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Male Hypogonadism in Children
(See also Male Hypogonadism.)
Male hypogonadism is decreased production of testosterone, sperm, or both or, rarely, decreased response to testosterone, resulting in delayed puberty, reproductive insufficiency, or both. Diagnosis is by measurement of serum testosterone, luteinizing hormone, and follicle-stimulating hormone and by stimulation tests with human chorionic gonadotropin or gonadotropin-releasing hormone. Treatment depends on the cause.
There are 3 types of hypogonadism: primary, secondary, and a type caused by defective androgen action, primarily due to defective androgen receptor activity.
In primary (hypergonadotropic) hypogonadism, damage to the Leydig cells impairs testosterone production, damages the seminiferous tubules, or does both; oligospermia or azoospermia and elevated gonadotropins result.
The most common cause is Klinefelter syndrome; other causes are disorders of sexual development such as gonadal dysgenesis (rare), cryptorchidism, bilateral anorchia, Leydig cell aplasia, Noonan syndrome, and myotonic dystrophy. Rare causes include orchitis due to mumps, testicular torsion, chemotherapy with alkylating drugs, and trauma.
Klinefelter syndrome is seminiferous tubule dysgenesis associated with the 47,XXY karyotype, in which an extra X chromosome is acquired through maternal or, to a lesser extent, paternal meiotic nondisjunction (see also Klinefelter Syndrome (47,XXY)). The syndrome is usually identified at puberty, when inadequate sexual development is noted, or later, when infertility is investigated. Diagnosis is based on elevated gonadotropin levels and low to low-normal testosteronelevels.
Errors of sex determination and gonadal development, such as gonadal dysgenesis (46,XX or 46,XY) and testicular and ovotesticular disorders of sex development, represent rare forms of male hypogonadism. They may result in a male or undervirilized male phenotype, ambiguous genitals at birth, and some degree of testicular and spermatogenic failure.
In cryptorchidism, one or both testes are undescended (see Cryptorchidism). Etiology is usually unknown. Sperm counts may be slightly low if one testis is undescended but are almost always very low if both are undescended.
In bilateral anorchia (vanishing testes syndrome), the testes were presumably present but were resorbed before or after birth. External genitals and wolffian structures are normal, but müllerian duct structures are lacking. Thus, testicular tissue must have been present during the first 12 wk of embryogenesis because testicular differentiation occurred and testosterone and müllerian-inhibiting factor were produced.
Leydig cell aplasia occurs when congenital absence of Leydig cells causes partially developed or ambiguous external genitals. Although wolffian ducts develop to some extent, testosterone production is insufficient to induce normal male differentiation of the external genitals. Müllerian ducts are absent because of normal production of müllerian-inhibiting hormone by Sertoli cells. Gonadotropin levels are high with low testosterone levels.
Noonan 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 (eg, pulmonic valve stenosis, atrial septal defect). Testes are often small or cryptorchid. Testosterone levels may be low with high gonadotropin levels.
Defective androgen synthesis is caused by enzyme defects that impair androgen synthesis, which may occur in any of the pathways leading from cholesterol to dihydrotestosterone. These congenital problems may occur in congenital adrenal hyperplasia (eg, steroidogenic acute regulatory [StAR] protein deficiency, 17α-hydroxylase deficiency, 3β-hydroxysteroid dehydrogenase deficiency—see Overview of Congenital Adrenal Hyperplasia) when the same enzyme defect occurs in the adrenal glands and the testes, resulting in defective androgen activity and ambiguous external genitals of varying degrees.
Causes of secondary hypogonadism include panhypopituitarism, hypothalamic or pituitary tumors, isolated gonadotropin deficiency, Kallmann syndrome, Laurence-Moon syndrome, isolated luteinizing hormone deficiency, Prader-Willi syndrome, and functional and acquired disorders of the CNS (eg, trauma, infection). Causes of secondary hypogonadism must be differentiated from constitutional delay of puberty, which is a functional form of secondary hypogonadism. Several acute disorders and chronic systemic disorders (eg, chronic renal insufficiency, anorexia nervosa) may lead to hypogonadotropic hypogonadism, which resolves after recovery from the underlying disorder. Relative hypogonadism is becoming more common among long-term survivors of childhood cancers treated with craniospinal irradiation.
Panhypopituitarism may occur congenitally or anatomically (eg, in septo-optic dysplasia or Dandy-Walker malformation), causing deficiency of hypothalamic-releasing factors or pituitary hormones. Acquired hypopituitarism may result from tumors, neoplasia, or their treatment, vascular disorders, infiltrative disorders (eg, sarcoidosis, Langerhans cell histiocytosis), infections (eg, encephalitis, meningitis), or trauma. Hypopituitarism in childhood may cause delayed growth, hypothyroidism, diabetes insipidus, hypoadrenalism, and lack of sexual development when puberty is expected. Hormone deficiencies, whether originating in the anterior or posterior pituitary, may be varied and multiple.
Kallmann syndrome is characterized by anosmia due to aplasia or hypoplasia of the olfactory lobes and by hypogonadism due to deficiency of hypothalamic gonadotropin-releasing hormone (GnRH). It occurs when fetal GnRH neurosecretory neurons do not migrate from the olfactory placode to the hypothalamus. The genetic defect is known; inheritance is classically X-linked but can also be autosomal dominant or autosomal recessive. Other manifestations include microphallus, cryptorchidism, midline defects, and unilateral kidney agenesis. Presentation is clinically heterogeneous, and some patients have normosmia.
Laurence-Moon syndrome is characterized by obesity, intellectual disability, retinitis pigmentosa, and polydactyly.
Isolated luteinizing hormone (LH) deficiency (fertile eunuch syndrome) is a rare cause of hypogonadism due to monotropic loss of LH secretion in boys; follicle-stimulating hormone (FSH) levels are normal. At puberty, growth of the testes is normal because most testicular volume consists of seminiferous tubules, which respond to FSH. Spermatogenesis may occur as tubular development proceeds. However, absence of LH results in Leydig cell atrophy and testosteronedeficiency. Therefore, patients do not develop normal secondary sexual characteristics, but they continue to grow, reaching eunuchoidal proportions because the epiphyses do not close.
Prader-Willi syndrome is characterized by diminished fetal activity, muscular hypotonia, and failure to thrive during early childhood followed later by obesity, intellectual disability, and hypogonadotropic hypogonadism. The syndrome is caused by deletion or disruption of a gene or genes on the proximal long arm of paternal chromosome 15 or by uniparental disomy of maternal chromosome 15. Failure to thrive due to hypotonia and feeding difficulties during infancy usually resolves after age 6 to 12 mo. From 12 to 18 mo onward, uncontrollable hyperphagia causes excessive weight gain and psychologic problems; plethoric obesity becomes the most striking feature. Rapid weight gain continues into adulthood; stature remains short and may be caused by growth hormone deficiency. Features include emotional lability, poor gross motor skills, facial abnormalities (eg, a narrow bitemporal dimension, almond-shaped eyes, a mouth with thin upper lips and down-turned corners), and skeletal abnormalities (eg, scoliosis, kyphosis, osteopenia). Hands and feet are small. Other features include cryptorchidism and a hypoplastic penis and scrotum.
Constitutional delay of puberty is absence of pubertal development before age 14 yr; it is more common in boys. By definition, children with constitutional delay show evidence of sexual maturation by age 18 yr, but pubertal delay and short stature may generate anxiety in adolescents and their families. Many children have a family history of delayed sexual development in a parent or sibling. Typically, stature is usually short during childhood, adolescence, or both but ultimately reaches the normal range. Growth velocity is nearly normal, and growth pattern parallels the lower percentile curves of the growth chart. The pubertal growth spurt is delayed, and at the expected time of puberty, height percentile begins to drop, which may contribute to psychosocial difficulties for some children. Skeletal age is delayed and is most consistent with the child's height age (age at which a child's height is at the 50th percentile) rather than chronologic age. Diagnosis is by exclusion of growth hormone deficiency, hypothyroidism, systemic conditions that may interfere with puberty (eg, inflammatory bowel disease, eating disorders), and hypogonadism (whether primary or due to gonadotropin deficiency).
Clinical presentation depends on whether, when, and how testosteroneand sperm production are affected. (For presentation in adulthood, see Male Hypogonadism : Symptoms and Signs.)
If androgen deficiency or defects in androgen activity occur during the 1st trimester (< 12 wk gestation), differentiation of internal wolffian ducts and external genitals is inadequate. Presentation may range from ambiguous external genitals to normal-appearing female external genitals. Androgen deficiency during the 2nd and 3rd trimesters may cause a microphallus and partially or completely undescended testes.
Androgen deficiency that develops early in childhood has few consequences, but if it occurs when puberty is expected, secondary sexual development is impaired. Such patients have poor muscle development, a high-pitched voice, inadequate phallic and testicular growth, a small scrotum, sparse pubic and axillary hair, and absent body hair. They may develop gynecomastia and grow to eunuchoidal body proportions (arm span exceeds height by 5 cm; pubic to floor length exceeds crown to pubic length by > 5 cm) because fusion of the epiphyses is delayed and long bone growth continues.
Diagnosis is often suspected based on developmental abnormalities or delayed puberty but requires confirmation by testing, including measurement of testosterone, LH, and FSH. LH and FSH levels are more sensitive than testosterone levels, especially for detecting primary hypogonadism.
LH and FSH levels also help determine whether hypogonadism is primary or secondary:
In boys with short stature, delayed pubertal development, low testosterone, and low FSH and LH levels may indicate constitutional delay. Elevated serum FSH levels with normal serum testosterone and LH levels typically indicate impaired spermatogenesis but not impaired testosterone production. In primary hypogonadism, it is important to determine the karyotype to investigate for Klinefelter syndrome.
Measurement of testosterone, FSH, and LH for diagnosis of hypogonadism requires an understanding of how the levels vary. Before puberty, serum testosterone levels are < 20 ng/dL (< 0.7 nmol/L) and in adulthood, levels are > 300 to 1200 ng/dL (12 to 42 nmol/L). Serum testosterone secretion is primarily circadian. In the 2nd half of puberty, levels are higher at night than during the latter part of the day. A single sample obtained in the morning can 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 alter total testosterone levels. Measurement of total serum testosterone (protein bound and free) is usually the most accurate indicator of testosterone secretion.
Although serum LH and FSH levels are pulsatile, testing can be valuable. Puberty begins when GnRH secretion increases and serum LH rises disproportionately to FSH. Early in puberty, early morning levels are preferred. Serum LH levels are usually below 0.3 mIU/mL before puberty and range from 2 to 12 mIU/mL during later stages of puberty and into adulthood. Serum FSH levels are usually < 3 mIU/mL before puberty and fluctuate between 5 and 10 mIU/mL during the 2nd half of puberty and into adulthood.
The human chorionic gonadotropin (hCG) stimulation test is done to assess the presence and secretory ability of testicular tissue. Multiple protocols exist. In one protocol, a one-time dose of hCG 100 units/kg IM is given. hCG stimulates Leydig cells, as does LH, with which it shares a structural subunit, and stimulates testicular production of testosterone. Testosterone levels should double after 3 to 4 days.
Cryptorchidism is corrected early to obviate concerns about cancer developing in later adulthood and to prevent testicular torsion (see Cryptorchidism).
For secondary hypogonadism, any underlying pituitary or hypothalamic disorder is treated. Overall, the goal is to provide androgen replacement starting with a low dose and progressively increasing the dose over 18 to 24 mo.
Adolescents with androgen deficiency should be given long-acting injectable testosterone enanthate or cypionate 50 mg q 2 to 4 wk; the dose is increased up to 200 mg over 18 to 24 mo. A transdermal patch or gel may be used instead.
Treatment of Kallmann syndrome with hCG can correct cryptorchidism and establish fertility. Puberty is typically induced using testosterone injectable or gel. GnRH therapy has been previously shown to help endogenous sex hormone secretion, progressive virilization, and even fertility.
In isolated LH deficiency, testosterone, via conversion to estrogen by aromatase, induces normal epiphyseal closure.
Constitutional delay of puberty can be treated with a 4- to 6-mo course of testosterone. After the course is complete, treatment is stopped and testosteronelevels are measured several weeks or months later to differentiate temporary from permanent deficiency. If testosterone levels are not higher than the initial value and/or pubertal development does not proceed after completion of this treatment, a second course of low-dose treatment can be given. If endogenous puberty has not begun after two courses of treatment, the likelihood of permanent deficiency increases, and patients need to be reevaluated for other causes of hypogonadism.
In primary hypogonadism, a congenital (or rarely acquired) testicular disorder impairs testosterone production and/or damages the seminiferous tubules.
In secondary hypogonadism, congenital or acquired disorders of the hypothalamus or pituitary cause gonadotropin deficiency and failure to stimulate normal testicles.
Manifestations and their timing vary widely depending on when testosteroneproduction is affected.
Prenatal androgen deficiency may result in manifestations ranging from partially undescended testes, microphallus, and ambiguous external genitals to normal-appearing female external genitals.
Androgen deficiency that occurs when puberty is expected impairs secondary sexual development.
Diagnose by measurement of testosterone, LH, and FSH levels.
Treat with hormone replacement and surgery as needed.
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