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InternalMed_Harrison. 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) 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. Aromatase inhibitors, such as testolactone and letrozole, have been used as an adjunct to antiandrogen and GnRH analogue therapy for children with familial male-limited precocious puberty, CAH, and McCune-Albright syndrome.


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InternalMed_Harrison. 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 411-1). 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:


InternalMed_Harrison

InternalMed_Harrison. APPROACH TO THE PATIENT: 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 2363 steroid therapy. Also, a small fraction of men with idiopathic hypogonadotropic hypogonadism may present with


InternalMed_Harrison

InternalMed_Harrison. hypogonadism, reversal of gonadotropin deficiency may occur in adult life after sex 2363 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.


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InternalMed_Harrison. 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 411-2), 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


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InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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


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InternalMed_Harrison. Disorders of the Testes and Male Reproductive System A. Hypogonadotropic Hypogonadism due to GnRH Deficiency A1. GnRH Deficiency Associated with Hyposmia or Anosmia KAL1 Xp22 X-linked Anosmia, renal agenesis, synkinesia, cleft lip/palate, oculomotor/visuospatial defects, gut malformations NELF 9q34.3 AR Anosmia, hypogonadotropic hypogonadism FGFR1 8p11-p12 AD Anosmia, cleft lip/palate, synkinesia, syndactyly PROK2R 20p12.3 AR Variable CHD7 8q12.1 Anosmia, other features of CHARGE syndrome A2. GnRH Deficiency with Normal Sense of Smell GNRHR 4q21 AR None GnRH1 8p21 AR None KISS1R 19p13 AR None TAC3 12q13 AR Microphallus, cryptorchidism, reversal of GnRH deficiency TAC3R 4q25 AR Microphallus, cryptorchidism, reversal B. Hypogonadotropic Hypogonadism not due to GnRH Deficiency


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InternalMed_Harrison. Abbreviations: ACTH, adrenocorticotropic hormone; AD, autosomal dominant; AR, autosomal recessive; CHARGE, eye coloboma, choanal atresia, growth and developmental retardation, genitourinary anomalies, ear anomalies; CPHD, combined pituitary hormone deficiency; DAX1, dosage-sensitive sex-reversal, adrenal hypoplasia congenita, X-chromosome; FGFR1, fibroblast growth factor receptor 1; FSH, follicle-stimulating hormone; FSHβ, follicle-stimulating hormone β-subunit; GH, growth hormone; GnRH, gonadotropinreleasing hormone; GNRHR, gonadotropin-releasing hormone receptor; GPR54, G protein– coupled receptor 54; HESX1, homeo box gene expressed in embryonic stem cells 1; KAL1, interval-1 gene; LEP, leptin; LEPR, leptin receptor; LH, luteinizing hormone; LHβ, luteinizing hormone β-subunit; LHX3, LIM homeobox gene 3; NELF, nasal embryonic LHRH factor; PC1, prohormone convertase 1; PROK2, prokineticin 2; PROP1, Prophet of Pit 1; SF1, steroidogenic factor 1; TAC3, tachykinin 3; TAC3R, tachykinin 3


InternalMed_Harrison

InternalMed_Harrison. homeobox gene 3; NELF, nasal embryonic LHRH factor; PC1, prohormone convertase 1; PROK2, prokineticin 2; PROP1, Prophet of Pit 1; SF1, steroidogenic factor 1; TAC3, tachykinin 3; TAC3R, tachykinin 3 receptor.


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InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 411-2). 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.


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InternalMed_Harrison. 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 (Chap. 83e). 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. 415e).


InternalMed_Harrison

InternalMed_Harrison. Acquired Hypogonadotropic Disorders • severe illness, sTress, malnuTri-Tion, 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


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. Hyperprolactinemia (See also Chap. 403) 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.


InternalMed_Harrison

InternalMed_Harrison. 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. 404).


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InternalMed_Harrison. HemocHromatoSiS (See also Chap. 428) 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. 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. 410 for disorders of testis development, androgen synthesis, and androgen action.


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InternalMed_Harrison. Klinefelter’s Syndrome (See also Chap. 410) 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


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InternalMed_Harrison. 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 2365 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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).


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InternalMed_Harrison. 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 longterm 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. Disorders of the Testes and Male Reproductive System 2366 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. 408). Sperm antibodies can cause isolated male infertility.


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InternalMed_Harrison. or antiandrogens may be partly responsible. Testicular failure also occurs as a part of polyglandular autoimmune insufficiency (Chap. 408). 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


InternalMed_Harrison

InternalMed_Harrison. 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


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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. 410). 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.


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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. 410). 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


InternalMed_Harrison

InternalMed_Harrison. 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.,


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InternalMed_Harrison. 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).


InternalMed_Harrison

InternalMed_Harrison. 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. 411-5). 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.


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InternalMed_Harrison. 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. Estrogen receptor antagonists, tamoxifen and raloxifene, have been reported in small trials to reduce breast size in men with pubertal gynecomastia, although complete regression of breast enlargement is unusual with the use of estrogen receptor antagonists. Aromatase inhibitors can be effective in the early proliferative phase of the disorder. However, in a randomized trial in men with established gynecomastia, anastrozole proved no more effective than


InternalMed_Harrison

InternalMed_Harrison. Aromatase inhibitors can be effective in the early proliferative phase of the disorder. However, in a randomized trial in men with established gynecomastia, anastrozole proved no more effective than placebo in reducing breast size. Tamoxifen is effective in the prevention and treatment of breast enlargement and breast pain in men with prostate cancer who are receiving antiandrogen therapy.


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InternalMed_Harrison. Increased aromatization of androgen to estrogen (obesity, feminizing adrenal tumors, Sertoli cell tumors, inherited dysregulation of aromatase) Breast enlargement True glandular enlargement Breast mass hard or fixed to the underlying tissue Recent onset and rapid growth Mammography and/or biopsy to exclude malignancy Follow-up with serial examinations Increased E2, normal T, altered E2/T ratio Increased hCG˜Exclude hCG secreting tumors Low T, high E2/T ratio Androgen deficiency syndrome Serum T, LH, FSH, estradiol, and hCG˜Onset in neonatal or peripubertal period Causative drugs Known liver disease Size <4 cm Clinical evidence of androgen deficiency Breast tenderness Very small testes Glandular tissue >4 cm in diameter Absence of causative drugs or liver disease Increased adipose tissue FIGURE 411-5 Evaluation of gynecomastia. E2, 17β-estradiol; hCGβ, human chorionic gonadotropin β; T, testosterone.


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InternalMed_Harrison. 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-pituitarytesticular 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


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InternalMed_Harrison. hypothalamic-pituitarytesticular 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


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InternalMed_Harrison. FIGURE 411-6 Evaluation of hypogonadism. GnRH, gonadotropinreleasing hormone; LH, luteinizing hormone; T, testosterone. 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. 411-6.


InternalMed_Harrison

InternalMed_Harrison. 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


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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. 411-7).


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InternalMed_Harrison. Disorders of the Testes and Male Reproductive System Spitzer 2012 4 70 2 70 2.06 [0.37; 11.63] 4.0% Hoyos 2012 1 33 0 34 3.18 [0.13; 81.01] 1.1% 0.01 0.1 1 10 100 + + + + + + + + + + + + + + + + + + + + + + + + + + 1.00 [0.06; 16.37] 1.5% Kaufman 2011 11 234 0 40 4.17 [0.24; 72.13] 1.5% Jones 2011 5 108 12 112 0.40 [0.14; 1.19] 10.3% Aversa 2010 0 40 1 10 0.08 [0.00; 2.07] 1.1% 6.05 [2.22; 16.51] 11.9% Kalinchenko 2010 0 113 2 71 0.12 [0.01; 2.59] 1.3% Srinivas-Shankar 2010 5 138 2 136 2.52 [0.48; 13.21] 4.4% Caminiti 2009 2 35 1 35 2.06 [0.18; 23.83] 2.0% Chapman 2009 1 11 1 12 1.10 [0.06; 20.01] 1.4% Legros 2009 1 237 0 79 1.01 [0.04; 25.01] 1.2% Emmelot-Vonk 2008 8 120 3 117 2.71 [0.70; 10.49] 6.6% Svartberg 2008 1 19 0 19 3.16 [0.12; 82.64] 1.1% 1.20 [0.34; 4.18] 7.7% Malkin 2006 4 37 4 39 1.06 [0.25; 4.59] 5.6% Merza 2006 0 20 1 19 0.30 [0.01; 7.85] 1.1% 1.32 [0.39; 4.50] 8.0% Amory 2004 1 24 0 24 3.13 [0.12; 80.68] 1.1% Kenny 2004 0 6 1 5 0.23 [0.01; 7.05] 1.0%


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InternalMed_Harrison. Merza 2006 0 20 1 19 0.30 [0.01; 7.85] 1.1% 1.32 [0.39; 4.50] 8.0% Amory 2004 1 24 0 24 3.13 [0.12; 80.68] 1.1% Kenny 2004 0 6 1 5 0.23 [0.01; 7.05] 1.0% Svartberg 2004 0 15 1 14 0.29 [0.01; 7.74] 1.1% Snyder 2001 9 54 5 54 1.96 [0.61; 6.29] 8.8% English 2000 2 25 0 25 5.43 [0.25; 118.96] 1.3% Sih 1997 1 17 1 15 0.88 [0.05; 15.33] 1.5% Hall 1996 0 17 2 18 0.19 [0.01; 4.23] 1.2% Marin 1993 1 11 0 10 3.00 [0.11; 82.40] 1.1% Copenhagen 1986 16 134 5 87 2.22 [0.78; 6.31] 11.0% Fixed effect model 115 1733 65 1261 1.54 [1.09; 2.18] 100% Heterogeneity: I-squared = 7.8%, tau-squared = 0.0742, p = 0.3484 A < Testosterone Favors Placebo >


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InternalMed_Harrison. Fixed effect model 115 1733 65 1261 1.54 [1.09; 2.18] 100% Heterogeneity: I-squared = 7.8%, tau-squared = 0.0742, p = 0.3484 A < Testosterone Favors Placebo > FIGURE 411-7 Meta-analyses of cardiovascular and prostate adverse events associated with testosterone therapy. A. A meta-analysis of cardiovascular-related events in randomized testosterone trials of 12 weeks or longer in duration. Randomization to testosterone was associated with a significantly increased risk of cardiovascular-related event (odds ratio [OR] 1.54). (Modified with permission from L Xu et al: Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials BMC Med 11:108, 2013.)


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InternalMed_Harrison. B. The relative risk of prostate events and the associated 95% confidence intervals (CIs) in a meta-analysis of randomized testosterone trials. PSA, prostate-specific antigen. (Data were derived from a meta-analysis by MM Fernández-Balsells et al: J Clin Endocrinol Metab 95:2560, 2010, and the figure was reproduced with permission from M Spitzer et al: Nat Rev Endocrinol 9:414, 2013.)


InternalMed_Harrison

InternalMed_Harrison. One randomized testosterone trial in older men with mobility limi-Population screening of all older men for low testosterone levtation and high burden of chronic conditions, such as diabetes, heart els is not recommended, and testing should be restricted to men disease, hypertension, and hyperlipidemia, reported a greater number who have symptoms or physical features attributable to androof cardiovascular events in men randomized to the testosterone arm of gen deficiency. Testosterone therapy is not recommended for all the study than in those randomized to the placebo arm. Since then, two older men with low testosterone levels. In older men with siglarge retrospective analyses of patient databases have reported higher nificant symptoms of androgen deficiency who have testosterone frequency of cardiovascular events, including myocardial infarction, in levels below 200 ng/dL, testosterone therapy may be considered on older men with preexisting heart disease (Fig. 411-7). an


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InternalMed_Harrison. frequency of cardiovascular events, including myocardial infarction, in levels below 200 ng/dL, testosterone therapy may be considered on older men with preexisting heart disease (Fig. 411-7). an individualized basis and should be instituted after careful discussion of the risks and benefits (see “Testosterone Replacement,” below).


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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).


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APPROACH TO THE PATIENT:

InternalMed_Harrison. APPROACH TO THE PATIENT:


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InternalMed_Harrison. Hypogonadism is often characterized by decreased sex drive, reduced frequency of sexual activity, inability to maintain erections, reduced beard growth, loss of muscle mass, decreased testicular size, and gynecomastia. Erectile dysfunction and androgen deficiency are two distinct clinical disorders that can coexist in middle-aged and older men. Less than 10% of patients with erectile dysfunction have testosterone deficiency. Thus, it is useful to evaluate men presenting with erectile dysfunction for androgen deficiency. Except when extreme, these clinical features of androgen deficiency may be difficult to distinguish from changes that occur with normal aging. Moreover, androgen deficiency may develop gradually. Several epidemiologic studies, such as the Framingham Heart Study, the Massachusetts Male Aging Study, the Baltimore Longitudinal Study of Aging, and the Study of Osteoporotic Fractures in Men, have reported a high prevalence of low testosterone levels in middle-aged and older


InternalMed_Harrison

InternalMed_Harrison. Male Aging Study, the Baltimore Longitudinal Study of Aging, and the Study of Osteoporotic Fractures in Men, have reported a high prevalence of low testosterone levels in middle-aged and older men. The age-related decline in testosterone should be distinguished from classical hypogonadism due to diseases of the testes, the pituitary, and the hypothalamus.


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InternalMed_Harrison. When symptoms or clinical features suggest possible androgen deficiency, the laboratory evaluation is initiated by the measurement of total testosterone, preferably in the morning using a reliable assay, such as LC-MS/MS that has been calibrated to an international testosterone standard (Fig. 411-6). A consistently low total testosterone level <300 ng/dL measured by a reliable assay, in association with symptoms, is evidence of testosterone deficiency. An early-morning testosterone level >400 ng/dL makes the diagnosis of androgen deficiency unlikely. In men with testosterone levels between 200 and 400 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.


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InternalMed_Harrison. When androgen deficiency has been confirmed by the consistently 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’s 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’s syndrome. Men who have low testosterone levels 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,


InternalMed_Harrison

InternalMed_Harrison. 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 the use of anabolic-androgenic steroids, opiates, marijuana, glucocorticoids, and alcohol. 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’s syndrome, to be diagnosed in young adults.


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InternalMed_Harrison. 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 LH 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 β subunit of recombinant hFSH has seven fewer amino acids. Recombinant hFSH is available in ampoules containing 75 IU (~7.5 μg FSH), which accounts for >99% of protein


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InternalMed_Harrison. in vivo, although the mature β subunit of recombinant hFSH has seven fewer amino acids. Recombinant hFSH is available in ampoules containing 75 IU (~7.5 μg 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.


InternalMed_Harrison

InternalMed_Harrison. Although a variety of treatment regimens are used, 1000–2000 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


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 preclude subsequent response to gonadotropin therapy, although some studies suggest that it may attenuate response to subsequent gonadotropin therapy.


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InternalMed_Harrison. Disorders of the Testes and Male Reproductive System 2370 TESTOSTERONE REPLACEMENT Androgen therapy is indicated to restore testosterone levels to normal to correct features of androgen deficiency. Testosterone replacement improves libido and overall sexual activity; increases energy, lean muscle mass, and bone density; and decreases fat mass. 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.


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InternalMed_Harrison. Testosterone is available in a variety of formulations with distinct pharmacokinetics (Table 411-3). Testosterone serves as a prohormone and is converted to 17β-estradiol by aromatase and to 5α-dihydrotestosterone by steroid 5α-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 aThese formulations are not approved for clinical use in the United States, but are available outside the United States in many countries. Physicians in those countries where these formulations are available should follow the approved drug regimens. Abbreviations: DHT, dihydrotestosterone; E2, estradiol; T, testosterone.


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InternalMed_Harrison. Abbreviations: DHT, dihydrotestosterone; E2, estradiol; T, testosterone. 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.


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InternalMed_Harrison. Oral Derivatives of Testosterone Testosterone is well-absorbed after oral administration but is quickly degraded during the first pass through the liver. Therefore, it is difficult to achieve sustained blood levels of testosterone after oral administration of crystalline testosterone. 17α-Alkylated derivatives of testosterone (e.g., 17α-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 17α-alkylated androgens are useful because they stimulate hepatic synthesis of the C1 esterase inhibitor.


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InternalMed_Harrison. Injectable Forms of Testosterone The esterification of testosterone at the 17β-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 is the hydrophobicity of the ester and the longer is the duration of action. Thus, testosterone enanthate, cypionate, and undecanoate 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


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 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 two 5-mg patches daily to achieve the targeted testosterone concentrations. The use of testosterone patches may be associated with skin irritation in some individuals.


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InternalMed_Harrison. Testosterone Gel Several transdermal testosterone gels (e.g., Androgel, Testim, Fortesta, and Axiron), when applied topically to the skin in appropriate doses (Table 411-3), can maintain total and free testosterone concentrations in the normal range in hypogonadal men. The current recommendations are to begin with an initial U.S. Food and Drug Administration–approved dose and adjust the dose based on testosterone levels. The advantages of the testosterone gel include the ease of 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 than in healthy men. Also, there is considerable intraand interindividual variation in serum testosterone levels in men treated with the transdermal gel due to variations in transdermal absorption and plasma clearance of


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InternalMed_Harrison. Also, there is considerable intraand interindividual variation in serum testosterone levels in men treated with the transdermal gel due to variations in transdermal absorption and plasma clearance of testosterone. Therefore, monitoring of serum testosterone levels and multiple dose adjustments may be required to achieve and maintain testosterone levels in the target range.


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InternalMed_Harrison. Buccal Adhesive Testosterone A buccal 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. 2371 The adverse effects include buccal ulceration and gum problems in a few subjects. The effects of food and brushing on absorption have not been studied in detail. 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. Two to six 200-mg implants can maintain testosterone in the midto 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.


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InternalMed_Harrison. 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. DHTto-testosterone ratios are higher in hypogonadal men treated with oral testosterone undecanoate, as compared to eugonadal men. 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.


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InternalMed_Harrison. Novel Androgen Formulations A number of androgen formulations with better pharmacokinetics or more selective activity profiles are under development. A long-acting ester, 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. 7α-Methyl-19-nortestosterone is an androgen that cannot be 5α-reduced; therefore, compared to testosterone, it has relatively greater agonist activity in muscle and gonadotropin suppression but lesser activity on the prostate.


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InternalMed_Harrison. Selective AR modulators (SARMs) are a class of AR ligands that bind the AR and display tissue-selective actions. A number of non-steroidal SARMs that act as full agonists on the muscle and bone and that spare the prostate to varying degrees have advanced to phase 3 human trials. Nonsteroidal SARMs do not serve as substrates for either the steroid 5α-reductase or the CYP19 aromatase. SARM binding to AR induces specific conformational changes in the AR protein, which then modulates protein-protein interactions between AR and its coregulators, resulting in tissue-specific regulation of gene expression.


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InternalMed_Harrison. Pharmacologic Uses of Androgens Androgens and SARMs 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 the recommendation 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


InternalMed_Harrison

InternalMed_Harrison. 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 is safe and effective in improving physical function, vitality, and health-related quality of life and reducing disability. Concerns about potential adverse effects of testosterone on prostate and cardiovascular event rates


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InternalMed_Harrison. Disorders of the Testes and Male Reproductive System 2372 have encouraged the development of SARMs 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 skeletal 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.


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InternalMed_Harrison. Male Hormonal Contraception Based on Combined Administration of Testosterone and Gonadotropin Inhibitors Supraphysiologic doses of testosterone (200 mg testosterone enanthate weekly) suppress LH and FSH secretion and induce azoospermia in 50% of Caucasian men and >95% of Chinese men. The WHO-supported multicenter efficacy trials have demonstrated that suppression of spermatogenesis to azoospermia or severe oligozoospermia (<3 million/mL) by administration of testosterone enanthate to men results in highly effective contraception. 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


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InternalMed_Harrison. 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, and its long-term safety has not been demonstrated. SARMs that are more potent inhibitors of gonadotropins than testosterone and spare the prostate hold promise for their contraceptive potential.


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InternalMed_Harrison. Recommended Regimens for Androgen Replacement Testosterone esters are administered typically at doses of 75–100 mg intramuscularly every week, 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 gels are typically applied over a covered area of skin at initial doses that vary with the formulation; 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.


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InternalMed_Harrison. Establishing Efficacy of Testosterone Replacement Therapy Because a clinically useful marker of androgen action is not available, restoration of testosterone levels to 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. There is substantial interindividual variability in serum testosterone levels, especially with transdermal gels, presumably due to genetic differences in testosterone clearance and transdermal absorption. 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 either in the dose or in the interval between injections. In men on transdermal patch, gel, or buccal testosterone therapy, testosterone levels should be in the


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InternalMed_Harrison. this range, adjustments should be made either in the dose or in the interval between injections. In men on transdermal patch, 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. Multiple dose adjustments are often necessary to achieve testosterone levels in the desired therapeutic range.


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InternalMed_Harrison. Restoration of sexual function, secondary sex characteristics, energy, and well-being and maintenance of muscle and bone health are important objectives of testosterone replacement therapy. The patient should 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 twenties or thirties 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. Contraindications for Androgen Administration Testosterone administration is contraindicated in men with a history of prostate or breast cancer (Table 411-4). Testosterone therapy should not be administered without further urologic evaluation to men with a palpable prostate nodule or induration; to men with prostate-specific antigen levels >4 ng/mL or >3 ng/mL in men at high risk for prostate cancer such as African Americans or men with first-degree relatives with prostate cancer; or to men with severe lower urinary tract symptoms (American Urological Association lower urinary tract symptom score >19). Testosterone replacement should not be administered to men with baseline hematocrit ≥50%, severe untreated obstructive sleep apnea, uncontrolled or poorly controlled congestive heart failure, or myocardial infarction, stroke, or acute coronary syndrome in the preceding 6 months.


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InternalMed_Harrison. Monitoring Potential Adverse Experiences The clinical effectiveness and safety of testosterone replacement therapy should be assessed 3 to 6 months after initiating testosterone therapy and annually thereafter (Table 411-5). 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 detection of prostate events. 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. Older men with preexisting heart disease may be at increased risk of cardiovascular events after initiation of testosterone therapy.


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InternalMed_Harrison. HemoGloBin levelS Administration of testosterone to androgen-deficient men is typically associated with a ~3% increase in hemoglobin 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: Conditions in which testosterone administration is associated with moderate to high risk of adverse outcomes: Undiagnosed prostate nodule or induration PSA >4 ng/mL (>3 ng/mL in individuals at high risk for prostate cancer, such as African Americans or men with first-degree relatives who have prostate cancer) Erythrocytosis (hematocrit >50%) Severe lower urinary tract symptoms associated with benign prostatic hypertrophy as indicated by American Urological Association/International Prostate Symptom Score >19 Uncontrolled or poorly controlled congestive heart failure Myocardial infarction, stroke, or acute coronary syndrome in the preceding 6 months


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InternalMed_Harrison. Uncontrolled or poorly controlled congestive heart failure Myocardial infarction, stroke, or acute coronary syndrome in the preceding 6 months Abbreviation: PSA, prostate-specific antigen. Source: Reproduced from the Endocrine Society Guideline for Testosterone Therapy of Androgen Deficiency Syndromes in Men (S Bhasin et al: J Clin Endocrinol Metab 95:2536, 2010). 1. Evaluate the patient 3–6 months after treatment initiation and then annually to assess whether symptoms have responded to treatment and whether the patient is suffering from any adverse effects. 2. Monitor testosterone level 3–6 months after initiation of testosterone therapy: Therapy should aim to raise serum testosterone level into the mid-normal range. Injectable testosterone enanthate or cypionate: Measure serum testosterone level midway between injections. If testosterone is >700 ng/dL (24.5 nmol/L) or >400 ng/dL (14.1 nmol/L), adjust dose or frequency.


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InternalMed_Harrison. Transdermal patches: Assess testosterone level 3–12 h after application of the patch; adjust dose to achieve testosterone level in the mid-normal range. Buccal testosterone bioadhesive tablet: Assess level immediately before or after application of fresh system. Transdermal gels and solution: Assess testosterone level 2–8 h after patient has been on treatment for at least 2 weeks; adjust dose to achieve serum testosterone level in the mid-normal range. Testosterone pellets: Measure testosterone levels at the end of the dosing interval. Adjust the number of pellets and/or the dosing interval to achieve serum testosterone levels in the normal range. Oral testosterone undecanoatea: Monitor serum testosterone level 3–5 h after ingestion. Injectable testosterone undecanoate: Measure serum testosterone level just prior to each subsequent injection and adjust the dosing interval to maintain serum testosterone in mid-normal range. 3.


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InternalMed_Harrison. Injectable testosterone undecanoate: 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 3–6 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. In men 40 years of age or older with baseline PSA >0.6 ng/mL, perform digital rectal examination and check PSA level before initiating treatment, at 3–6 months, and then in accordance with guidelines for prostate cancer screening depending on the age and race of the patient. 6. Obtain urologic consultation if there is:


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InternalMed_Harrison. 6. Obtain urologic consultation if there is: 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 per 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 prostate symptom score 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, cypionate, and undecanoate): Ask about fluctuations in mood or libido and, rarely, cough after injections. Testosterone patches: Look for skin reaction at the application site.


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InternalMed_Harrison. 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, because 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 h after application of the testosterone gel. • Testosterone pellets: Look for signs of infection, fibrosis, or pellet extrusion. aNot approved for clinical use in the United States. Abbreviations: AUA/IPSS, American Urological Association/International Prostate Symptom Score; PSA, prostate-specific antigen. Source: Reproduced with permission from the Endocrine Society Guideline for Testosterone Therapy of Androgen Deficiency Syndromes in Adult Men (S Bhasin et al: J Clin Endocrinol Metab 95:2536, 2010).


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InternalMed_Harrison. Disorders of the Testes and Male Reproductive System levels, due to increased erythropoiesis, suppression of hepcidin, and increased iron availability for erythropoiesis. The magnitude of hemoglobin increase during testosterone therapy is greater in older men than younger men and in men who have sleep apnea, a significant smoking history, or chronic obstructive lung disease. The frequency of erythrocytosis is 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. 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. 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


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InternalMed_Harrison. discontinuation in these trials. 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.


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InternalMed_Harrison. proState and Serum proState-Specific antiGen levelS Testosterone replacement therapy increases prostate volume to the size seen in age-matched controls but does not increase prostate volume beyond that expected for age. There is no evidence that testosterone therapy causes prostate cancer. However, androgen administration can exacerbate preexisting metastatic 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.


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InternalMed_Harrison. Prostate-specific antigen (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. 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 3to 6-month period are unusual. The 90% confidence interval for the change in PSA values in men with benign prostatic hypertrophy, measured 3–6 months apart, is 1.4 ng/mL. Therefore, the Endocrine Society expert panel suggested that an increase in PSA >1.4 ng/mL in any 1 year after starting testosterone therapy, if confirmed, should lead to urologic evaluation. 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.


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InternalMed_Harrison. cardiovaScular riSK In epidemiologic studies, testosterone concentrations are negatively related to the risk of diabetes mellitus, heart disease, and all-cause and cardiovascular mortality. A recent testosterone trial in older men with mobility limitation was stopped early because of the higher rates of cardiovascular events in the testosterone arm than in the placebo arm of this trial. Meta-analyses 2374 of testosterone trials have found a significant increase in cardiovascular event rates in older men receiving testosterone therapy. Inferences about adverse events from previous trials included in these meta-analyses are limited by poor ascertainment, small numbers of events, heterogeneity of study populations, and small numbers of participants. Two retrospective analyses also found a higher frequency of cardiovascular events in association with testosterone therapy in older men with preexisting heart disease. Retrospective database analyses are limited by their inherent inability to


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InternalMed_Harrison. frequency of cardiovascular events in association with testosterone therapy in older men with preexisting heart disease. Retrospective database analyses are limited by their inherent inability to verify the indication for treatment, diagnoses, or other relevant quantitative information and are susceptible to confounding by many other factors. Adequately powered prospective studies are needed to determine the effect on testosterone replacement on cardiovascular risk.


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InternalMed_Harrison. Androgen Abuse by Athletes and Recreational Bodybuilders The illicit use of androgenic-anabolic steroids (AAS) to enhance athletic performance first surfaced in the 1950s among power lifters and spread rapidly to other sports, professional as well as high school athletes, and recreational bodybuilders. In the early 1980s, the use of AAS spread beyond the athletic community into the general population, and now as many as 3 million Americans, most of them men, have likely used these compounds. Most AAS users are not athletes, but rather recreational weightlifters, who use these drugs to look lean and more muscular. The most commonly used AAS include testosterone esters, nandrolone, stanozolol, methandienone, and methenolol. AAS users generally use increasing doses of multiple steroids in a practice known as stacking.


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InternalMed_Harrison. The adverse effects of long-term AAS abuse remain poorly understood. Most of the information about the adverse effects of AAS has emerged from case reports, uncontrolled studies, or clinical trials that used replacement doses of testosterone. The adverse event data from clinical trials using physiologic replacement doses of testosterone have been extrapolated unjustifiably to AAS users who may administer 10–100 times the replacement doses of testosterone over many years and to support the claim that AAS use is safe. A substantial fraction of androgenic steroid users also use other drugs that are perceived to be muscle building or performance enhancing, such as GH; erythropoiesis-stimulating agents; insulin; and stimulants such as amphetamine, clenbuterol, cocaine, ephedrine, and thyroxine; and drugs perceived to reduce adverse effects such as hCG, aromatase inhibitors, or estrogen antagonists. The men who abuse androgenic steroids are more likely to engage in other high-risk behaviors


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InternalMed_Harrison. and drugs perceived to reduce adverse effects such as hCG, aromatase inhibitors, or estrogen antagonists. The men who abuse androgenic steroids are more likely to engage in other high-risk behaviors than nonusers. The adverse events associated with AAS use may be due to AAS themselves, concomitant use of other drugs, high-risk behaviors, and host characteristics that may render these individuals more susceptible to AAS use or to other high-risk behaviors.


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InternalMed_Harrison. The high rates of mortality and morbidities observed in AAS users are alarming. One Finnish study reported 4.6 times the risk of death among elite power lifters than in age-matched men from the general population. The causes of death among power lifters included suicides, myocardial infarction, hepatic coma, and non-Hodgkin’s lymphoma. A retrospective review of patient records in Sweden also reported higher standardized mortality ratios for AAS users than for nonusers. Thiblin and colleagues found that 32% of deaths among AAS users were suicidal, 26% homicidal, and 35% accidental. The median age of death among AAS users (24 years) is even lower than that for heroin or amphetamine users.


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InternalMed_Harrison. Numerous reports of cardiac death among young AAS users raise concerns about the adverse cardiovascular effects of AAS. High doses of AAS may induce proatherogenic dyslipidemia, increase thrombosis risk via effects on clotting factors and platelets, and induce vasospasm through their effects on vascular nitric oxide. Replacement doses of testosterone, when administered parenterally, are associated with only a small decrease in HDL cholesterol and little or no effect on total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels. In contrast, supraphysiologic doses of testosterone and orally administered, 17α-alkylated, nonaromatizable AAS are associated with marked reductions in HDL cholesterol and increases in LDL cholesterol.


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InternalMed_Harrison. Recent studies of AAS users using tissue Doppler and strain imaging and MRI have reported diastolic and systolic dysfunction, including significantly lower early and late diastolic tissue velocities, reduced E/A ratio, and reduced peak systolic strain in AAS users than in nonusers. Power athletes using AAS often have short QT intervals but increased QT dispersion, which may predispose them to ventricular arrhythmias. Long-term AAS use may be associated with myocardial hypertrophy and fibrosis. Myocardial tissue of power lifters using AAS has been shown to be infiltrated with fibrous tissue and fat droplets. The finding of ARs on myocardial cells suggests that AAS might be directly toxic to myocardial cells.


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InternalMed_Harrison. Long-term AAS use suppresses LH and FSH secretion and inhibits endogenous testosterone production and spermatogenesis. Men who have used AAS for more than a few months experience marked suppression of the hypothalamic-pituitary-testicular (HPT) axis after stopping AAS that may be associated with sexual dysfunction, fatigue, infertility, and depression; in some AAS users, HPT suppression may last more than a year, and in a few individuals, complete recovery may never occur. The symptoms of androgen deficiency caused by androgen withdrawal may cause some men to revert back to using AAS, leading to continued use and AAS dependence. As many as 30% of AAS users develop a syndrome of AAS dependence, characterized by long-term AAS use despite adverse medical and psychiatric effects. Supraphysiologic doses of testosterone may also impair insulin sensitivity. Orally administered androgens also have been associated with insulin resistance and diabetes.


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InternalMed_Harrison. Supraphysiologic doses of testosterone may also impair insulin sensitivity. Orally administered androgens also have been associated with insulin resistance and diabetes. Unsafe injection practices, high-risk behaviors, and increased rates of incarceration render AAS users at increased risk of HIV and hepatitis B and C. In one survey, nearly 1 in 10 gay men had injected AAS or other substances, and AAS users were more likely to report high-risk unprotected anal sex than other men. Some AAS users develop hypomanic or manic symptoms during AAS exposure (irritability, aggressiveness, reckless behavior, and occasional psychotic symptoms, sometimes associated with violence) and major depression (sometimes associated with suicidality) during AAS withdrawal. Users may also develop other forms of illicit drug use, which may be potentiated or exacerbated by AAS.


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InternalMed_Harrison. Elevated liver enzymes, cholestatic jaundice, hepatic neoplasms, and peliosis hepatis have been reported with oral, 17α-alkylated AAS. AAS use may cause muscle hypertrophy without compensatory adaptations in tendons, ligaments, and joints, thus increasing the risk of tendon and joint injuries. AAS use is associated with acne, baldness, and increased body hair.


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InternalMed_Harrison. The suspicion of AAS use may be raised by the increased hemoglobin and hematocrit, suppressed LH and FSH and testosterone levels, low high-density lipoproteins cholesterol, and low testicular volume and sperm density in a person who looks highly muscular. 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 the 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 >4 suggest


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InternalMed_Harrison. combustion mass spectrometry. Exogenous testosterone administration increases urinary testosterone glucuronide excretion and consequently the testosterone-to-epitestosterone ratio. Ratios >4 suggest exogenous testosterone use but can also reflect genetic variation. Genetic variations in the uridine diphosphoglucuronyl transferase 2B17 (UGT2B17), the major enzyme for testosterone glucuronidation, affect the testosterone-to-epitestosterone ratio. 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.