سونوگرافی عادی کنترل و بررسی شود . کیستهای بزرگ و مزمن ممکن است تخلیه یا برداشته شوند . در صورتیکه احتمال کیست سرطانی وجود داشته باشد ، باید برداشته شود . در صورت امکان تخمدان و لوله های رحم باقی گذارده می شوند . کیستهای تخمدان ممکن است در صورتیکه تخمدان برداشته نشوند ، عود نمایند .

اندومتریوز

                       آندومتریوز                         

 Endometriosis                                               

آندومتریوز به حالتی اطلاق می شود که بافت آندومتر که لایه داخلی رحم می باشد ، در سایر جاهای بدن یافته شود.

سن : بیشترین شیوع بین 45- 30 سالگی است .

نحوه زندگی : نداشتن فرزند از علائم خطر است .

ژنتیک : گاهی شیوع خانوادگی می یابد .

آندومتریوز لایه داخلی رحم می باشد که به طور طبیعی هر ماه به هنگام پریود ریزش می یابد و سپس مجدداً رشد می کند . در آندومتریوز تکه هایی از آندومتر به سایر اعضاء در حفره لگن مانند تخمدانها و روده تحتانی می چسبند . این تکه های آندومتر جایگزین شده در سایر نقاط تحت تأثیر هورمونهای سیکل قاعدگی قرار گرفته و واکنش نشان می دهند و در طی پریود خونریزی می نمایند . خون نمی تواند از طریق واژن از بدن خارج شود و باعث حساسیت و تحریک پذیری بافت اطراف می گردد که منجر به درد شکمی و در نهایت منجر ه اسکار ( جای زخم ) می گردد . تحریک پذیری و حساسیت تخمدانها ممکن است منجر به کیستهای دردناک گردد . آندومتریوز حالت شایعی است و بیشتر از یک پنجم خانمها را در سن بارداری متلا می سازد . خانمهایی که فرزندی تا سن 30 سالگی ندارند و آنهایی که بدون فرزند مانده اند بیشتر مستعد ابتلا به این حالت هستند . آندومتریوز شدید می تواند اغلب موج مشکلات ناباروری گردد . علت واقعی آندومتریوز ناشناخته است ، اما تئوریهای متعددی وجود دارد . یک تئوری این است که تکه هایی از آندومتر که در طی قاعدگی ریزش می نماید از راه واژن خارج نمی شوند ، در عوض آنها در طول لوله های رحم حرکت نموده و به حفرع لگن وارد می شوند و به سطح اعضاء مجاور آنها می چسبند .

علائم بیماری  

آندومتریوز ممکن است علامتی ایجاد ننماید . در صورت بروز علائم ، میزان شدت آن در خانمها متفاوت می باشد . همچنین علائم ممکن است متفاوت باشند و بستگی به این دارند که کدام عضوء مبتلا شده است و آنها عبارتند از :

• درد ناحیه تحتانی شکم که معمولاً درست قبل و در طی دوره پریود شدیدتر می شود .
• بی نظمی پریود یاخونریزی بسیار شدید در طی پریود .
• درد به هنگام مقاربت .
• درد تحتانی شکم در طی دفع ادرار .

در صورتیکه آندومترروی قسمت تحتانی روده رشد نماید ممکن است اسهال یا یبوست روز نماید و نیز در طی حرکات روده ایجاد شود و در موارد نادر خونریزی از رکتوم به هنگام پریود ایجاد شود .

اقدامات درمانی

در خانمی که آندومتریوز علامتی ندارد ، ممکن است به هنگام جستجوی علت ناباروری به آن مشکوک شد . برای کمک به تشخیص ، پزشک معاینه لگنی انجام خواهد داد . تشخیص ممکن است توسط لاپراسکوپی تأیید شود که در این اقدام ، اعضای حفره لگن و شکم با استفاده از یک وسیله ، بازدید و معاینه می شوند . درمانهای بسیاری برای آندومتریوز وجود دارد و انتخاب روش درمانی به سن ، اعضای مبتلا ، شدت علائم و تمایل فرد به بچه دار شدن در آینده بستگی دارد . ممکن است درمانهای هورمونی یا جراحی پیشنهاد و توصیه شوند . در انواع خفیف ، ممکن است درمان ضرورت نداشته باشد . اگر علائم باعث درد سر و آزار هستند ، پزشک ممکن است یک نوع از چندین نوع درمان هورمونی که باعث توقف قاعدگی برای چند ماه می شود را توصیه نماید . این داروها ممکن است شامل هورمونهای گنادورلینgonadorelin ) ( صناعی ، شبه گنادورلین ( gonadorelin analogues ) و دانازول ( danazol )  باشند ، تمامی این داروها تولید هورمون استروژن را کم نموده و قاعدگی را متوقف می سازند . در روش انتخابی دیگر ، ممکن است قرصهای ضد بارداری ترکیبی تجویز شود . این درمان معمولاً حدود 12- 6 ماه ادامه می یابد . در طول این مدت ، باید آندوممتریوز بهبود یابد . در صورت عود مجدد این حالت معمولاً از دفعه قبل خفیف تر خواهد بود . تکه های کوچک آنذومتر که در دوره درمان هورمونی به درمان پاسخ نداده اند ، ممکن است به وسیله جراحی توسط لیز در طی لاپاروسکوپی از بین برده و تخریب شوند . به هر حال گاهی آندومتریوز پس از درمان ، عود می نماید و ممکن است بعداً جراحی ضرورت یابد .

در صورتیکه فرد آندومتریوز شدید داشته و تصمیم به داشتن فرزند نداشته و یا نزدیک به یائسگی باشد ، پزشک ممکن است توصیه به هیسترکتومی Hysterectomy نماید . در این عمل رحم برداشته می شود . تخمدانها نیز برداشته خواهد شد و به همراه آن سایر نواحی مبتلا به آندومتریوز نیز برداشته می شوند . در صورت برداشتن تخمدانها قبل از اینکه بیمار به سن طبیعی یائسگی برسد ، یائسگی بروز خواهد نمود . رای تسکین و بهبود علائم ، پزشک احتمالاً درمان جایگزینی هورمونی توصیه خواهد نمود .

لاپاراسکوپی LAPARAOSCOPY

در طی لاپاراسکوپی از یک آلت سفت معاینه به نام لاپاروسکوپ برای مشاهده لگن و شکم از طریق ایجاد شکاف کوچکی در شکم استفاده می شود . لاپاراسکوپی ممکن است برای جستجوی بیماری اعضاء تولید مثل زنانه نظیر آندومتریوز کار رود و همچنین رای بررسی سایر بیماریهای شکمی نظیر آپاندیسیت استفاده شود . بعضی از اعضاء جراحیها نظیر استریل نمودن زنانه ( عقیم سازی ) ، ممکن است در طی این اقدام انجام شوند . لاپاراسکوپی همیشه تحت بیهوشی عمومی انجام می شود . بهبودی نسبت به اعمال جراحی معمولی ، به علت برش کوچکی که در این روش ایجاد می شود ، سریعتر است .

پیش آگهی

هر چند درمان معمولاً موفقیت آمیز است ، احتمال عود مجدد آندومتریوز تا هنگام یائسگی و ختم قاعدگی وجود دارد . در صورت برداشتن تخمدانها عود آندومتریوز غیر متحمل است .

ناباروری و نازایی

ناباروری و نازایی

ناباروری در مردان یعنی این که مردی نتواند زنی را پس از یک سال آمیزش باردار کند و در زنان یعنی این که زنی پس از این زمان باردار نشود. همچنین، اگر زنی نتواند جنین را در رحم خود نگه دارد و آن را سقط کند، نابارور به شمار می‌آید. گاهی در زنان واژه‌ی نازایی را به جای ناباروری به کار می‌برند.

---

از هر 6 زوج یکی به ناباروری دچار می‌شود. در 30 درصد موارد، ناباروری و نازایی به زنان مربوط می‌شود و عامل 30 درصد دیگر ناباروری‌ها و نازایی‌ها، مردان هستند. در 30 درصد دیگر نیز هم مردان و هم زنان درگیرند و در بقیه‌ی موارد، دلیل آن هنوز روشن نیست.

اگر فردی تصور می‌کند نازا یا نابارور است، بهتر است نخست با پزشک در میان بگذارد. برای مردان، نخستین گام اغلب آزمایش اسپرم است. برای زنان، پزشکان آزمایش‌هایی در نظر می‌گیرند تا ببینند آیا تخمدان‌هایشان به درستی کار می‌کنند. زنانی که در 30 سالگی هستند و پس از 6 ماه باردار نشده‌اند، بهتر است با پزشک در میان بگذارند. بخت یک زن برای بچه‌دار شدن پس از 30 سالگی سال به سال کاهش می‌یابد.

دارو و جراحی درمان‌های معمول ناباروری هستند. جای نگرانی نیست، زیرا دو سوم زوج‌هایی که درمان ناباروری را پی‌گیری می‌کنند، بچه‌دار می‌شوند. امروزه روش‌های پیشرفته‌ای مانند لقاح در لوله‌ی آزمایش( IVF ) کارایی درمان ناباروری را افزایش داده‌اند.

عوامل ناباروری و نازایی

 عوامل گوناگونی در یک فرآیند چند مرحله‌های دست به دست هم می‌دهند تا یک زن باردار شود و دوره‌ی بارداری را به خوبی به پایان برساند. بنابراین، ناباروری و نازایی فقط به یک عامل وابسته نیست و عوامل بسیاری در آن دخالت دارند.

---

مراحل بارداری یک زن را می‌توان به زبانی ساده در چند مرحله‌ی زیر بیان کرد:

• تخمدان‌های زن باید بتوانند تخمک سالمی آزاد کنند که بتواند از لوله‌های رحم(لوله‌های فالوپ) به سوی رحم جابه جا شوند.
• مرد باید بتواند اسپرم خود را در مجرای تناسلی زن تخلیه کند و این اسپرم‌ها باید بتوانند خود را به لوله‌های رحم(لوله‌های فالوپ) برسانند.
• اسپرم و تخمک باید با هم درآمیزند تا تخمک بارور شده (تخم) به وجود آید.
• تخم باید بتواند خود را به دیواره‌ی رحم پیوند دهد و از رگ‌های آن غذا دریافت کند تا به جنین نمو یابد و برای چشم گشودن به جهان بیرون آماده شود.

---

هر گونه نارسایی در هر کدام از این مراحل می‌تواند باعث ناباروری شود. بنابراین، علت ناباروری می‌تواند در کارکرد دستگاه تناسلی مرد یا زن (یا هر دو) نهفته باشد که برخی از آن‌ها برای ما روشن شده و برخی هنوز ناشناخته‌اند. این عوامل می‌توانند خاستگاه ژنتیکی یا محیطی داشته باشند.

نازایی در زنان

 همان گونه که در بالا گفته شد، برای این که یک زن بتواند بچه‌دار شود، عوامل گوناگونی باید دست به دست هم بدهند و شرایط مناسب را فراهم کنند. اگر حتی یکی از شرایط فراهم نباشد یا تا زمان کافی فراهم نباشد، بارداری رخ نمی‌دهد یا پیش از تولد بچه به پایان می‌رسد.

در بیشتر موارد، نازایی در زنان از نارسایی‌هایی در تخمک‌گذاری ناشی می‌شود. گاهی تخمدان‌ها بسیار زودتر از زمان یائسگی طبیعی از کار می‌افتند که از آن با عنوان از کار افتادگی پیش‌رس تخمدان‌ها( POF ) یاد می‌شود. گاهی نیز تخمدان‌ها به طور منظم تخمک آزاد نمی‌کنند یا تخمکی که آزاد می‌کنند سالم و پایدار نیست. در این حالت گفته می‌شود که بیمار به نشانگان تخمدان پرکیستی ( PCOS ) دچار شده است. در این بیماران حتی هنگامی که تخمک سالمی آزاد و بارور می‌شود، ممکن است رحم برای لانه‌گزینی تخمک بارور شده مناسب نباشد که باز هم به نازایی می‌انجامد.

عوامل دیگر نازایی در زنان ممکن است این‌ها باشند:

• بسته شدن لوله‌های رحم(لوله‌های فالوپ) در پی رشد نابجای بافت رحم (اندومتریوز)، بیماری التهابی لگن یا جراحی
• نارسایی‌هایی فیزیکی در دیواره‌ی رحم
• فیبروز رحم (رشد بیش از اندازه‌ی بافت دیواره ی رحم)
• شیوه‌ی زندگی و عوامل محیطی نیز می‌توانند بر زنی که زمینه‌ی نازایی را دارد، اثر بگذارند که برخی از آن‌ها عبارتند از: سن بالا، تنش(استرس)، غذای نامناسب، بیش وزنی یا کم وزنی، سیگار، مواد مخدر و الکل برخی داروها، مواد زهرآگین محیطی، بیماری‌های مقاربتی،
• برخی بیماری‌های ژنتیکی، مانند نشانگان کروموزوم ایکس شکننده، نیز می‌تواند در نازایی موثر باشند.

ناباروری در مردان

فرایند باروری در مردان شامل تولید اسپرم بالغ و فراهم کردن شرایط رسیدن آن به تخمک و بارورسازی آن است. ممکن است این فرآیند در مقایسه با فرآیند باروری در زنان، ساده به نظر برسد، اما باز هم باید شرایط بسیاری فراهم باشد تا باروری به سرانجام خوشایندی برسد: توانایی داشتن نعوظ در آلت تناسلی و پایدار ماندن آن، داشتن اسپرم کافی، داشتن منی کافی برای رساندن اسپرم به تخمک و داشتن اسپرم‌هایی با ریخت مناسب تا بتوانند مسیر درستی را به سوی تخمک بپیمایند. اگر هر کدام از این شرایط فراهم نباشد، ناباروری را در پی خواهد داشت.

ناباروی در مردان مانند نازایی در زنان ممکن است از نارسایی‌های فیزیکی(مانند این که بیضه‌ها اسپرم عادی را به میزان کافی نسازند)، مشکلات هورمونی و شیوه‌ی زندگی و عوامل محیطی ناشی شود.

برخی از عوامل محیطی عبارتند از:

• سن بالا
• تنش(استرس)
• قرار گرفتن بیضه‌ها در دمای بالا که بر توانایی اسپرم‌ها در رفتن به سوی تخمک اثر منفی دارد. برای مثال، گاهی بیضه‌ها به درون بیضه‌دان نمی‌روند و درون شکم می‌مانند. این حالت به طور معمول بر نعوظ آلت تناسلی اثری ندارد، اما دمای بالای درون شکم به بیضه‌ها آسیب می‌رساند. در برخی مردان پوشیدن لباس زیر تنگ نیز ممکن است باعث افزایش دمای بیضه‌ها شود.
• سیگار، مواد مخدر و الکل
• برخی داروها
• مواد زهرآگین محیطی
• بیماری‌های مقاربتی

برخی بیماری‌های ژنتیکی، مانند نشانگان کلاین‌فلتر، نیز می‌تواند در ناباروری موثر باشند. با وجود آن چه گفته شد، در برخی موارد پزشکان و کارشناسان نمی‌توانند علت ناباروی و نازایی را در مرد یا زن تعیین کنند. هم چنین، برخی از علت‌های شناخته‌شده‌ی ناباروی هنوز درمانی ندارند.

تشخیص ناباروری و نازایی

 گرچه باردار نشدن یکی از مشخصه‌های نازایی و ناباروری است، فقط پزشک یا کارشناس بهداشت می‌تواند ناباروری و نازایی را تشخیص دهد. آن‌هایی که تصور می‌کنند نابارور و نازا هستند باید به کارشناس بهداشت یا پزشک مراجعه کنند. چنین افرادی عبارتند از:

• زوج‌هایی که پس از یک سال آمیزش باردار نشده‌اند.
• زنانی که بی نظمی‌هایی در چرخه‌ی قاعدگی ماهانه‌ی خود دارند یا به اندومتریوز یا فیبروزحمی دچار شده‌اند.
• زنانی که باردار شده‌اند، اما بیش از یک بار سقط جنین داشته‌اند.
• مردان و زنانی که نارسایی‌ها ژنتیکی خاص دارند.

درمان ناباروری و نازایی

راه‌های گوناگونی برای درمان ناباروری و نازایی وجود دارد، از جمله:

• درمان دارویی
• جراحی
• تلقیح مصنوعی(وارد کردن اسپرم آماده شده‌ی شوهر به دستگاه تولیدمثلی زن)
• فناوری‌های پیشرفته‌ای مانند لقاح در لوله ی آزمایش( IVF )

پزشکان و کارشناسان در بیشتر موارد ناباروری را با درمان دارویی یا جراحی اندام‌های تولیدمثلی درمان می‌کنند. هم چنین، دگرگونی‌هایی در شیوه‌ی زندگی ممکن است به درمان ناباروری کمک کند، از جمله کاهش تنش‌ها، بهبود برنامه‌ی غذایی، دست‌کشیدن از مواد مخدر و الکل یا کاستن دمای پیرامون بیضه ها.