Male Hypogonadism

[dj75]

Male Hypogonadism
Decreased functional activity of the testes (either endocrinologic, gametogenic, or both) that results in retardation of puberty and/or reproductive insufficiency.

(For syndromes of androgen resistance, see Intersex States in Ch. 261; for congenital disorders of the testes and scrotum, see under Renal and Genitourinary Defects also in Ch. 261.)

Classification
Hypogonadism can be classified into three categories: (1) In primary (hypergonadotropic) hypogonadism, damage to the Leydig cells impairs androgen (testosterone) production and/or damages the seminiferous tubules, with consequent oligospermia or azoospermia and elevated gonadotropins. (2) In secondary (hypogonadotropic) hypogonadism, disorders of the hypothalamus or pituitary impair gonadotropin secretion, which may result in impotency and/or infertility. (3) In resistance to androgen action, response to available androgen is inadequate (see also Intersex States in Ch. 261).

Primary hypogonadism: Klinefelter syndrome, which is the most frequent cause of primary hypogonadism, is seminiferous tubule dysgenesis associated with the 47,XXY karyotype, in which an extra X chromosome is acquired through maternal (and to a lesser extent paternal) meiotic nondisjunction. Clinical features are discussed under Sex Chromosome Abnormalities in Ch. 261. The diagnosis remains undetected in most patients until puberty, when inadequate sexual development is noted, or later when infertility is investigated. Gonadotropins are elevated once the normal time of puberty is reached, while testosterone remains in the low-normal to low range.

In bilateral anorchia (vanishing testes syndrome), the testes were presumably present but were resorbed before birth or postnatally. These patients have normal external genitalia and normal wolffian structures but lack müllerian duct structures. Therefore, testicular tissue must have been present during the first 12 wk of embryogenesis for testicular differentiation to have occurred and both testosterone and müllerian-inhibiting factor to have been produced. These patients present a clinical picture similar to that of bilateral cryptorchidism, except that there is no rise in circulating testosterone after human chorionic gonadotropin (hCG) injections.

Early correction of cryptorchidism is indicated to try to prevent malignancy or testicular torsion. (See also undescended testes under Renal and Genitourinary Defects in Ch. 261.)

In Leydig cell aplasia, congenital absence of Leydig cells is a cause of male pseudohermaphroditism associated with ambiguity of the external genitalia. Although there is some wolffian duct development, there is insufficient testosterone production to induce normal male differentiation of the external genitalia. Müllerian duct structures are absent because of normal Sertoli cell production of the müllerian-inhibiting hormone. Elevated gonadotropins and low testosterone concentrations are found, and there is no rise in circulating testosterone after hCG injections.

Noonan syndrome (male Turner syndrome) may occur sporadically or as an autosomal dominant disorder. Phenotypic abnormalities include hyperelasticity of the skin, hypertelorism, ptosis, low-set ears, short stature, shortened 4th metacarpals, high-arched palate and primarily right-sided cardiovascular abnormalities such as pulmonic valve stenosis, and atrial septal defect. Testes are often small or cryptorchid. Testosterone may be low with high gonadotropin levels.

About 80% of males with myotonic dystrophy have primary testicular failure, with testicular biopsies that show derangement of spermatogenesis, hyalinization, and fibrosis. In addition to the muscle weakness and atrophy, frontal balding, mental retardation, cataracts, diabetes mellitus, primary hypoparathyroidism, and cranial hyperostosis may be found. As with other causes of primary hypogonadism, gonadotropins are elevated and testosterone levels are low or low-normal.

Adult seminiferous tubular disorders: Oligospermia or azoospermia associated with infertility may be found in men who have idiopathic seminiferous tubule failure or who have developed such failure after testicular infections (eg, mumps or gonorrhea), cryptorchidism, uremia, antineoplastic agents, alcoholism, irradiation, vascular damage, or trauma. In addition to an abnormal semen analysis, serum follicle-stimulating hormone (FSH) may be elevated, although with mild oligospermia the levels may be normal. Serum testosterone and luteinizing hormone (LH) concentrations are usually in the normal range, although there may be an excessive rise in LH after gonadotropin-releasing hormone (GnRH) stimulation, suggesting mild androgen deficiency. In adolescents or adults, a semen sample collected by masturbation 2 days after abstinence from ejaculation provides an excellent index of seminiferous tubular function. A normal semen has a volume of 1 to 6 mL, > 20 × 106 sperm/mL, of which 60% are of normal morphology and are motile (see also Sperm Disorders in Ch. 245).

Enzymatic defects: Defects in all the enzymatic pathways leading to dihydrotestosterone have been described. These congenital problems may be associated with congenital adrenal hyperplasia and can cause varying degrees of ambiguity of the external genitalia, ie, male pseudohermaphroditism.

Secondary hypogonadism: Panhypopituitarism may occur on a congenital or anatomic basis, such as in septo-optic dysplasia or Dandy-Walker malformation, causing deficiency of either hypothalamic-releasing factors or of pituitary hormones. Acquired hypopituitarism may result from tumors and neoplasia or from their therapy, vascular disorders, infiltrative disorders such as sarcoidosis or Langerhans' histiocytosis, infections such as encephalitis or meningitis, and trauma. Hypopituitarism in childhood may cause growth delay, hypothyroidism, diabetes insipidus, hypoadrenalism, and lack of sexual development at the expected time of puberty. Acquired hypopituitarism in adulthood may cause hypothyroidism, diabetes insipidus, hypoadrenalism, impotence, decreased libido, and testicular atrophy. These disorders can be identified by CNS imaging techniques. Hormone deficiencies may be varied and multiple, whether arising from the anterior or the posterior pituitary.

Kallmann syndrome is characterized by anosmia due to agenesis of the olfactory lobes and hypogonadism secondary to deficiency of hypothalamic GnRH. The cause is failure of fetal GnRH neurosecretory neurons to migrate from the olfactory placode to the hypothalamus. Inheritance is usually X-linked. Other manifestations include microphallus and cryptorchidism, associated midline defects, and unilateral kidney agenesis.

Constitutional delay of puberty is an absence of pubertal development in a boy of at least 14 yr of age (see Short Stature due to Hypopituitarism, above). Often, there is a family history of delay in sexual development in a parent or sibling. Most boys have some evidence of sexual maturation by 18 yr of age or when the skeletal age reaches 12 yr, the average age when testicular enlargement is first noted. Such boys usually exhibit short stature during childhood and/or adolescence but ultimately reach their genetic target. Constitutional delay is a diagnosis of exclusion; ie, GH deficiency, hypothyroidism, hypogonadism, whether primary or due to gonadotropin deficiency, need to be excluded. Typically, children with constitutional delay have a near-normal height velocity with a growth pattern that parallels the lower percentile curves of the growth chart. When the bone age is plotted on the growth curve, it essentially equals the percentile curve of the genetic target.

In isolated LH deficiency (fertile eunuch syndrome), patients have a monotropic loss of LH secretion while FSH remains normal. At puberty, these boys have growth of the testes, since the vast majority of testicular volume is made up of seminiferous tubules responsive to FSH. Spermatogenesis may occur as tubular development proceeds. However, the absence of LH results in Leydig cell atrophy and testosterone deficiency. Therefore, these patients do not develop normal secondary sexual characteristics and continue to grow, attaining eunuchoidal proportions from lack of closure of their epiphyses.

Prader-Willi syndrome is characterized by diminished fetal activity, obesity, muscular hypotonia, mental retardation, and hypogonadotropic hypogonadism. The syndrome is caused by deletion or disruption of a gene or genes on the proximal long arm of the paternal chromosome 15 or by maternal uniparental disomy of chromosome 15. Abnormalities of growth in infancy include failure to thrive due to hypotonia and feeding difficulties, which generally improve after 6 to 12 mo of age. From 12 to 18 mo onward, uncontrollable hyperphagia causes worsening weight gain as well as psychologic problems, as insatiable hunger with plethoric obesity becomes the most striking feature. Rapid weight gain continues but with ultimate short stature in adulthood. Behavioral features include emotional lability, poor gross motor skills, cognitive impairment, and insatiable hunger. Facial abnormalities include a narrow bitemporal dimension, almond-shaped eyes, and a mouth with thin upper lips and downturned corners. Hypogonadotropic hypogonadism, cryptorchidism, and a hypoplastic penis and scrotum in males or hypoplastic labia in females are present. Skeletal abnormalities include scoliosis, kyphosis, and osteopenia. Limb abnormalities include small hands and feet.

Acute illness as well as chronic systemic disorders, such as chronic renal insufficiency or anorexia nervosa, may be associated with hypogonadotropic hypogonadism, which lessens after recovery from the underlying disorder.

Symptoms and Signs
The age of onset of sex steroid deficiency dictates the clinical presentation.

Androgen deficiency or defects in androgen action in the 1st trimester (< 12 wk in utero) result in inadequate differentiation of the internal wolffian ducts and of the external genitalia. The clinical presentation may range from ambiguity of the external genitalia or male pseudohermaphroditism to fully normal-appearing female external genitalia.

Androgen deficiency in the 2nd and 3rd trimesters may cause a microphallus and descent of the testes that is incomplete or lacking.

In childhood, androgen deficiency has few consequences, but if it occurs at the expected time of puberty, secondary sexual development is impaired. Patients with hypogonadism have poor muscle development, a high-pitched voice, inadequate phallic and testicular growth, small scrotum, sparse pubic and axillary hair, and absent body hair. They may develop gynecomastia and attain eunuchoidal body proportions (span > height by 2 in and pubic to floor length > crown to pubic length by > 2 in) because of delayed fusion of the epiphyses and continued long bone growth.

In adulthood, androgen deficiency has varied manifestations depending on the degree and length of deficiency. Decreased libido, potency, and overall strength are common. Testicular atrophy, fine wrinkling of the skin around the eyes and lips, and sparse body hair may occur with long-standing hypogonadism. Osteopenia and gynecomastia may also develop.

Laboratory Findings
Measuring serum testosterone: Testosterone levels increase throughout puberty from < 20 ng/dL (< 0.7 nmol/L) to between 300 and 1200 ng/dL (10.5 and 41.5 nmol/L) in adulthood. Serum testosterone secretion is pulsatile as well as circadian. In the second half of puberty, levels are higher at night than during the day. A single sample is sufficient to establish that circulating testosterone levels are normal. Because 98% of testosterone is bound to carrier proteins in serum (testosterone-binding globulin), alterations in these protein levels will alter total testosterone levels.

Measuring serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH): LH and FSH should be measured in three blood samples at 20-min intervals because pulsatile secretions occur at 90- to 120-min intervals and their presence or absence must be documented. Serum LH and FSH levels are usually < 5 mIU/mL before puberty, have nocturnal augmentation in the latter half of puberty, and have pulsatile fluctuation between 5 and 20 mIU/mL in adulthood. In adult males with low serum testosterone and elevated gonadotropin levels, primary testicular failure should be suspected, whereas low or normal gonadotropin and low testosterone levels suggest a hypothalamic or pituitary disorder. In children of short stature with delayed pubertal development, low testosterone and low gonadotropin levels may also be consistent with constitutional delay.

Human chorionic gonadotropin (hCG) stimulation test: hCG stimulates Leydig cells, as does LH, with which it shares a structural subunit, and stimulates testicular production of testosterone. The hCG stimulation test examines the integrity of testicular function and consists of administering 500 IU/1.7 m2 in adults or 100 IU/kg in children. Testosterone levels should at least double after 3 to 4 days.

Clomiphene citrate test: Clomiphene citrate is a weak estrogen that inhibits the binding of estradiol on estrogen receptors and does not stimulate receptor activation. Because estradiol is an important inhibitor of serum gonadotropin secretion, receptor occupancy by clomiphene causes decreased negative feedback on gonadotropin secretion by circulating estrogens. The normal adult response to clomiphene citrate, 100 mg po bid, is a 50 to 250% increase in LH, a 30 to 200% increase in FSH, and a 30 to 200% increase in testosterone. These increases are impaired or are absent in hypothalamic or pituitary disorders.

Gonadotropin-releasing hormone (GnRH) stimulation test: The administration of 100 µg (2.5 µg/kg in children) GnRH by rapid IV injection directly stimulates the pituitary to secrete LH and FSH, which are measured every 20 to 30 min for 2 h. The response to GnRH in childhood is predominantly an increase in FSH with little to no increase in LH. During puberty, LH and FSH rise more or less equally by two- to threefold. In adulthood, LH rises two- to fivefold over baseline while FSH rises twofold. In patients with hypopituitarism, this test elicits an inadequate to absent increase in gonadotropins, whereas patients with hypothalamic disease may have a normal or insufficient rise, the latter owing to gonadotroph atrophy from insufficient endogenous stimulation by GnRH. In patients with hypothalamic disease, such as Kallmann syndrome (see above), the repeated pulsatile administration of GnRH may restore gonadotroph secretion to normal.

Testicular biopsy: This is rarely needed to establish the diagnosis of hypogonadism. It is generally restricted to men who have azoospermia with normal-sized testes to distinguish between ductal obstruction and failure at spermatogenesis.

Treatment
Patients with hypogonadotropic hypogonadism should receive therapy directed toward the underlying pituitary hypothalamic disorder, if any is found.

Children with constitutional delay of puberty who approach 15 yr of age without any evidence of pubertal development may be given a 4- to 8-mo course of IM testosterone enanthate at 50 mg once a month. These low doses will bring about some degree of virilization and induce puberty without jeopardizing adult height potential.

Adolescents with androgen deficiency should be treated with long-acting injectable testosterone enanthate or cypionate at a dose that increases over an 18- to 24-mo period from 50 to up to 200 mg q 2 to 4 wk.

Adults with androgen deficiency should be treated until normal male menopause with a dose of 200 mg of injectable testosterone q 2 to 4 wk or with transdermal testosterone applied by skin patch, two patches daily unless there is a major contraindication. Potential adverse effects include fluid retention, acne, and, occasionally, transient gynecomastia. Therapy prevents or reduces the risk of osteopenia and vasomotor instability, increases libido, and prevents impotence. Because they carry the risk of hepatocellular dysfunction or tumor formation, oral androgens should not be used. Men with hypogonadotropic hypogonadism who want to develop spermatogenesis may be treated with menopausal gonadotropins that contain 75 IU each of FSH and LH at a dose of 1 to 2 vials IM 3 times/wk along with 2000 IU of hCG IM 3 times/wk. This therapy must be given for at least 3 mo to affect spermatogenesis. Alternatively, pulsatile subcutaneous administration of GnRH through a portable infusion pump may be tried if there is sufficient gonadotroph reserve, such as in Kallmann syndrome.

Treatment of Kallmann syndrome with chorionic gonadotropin (hcG) can correct cryptorchidism and establish fertility, even in adult males. Pulsatile GnRH therapy delivered subcutaneously by a portable pump leads to endogenous sex steroid secretion, progressive virilization, and even fertility.

In isolated FSH deficiency, epiphyseal closure is normally induced by testosterone through its conversion to estrogen by aromatase.

[earthdog]

A lot of information... Thanks for posting this!

[ciobl]

dj75 -> thank you for the post. we need posts like this on the sticky list

I have something on the computer very similar to this one. I'll open a new thread and post it.

[Madball99]

ttt

[Madball99]

ttt