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).
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.
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).
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.
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.
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 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 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
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
2. Hypothalamic hamartoma or other lesions
3. CNS tumor or inflammatory state
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
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
E. Gonadal causes of pubertal failure (elevated gonadotropins)
1. Klinefelter syndrome
2. Bilateral undescended testes or anorchia
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).
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.
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
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
Anosmia, renal agenesis, synkinesia, cleft lip/palate, oculomotor/visuospatial defects, gut malrotations
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.
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.
(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).
(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.
(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 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 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.
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.
Evaluation of gynecomastia. T, testosterone; LH, luteinizing hormone; FSH, follicle-stimulating hormones; hCG, human chorionic gonadotropin ; E2, 17-estradiol.
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.
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
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.
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.
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
DHT and Estradiol
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
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
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)
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.
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.
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
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).
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.
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]
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]