Hypogonadotropic hypogonadism is a deficiency in the secretion of gonadotropins (LH and follicle-stimulating hormone) due to an intrinsic or functional abnormality in the hypothalamus or pituitary gland. Such disorders result in secondary Leydig cell dysfunction. The clinical manifestations will depend on the age of onset. Since many patients with hypogonadotropic hypogonadism have a congenital deficiency in gonadorropin-releasing hormone (GnRH) secretion, the manifestations include a small phallus, failure to undergo secondary sexual development at the time of puberty, diminished sexual drive (libido), and decreased metabolic effects of testosterone (decreased muscle and bone mass). Acquired loss of gonadotropin secretion such as that occurring after trauma, pituitary tumors, and hypothalamic or pituitary inflammatory disease may present due to the local effects of the CNS disorder (i.e., visual field impairment, hypopituitarism, and headaches) or be clinically indistinguishable from primary gonadal failure. In the latter case, suspicion of a central defect (hypothalamic hypogonadism) comes from the laboratory pattern of low serum testosterone and low or inappropriately normal serum luteinizing hormone and follicle-stimulating hormone levels. The distinction between central and tubular causes of hypogonadism is important because secondary hypogonadism may imply a progressive and / or specifically treatable disorder; the unintended effect of drugs that inhibit the hypothalamic-pituitary axis, such as tranquilizers, antidepressants and estrogens; systemic illness; and malnutrition, or anorexia nervosa. The infertility associated with hypogonadotropic hypogonadism may be treatable with gonadotropin or gonadotropin-releasing hormone replacement therapy.

The site of the hypothalamic or pituitary lesion should be localized, if possible, by MRI. A serum pro-lactin must be measured to exclude the presence of hyperprolactinemia. A single test dose of gonadotropin-releasing hormone (usually 100 tig intravenously) does not distinguish hypo-thalamic from pituitary disease. A gonadotropin-releasing hormone test preceded by a period of “priming” the pituitary gonadotrophs with repeated low-dose stimulation has been used to diagnose hypothalamic disorders. With prior priming, the gonadotropin-releasing hormone test can demonstrate that low or absent luteinizing hormone responses to a single dose of gonadotropin-releasing hormone in hypothalamic disorders can be augmented to give normal luteinizing hormone levels, whereas priming has no effect in pituitary disorders. Difficulty also exists in separating delayed sexual maturation from incomplete hypogonadotropic hypogonadism, because basal luteinizing hormone and follicle-stimulating hormone levels may be similarly low in both circumstances. Gonadotropin-releasing hormone testing may be of potential value but is limited by the smaller luteinizing hormone response in normal prepubertal children that can overlap with the response of patients with incomplete hypogonadotropic hypogonadism. Newborns with hypogonadotropic hypogonadism may be identified by measuring the tesricular volume sequentially during the first three months of life. Normal children double the tesricular volume during this period.

Kallmann’s Syndrome And Idiopathic Hypogonadotropic Hypogonadism

A syndrome characterized by delayed or arrested sexual development and anosmia was first described in 1944. All the data available to date point to selective gonadotropin deficiency resulting from an isolated defect in gonadotropin-releasing hormone secretion in this disorder. Thus, the primary pathogeneric defect in these patients is hypothalamic, and the impaired gonadotropin secretion is secondary to the hypothalamic abnormality. The evidence of this disorder is approximately 1 in 10,000 male births. Although anosmia and hyposmia are the first described and most well-known associations of this syndrome, a large number of other somatic abnormalities have been recorded. The more common associations include color blindness, cleft lip and palate, and cranial nerve defects (including eighth nerve deafness). Horseshoe-shaped kidneys, cryptorchidism, and optic atrophy have also been described. In the molecular pathogenesis of idiopathic hypogonadotropic hypogonadism (IHH), abnormalities of the gonadotropin-releasing hormone receptor (GnRH-R) and associated proteins have explained some of the defects.

GnRH germ-like mutations with associated impaired gonadotropin-releasing hormone binding and ligand-induced signal transducrion have been identified. Schwanzel-Fukuda and Pfaff have studied the migration of the gonadotropin-releasing hormone neurons in the mouse embryo. These first appear in the epithelium of the olfactory placode in the mouse embryo and then migrate with the olfactory nerves to the forebrain and finally to their ultimate hypothalamic location. Such observations have led to speculation that idiopathic hypogonadotropic hypogonadism may be a developmental defect resulting from an abnormal migration of the luteinizing hormone-releasing hormone or gonadotropin-releasing hormone neurons. IHH associated with impaired olfactory function may be caused by mutations of the X chromosomal KAL gene (encoding anosmia) or the fibroblast growth factor (FGFR, both leading to agenesis of olfactory ad gonadotropin-releasing hormone secretory neurons. Further support for this hypothesis comes from MRI studies that show that olfactory bulbs and sulci are poorly developed in patients with IHH and anosmia / hyposmia. Recent studies have demonstrated that familial IHH patients are deficient in the KAL gene, which controls the production of an adhesion protein possibly responsible for the co-migration of the olfactory and gonadotropin-releasing hormone neurons.

IHH occurs both in sporadic (nonfamilial) and familial forms, although there are no differences in the clinical presentations of the two subgroups. Earlier studies had suggested that a positive family history is present in about 50% of patients. In over 120 patients comprehensively studied by Crowley’s laboratory, however, the majority of cases were sporadic. Hundreds of cases with both an autosomal-dominant and autosomal-recessive mode of inheritance have been described. Overall, the data are most consistent with an autosomal-dominant inheritance with variable penetrance.

There is significant heterogeneity in the clinical presentation of idiopathic hypogonadotropic hypogonadism. The phenotype, to a large degree, is determined by the severity of gonadotropin-releasing hormone deficiency. Those with the most severe deficiency may present with complete absence of pubertal development and sexual infantilism. Male patients may have complete absence of secondary sex characteristics, infantile testes, and azoospermia, while female patients have primary amenorrhea. At least 10% of the patients have partial gonadotropin-releasing hormone deficiency and varying degrees of delay in sexual development in proportion to the severity of gonadotropin deficiency.

Two variants of idiopathic hypogonadotropic hypogonadism (fertile eunuch syndrome and isolated follicle-stimulating hormone deficiency) are particularly interesting. The term “fertile eunuch syndrome” has been used to describe patients with eunuchoidal proportions and delayed sexual development but with normal-sized testes. Such individuals appear to have sufficient gonadorropins to stimulate high intratesticular levels to initiate spermatogenesis but not enough testosterone secretion into the blood to adequately virilize the peripheral tissues; they are, in fact, partially gonadotropin deficient. Another variant with predominantly follicle-stimulating hormone deficiency has also been described, although these patients are extremely rare. These men are normally androgenized but have decreased or absent sperm in their ejaculate without concomitant increases in follicle-stimulating hormone.

The secretory profiles of luteinizing hormone and follicle-stimulating hormone in men and women with IHH are quite heterogenous in their luteinizing hormone secretory patterns. The largest subset comprises patients who display no pulsatile luteinizing hormone secretion at all. This apulsarile group probably represents one extreme characterized by perhaps the most severe gonadotropin-releasing hormone deficiency. A smaller subset displays low-amplitude pulses. Another subset of patient has luteinizing hormone pulses at a markedly reduced frequency. A third subset is characterized by “sleep-entrained” pulses reminiscent of the pattern seen in early stages of puberty. This subset can thus be considered to suffer from a “developmental arrest.”

Congenital Syndromes (Non-Idiopathic Hypogonadotropic Hypogonadism And Kallmann’s)

A number of congenital syndromes have hypogonado-tropic hypogonadism as part of the syndrome complex. Most of these syndromes are associated with neurologic damage and mental retardation. A few of these are described below.

Prader-Willi Syndrome

Prader-Willi syndrome (PWS) has been well described and is a syndrome consisting of obesity, hypotonic musculature, mental retardation, hypogonadism, short stature, and small hands and feet. Hypogonadism, cryptorchidism, and micropenis are common. Testicular histology shows that the tesris is immature without germinal cells but with Sertoli cells and diminutive tubules. The degree of gonadotropin deficiency in these patients is variable. A few patients with hypergonadotropic hypogonadism have also been described. Pauli et al. recently described the 15q chromosome in a boy with PWS. Subsequent studies have shown that chromosome-15 abnormalities are found in approximately 70% of the patients with PWS, and maternal disomy of 15 accounts for 25% of cases. The remaining cases result either from genomic imprinting defects (microdelerions or epimutations) of the imprinting center of the 15qll-ql3 region or from chromosome 15 translocations. Clomiphene has been shown to “turn on” the pituitary-gonadal axis of individuals of either sex with PWS to secrete gonadotro-pins and gonadal steroids.

Other Congenital Causes of Secondary Leydig Cell Dysfunction

Laurence-Moon-Biedl, basal encephalocele, multiple lenrigines, Rud, and cerebellar ataxia are all complex syndromes associated with hypogonadotropic hypogonadism.

Acquired Hypogonadotropic Disorders and Functional Disorders

Anorexia nervosa and weight loss are examples of functional defects resulting in low serum testosterone levels. Anorexia nervosa is predominantly a disorder of adolescent girls characterized by excessive weight loss as the result of voluntary dietary restriction. Occasionally, the disorder is seen in men but usually implies a more severe variant of the psychiatric disorder. Both women and men may present with the manifestation of hypogonadotropic hypogonadism. Although all investigators agree that anorexia nervosa is associated with profound psychological dysfunction, the nature of the primary pathophysiologic abnormality remains controversial. The anorexic patient is usually born to older, middle- to upper-class Caucasian parents in a female-dominated family. Typical family values emphasize outward appearance, proper behavior, and achievement more than self-realization and close interpersonal relationships. Poor self-esteem and a sense of ineffectiveness are often described. The onset of illness around the time of puberty suggests that an inability to cope with developing sexuality and a widening social circle plays a role in the pathogenesis of this disorder.

Starvation from other, nonpsychological causes may also reduce gonadotropin secretion. Females also seem to be more susceptible to this disorder.

Strenuous exercise has minimal effects on testicular function in men; this contrasts greatly with the well-known phenomenon of dysfunctional reproduction in female long-distance runners and dancers.

Severe stress and systemic illnesses will also lower gonadotropin and testosterone levels. Many severe systemic illnesses may result in hypogonadism. The pathogenic mechanisms include suppression of the hypothalamic-pituitary secretion of gonadotropin-releasing hormone and luteinizing hormone. Chronic hepatic and renal disease, cancer, and HIV infection are commonly associated with low testosterone levels. Hepatic cirrhosis, sickle-cell disease, hemochromatosis (disorder of iron storage), and severe obesity are disorders in which a combined hypothalamic-pituitary and primary gonadal dysfunction may coexist.

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