Chapter 11: Disorders of the Testes and Male Reproductive System

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, stimulation of libido and normal sexual function, and maintenance of muscle and bone mass. 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. 19, and 12, respectively.

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. 10). 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.

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. 11-1). 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 restrained until the early stages of puberty by a neuroendocrine brake imposed by the inhibitory actions of glutamate, γ-aminobutyric acid (GABA), and neuropeptide Y. Although the pathways that initiate reactivation of the GnRH pulse generator at the onset of puberty have been elusive, mounting evidence supports involvement of GPR54, a G protein–coupled receptor that binds an endogenous ligand, kisspeptin. 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. Kisspeptin signaling plays an important role in mediating the feedback action of sex steroids on gonadotropin secretion and in regulating the tempo of sexual maturation at puberty. Leptin, a hormone produced by adipose cells, plays a permissive role in the resurgence of GnRH secretion at the onset of puberty, as leptin-deficient individuals also fail to enter puberty (Chap. 20). The adipocyte hormone leptin, gut hormone ghrelin, neuropeptide Y, and kisspeptin integrate the signals originating in energy stores and metabolic tissues with mechanisms that control onset of puberty through regulation of GnRH secretion. Energy deficit and excess and metabolic stress are associated with disturbed reproductive maturation and timing of pubertal onset.

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 I (IGF-I), 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 THE HYPOTHALAMIC-PITUITARY-TESTIS AXIS IN ADULT MAN

Hypothalamic GnRH regulates the production of the pituitary gonadotropins LH and FSH (Fig. 11-2). 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; and numerous paracrine interactions between Leydig and Sertoli cells are necessary for normal testis function.

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. 11-3. After cholesterol transport into the mitochondrion, the formation of pregnenolone by CYP11A1 (side chain cleavage enzyme) is a limiting enzymatic step. The 17α-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 5α-reductase, or it can be aromatized to estradiol by CYP19 (aromatase). Two isoforms of steroid 5α-reductase, SRD5A1 and SRD5A2, have been described; all known kindreds with 5α-reductase deficiency have had mutations in SRD5A2, the predominant form in the prostate and the skin.

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 μg/d) is secreted directly by the testis; most circulating DHT is derived from peripheral conversion of testosterone. Most of the daily production of estradiol (~45 μg/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. 11-4). 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. SHBG-bound testosterone also may be internalized through endocytic pits by binding to a protein called megalin. SHBG concentrations are decreased by androgens, obesity, diabetes mellitus, insulin, and nephrotic syndrome. Conversely, estrogen administration, hyperthyroidism, many chronic inflammatory illnesses, infections such as HIV or hepatitis B and C, and aging are associated with high SHBG concentrations.

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 5α- and 5β-reductases, 3α- and 3β-hydroxysteroid dehydrogenases, and 17β-hydroxysteroid dehydrogenase into androsterone, etiocholanolone, DHT, and 3-α-androstanediol. These compounds undergo glucuronidation or sulfation before being excreted by the kidneys.

Mechanism of androgen action

Testosterone exerts some of its biologic effects by binding to androgen receptor, either directly or after its conversion to DHT by the steroid 5-α reductase. Testosterone’s effects on the skeletal muscle, erythropoiesis, and bone in men do not require its obligatory conversion to DHT. However, the conversion of testosterone to DHT is necessary for the masculinization of the urogenital sinus and genital tubercle. Aromatization of testosterone to estradiol mediates additional effects of testosterone on the bone resorption, epiphyseal closure, sexual desire, vascular endothelium, and fat. DHT can also be converted in some tissues by 3-keto reductase/3β-hydroxysteroid dehydrogenase enzymes to 5α-androstane-3β,17β-diol, which is a high-affinity ligand and agonist of estrogen receptor β.

The androgen receptor (AR) is structurally related to the nuclear receptors for estrogen, glucocorticoids, and progesterone (Chap. 2). 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. The ligand binding to the AR induces conformational changes that allow the recruitment and assembly of tissue-specific cofactors and causes it to translocate into the nucleus, where it binds to DNA or other transcription factors already bound to DNA. Thus, the AR is a ligand-regulated transcription factor that regulates the expression of androgen-dependent genes in a tissue-specific manner. 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.  11-2). 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 compose 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 FSHβ 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. The cooperative actions of FSH and testosterone are important in the progression of meiosis and spermiation. FSH and testosterone regulate germ cell survival via the intrinsic and the extrinsic apoptotic mechanisms. FSH may also play an important role in supporting spermatogonia. Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25), a testis-specific gonadotropin/androgen-regulated RNA helicase, is present in germ cells and Leydig cells and may be an important factor in the paracrine regulation of germ cell development. 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.

TREATMENT

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. 17). 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’s 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. Selective increase in 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 α-β_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 μg of GnRH. A minimally acceptable response is a twofold LH increase and a 50% FSH increase. In the prepubertal period or with severe GnRH deficiency, the gonadotrope may not respond to a single bolus of GnRH because it has not been primed by endogenous hypothalamic GnRH; in these patients, GnRH responsiveness may be restored by chronic, pulsatile GnRH administration. With the availability of sensitive and specific LH assays, GnRH stimulation testing is used rarely except to evaluate gonadotrope function in patients who have undergone pituitary surgery or have a space-occupying lesion in the hypothalamic-pituitary region.

TESTOSTERONE ASSAYS

Total testosterone

Total testosterone includes both unbound and protein-bound testosterone and is measured by radioimmunoassays, immunometric assays, or liquid chromatography tandem mass spectrometry (LC-MS/MS). LC-MS/MS involves extraction of serum by organic solvents, separation of testosterone from other steroids by high-performance liquid chromatography and mass spectrometry, and quantitation of unique testosterone fragments by mass spectrometry. LC-MS/MS provides accurate and sensitive measurements of testosterone levels even in the low range and is emerging as the method of choice for testosterone measurement. Laboratories that have been certified by the Centers for Disease Control and Prevention (CDC) Hormone Standardization Program for Testosterone (HoST) can ensure that testosterone measurements are accurate and calibrated to an international standard. A single fasting morning 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, and efforts are under way to generate harmonized population-based reference ranges that can be applied to all CDC-certified laboratories. Alterations in SHBG levels due to aging, obesity, diabetes mellitus, hyperthyroidism, some types of medications, or chronic illness or on a congenital basis can affect total testosterone levels. Heritable factors contribute substantially to the population-level variation in testosterone levels, and genome-wide association studies have revealed polymorphisms in the SHBG gene as important contributors to variation in 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. Recent research has shown that testosterone binding to SHBG is a multistep process that involves complex homoallostery within the SHBG dimer; a novel allosteric model of testosterone binding to SHBG dimers provides good estimates of free testosterone concentrations. The previous law of mass action equations based on linear models of testosterone binding to SHBG have been shown to be erroneous. 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 determined by the ammonium sulfate precipitation method.

hCG stimulation test

The hCG stimulation test is performed by administering a single injection of 1500–4000 IU of hCG intramuscularly and measuring testosterone levels at baseline and 24, 48, 72, and 120 h after hCG injection. An alternative regimen involves three injections of 1500 units of hCG on successive days and measuring testosterone levels 24 h after the last dose. An acceptable response to hCG is a doubling of the testosterone concentration in adult men. In prepubertal boys, an increase in testosterone to >150 ng/dL indicates the presence of testicular tissue. No response may indicate an absence of testicular tissue or marked impairment of Leydig cell function. Measurement of MIS, a Sertoli cell product, is also used to detect the presence of testes in prepubertal boys with cryptorchidism.

SEMEN ANALYSIS

Semen analysis is the most important step in the evaluation of male infertility. Samples are collected by masturbation following a period of abstinence for 2–3 days. Semen volumes and sperm concentrations vary considerably among fertile men, and several samples may be needed before concluding that the results are abnormal. Analysis should be performed within an hour of collection. Using semen samples from over 4500 men in 14 countries, whose partners had a time-to-pregnancy of less than 12 months, the World Health Organization (WHO) has generated the following one-sided reference limits for semen parameters: semen volume, 1.5 mL; total sperm number, 39 million per ejaculate; sperm concentration, 15 million/mL; vitality, 58% live; progressive motility, 32%; total (progressive + nonprogressive) motility, 40%; morphologically normal forms, 4.0%. Some men with low sperm counts are nevertheless fertile. A variety of tests for sperm function can be performed in specialized laboratories, but these add relatively little to the treatment options.

TESTICULAR BIOPSY

Testicular biopsy is useful in some patients with oligospermia or azoospermia as an aid in diagnosis and indication for the feasibility of treatment. Using local anesthesia, fine-needle aspiration biopsy is performed to aspirate tissue for histology. Alternatively, open biopsies can be performed under local or general anesthesia when more tissue is required. A normal biopsy in an azoospermic man with a normal FSH level suggests obstruction of the vas deferens, which may be correctable surgically. Biopsies are also used to harvest sperm for ICSI and to classify disorders such as hypospermatogenesis (all stages present but in reduced numbers), germ cell arrest (usually at primary spermatocyte stage), and Sertoli cell–only syndrome (absent germ cells) or hyalinization (sclerosis with absent cellular elements).

See Chap. 10.

The onset and tempo of puberty varies greatly in the general population and is affected by genetic and environmental factors. Although some of the variance in the timing of puberty is explained by heritable factors, the genes involved remain unknown.

PRECOCIOUS PUBERTY

Puberty in boys before age 9 is considered precocious. Isosexual precocity refers to premature sexual development consistent with phenotypic sex and includes features such as the development of facial hair and phallic growth. Isosexual precocity is divided into gonadotropin-dependent and gonadotropin-independent causes of androgen excess (Table 11-1). Heterosexual precocity refers to the premature development of estrogenic features in boys, such as breast development.

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. Magnetic resonance imaging (MRI) should be performed to exclude a mass, structural defect, infection, or inflammatory process. Mutations in MKRN3, an imprinted gene encoding makorin ring-finger protein 3, which is expressed only from the paternally inherited allele, have been associated with CPP.

Gonadotropin-independent precocious puberty

In 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 G_sα 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), AR antagonists (e.g., flutamide and bicalutamide), and aromatase inhibitors (e.g., anastrazole).

Mccune-Albright syndrome

This is a sporadic disorder caused by somatic (postzygotic) activating mutations in the G_sα subunit that links G protein–coupled receptors to intracellular signaling pathways (Chap. 36). The mutations impair the guanosine triphosphatase activity of the G_sα 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. 8 and 10). LH is low, and the testes are small. Adrenal rests may develop within the testis of poorly controlled patients with CAH because of chronic ACTH stimulation; adrenal rests do not require surgical removal and regress with effective glucocorticoid therapy. Some children with CAH may develop gonadotropin-dependent precocious puberty with early maturation of the hypothalamic-pituitary-gonadal axis, elevated gonadotropins, and testicular growth.

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 PATIENT

TREATMENT

DELAYED PUBERTY

Puberty is delayed in boys if it has not ensued by age 14, an age that is 2–2.5 standard deviations above the mean for healthy children. Delayed puberty is more common in boys than in girls. There are four main categories of delayed puberty: (1) constitutional delay of growth and puberty (~60% of cases); (2) functional hypogonadotropic hypogonadism caused by systemic illness or malnutrition (~20% of cases); (3) hypogonadotropic hypogonadism caused by genetic or acquired defects in the hypothalamic-pituitary region (~10% of cases); and (4) hypergonadotropic hypogonadism secondary to primary gonadal failure (~15% of cases) (Table 11-1). 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 PATIENT

TREATMENT

HYPOGONADOTROPIC HYPOGONADISM

Because LH and FSH are trophic hormones for the testes, impaired secretion of these pituitary gonadotropins results in secondary hypogonadism, which is characterized by low testosterone in the setting of low LH and FSH. Those with the most severe deficiency have complete absence of pubertal development, sexual infantilism, and, in some cases, hypospadias and undescended testes. Patients with partial gonadotropin deficiency have delayed or arrested sex development. The 24-h LH secretory profiles are heterogeneous in patients with hypogonadotropic hypogonadism, reflecting variable abnormalities of LH pulse frequency or amplitude. In severe cases, basal LH is low and there are no LH pulses. A smaller subset of patients has low-amplitude LH pulses or markedly reduced pulse frequency. Occasionally, only sleep-entrained LH pulses occur, reminiscent of the pattern seen in the early stages of puberty. Hypogonadotropic hypogonadism can be classified into congenital and acquired disorders. Congenital disorders most commonly involve GnRH deficiency, which leads to gonadotropin deficiency. Acquired disorders are much more common than congenital disorders and may result from a variety of sellar mass lesions or infiltrative diseases of the hypothalamus or pituitary.

Congenital disorders associated with gonadotropin deficiency

Congenital hypogonadotropic hypogonadism is a heterogeneous group of disorders characterized by decreased gonadotropin secretion and testicular dysfunction either due to impaired function of the GnRH pulse generator or the gonadotrope. The disorders characterized by GnRH deficiency represent a family of oligogenic disorders whose phenotype spans a wide spectrum. Some individuals with GnRH deficiency may suffer from complete absence of pubertal development, while others may manifest varying degrees of gonadotropin deficiency and pubertal delay, and a subset that carries the same mutations as their affected family members may even have normal reproductive function. In approximately 10% of men with idiopathic hypogonadotropic hypogonadism, reversal of gonadotropin deficiency may occur in adult life after sex steroid therapy. Also, a small fraction of men with idiopathic hypogonadotropic hypogonadism may present with androgen deficiency and infertility in adult life after having gone through apparently normal pubertal development. Nutritional, emotional, or metabolic stress may unmask gonadotropin deficiency and reproductive dysfunction (analogous to hypothalamic amenorrhea) in some patients who harbor mutations in the candidate genes but who previously had normal reproductive function. The clinical phenotype may include isolated anosmia or hyposmia. These striking variations in phenotypic presentation of GnRH deficiency have highlighted the important role of oligogenicity and gene-gene and gene-environment interactions in shaping the clinical phenotype.

Mutations in a number of genes involved in the development and migration of GnRH neurons or in the regulation of GnRH secretion have been linked to GnRH deficiency, although the genetic defect remains elusive in nearly two-thirds of cases. 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. The genetic defects associated with GnRH deficiency can be conveniently classified as anosmic (Kallmann’s syndrome) or normosmic (Table 11-2), although the occurrence of both anosmic and normosmic forms of GnRH deficiency in the same families suggests commonality of pathophysiologic mechanisms. Kallmann’s syndrome, the anosmic form of GnRH deficiency, can result from mutations in one or more genes associated with olfactory bulb morphogenesis and the migration of GnRH neurons from their origin in the region of the olfactory placode, along the scaffold established by the olfactory nerves, through the cribriform plate into their final location into the preoptic region of the hypothalamus. Thus, mutations in KAL1, FGF8, FGFR1, NELF, PROK2, PROK2R, and CHD7 have been described in patients with Kallmann’s syndrome. An X-linked form of IHH is 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. Mutations in the FGFR1 gene cause an autosomal dominant form of hypogonadotropic hypogonadism that clinically resembles Kallmann’s syndrome; mutations in its putative ligand, FGF8 gene product, have also been associated with IHH. Prokineticin 2 (PROK2) also encodes a protein involved in migration and development of olfactory and GnRH neurons. Recessive mutations in PROK2 or in its receptor, PROKR2, have been associated with both anosmic and normosmic forms of hypogonadotropic hypogonadism.

Normosmic GnRH deficiency results from defects in pulsatile GnRH secretion, its regulation, or its action on the gonadotrope and has been associated with mutations in GnRHR, GNRH1, KISS1R, TAC3, TACR3, and NROB1 (DAX1). Some mutations, such as those in PROK2, PROKR2, and CHD7, have been associated with both the anosmic and normosmic forms of IHH. GnRHR mutations, the most frequent identifiable cause of normosmic IHH, 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. Mutations of the GnRH1 gene have also been reported in patients with hypogonadotropic hypogonadism, although they are rare. G protein–coupled receptor KISS1R (GPR54) and its cognate ligand, kisspeptin (KISS1), are important regulators of sexual maturation in primates. Recessive mutations in GPR54 cause gonadotropin deficiency without anosmia. Patients retain responsiveness to exogenous GnRH, suggesting an abnormality in the neural pathways controlling GnRH release. The genes encoding neurokinin B (TAC3), which is involved in preferential activation of GnRH release in early development, and its receptor (TAC3R) have been implicated in some families with normosmic IHH. Mutations in more than one gene (digenicity or oligogenicity) may contribute to clinical heterogeneity in IHH patients. 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, most 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). Rarely, recessive mutations in the LHβ or FSHβ gene have been described in patients with selective deficiencies of these gonadotropins. In approximately 10% of men with IHH, reversal of gonadotropin deficiency may occur in adult life. Also, a small fraction of men with IHH may present with androgen deficiency and infertility in adult life after having gone through apparently normal pubertal development.

A number of homeodomain transcription factors are involved in the development and differentiation of the specialized hormone-producing cells within the pituitary gland (Table 11-2). 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 septo-optic dysplasia and combined pituitary hormone deficiency.

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 the paternally derived chromosome 15q11-15q13 region, which contains a bipartite imprinting center, uniparental disomy of the maternal alleles, or mutations of the genes/loci involved in imprinting. 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. 20).

Acquired hypogonadotropic disorders

Severe illness, stress, malnutrition, and exercise

These factors 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 and high prevalence of sexual dysfunction and osteoporosis; the degree of suppression is dose-related and particularly severe with long-acting opioids such as methadone. 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. Androgen deprivation therapy in men with prostate cancer has been associated with increased risk of bone fractures, diabetes mellitus, cardiovascular events, fatigue, sexual dysfunction, and poor quality of life.

Obesity

In men with mild to moderate obesity, SHBG levels decrease in proportion to the degree of obesity, resulting in lower total testosterone levels. However, free testosterone levels usually remain within the normal range. The decrease in SHBG levels is caused by increased circulating insulin, which inhibits SHBG production. Estradiol levels are higher in obese men compared to healthy, nonobese controls, because of aromatization of testosterone to estradiol in adipose tissue. Weight loss is associated with reversal of these abnormalities including an increase in total and free testosterone levels and a decrease in estradiol levels. A subset of obese men with moderate to severe obesity may have a defect in the hypothalamic-pituitary axis as suggested by low free testosterone in the absence of elevated gonadotropins. Weight gain in adult men can accelerate the rate of age-related decline in testosterone levels.

Hyperprolactinemia

(See also Chap. 5) 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 μg/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. 6).

Hemochromatosis

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’s 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. 10 for disorders of testis development, androgen synthesis, and androgen action.

Klinefelter’s syndrome

(See also Chap. 10) Klinefelter’s syndrome is the most common chromosomal disorder associated with testicular dysfunction and male infertility. It occurs in about 1 in 600 live-born males. Azoospermia is the rule in men with Klinefelter’s syndrome who have the 47,XXY karyotype; however, men with mosaicism may have germ cells, especially at a younger age. The clinical phenotype of Klinefelter’s syndrome can be heterogeneous possibly because of mosaicism, polymorphisms in AR gene, variable testosterone levels, or other genetic factors. 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’s syndrome are at increased risk of systemic lupus erythematosus, Sjögren’s syndrome, breast cancer, diabetes mellitus, osteoporosis, 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’s syndrome. Fertility has been achieved by intracytoplasmic injection of sperm retrieved surgically from testicular biopsies of men with Klinefelter’s syndrome, including some men with the nonmosaic form of Klinefelter’s syndrome. The karyotypes 48,XXXY and 49,XXXXY are associated with a more severe phenotype, increased risk of congenital malformations, and lower intelligence than 47,XXY individuals.

Cryptorchidism

Cryptorchidism occurs when there is incomplete descent of the testis from the abdominal cavity into the scrotum. About 3% of full-term and 30% of premature male infants have at least one undescended 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. Androgens regulate predominantly the inguinoscrotal descent of the testes through degeneration of the craniosuspensory ligament and a shortening of the gubernaculums, respectively. Mutations in INSL3 and leucine-rich repeat family of G protein–coupled receptor 8 (LGR8), which regulate the transabdominal portion of testicular descent, have been found in some patients with cryptorchidism.

Cryptorchidism is associated with increased risk of malignancy, infertility, inguinal hernia, and torsion. 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 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, vincristine, procarbazine, prednisone) therapy develop azoospermia or extreme oligozoospermia; newer regimens that do not include procarbazine, such as ABVD (doxorubicin, 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 pesticides (e.g., vinclozolin, dicofol, atrazine), sewage contaminants (e.g., ethinyl estradiol in birth control pills, surfactants such as octylphenol, nonyphenol), plasticizers (e.g., pthalates), flame retardants (e.g., polychlorinated biphenyls, polybrominated diphenol ethers), industrial pollutants (e.g., heavy metals cadmium and lead, dioxins, polycyclic aromatic hydrocarbons), microwaves, and ultrasound. 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. 29). 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. 10). Although not technically hormone-insensitivity syndromes, two genetic disorders impair testosterone conversion to active sex steroids. Mutations in the SRD5A2 gene, which encodes 5α-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-to-androgen ratio. True gynecomastia is associated with glandular breast tissue that is >4 cm in diameter and often tender. Glandular tissue enlargement should be distinguished from excess adipose tissue: glandular tissue is firmer and contains fibrous-like cords. Gynecomastia occurs as a normal physiologic phenomenon in the newborn (due to transplacental transfer of maternal and placental estrogens), during puberty (high estrogen-to-androgen ratio in early stages of puberty), and with aging (increased fat tissue and increased aromatase activity), but it can also result from pathologic conditions associated with androgen deficiency or estrogen excess. The prevalence of gynecomastia increases with age and body mass index (BMI), likely because of increased aromatase activity in adipose tissue. Medications that alter androgen metabolism or action may also cause gynecomastia. The relative risk of breast cancer is increased in men with gynecomastia, although the absolute risk is relatively small.

PATHOLOGIC GYNECOMASTIA

Any cause of androgen deficiency can lead to gynecomastia, reflecting an increased estrogen-to-androgen ratio, because estrogen synthesis still occurs by aromatization of residual adrenal and gonadal androgens. Gynecomastia is a characteristic feature of Klinefelter’s syndrome (Chap. 10). 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-Jeghers 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 of 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) or by 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. 11-5). 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’s syndrome. Despite extensive evaluation, the etiology is established in fewer than one-half of patients.

TREATMENT

A number of cross-sectional and longitudinal studies (e.g., The Baltimore Longitudinal Study of Aging, the Framingham Heart Study, the Massachusetts Male Aging Study, and the European 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 in obese men, men with chronic illness, and 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. The approach to evaluating hypogonadism is summarized in Fig. 11-6.

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, although the associations are weak. An analysis of signs and symptoms in older men in the European Male Aging Study revealed a syndromic association of sexual symptoms with total testosterone levels below 320 ng/dL and free testosterone levels below 64 pg/mL in community-dwelling older men. 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 compared 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, response to phosphodiesterase inhibitors, or clinical outcomes in older men. Furthermore, neither the long-term risks nor clinical benefits of testosterone therapy in older men have been demonstrated in adequately powered trials. Although there is no evidence that testosterone causes prostate cancer, there is concern that testosterone therapy might cause subclinical prostate cancers to grow. Testosterone therapy is associated with increased risk of detection of prostate events (Fig. 11-7).

One randomized testosterone trial in older men with mobility limitation and high burden of chronic conditions, such as diabetes, heart disease, hypertension, and hyperlipidemia, reported a greater number of cardiovascular events in men randomized to the testosterone arm of the study than in those randomized to the placebo arm. Since then, two large retrospective analyses of patient databases have reported higher frequency of cardiovascular events, including myocardial infarction, in older men with preexisting heart disease (Fig.  11-7).

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, there is no clear evidence that the frequency of chromosomal aneuploidy is increased in the sperm of older men. However, the incidence of autosomal dominant diseases, such as achondroplasia, polyposis coli, Marfan’s syndrome, and Apert’s syndrome, increases in the offspring of men who are advanced in age, consistent with transmission of sporadic missense mutations. Advanced paternal age may be associated with increased rates of de novo mutations, which may contribute to an increased risk of neurodevelopmental diseases such as schizophrenia and autism. The somatic mutations in male germ cells that enhance the proliferation of germ cells could lead to within-testis expansion of mutant clonal lines, thus favoring the propagation of germ cells carrying these pathogenic mutations and increasing the risk of mutations in the offspring of older fathers (the “selfish spermatogonial selection” hypothesis).

APPROACH TO PATIENT

TREATMENT