3012 PART 12 Endocrinology and Metabolism

deliberate exogenous sex steroid administration; hypothyroidism; and

activating mutations of the LH receptor or Gs

α subunit.

Familial Male-Limited Precocious Puberty Also called testotoxicosis, familial male-limited precocious puberty is an autosomal

dominant disorder caused by activating mutations in the LH receptor,

leading to constitutive stimulation of the cyclic AMP pathway and

testosterone production. Clinical features include premature androgenization in boys, growth acceleration in early childhood, and advanced

bone age followed by premature epiphyseal fusion. Testosterone is

elevated, and LH is suppressed. Treatment options include inhibitors

of testosterone synthesis (e.g., ketoconazole, medroxyprogesterone acetate), AR antagonists (e.g., flutamide and bicalutamide), and aromatase

inhibitors (e.g., anastrozole).

MCCUNE-ALBRIGHT SYNDROME This is a sporadic disorder caused

by somatic (postzygotic) activating mutations in the Gs

α subunit that

links G protein–coupled receptors to intracellular signaling pathways

(Chap. 412). The mutations impair the guanosine triphosphatase

activity of the Gs

α protein, leading to ligand-independent signaling of

the Gs

-coupled receptor and constitutive activation of adenylyl cyclase.

Like activating LH receptor mutations, this stimulates testosterone production and causes gonadotropin-independent precocious puberty. In

addition to sexual precocity, affected individuals may have autonomy

in the adrenals, pituitary, and thyroid glands. Café au lait spots are

characteristic skin lesions that reflect the onset of the somatic mutations in melanocytes during embryonic development. Constitutive

Gs

α activation in the postnatal multipotent skeletal stem cells leads to

the formation of immature woven bone and replacement of the bone

marrow with fibrotic stroma (polyostotic fibrous dysplasia). Treatment

is similar to that in patients with activating LH receptor mutations.

Bisphosphonates have been used to treat bone lesions.

CONGENITAL ADRENAL HYPERPLASIA Boys with CAH who are not

well controlled with glucocorticoid suppression of adrenocorticotropic

hormone (ACTH) can develop premature virilization because of excessive androgen production by the adrenal gland (Chaps. 386 and 390).

LH is low, and the testes are small. Adrenal rests may develop within

the testis of poorly controlled patients with CAH because of chronic

ACTH stimulation; adrenal rests do not require surgical removal

and regress with effective glucocorticoid therapy. Some children with

CAH may develop gonadotropin-dependent precocious puberty with

early maturation of the hypothalamic-pituitary-gonadal axis, elevated

gonadotropins, and testicular growth.

Heterosexual Sexual Precocity Breast enlargement in prepubertal boys can result from familial aromatase excess, estrogen-producing

tumors in the adrenal gland, Sertoli cell tumors in the testis, marijuana

smoking, or exogenous estrogens or androgens. Occasionally, germ cell

tumors that secrete hCG can be associated with breast enlargement due

to excessive stimulation of estrogen production (see “Gynecomastia,”

below).

APPROACH TO THE PATIENT

Precocious Puberty

After verification of precocious development, serum testosterone, LH, and FSH levels should be measured to determine

whether gonadotropins are increased in relation to chronologic age

(gonadotropin-dependent) or whether sex steroid secretion is occurring independent of LH and FSH (gonadotropin-independent). In

children with gonadotropin-dependent precocious puberty, CNS

lesions should be excluded by history, neurologic examination,

and MRI scan of the head. If organic causes are not found, one

is left with the diagnosis of idiopathic central precocity. Patients

with high testosterone but suppressed LH concentrations have

gonadotropin-independent sexual precocity; in these patients,

DHEA sulfate (DHEAS) and 17α-hydroxyprogesterone should be

measured. High levels of testosterone and 17α-hydroxyprogesterone suggest the possibility of CAH due to 21α-hydroxylase or

11β-hydroxylase deficiency. If testosterone and DHEAS are elevated, adrenal tumors should be excluded by obtaining a CT scan of

the adrenal glands. Patients with elevated testosterone but without

increased 17α-hydroxyprogesterone or DHEAS should undergo

careful evaluation of the testis by palpation and ultrasound to exclude

a Leydig cell neoplasm. Activating mutations of the LH receptor

should be considered in children with gonadotropin-independent

precocious puberty in whom CAH, androgen abuse, and adrenal

and testicular neoplasms have been excluded.

TREATMENT

Precocious Puberty

In patients with a known cause (e.g., a CNS lesion or a testicular

tumor), therapy should be directed toward the underlying disorder.

In patients with idiopathic CPP, treatment with long-acting GnRH

analogues is indicated in boys showing rapid pubertal progression,

who are more advanced in pubertal development (e.g., Tanner

stage 3 or greater genital development) and experiencing rapid

linear growth apparent at their first visit. GnRH analogues suppress

gonadotropins and testosterone, halt early pubertal development,

delay accelerated bone maturation, prevent early epiphyseal closure,

promote final height gain, and mitigate the psychosocial consequences of early pubertal development without causing osteoporosis. The treatment is most effective for increasing final adult height

TABLE 391-1 Causes of Precocious or Delayed Puberty in Boys

I. Precocious puberty

A. Gonadotropin-dependent

1. Idiopathic

2. Hypothalamic hamartoma or other lesions

3. CNS tumor or inflammatory state

4. Mutations in genes that regulate GnRH secretion, such as kisspeptin

(KISS1), kisspeptin receptor (KISS1R), and makorin ring finger protein

3 (MKRN3)

B. Gonadotropin-independent

1. Congenital adrenal hyperplasia

2. hCG-secreting tumor

3. McCune-Albright syndrome

4. Activating LH receptor mutation

5. Exogenous androgens

6. Androgen producing tumors of the adrenal or the testis

II. Delayed puberty

A. Constitutional delay of growth and puberty

B. Systemic disorders

1. Chronic disease

2. Malnutrition

3. Anorexia nervosa

C. CNS tumors and their treatment (radiotherapy and surgery)

D. Hypothalamic-pituitary causes of pubertal failure (low gonadotropins)

1. Congenital disorders associated with GnRH or gonadotropin deficiency

(Table 391-2)

2. Acquired disorders

a. Pituitary tumors

b. Hyperprolactinemia

c. Infiltrative disorders, such as hemochromatosis

E. Gonadal causes of pubertal failure (elevated gonadotropins)

1. Klinefelter syndrome

2. Bilateral undescended testes

3. Orchitis

4. Chemotherapy or radiotherapy

5. Anorchia

F. Androgen insensitivity

Abbreviations: CNS, central nervous system; GnRH, gonadotropin-releasing

hormone; hCG, human chronic gonadotropin; LH, luteinizing hormone.

3013 Disorders of the Testes and Male Reproductive System CHAPTER 391

if it is initiated before age 6. Puberty resumes after discontinuation

of the GnRH analogue. Counseling is an important aspect of the

overall treatment strategy.

In children with gonadotropin-independent precocious puberty,

inhibitors of steroidogenesis, such as ketoconazole, AR antagonists,

and aromatase inhibitors 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 adjuncts to antiandrogen therapy for children

with familial male-limited precocious puberty, CAH, and McCuneAlbright syndrome. More potent novel inhibitors of testosterone

synthesis, such as abiraterone, have not been evaluated in boys with

gonadotropin-independent precocious puberty.

■ DELAYED PUBERTY

Puberty is considered 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. Pubertal delay is not necessarily pathologic and may be a

variant of normal pubertal development in some children. Delayed

puberty has been associated with lower peak bone mass, higher risk for

metabolic and cardiovascular disorders, and lower risk for breast and

endometrial cancer in women.

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 391-1). The constitutional delay of growth and puberty

is the most common cause that accounts for nearly two-thirds of boys

and one-third of girls with delayed puberty. The constitutional delay of

growth and puberty clusters in families and displays a complex inheritance pattern, having an autosomal dominant pattern of inheritance in

some families, but autosomal recessive, X-linked, or bilineal pattern in

other families. Only rarely have mutations in genes known to disrupt

the hypothalamic-pituitary-gonadal axis been identified in cases of

pubertal delay; most of these mutations have been reported in relatives

of patients with idiopathic hypogonadotropic hypogonadism. Functional hypogonadotropic hypogonadism is more common in girls than

in boys. Permanent causes of hypogonadotropic or hypergonadotropic

hypogonadism are identified in <25% of boys with delayed puberty.

APPROACH TO THE PATIENT

Delayed Puberty

History of systemic illness, eating disorders, excessive exercise,

social and psychological problems, and abnormal patterns of linear

growth during childhood should be verified. Boys with pubertal

delay may have accompanying emotional and physical immaturity

relative to their peers, which can be a source of anxiety. Physical

examination should focus on height; arm span; weight; visual fields;

and secondary sex characteristics, including hair growth, testicular

volume, phallic size, and scrotal reddening and thinning. Testicular

size >2.5 cm generally indicates that the child has entered puberty.

The main diagnostic challenge is to distinguish those with constitutional delay, who will progress through puberty at a later age,

from those with an underlying pathologic process. Constitutional

delay should be suspected when there is a family history and when

there are delayed bone age and short stature. Pituitary priming by

pulsatile GnRH is required before LH and FSH are synthesized and

secreted normally. Thus, blunted responses to exogenous GnRH

can be seen in patients with constitutional delay, GnRH deficiency, or pituitary disorders. 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.

TREATMENT

Delayed Puberty

If therapy is considered appropriate, it can begin with 25–50 mg

of testosterone enanthate or testosterone cypionate every 2 weeks

or by using a 2.5-mg testosterone patch or 25-mg testosterone gel.

Because aromatization of testosterone to estrogen is obligatory

for mediating androgen effects on epiphyseal fusion, concomitant treatment with aromatase inhibitors may allow attainment of

greater final adult height. Testosterone treatment should be interrupted after 6 months to determine if endogenous LH and FSH

secretion have ensued. Other causes of delayed puberty should be

considered when there are associated clinical features or when boys

do not enter puberty spontaneously after a year of observation or

treatment.

Reassurance without hormonal treatment is appropriate for

many individuals with presumed constitutional delay of puberty.

However, the impact of delayed growth and pubertal progression

on a child’s social relationships and school performance should be

weighed. 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. Furthermore, the time of onset of puberty is negatively

associated with bone mineral content and density in boys at skeletal

maturity. Judicious use of androgen therapy in carefully selected

boys with constitutional delay can induce pubertal induction and

progression and promote short-term growth without compromising final height, and when administered with an aromatase inhibitor, it may improve final height.

DISORDERS OF THE MALE REPRODUCTIVE

AXIS DURING ADULTHOOD

■ HYPOGONADOTROPIC HYPOGONADISM

Because LH and FSH are trophic hormones for the testes, impaired

secretion of these pituitary gonadotropins results in secondary hypogonadism, which is characterized by low testosterone in the setting

of low or inappropriately normal LH and FSH. Those with the most

severe gonadotropin deficiency have complete absence of pubertal

development, sexual infantilism, and, in some cases, hypospadias and

undescended testes. Patients with partial gonadotropin deficiency have

delayed or arrested sex development. The 24-h LH secretory profiles

are heterogeneous in patients with hypogonadotropic hypogonadism,

reflecting variable abnormalities of LH pulse frequency or amplitude.

In severe cases, basal LH is low, and there are no LH pulses. A smaller

subset of patients has low-amplitude LH pulses or markedly reduced

pulse frequency. Occasionally, only sleep-entrained LH pulses occur,

reminiscent of the pattern seen in the early stages of puberty. Hypogonadotropic hypogonadism can be classified into congenital and

acquired disorders. Congenital disorders most commonly involve

GnRH deficiency, which leads to gonadotropin deficiency. Acquired

disorders are much more common than congenital disorders and may

result from a variety of sellar mass lesions or infiltrative diseases of the

hypothalamus or pituitary or be due to the effects of drugs, nutritional

or psychiatric disorders, or systemic diseases.

Congenital Disorders Associated with Gonadotropin

Deficiency (See Chap. 379) 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.

3014 PART 12 Endocrinology and Metabolism

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 ~10% of men with idiopathic

hypogonadotropic hypogonadism (IHH), reversal of gonadotropin

deficiency may occur in adult life after sex steroid therapy. 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. Nutritional, emotional, or metabolic stress may

unmask gonadotropin deficiency and reproductive dysfunction (e.g.,

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. Oligogenicity and gene-gene and gene-environment interactions

may contribute to variations in clinical phenotype.

Mutations in a number of genes involved in the development and

migration of GnRH neurons or in the regulation of GnRH secretion

have been linked to GnRH deficiency, although the genetic defect

remains elusive in nearly two-thirds of cases. Familial hypogonadotropic hypogonadism can be transmitted as an X-linked (20%),

autosomal recessive (30%), or autosomal dominant (50%) trait. Some

individuals with IHH have sporadic mutations in the same genes that

cause inherited forms of the disorder. The genetic defects associated

with GnRH deficiency can ben conveniently classified as anosmic

(Kallmann syndrome) or normosmic (Table 391-2), although the

occurrence of both anosmic and normosmic forms of GnRH deficiency in the same families suggests commonality of pathophysiologic

mechanisms. Kallmann syndrome, the anosmic form of GnRH deficiency, can result from mutations in one or more neurodevelopmental

genes associated with olfactory bulb morphogenesis or 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, NMDA receptor synaptonuclear signaling and neuronal migration factor (NSMF), genes

involved in fibroblast growth factor (FGF) signaling (FGF8, FGFR1,

FGF17, IL17RD, DUSP6, SPRY4, and FLRT3), NELF, genes involved

in PROK signaling (PROK2 and PROK2R), WDR11, SOX10, TUBB3

SEMA3, HS6ST1, CHD7, and FEZF1 have been described in patients

with Kallmann 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. Proteins such

as those involved in FGF and prokineticin signaling and KAL1, which

account for the great majority of Kallmann syndrome cases, interact

with heparin sulfate glycosaminoglycan compounds within the extracellular matrix in supporting GnRH neuronal migration. Mutations in

the FGFR1 gene cause an autosomal dominant form of hypogonadotropic hypogonadism that clinically resembles Kallmann syndrome;

mutations in its putative ligand, the FGF8 gene product, have also been

associated with IHH. Craniofacial tissues and olfactory ensheathing

cells also play important roles in neurogenesis and migration of the

GnRH neurons, and additional proteins that regulate these cell types

may also be involved in the pathogenesis of Kallmann syndrome. The

co-occurrence of tooth anomalies, cleft palate, craniofacial anomalies,

pigmentation, and neurologic defects in patients with Kallmann syndrome suggests that the syndrome may be a part of the spectrum of

neurocristopathies. Other dysmorphic features associated with some

forms of IHH include renal agenesis, hearing loss, synkinesia, short

metacarpals, eye movement abnormalities, cerebellar ataxia, and dental

agenesis. The presence of these dysmorphic features can offer clues to

the underlying genetic abnormality and guide genetic testing.

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, NROB1 (DAX1), leptin, or leptin receptor. Some

mutations, such as those in PROK2, PROKR2, NSMF, FGFR1, FGF8,

SEMA3A, WDR11, and CHD7, have been associated with both anosmic and normosmic forms of IHH; it is possible that these genes are

involved in GnRH neuronal migration as well in regulation of GnRH

secretion. 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. The

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 NKB (TAC3), which is involved in

preferential activation of GnRH release in early development, and its

receptor (TAC3R) have been implicated in some families with normosmic IHH. The neurokinin pathway plays an important role in GnRH

activation during “mini-puberty” as well as in puberty. Prokineticin

2 (PROK2) and its receptor (PROK2R) are highly expressed in the

olfactory ventricle and subventricular zone of the lateral ventricle and

are associated with neurogenesis of the olfactory bulbs and the migration of the olfactory neuronal cells. Mutations in the CHD7 gene that

encodes for the chromodomain helicase DNA binding protein 7 causes

CHARGE syndrome characterized by eye coloboma, heart anomalies,

choanal atresia, growth and developmental retardation, genitourinary

anomalies, hypogonadism, and ear abnormalities. X-linked hypogonadotropic hypogonadism also occurs in adrenal hypoplasia congenita,

a disorder caused by mutations in the DAX1 gene, which encodes a

nuclear receptor in the adrenal gland and reproductive axis. Adrenal

hypoplasia congenita is characterized by absent development of the

adult zone of the adrenal cortex, leading to neonatal adrenal insufficiency. Puberty usually does not occur or is arrested, reflecting variable

degrees of gonadotropin deficiency. Although sexual differentiation is

normal, some patients have testicular dysgenesis and impaired spermatogenesis despite gonadotropin replacement. Less commonly, adrenal

hypoplasia congenita, sex reversal, and hypogonadotropic hypogonadism can be caused by mutations of steroidogenic factor 1 (SF1). Rarely,

recessive mutations in the LHβ or FSHβ genes have been described in

patients with selective deficiencies of these gonadotropins.

A number of homeodomain transcription factors are involved

in the development and differentiation of the specialized hormoneproducing cells within the pituitary gland (Table 391-2). 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. Mutations of ARNT1, inherited as an autosomal

recessive disorder, are associated with diabetes insipidus; ACTH, GH,

LH, and FSH deficiency; anterior pituitary hypoplasia; hypoplastic

frontal and temporal lobes; thin corpus callosum; prominent forehead;

and retrognathia. Patients with SOX2 mutations can have gonadotropin deficiency, variable deficiencies of TSH and ACTH, pituitary

hypoplasia, microphthalmia, and intellectual disability.

Prader-Willi syndrome (PWS) is characterized by obesity, hypotonic musculature, intellectual disability, 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. 466). Recent studies suggest that at least some of the major

3015 Disorders of the Testes and Male Reproductive System CHAPTER 391

TABLE 391-2 Causes of Congenital Hypogonadotropic Hypogonadism

GENE LOCUS INHERITANCE ASSOCIATED FEATURES

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

FGF8 10q24 AR Anosmia (some patients may be normosmic), skeletal abnormalities

FGF17 8p21.3 AR Anosmia (some patients may be normosmic)

FGFR1 8p11-p12 AD Anosmia, cleft lip/palate, synkinesia, syndactyly

PROK2 3p21 AR Anosmia/sleep dysregulation

PROK2R 20p12.3 AR Variable

CHD7 8q12.1 Anosmia, other features of CHARGE syndrome

FEZ1 8p22 AR Anosmia, olfactory bulb aplasia

WDR11 10q26 AD Anosmia

SOX10 22q13 Deafness

SEMA3A 7q21 Anosmia; some persons with mutations are normal

HS6ST1 2q14 Complex Anosmia

TUBB3 Tubulin β

3

AR Anosmia

NSMF 9q34.3 AR Anosmia (some patients may be normosmic)

DUSP6 12q21.33 AR Anosmia

GLCE 15q23 AR Anosmia (some patients may be normosmic)

FLRT3 20p12.1 AR Anosmia (some patients may be normosmic)

SPRY4 5q31.3 AR Anosmia (some patients may be normosmic)

IL17RD 3p14.3 AR Anosmia

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 of GnRH deficiency

LEPR 1p31 AR Obesity

LEP 7q31 AR Obesity

DMXL2 15q21.2 AR Polyendocrine polyneuropathy syndrome

OTUD4 4q31.21 AR Ataxia

RNF216 7p22.1 AR Ataxia

STUB1 16p13.3 AR Ataxia

POLR3B 12q23.3 AR Ataxia

PNPLA6 19p13.2 AR Ataxia

NR0B1 Xp21.2 X-linked Primary adrenal failure

B. Hypogonadotropic Hypogonadism Not Due to GnRH Deficiency

PC1 5q15-21 AR Obesity, diabetes mellitus, ACTH deficiency

HESX1 3p21 AR Septo-optic dysplasia, CPHD

AD Isolated GH insufficiency

LHX3 9q34 AR CPHD (ACTH spared), cervical spine rigidity

PROP1 5q35 AR CPHD (ACTH usually spared)

FSHβ 11p13 AR ↑ LH

LHβ 19q13 AR ↑ FSH

SF1 (NR5A1) 9p33 AD/AR Primary adrenal failure, XY sex reversal

Abbreviations: ACTH, adrenocorticotropic hormone; AD, autosomal dominant; AR, autosomal recessive; CHARGE syndrome, eye coloboma, heart defects, 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; DMXL2, DMX like 2; DUSP6, dual specificity phosphatase 6; FGFR1, fibroblast growth factor receptor 1; FGF17, fibroblast

growth factor 17; FSHβ, follicle-stimulating hormone β-subunit; FLRT3, fibronectin like domain containing leucine rich transmembrane protein 3; GH, growth hormone; GLCE,

glucuronic acid epimerase; GNRHR, gonadotropin-releasing hormone receptor; GPR54, G protein–coupled receptor 54; HESX1, homeobox gene expressed in embryonic

stem cells 1; KAL1, Kallmann syndrome interval gene 1, also known as anosmin 1; LEP, leptin; LEPR, leptin receptor; LHX3, LIM homeobox gene 3; LHβ, luteinizing hormone

β-subunit; NELF, nasal embryonic luteinizing hormone–releasing hormone factor; NSMF, NMDA receptor synaptonuclear signaling and neuronal migration factor; NR0B1,

nuclear receptor subfamily 0, group B, member 1; OTUD4, OUT domain containing protein 4; PNPLA6, patatin-like phospholipase domain-containing protein 6; PC1,

prohormone convertase 1; PROK2, prokineticin 2; PROP1, prophet of pit 1; RNF216, ring finger protein 216; POLR3B, polymerase III RNA subunit B; SF1, steroidogenic factor

1; SPRY4, sprouty RTK signaling antagonist 4; STUB1, srip 1 homologous and U box containing protein 1; TUBB3, tubulin beta 3; IL17RD, interleukin 17 receptor D.

3016 PART 12 Endocrinology and Metabolism

manifestations of PWS may be due to reduced expression of prohormone convertase 1.

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. 401).

Acquired Hypogonadotropic Disorders • SEVERE ILLNESS,

STRESS, MALNUTRITION, AND EXERCISE These may cause reversible gonadotropin deficiency. Although gonadotropin deficiency and

reproductive dysfunction are well documented in these conditions in

women, men exhibit similar but less pronounced responses. Unlike

women, most male runners and other endurance athletes have normal

gonadotropin and sex steroid levels, despite low body fat and frequent

intensive exercise. Testosterone levels fall at the onset of illness and

recover during recuperation. The magnitude of gonadotropin suppression generally correlates with the severity of illness. Although hypogonadotropic hypogonadism is the most common cause of androgen

deficiency in patients with acute illness, some have elevated levels

of LH and FSH, which suggest primary gonadal dysfunction. The

pathophysiology of reproductive dysfunction during acute illness is

unknown but likely involves a combination of cytokine and/or glucocorticoid effects. There is a high frequency of low testosterone levels in

patients with chronic illnesses such as HIV infection, end-stage renal

disease, chronic obstructive lung disease, and many types of cancer

and in patients receiving glucocorticoids. About 20% of HIV-infected

men with low testosterone levels have elevated LH and FSH levels;

these patients presumably have primary testicular dysfunction. The

remaining 80% have either normal or low LH and FSH levels; these

men have a central hypothalamic-pituitary defect or a dual defect

involving both the testis and the hypothalamic-pituitary centers.

Muscle wasting is common in chronic diseases associated with hypogonadism, which also leads to debility, poor quality of life, and adverse

outcome of disease. There is great interest in exploring strategies that

can reverse androgen deficiency or attenuate the sarcopenia associated

with chronic illness.

Men using opioids for relief of cancer or noncancerous pain or

because of addiction often have suppressed testosterone and LH levels

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, tender gynecomastia,

and poor quality of life.

OBESITY In men with mild to moderate obesity, SHBG levels decrease

in proportion to the degree of obesity, resulting in lower total testosterone levels. However, free testosterone levels usually remain within

the normal range. SHBG production in the liver is inhibited by hepatic

lipids and by tumor necrosis factor α and interleukin 1, but it is not

affected by insulin. Thus, the low SHBG levels seen in obesity and diabetes are likely the result of low-grade inflammation and the increased

amount of hepatic lipids rather than high insulin levels. Estradiol levels are higher in obese men compared to healthy, nonobese controls,

because of aromatization of testosterone to estradiol in adipose tissue.

Weight loss is associated with reversal of these abnormalities including

an increase in total and free testosterone levels and a decrease in estradiol levels. A subset of obese men with moderate to severe obesity

may have a defect in the hypothalamic-pituitary axis as suggested by

low free testosterone in the absence of elevated gonadotropins. Weight

gain in adult men can accelerate the rate of age-related decline in testosterone levels.

HYPERPROLACTINEMIA (See also Chap. 380) Elevated PRL levels

are associated with hypogonadotropic hypogonadism. PRL inhibits

hypothalamic GnRH secretion either directly or through modulation of tuberoinfundibular dopaminergic pathways. A PRL-secreting

tumor may also destroy the surrounding gonadotropes by invasion or

compression of the pituitary stalk. Treatment with dopamine agonists

reverses gonadotropin deficiency, although there may be a delay relative to PRL suppression.

SELLAR MASS LESIONS Neoplastic and nonneoplastic lesions in the

hypothalamus or pituitary can directly or indirectly affect gonadotrope function. In adults, pituitary adenomas constitute the largest

category of space-occupying lesions affecting gonadotropin and other

pituitary hormone production. Pituitary adenomas that extend into

the suprasellar region can impair GnRH secretion and mildly increase

PRL secretion (usually <50 μg/L) because of impaired tonic inhibition

by dopaminergic pathways. These tumors that cause hyperprolactinemia by stalk compression should be distinguished from prolactinomas,

which typically are associated with higher PRL levels. The presence

of diabetes insipidus suggests the possibility of a craniopharyngioma,

infiltrative disorder, or other hypothalamic lesions (Chap. 381).

HEMOCHROMATOSIS (See also Chap. 414) Both the pituitary and testis can be affected by excessive iron deposition. However, the pituitary

defect is the predominant lesion in most patients with hemochromatosis and hypogonadism. The diagnosis of hemochromatosis is suggested

by the association of characteristic skin discoloration, hepatic enlargement or dysfunction, diabetes mellitus, arthritis, cardiac conduction

defects, and hypogonadism.

■ PRIMARY TESTICULAR CAUSES OF

HYPOGONADISM

Common causes of primary testicular dysfunction include Klinefelter

syndrome, uncorrected cryptorchidism, cancer chemotherapy, radiation to the testes, trauma, torsion, infectious orchitis, HIV infection,

anorchia syndrome, and myotonic dystrophy. Primary testicular disorders may be associated with impaired spermatogenesis, decreased

androgen production, or both. See Chap. 390 for disorders of testis

development, androgen synthesis, and androgen action.

Klinefelter Syndrome (See also Chap. 390) Klinefelter 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 syndrome who

have the 47,XXY karyotype due to the progressive loss of 47,XXY

spermatogonial stem cells; however, men with mosaicism may have

germ cells, especially at a younger age. The clinical phenotype of

Klinefelter syndrome can be variable, possibly because of mosaicism,

polymorphisms in AR gene, the parental origin of the X chromosome,

X-linked copy number variations, gene-dosage effects in conjunction

with X chromosome inactivation, variable testosterone levels, or other

genetic factors. Testicular histology shows hyalinization of seminiferous tubules and germ cell aplasia. However, spermatogenesis can

be observed in a small number of tubules from which sperm can be

harvested during testicular sperm extraction for IVF. Although their

function is impaired, the number of Leydig cells appears to increase.

Testosterone is decreased and estradiol is increased, leading to clinical

features of undervirilization and gynecomastia. Men with Klinefelter syndrome are at increased risk of systemic lupus erythematosus,

Sjögren’s syndrome, breast cancer, diabetes mellitus, osteoporosis, nonHodgkin’s lymphoma, and some types of lung cancer and at reduced

risk of prostate cancer. Periodic mammography for breast cancer surveillance is recommended for men with Klinefelter syndrome. Fertility

can be achieved by intracytoplasmic injection of sperm retrieved surgically from the testes of men with Klinefelter syndrome, including some

men with nonmosaic form of Klinefelter syndrome. Although sperm

retrieval for fertility preservation offers no benefit over harvesting

in adulthood, fertility counseling, including the potential for sperm

retrieval, should be offered prior to starting testosterone replacement

therapy. The karyotypes 48,XXXY and 49,XXXXY are associated with

3017 Disorders of the Testes and Male Reproductive System CHAPTER 391

a more severe phenotype, increased risk of congenital malformations,

and lower intelligence than 47,XXY individuals.

Cryptorchidism Cryptorchidism occurs when there is incomplete

descent of the testis from the abdominal cavity into the scrotum.

About 1–4% 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. Fifty percent of undescended testes at

birth will descend spontaneously within the first 6–18 months of life;

consequently, the incidence of cryptorchidism is <1% by 9 months of

age. Cryptorchidism should be distinguished from retractile testes that

can be pulled down into the scrotum during physical examination and

require no treatment.

Androgens regulate predominantly the inguinoscrotal descent of

the testes through degeneration of the cranio-suspensory ligament and

a shortening of the gubernaculums, respectively. Mutations in INSL3

and leucine-rich repeat family of G-protein-coupled receptor 8 (LGR8),

which regulate the transabdominal portion of testicular descent, have

been found in some patients with cryptorchidism.

Cryptorchidism is associated with increased risk of malignancy,

infertility, inguinal hernia, and torsion. Unilateral cryptorchidism,

even when corrected before puberty, is associated with decreased

sperm count, possibly reflecting unrecognized damage to the fully

descended testis or other genetic factors. Therefore, surgical correction

is usually performed between 6 and 18 months of age depending on

the location of the testes, the child’s body size, and parental preference.

Epidemiologic, clinical, and molecular evidence supports the idea that

cryptorchidism, hypospadias, impaired spermatogenesis, and testicular cancer may be causally related to common genetic and environment perturbations and are components of the testicular dysgenesis

syndrome.

Acquired Testicular Defects Viral orchitis may be caused by

the mumps virus, echovirus, lymphocytic choriomeningitis virus,

and group B arboviruses. Orchitis occurs in as many as one-fourth of

adult men with mumps; the orchitis is unilateral in about two-thirds

and bilateral in the remainder. Orchitis usually develops a few days

after the onset of parotitis but may precede it. The testis may return to

normal size and function or undergo atrophy. Semen analysis returns

to normal for three-fourths of men with unilateral involvement but

for only one-third of men with bilateral orchitis. Trauma, including

testicular torsion, can also cause secondary atrophy of the testes. The

exposed position of the testes in the scrotum renders them susceptible

to both thermal and physical trauma, particularly in men with hazardous occupations.

The late-term adverse effects of cancer treatment on reproductive

health have emerged as an important concern among cancer survivors. Many professional cancer societies have published guidelines on

the fertility preservation in patients with cancer and endorsed formal

consideration of fertility preservation measures prior to initiation of

cancer treatment. The testes are sensitive to radiation damage due to

the direct effects of ionized radioactive particles as well as indirect

effects of free radicals generated from water. Although radiation doses

as low as 0.75 Gy can transiently raise LH, only doses >20 Gy are associated with Leydig cell dysfunction and increased FSH and LH levels.

Radiation doses <1.0 Gy are associated with only a transient decline in

sperm density; doses between 1.0 and 2.0 Gy are associated with temporary azoospermia, and doses >2.0 Gy are generally associated with

permanent azoospermia. 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. Direct testicular radiation

and whole-body radiation before bone marrow transplantation pose

the greatest risk of permanent testicular damage.

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 the high response rates and the young age of these

men, infertility and androgen deficiency have emerged as important

long-term complications of cancer chemotherapy. Cyclophosphamide

and combination regimens containing alkylating agents such as procarbazine are particularly toxic to germ cells. Thus, 90% of men with

Hodgkin’s lymphoma receiving MOPP (mechlorethamine, oncovin,

procarbazine, prednisone) therapy develop azoospermia or extreme

oligozoospermia; newer regimens that do not include procarbazine,

such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), are

less toxic to germ cells. Azoospermia is uncommon with cyclophosphamide equivalent doses of <4000 mg/m2

, and higher doses of alkylating agents are generally associated with varying degree of damage

to germ cells. The outcomes of assisted reproductive technologies in

cancer survivors using cryopreserved sperm collected prior to cancer

treatment are similar to those in infertile men who do not have cancer.

A smaller subset of cancer survivors treated with large doses of alkylating agents may also suffer from testosterone deficiency and sexual

dysfunction.

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), and toxic effects on spermatogenesis (e.g.,

chemotherapy).

Alcohol, when consumed in excess for prolonged periods, decreases

testosterone, independent of liver disease or malnutrition. Elevated

estradiol and decreased testosterone levels may occur in men taking

digitalis.

The occupational and recreational history should be carefully

evaluated in all men with infertility because of the toxic effects of

many chemical agents on spermatogenesis. Known environmental

hazards include pesticides (e.g., vinclozolin, dicofol, atrazine), sewage

contaminants (e.g., ethinyl estradiol in birth control pills, surfactants

such as octylphenol, nonylphenol), plasticizers (e.g., phthalates), flame

retardants (e.g., polychlorinated biphenyls, polybrominated diphenol

ethers), industrial pollutants (e.g., heavy metals such as 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. 388). Sperm antibodies can cause isolated male

infertility. In some instances, these antibodies are secondary phenomena resulting from duct obstruction or vasectomy. Granulomatous

diseases can affect the testes, and testicular atrophy occurs in 10–20%

of men with lepromatous leprosy because of direct tissue invasion by

the mycobacteria. The tubules are involved initially, followed by endarteritis and destruction of Leydig cells.

Systemic disease can cause primary testis dysfunction in addition

to suppressing gonadotropin production. In cirrhosis, a combined

testicular and pituitary abnormality leads to decreased testosterone

production independent of the direct toxic effects of ethanol. Impaired

hepatic extraction of adrenal androstenedione leads to extraglandular

conversion to estrone and estradiol, which partially suppresses LH.

Testicular atrophy and gynecomastia are present in approximately onehalf of men with cirrhosis. In chronic renal failure, androgen synthesis

and sperm production decrease despite elevated gonadotropins. The

elevated LH level is due to reduced clearance, but it does not restore

normal testosterone production. About one-fourth of men with renal

failure have hyperprolactinemia. Improvement in testosterone production with hemodialysis is incomplete, but successful renal transplantation may return testicular function to normal. Testicular atrophy is

present in one-third of men with sickle cell anemia. The defect may be

at either the testicular or the hypothalamic-pituitary level. Sperm density can decrease temporarily after acute febrile illness in the absence

of a change in testosterone production. Infertility in men with celiac

disease is associated with a hormonal pattern typical of androgen resistance, namely elevated testosterone and LH levels.

Neurologic diseases associated with altered testicular function

include myotonic dystrophy, spinobulbar muscular atrophy, and paraplegia. In myotonic dystrophy, small testes may be associated with

3018 PART 12 Endocrinology and Metabolism

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 injury that causes paraplegia is often associated with low testosterone levels and may cause persistent defects in

spermatogenesis; some patients retain the capacity for penile erection

and ejaculation.

■ ANDROGEN INSENSITIVITY SYNDROMES

Mutations in the AR cause resistance to the action of testosterone

and DHT. These X-linked mutations are associated with variable

degrees of defective male phenotypic development and undervirilization (Chap. 390). 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,

visceral adiposity, and osteoporosis, consistent with evidence from an

estrogen receptor–deficient individual that these testosterone actions

are mediated via estrogen.

GYNECOMASTIA

Gynecomastia refers to enlargement of the male breast. It is caused by

excess estrogen action and is usually the result of an increased estrogen/androgen ratio. True gynecomastia is associated with glandular

breast tissue that is >4 cm in diameter and often tender. Glandular

tissue enlargement should be distinguished from excess adipose tissue:

glandular tissue is firmer and contains fibrous-like cords. Gynecomastia occurs as a normal physiologic phenomenon in the newborn (due

to transplacental transfer of maternal and placental estrogens), during

puberty (high estrogen-to-androgen ratio in early stages of puberty),

and with aging (increased fat tissue and increased aromatase activity

along with the age-related decline in testosterone levels), but it can also

result from pathologic conditions associated with androgen deficiency

or estrogen excess. The prevalence of gynecomastia increases with age

and body mass index (BMI), likely because of increased aromatase

activity in adipose tissue. Medications that alter androgen metabolism

or action may also cause gynecomastia. The relative risk of breast cancer is increased in men with gynecomastia, although the absolute risk

is relatively small.

■ PATHOLOGIC GYNECOMASTIA

Any cause of androgen deficiency can lead to gynecomastia, reflecting an increased estrogen/androgen ratio, as estrogen synthesis still

occurs by aromatization of residual adrenal and gonadal androgens.

Gynecomastia is a characteristic feature of Klinefelter syndrome

(Chap. 390). Androgen insensitivity disorders also cause gynecomastia. Excess estrogen production may be caused by tumors, including

Sertoli cell tumors in isolation or in association with Peutz-Jeghers

syndrome or Carney complex. Tumors that produce hCG, including some testicular tumors, stimulate Leydig cell estrogen synthesis.

Increased conversion of androgens to estrogens can be a result of

increased availability of substrate (androstenedione) for extraglandular estrogen formation (CAH, hyperthyroidism, and most feminizing

adrenal tumors) or of diminished catabolism of androstenedione

(liver disease) so that estrogen precursors are shunted to aromatase in

peripheral sites. Obesity is associated with increased aromatization of

androgen precursors to estrogens. Extraglandular aromatase activity

can also be increased in tumors of the liver or adrenal gland or rarely

as an inherited disorder. Several families with increased peripheral aromatase activity inherited as an autosomal dominant or as an X-linked

disorder have been described. In some families with this disorder,

an inversion in chromosome 15q21.2-3 causes the CYP19 gene to be

activated by the regulatory elements of contiguous genes, resulting in

excessive estrogen production in the fat and other extragonadal tissues.

The familial aromatase excess syndrome due to CYP19 mutation or

chromosomal rearrangement is characterized by pre- or peripubertal

onset of gynecomastia, advanced bone age, short adult height due to

premature epiphyseal closure, and hypogonadotropic hypogonadism.

Peutz-Jeghers syndrome is characterized by intestinal hamartomas,

mucocutaneous pigmentation, calcifying Sertoli cell tumors, and prepubertal gynecomastia due to increased aromatization and premature

epiphyseal closure. Drugs can cause gynecomastia by acting directly as

estrogenic substances (e.g., oral contraceptives, phytoestrogens, digitalis) or inhibiting androgen synthesis (e.g., ketoconazole) or action

(e.g., spironolactone, AR blockers such as enzalutamide); for many

drugs, such as cimetidine, imatinib, or some antiretroviral drugs for

HIV, the precise mechanism is unknown. Unintentional exposure to

estrogenic agents in skin care products has been reported as a cause of

gynecomastia in prepubertal children.

Because up to two-thirds of pubertal boys and about 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. 391-6). 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, androstenedione, LH, and hCG. Markedly elevated estradiol concentrations

along with suppressed LH should prompt a search for a testicular or

adrenal estrogen-secreting tumor. A karyotype should be obtained in

men with very small testes to exclude Klinefelter syndrome. Despite

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 hCGβ

Exclude hCG

 secreting tumors

Low T, high

 E2/T ratio

Androgen deficiency

 syndrome

Serum T, LH, FSH,

 estradiol, and hCGβ

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 391-6 Evaluation of gynecomastia. E2

, 17β-estradiol; FSH, folliclestimulating hormones; hCGβ, human chorionic gonadotropin β; LH, luteinizing

hormone; T, testosterone.

3019 Disorders of the Testes and Male Reproductive System CHAPTER 391

extensive evaluation, the etiology is established in fewer than one-half

of patients.

TREATMENT

Gynecomastia

When the primary cause can be identified and corrected shortly

after the onset of gynecomastia, 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. The

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 placebo in

reducing breast size. Tamoxifen is effective in prevention and treatment of breast enlargement and breast pain in men with prostate

cancer who are receiving antiandrogen therapy.

AGING-RELATED CHANGES IN MALE

REPRODUCTIVE FUNCTION

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

[EMAS]) 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, in men with chronic illness, and

in those taking medications. Because SHBG concentrations are higher

in older men than in younger men, free or bioavailable testosterone

concentrations decline with aging to a greater extent than total testosterone concentrations. The age-related decline in testosterone is due to

defects at all levels of the hypothalamic-pituitary-testicular axis: pulsatile GnRH secretion is attenuated, LH response to GnRH is reduced,

and testicular response to LH is impaired. However, the gradual rise

of LH with aging suggests that testis dysfunction is the main cause

of declining androgen levels. The term andropause has been used to

denote age-related decline in testosterone concentrations; this term is a

misnomer because there is no discrete time when testosterone concentrations decline abruptly.

Several epidemiologic studies, such as the Framingham Heart Study,

the EMAS, and the Study of Osteoporotic Fractures in Men (MrOS),

that used mass spectrometry for measuring testosterone levels have

reported ~10% prevalence of low testosterone levels in middle-aged

and older men; the prevalence of unequivocally low testosterone and

sexual symptoms in men aged 40–70 years in the EMAS was 2.1%

and increased with age from 0.1% for men aged 40–49 years of age

to 5.1% for those aged 70–79 years. The age-related decline in testosterone should be distinguished from classical hypogonadism due to

diseases of the testes, the pituitary, and the hypothalamus. 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. An

analysis of signs and symptoms in older men in the EMAS revealed

a syndromic association of sexual symptoms with total testosterone

levels <320 ng/dL and free testosterone levels <64 pg/mL in communitydwelling older men.

A series of placebo-controlled testosterone trials have provided

important information about the efficacy of testosterone in improving

outcomes in older men. Testosterone replacement in older men, aged

≥65, with sexual symptoms improved sexual activity, sexual desire,

and erectile function more than placebo. Testosterone replacement

did not improve fatigue or cognitive function and had only a small

effect on mood and mobility. Among older men with low testosterone

and age-associated memory impairment, testosterone replacement

did not improve memory or other measures of cognition relative to

placebo. Testosterone replacement was associated with significantly

greater increase in vertebral as well as femoral volumetric bone mineral

density and estimated bone strength relative to placebo. Testosterone

replacement was associated with a greater increase in hemoglobin levels and corrected anemia in a greater proportion of men who had unexplained anemia of aging. Testosterone administration was associated

with a significantly greater increase in coronary artery noncalcified

plaque volume, as measured by coronary artery computed tomography

angiography. Neither the testosterone trials nor a randomized trial

of the effects of testosterone on atherosclerosis progression in aging

men (TEAAM trial) with low or low normal testosterone levels found

significant differences between testosterone and placebo arms in the

rates of change in either the coronary artery calcium scores or the

common carotid artery intima-media thickness. Neither of the trials

was long enough or large enough to determine the effects of testosterone replacement therapy on prostate or major adverse cardiovascular

events. In systematic reviews of randomized controlled trials, testosterone therapy of healthy older men with low or low-normal testosterone

levels was associated with greater increments in lean body mass, grip

strength, and self-reported physical function than that associated with

placebo. Testosterone therapy has not been shown to improve clinical

depression, fracture risk, progression to dementia, progression from

prediabetes to diabetes, or response to phosphodiesterase inhibitors

in older men.

The long-term risks of testosterone therapy remain largely unknown.

While there is no evidence that testosterone causes prostate cancer,

there is concern that testosterone therapy might cause subclinical prostate cancers to grow. Testosterone therapy is associated with increased

risk of detection of prostate events.

The data relating cardiovascular disease (CVD) and venous thromboembolic (VTE) risk with the use of testosterone supplementation in

men with low testosterone levels and hypogonadal symptoms are few

and inconclusive. The relationship between testosterone and cardiovascular events in cross-sectional and prospective cohort studies has been

inconsistent. A small number of epidemiologic studies have reported

an inverse relationship between testosterone concentrations and common carotid artery intima-media thickness. Low testosterone level has

been associated with increased risk of all-cause mortality, especially

cardiovascular mortality. It is possible that testosterone is a marker

of health; older men with multiple comorbid conditions who are at

increased risk of death may have low testosterone levels as a result of

comorbid conditions.

Most meta-analyses have not shown a statistically significant association between testosterone and cardiovascular events, major adverse

cardiovascular events, or deaths. No adequately powered randomized

trials have been conducted to determine the effects of testosterone

replacement on major adverse cardiovascular events. Thus, there are

insufficient data to establish a causal link between testosterone therapy

and cardiovascular events.

Population screening of all older men for low testosterone levels is

not recommended, and testing should be restricted to men who have

symptoms or signs attributable to androgen deficiency. Testosterone

therapy is not recommended for all older men with low testosterone

levels. In older men with significant symptoms of androgen deficiency

who have unequivocally low testosterone levels, testosterone therapy

may be considered on an individualized basis and should be instituted

after careful discussion of the risks and benefits (see “Testosterone

Replacement,” below).

Testicular morphology, semen production, and fertility are maintained up to a very old age in men. Although concern has been

expressed about age-related increases in germ cell mutations and

impairment of DNA repair mechanisms, there is no clear evidence

that the frequency of chromosomal aneuploidy is increased in the

3020 PART 12 Endocrinology and Metabolism

sperm of older men. However, the incidence of autosomal dominant

diseases, such as achondroplasia, polyposis coli, Marfan syndrome, and

Apert syndrome, increases in the offspring of men who are advanced

in age, consistent with transmission of sporadic missense mutations.

Advanced paternal age may be associated with increased rates of de

novo mutations, which may contribute to an increased risk of neurodevelopmental diseases such as schizophrenia and autism. The somatic

mutations in male germ cells that enhance the proliferation of germ

cells could lead to within-testis expansion of mutant clonal lines,

thus favoring the propagation of germ cells carrying these pathogenic

mutations and increasing the risk of mutations in the offspring of older

fathers (the “selfish spermatogonial selection” hypothesis).

APPROACH TO THE PATIENT

Androgen Deficiency

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. Some, but not all, 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.

When symptoms or clinical features suggest possible androgen

deficiency, the laboratory evaluation is initiated by the measurement of total testosterone in a fasting specimen, preferably in the

morning using a reliable assay, such as LC-MS/MS that has been

calibrated to an international testosterone standard (Fig. 391-7).

A consistently low total testosterone level below the lower limit

of the normal male range, measured by an LC-MS/MS assay in a

CDC-certified laboratory, 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.

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 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 diagnose Klinefelter syndrome. Men who

have a low testosterone but “inappropriately normal” or low LH

levels have secondary hypogonadism; their defect resides at the

hypothalamic-pituitary level. Common causes of acquired secondary hypogonadism include space-occupying lesions of the sella,

hyperprolactinemia, chronic illness, hemochromatosis, excessive

exercise, and 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 syndrome, to

be diagnosed in young adults.

Ascertain signs and symptoms; exclude systemic causes, eating and

body image disorders, medications, and substance use

Measure fasting, early morning total T and, if indicated, free T

Measure LH and FSH

Low T, low or inappropriately

normal LH (hypogonadotropic)

Low T, high LH

(hypergonadotropic)

• Rule out systemic illness

• Measure prolactin and ferritin

• Evaluate other pituitary hormones

• MRI scan

Primary testicular dysfunction

• Karyotype to exclude

Klinefelter syndrome

Low <200 ng/dL Borderline 200–350 ng/dL >350 ng/dL

Total and/or free T low Total and free T normal

Evaluate for other

causes of symptoms;

follow, if indicated

Repeat total T and free T

FIGURE 391-7 Evaluation of hypogonadism. FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; T, testosterone.

3021 Disorders of the Testes and Male Reproductive System CHAPTER 391

TREATMENT

Androgen Deficiency

GONADOTROPINS

Gonadotropin therapy is used to establish or restore fertility in

patients with gonadotropin deficiency of any cause. Several gonadotropin preparations are available. Human menopausal gonadotropin

(hMG; purified from the urine of postmenopausal women) contains

75 IU FSH and 75 IU LH per vial. hCG (purified from the urine of

pregnant women) has little FSH activity and resembles LH in its

ability to stimulate testosterone production by Leydig cells. Recombinant LH is also available. 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 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 content. Once

spermatogenesis is restored using combined FSH and LH therapy,

hCG alone is often sufficient to maintain spermatogenesis.

Although a variety of treatment regimens are used, 1000 IU of

hCG or recombinant human LH (rhLH) administered intramuscularly three times weekly is a reasonable starting dose. Testosterone

levels should be measured 6–8 weeks later and 48–72 h after the

hCG or rhLH injection; the hCG/rhLH dose should be adjusted to

achieve testosterone levels in the mid-normal range. Sperm counts

should be monitored on a monthly basis. It may take several months

for spermatogenesis to be restored; therefore, it is important to

forewarn patients about the potential length and expense of the

treatment and to provide conservative estimates of success rates. If

testosterone levels are in the mid-normal range but the sperm concentrations are low after 6 months of therapy with hCG alone, FSH

should be added. This can be done by using hMG, highly purified

urinary hFSH, or recombinant hFSH. The selection of FSH dose

is empirical. A common practice is to start with the addition of 75

IU FSH three times each week in conjunction with the hCG/rhLH

injections. If sperm densities are still low after 3 months of combined

treatment, the FSH dose should be increased to 150 IU. Occasionally,

it may take ≥18–24 months for spermatogenesis to be restored.

The two best predictors of the success of gonadotropin therapy

in hypogonadotropic men are testicular volume at presentation

and time of onset of gonadotropin deficiency. In general, men with

testicular volumes >8 mL have better response rates than those who

have testicular volumes <4 mL. Patients who become 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.

TESTOSTERONE REPLACEMENT

Androgen therapy is indicated to restore testosterone levels to normal to correct features of androgen deficiency in men with organic

hypogonadism due to known diseases of the testes, pituitary, and

the hypothalamus. Testosterone replacement induces secondary sex

characteristics; improves libido and overall sexual activity; increases

lean muscle mass, hemoglobin, hematocrit, and bone mineral density; and decreases fat mass. The benefits of testosterone replacement therapy have only been proven in men who have documented

symptomatic androgen deficiency, as demonstrated by testosterone

levels that are well below the lower limit of normal.

Testosterone is available in a variety of formulations with distinct pharmacokinetics (Table 391-3). Testosterone serves as a

prohormone and is converted to 17β-estradiol by aromatase and

to 5α-DHT 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.

The current recommendation is to restore testosterone levels to the

mid-normal range.

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.

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 longer the duration of action. Thus,

testosterone enanthate, cypionate, and undecanoate with longer

side chains have longer durations 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 may be accompanied

by changes in a patient’s mood, sexual desire, and energy level;

weekly administration of testosterone enanthate or cypionate can

reduce these variations in testosterone levels during the dosing

interval. The kinetics of testosterone enanthate and cypionate are

similar. Estradiol and DHT levels are normal if testosterone replacement is physiologic.

A long-acting testosterone undecanoate in oil, administered at

an initial priming dose of 750 mg intramuscularly followed by a

second dose of 750 mg 4 weeks later, and then at a maintenance

dose of 750 mg every 10 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, its

relative drawbacks are the large injection volume and the risk of

pulmonary oil microembolism (POME) reaction in a very small

proportion of patients.

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 4-mg patch may not be

sufficient to increase testosterone into the mid-normal male range

in all hypogonadal men; many patients may need two 4-mg patches

daily to achieve the targeted testosterone concentrations. The use of

testosterone patches may be associated with skin irritation in some

individuals.

Testosterone Gel Several transdermal testosterone gels, Androgel,

Testim, Fortesta, and Axiron, and some generic versions, when

applied topically to the skin in appropriate doses (Table 391-3),

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–

recommended dose and adjust the dose based on testosterone levels.

3022 PART 12 Endocrinology and Metabolism

TABLE 391-3 Clinical Pharmacology of Some Testosterone Formulations

FORMULATION REGIMEN PHARMACOKINETIC PROFILE DHT AND E2 ADVANTAGES DISADVANTAGES

T enanthate or

cypionate

150–200 mg IM q2wk

or 70–100 mg/wk

After a single IM injection, serum T

levels rise into the supraphysiologic

range, then decline gradually into the

low-normal or the hypogonadal range

by the end of the dosing interval

DHT and E2 levels rise

in proportion to the

increase in T levels;

T:DHT and T:E2 ratios

do not change

Corrects symptoms of

androgen deficiency;

relatively inexpensive

if self-administered;

flexibility of dosing

Requires IM injection; peaks and

valleys in serum T levels that are

associated with fluctuations in

patient’s mood, energy level, and

sex drive

Topical T gels

and axillary T

solution

Available in sachets,

tubes, and pumps

When used in appropriate doses,

these topical formulations restore

serum T and E2 levels to the

physiologic male range

Serum DHT levels

and DHT:T ratio are

higher in hypogonadal

men treated with the

transdermal gels than

in healthy eugonadal

men

Corrects symptoms of

androgen deficiency,

ease of application,

good skin tolerability

Potential of transfer to a female

partner or child by direct skinto-skin contact; skin irritation

in a small proportion of treated

men; moderately high DHT levels;

considerable interindividual

and intraindividual variation in

on-treatment testosterone levels

Transdermal T

patch

1 or 2 patches,

designed to nominally

deliver 4–8 mg T over

24 h applied daily on

nonpressure areas

Restores serum T, DHT, and E2 levels

to the physiologic male range

T:DHT and T:E2 levels

are in the physiologic

male range

Ease of application,

corrects symptoms of

androgen deficiency

Serum T levels in some androgendeficient men may be in the

low-normal range; these men

may need application of 2

patches daily; skin irritation at the

application site occurs frequently

in many patients

Buccal,

bioadhesive,

T tablets

30-mg, controlledrelease, bioadhesive

tablets bid

Absorbed from the buccal mucosa Normalizes serum

T and DHT levels in

hypogonadal men

Corrects symptoms of

androgen deficiency

Gum-related adverse events in

16% of treated men

T pellets Several pellets

implanted SC; dose

and regimen vary with

formulation

Serum T peaks at 1 month and then is

sustained in normal range for

3–4 months, depending on

formulation

T:DHT and T:E2 ratios

do not change

Corrects symptoms of

androgen deficiency

Requires surgical incision for

insertions; pellets may extrude

spontaneously

17α-Methyl T This 17α-alkylated

compound should

not be used because

of potential for liver

toxicity

Orally active Clinical responses are variable;

potential for liver toxicity; should

not be used for treatment of

androgen deficiency

Oral T

undecanoate

(TU)

237 mg PO bid with

food

TU formulated in a self-emulsifying

drug delivery system that includes

hydrophilic and lipophilic excipients

to enable the solubilization of TU and

its absorption through the lymphatics

after oral ingestion with a typical

meal. After each administration,

serum T levels rise and return to

baseline by 12 h. When administered

at the recommended dose, average

serum T levels are maintained in the

normal range in a majority of treated

men

High DHT:T ratio Convenience of oral

administration

High DHT:T ratio

Injectable longacting TU in oil

U.S. regimen 750 mg

IM, followed by 750 mg

at 4 weeks, and

750 mg every 10 weeks

When administered at the

recommended dose, serum T levels

are maintained in the normal range in

a majority of treated men

DHT and E2 levels rise

in proportion to the

increase in T levels;

T:DHT and T:E2 ratios

do not change

Corrects symptoms of

androgen deficiency;

requires infrequent

administration

Requires IM injection of a large

volume; serious pulmonary oil

microembolism (POME) reactions,

characterized by cough, dyspnea,

throat tightening, chest pain,

dizziness, and syncope, and

episodes of anaphylaxis have

been reported to occur during or

immediately after the injection in

a very small number of patients;

patients should be watched for

POME reaction for 30 min after

each injection

T-in-adhesive

matrix patcha

2 × 60 cm2

 patches

delivering ~4.8 mg

of T/d

Restores serum T, DHT, and E2 to the

physiologic range

T:DHT and T:E2 are in

the physiologic range

Lasts 2 d Some skin irritation

Intranasal T 2 actuations of the

metered-dose pump

(11 mg) applied into

the nostrils 3 times

daily

Restores T into the normal male

range

T:DHT and T:E2 ratio in

the physiologic range

Requires 3 times daily application;

nasal irritation, epistaxis,

nasopharyngitis

a

These 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.

3023 Disorders of the Testes and Male Reproductive System CHAPTER 391

The advantages of the testosterone gel include the ease of application. 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 intra- and 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.

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.

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.

Pellets of crystalline testosterone can be inserted in the subcutaneous tissue through a small skin incision. Testosterone is released

by surface erosion of the implant and absorbed into the systemic

circulation, and testosterone levels can be maintained in the normal

range for 3–4 months. Potential drawbacks include incising the skin

for insertion and removal and spontaneous extrusions and fibrosis

at the site of the implant.

Testosterone undecanoate, formulated in a self-emulsifying drug

delivery system that includes hydrophilic and lipophilic excipients

to enable its solubilization in the gut, is absorbed through the lymphatics after oral ingestion with a typical meal and is spared the

first-pass degradation in the liver. After each administration, serum

testosterone levels rise and return to baseline by 12 h. When administered at the recommended dose, average serum testosterone levels

are maintained in the normal range in a majority of treated men, but

DHT-to-testosterone ratios are higher in hypogonadal men treated

with oral testosterone undecanoate, as compared to eugonadal men.

An intranasal testosterone gel is now available as a metered-dose

pump and is administered typically at a starting dose of 11 mg testosterone in the form of two pump actuations, one in each nostril

three times daily. Formulation-specific adverse effects include rhinorrhea, nasal discomfort, epistaxis, nasopharyngitis, and nasal scab.

Novel Androgen Formulations A number of androgen formulations with better pharmacokinetics or more selective

activity profiles are under development. Long-acting biodegradable microsphere formulations have also been investigated.

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.

Selective AR modulators (SARMs) are a class of AR ligands that

bind the AR and display tissue-selective actions. A number of nonsteroidal SARMs that act as 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. SARMs that are strong agonists for the

muscle, bone, and sexual function and antagonists for the prostate

may be valuable in treating men with prostate cancer who are

receiving androgen deprivation therapy.

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.

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 the prostate and cardiovascular event rates 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 binding to AR promotes the association of liganded

AR with β-catenin and its translocation into the nucleus where it

binds TCF-4 and activates Wnt-target genes, including follistatin,

which blocks signaling through the transforming growth factor β

pathway, thereby promoting myogenic differentiation of muscle

progenitor cells. Testosterone may have additional effects on satellite cell replication and polyamine pathway, 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.

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 supraphysiologic doses 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 have been investigated. Regimens

containing an androgen plus a progestin such as depo-medroxyprogesterone acetate, etonogestrel, or norethisterone enanthate have

been highly effective in inducing azoospermia or severe oligozoospermia (sperm density <1 million/mL) in nearly 99% of treated

men over a 1-year period. The combined regimens of testosterone

plus a progestin have been associated with weight gain, acne, mood

changes including depressed mood, libido changes, and decreased

plasma high-density lipoprotein (HDL) cholesterol, and their

long-term safety has not been demonstrated. One such trial of a

combined regimen of testosterone undecanoate plus norethisterone

enanthate was stopped early due to adverse events. SARMs, which

are more potent inhibitors of gonadotropins than testosterone and

spare the prostate, hold promise for their contraceptive potential.

Recommended Regimens for Androgen Replacement Testosterone esters are administered typically at doses of 70–100 mg intramuscularly every week or 140–200 mg every 2 weeks. Testosterone

undecanoate is administered at an initial dose of 750 mg followed

4 weeks later by a second injection of 750 mg and then 750 mg

every 10 weeks. 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 and keep

the area of gel application covered with clothing to minimize the

risk of gel transfer to another person. One or two 4-mg nongenital

3024 PART 12 Endocrinology and Metabolism

testosterone patches are applied daily over the skin of the back,

thigh, or upper arm away from pressure areas. Bioadhesive buccal

testosterone tablets at a dose of 30 mg are applied twice daily on the

buccal mucosa. Oral testosterone undecanoate is taken twice daily

with meals at a starting dose of 237 mg. Intranasal testosterone is

administered as a spray in each nostril three times a day (33 mg/d).

Evaluating Efficacy of Testosterone Replacement Therapy Because

a clinically useful marker of androgen action is not available, correction of symptoms, induction and maintenance of secondary

sex characteristics, and restoration of testosterone levels into the

mid-normal range remain the goals 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 substantial variation in 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 midnormal range (400–750 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.

Restoration of sexual function, induction and maintenance of

secondary sex characteristics, 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. 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 occur with androgen treatment.

Contraindications for Androgen Administration Testosterone

administration is contraindicated in men with prostate or breast cancer (Table 391-4). Testosterone therapy should not be administered

without further urologic evaluation to men with a palpable prostate

nodule or induration, a prostate-specific antigen >3 ng/mL, or 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, or uncontrolled or poorly

controlled congestive heart failure, or with myocardial infarction,

stroke, or acute coronary syndrome in the preceding 3 months.

Monitoring Potential Adverse Experiences The clinical effectiveness and safety of testosterone replacement therapy should be

assessed 3–6 months after initiating testosterone therapy and annually thereafter (Table 391-5). Potential adverse effects include acne,

oiliness of skin, erythrocytosis, breast tenderness and enlargement,

leg edema, 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; pain and mood fluctuation with injectable

testosterone esters; cough and injection site pain with long-acting

testosterone undecanoate; and nasal irritation, epistaxis, and nasal

scab with intranasal formulation.

Hemoglobin Levels Administration of testosterone to androgen-deficient men is typically associated with only a small (~3%)

increase in hemoglobin levels, due to direct effects of testosterone on

hematopoietic progenitors in the bone marrow, stimulation of erythropoietin, 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 or who live at high altitude. 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

apnea, testosterone therapy may be reinitiated at a lower dose.

Prostate and Serum Prostate-Specific Antigen (PSA)

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.

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 androgendeficient men are generally <0.5 ng/mL, and increments >1.0 ng/

mL over a 3–6-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. PSA level >4 ng/mL during treatment, if

confirmed by repeat testing, requires further urologic evaluation.

Cardiovascular Risk As discussed above, there is insufficient

evidence to determine whether testosterone replacement therapy

increases the risk of major adverse cardiovascular events in hypogonadal men. In two randomized, placebo-controlled trials, the

TABLE 391-4 Conditions in Which Testosterone Administration Is

Associated with an Increased Risk of Adverse Outcomes

Conditions in which testosterone administration is associated with very high

risk of serious adverse outcomes:

Metastatic prostate cancer

Breast cancer

Conditions in which testosterone administration is associated with moderate to

high risk of adverse outcomes:

Undiagnosed prostate nodule or induration

PSA >3

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

3 months

Abbreviation: PSA, prostate-specific antigen.

Source: Modified with permission from S Bhasin et al: Testosterone therapy in

men with androgen deficiency syndromes: an Endocrine Society clinical practice

guideline. J Clin Endocrinol Metab 95:2536, 2010.