Adequate functioning at all levels of the hypothalamic-pituitary-gonadal axis is necessary for normal gonadal development and subsequent sex steroid production. Deficiencies at any level of the axis can lead to a hypogonadal state. The causes of hypogonadism are heterogeneous and may involve any level of the reproductive system. This review discusses various causes of hypogonadism, describes the evaluation of hypogonadal states, and outlines treatment options for the induction of puberty in affected adolescents. Whereas some conditions are clearly delineated, the exact etiology and underlying pathogenesis of many disorders is unknown.
Factors that mitigate the onset of puberty have yet to be fully elucidated. Gonadarche refers to the onset of gonadal sex steroid production during puberty. Gonadarche results from pulsatile gonadotropin releasing hormone (GnRH) secretion from the hypothalamus. GnRH secretion occurs every 60 to 90 minutes, and there is subsequent release of the pituitary gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH) initially during sleep, which leads to gonadal stimulation. LH stimulates Leydig cell hyperplasia in males and subsequent testosterone release. FSH has little effect in males until the onset of spermarche (sperm maturation). In females, FSH stimulates the production of estradiol via ovarian follicular development. Testosterone and estradiol secretion lead to the development of secondary sexual characteristics. Adequate functioning at all levels of the hypothalamic-pituitary-gonadal axis is necessary for normal gonadal development and subsequent sex steroid production. Deficiencies at any level of the axis can lead to a hypogonadal state.
In boys, hypogonadism can manifest as a complete lack of secondary sexual development or failure of normal pubertal progression. In girls, it can present with failure of pubertal initiation, failure of pubertal progression, or menstrual irregularities. Abnormalities within the hypothalamus or pituitary lead to hypogonadotropic hypogonadism whereas primary gonadal failure is characterized as hypergonadotropic hypogonadism .
Hypogonadotropic hypogonadism
Hypogonadotropic hypogonadism can be attributed to a variety of congenital origins including single gene mutations, idiopathic forms, and genetic syndromes. Acquired causes of hypogonadotropic hypogonadism include central nervous system (CNS) insults such as trauma, irradiation, and intracranial tumors. By far the most common cause of hypogonadotropic hypogonadism is transient, and is termed constitutional delay of growth and puberty (CDGP). Each of these causes is briefly discussed here, and the molecular genetic causes of hypogonadotropic hypogonadism are shown in Table 1 .
| Gene | Product | Inheritance | Target Sites | Additional Clinical Manifestations |
|---|---|---|---|---|
| SF-1 | Orphan nuclear receptor | Autosomal recessive | Steroidogenesis in males Hypothalamus Pituitary Adrenals | XY sex reversal, adrenal failure In females: adrenal failure, normal ovarian function |
| DAX-1 | Orphan nuclear receptor | X-linked recessive | Steroidogenesis Hypothalamus Pituitary Adrenals | In males: spectrum of hypogonadotropic hypogonadism and adrenal insufficiency |
| KAL-1 | Anosmin | X-linked recessive | Hypothalamic neuronal migration | Anosmia |
| FGFR1 | FGF receptor | Autosomal dominant | FGF receptor in hypothalamus Pituitary | Cleft palate Agenesis of corpus callosum |
| GPR54 | G protein coupled receptor | Autosomal recessive | GnRH-secreting neurons Pituitary | Isolated hypogonadotropic hypogonadism |
| Prop-1 | Transcription factor | Sporadic autosomal recessive | Pituitary gonadotrope development | Growth hormone deficiency Central hypothyroidism |
| Hesx1 | Transcription factor | Sporadic | Prop-1 Pituitary gonadotrope development | Septo-optic dysplasia Central hypothyroidism Central hypocortisolism Diabetes insipidus |
| LEP | Leptin | Autosomal dominant | Hypothalamus | Obesity Hyperphagia T-cell immune dysfunction |
| LEPR | Leptin receptor | Autosomal dominant | Hypothalamus | Obesity Hyperphagia T-cell immune dysfunction |
Constitutional Delay of Growth and Puberty
CDGP is a variation of normal development that can be difficult to differentiate from pathologic hypogonadotropic hypogonadism. In this condition, puberty and the pubertal growth spurt occur at or later than the extreme upper end of the normal age. The diagnosis is made more often in boys than girls, likely due to referral bias, and has a strongly familial pattern. Skeletal maturation is delayed in comparison with chronologic age. CDGP results in delayed but normal puberty; thus puberty progresses through the normal stages but starts at a later time. Children with CDGP achieve their genetic potential for height, and laboratory evaluation is normal. Some patients benefit from short-term treatment to augment secondary sexual development and boost linear growth.
Congenital Origins
Gene defects
Nuclear receptor mutations
Nuclear receptors influence gene transcription at multiple levels, and exert their effects in a time- and dosage-specific fashion. An important nuclear receptor involved in gonadotropin secretion is steroidogenic factor-1 (SF-1), a key regulator of genes involved in sexual differentiation, steroidogenesis, and reproduction. SF-1 knockout mice show marked abnormalities in the development of the hypothalamus and impaired development of pituitary gonadotropes, with decreased levels of serum gonadotropins as well as gonadal dysgenesis. Target genes of SF-1 within the hypothalamus and pituitary include the gonadotropin releasing hormone receptor (GnRHR) and the β subunit of LH. Both heterozygous and homozygous mutations in the DNA binding domain of SF-1 result in complete XY sex reversal, testicular dysgenesis, and adrenal failure in genotypic males. A milder phenotype has also been described in which there is impaired gonadal but intact adrenal function. In a genetic female, a heterozygous SF-1 mutation has been associated with primary adrenal failure but normal ovarian development. Thus, SF-1 mutations exist within a broad clinical spectrum that will undoubtedly continue to expand.
DAX-1 is an orphan nuclear receptor that is involved in steroidogenesis and functions as a repressor of SF-1 mediated transcription. Mutations have been identified in NROB1 , the gene that encodes DAX1, on the Xp21 locus. Males with DAX1 mutations typically present with early-onset adrenal insufficiency and subsequent delayed puberty secondary to hypogonadotropic hypogonadism. However, a delayed presentation of primary adrenal insufficiency has also been reported. DAX1 mutations can lead to both hypothalamic and pituitary dysfunction with decreased GnRH and gonadotropin secretion. DAX1 mutations can also cause defects in spermatogenesis, and in one study affected males also had evidence of azospermia. Therefore, mutations in DAX-1, as in SF-1, can lead to the development of hypogonadism in a multitude of ways.
Kallman syndrome
Impairment of GnRH secretion can also occur from defects in migration of GnRH producing neurons. Kallman syndrome (KS) refers to the combination of hypogonadotropic hypogonadism and anosmia. The X-linked form results from a defect in the migration of GnRH and olfactory neurons due to a mutation in the KAL1 gene. This gene encodes for anosmin-1, a glycoprotein essential for neuronal migration and growth. Individuals with KS also have aplasia of the olfactory bulb as noted on magnetic resonance imaging (MRI). Although KAL1 gene defects have been the prototype of KS, there is emerging evidence that autosomal forms may be more prevalent than previously thought. In one study, KAL1 gene defects accounted for only 14% of cases with familial KS. Mutations in unidentified autosomal genes were postulated to cause the remainder. Subjects with presumed autosomal gene defects had some response to GnRH pulses, indicating partial preservation of hypothalamic GnRH-secreting neurons, though still with phenotypic similarity to the X-linked version of the syndrome. Fibroblast growth receptor 1 (FGFR1) mutations may account for as many as 10% of cases, and mutations in the prokineticin 2 (PROK2) gene have also been identified in individuals with KS and normosmic hypogonadotropic hypogonadism. No matter what the underlying molecular genetic cause, lack of adequate GnRH secretion leads to decreased circulating gonadotropins in both autosomal and X-linked cases.
Isolated hypogonadotropic hypogonadism
Isolated hypogonadotropic hypogonadism (IHH) refers to cases in which anosmia is absent. One potential cause is loss of function mutations of the GnRHR, a G-protein coupled receptor. At least 8 mutations of the GnRHR in 7 families have been identified. Notable genotype-phenotype variation exists even within members of the same kindred due to incomplete activation of GnRHR function. Males with these mutations display signs of hypogonadism and small testes. Females typically present with primary amenorrhea. Another important cause of IHH has been traced to mutations in GPR54, which has a critical role in hypothalamic GnRH signaling and release. Of note, both KS and IHH may be found in the same kindred. IHH has also been noted to be reversible in some patients.
Transcription factor mutations
Even with intact GnRH production and signal transduction, pituitary gonadotropin synthesis may still be deficient due to mutations in a variety of transcription factors. An important transcription factor involved in the developmental cascade of pituitary gonadotrope cells is Prop-1. Prop-1 is the prophet of the pituitary transcription factor Pit 1, a paired-like homeodomain transcription factor that is responsible for early embryonic pituitary development. Prop-1 gene mutations can result in familial combined pituitary hormone deficiency including growth hormone deficiency, central hypothyroidism, and hypogonadotropic hypogonadism. In one analysis of 8 members of a consanguineous family with Prop-1 gene mutations, all 8 family members had gonadotropin deficiency and failure of spontaneous sexual maturation. There is also a variable pattern of phenotypic expressivity associated with Prop-1 mutations, with different deficiencies appearing at different time periods within the same family.
Like Prop-1, the transcription factor HESX1 is needed for normal pituitary development. Deficiencies in HESX1, initially identified in 1998, are a rare cause of septo-optic dysplasia which may be associated with hypogonadotropic hypogonadism. Other transcription factors implicated in rare cases of hypogonadotropic hypogonadism include LHX4 and SOX 2. All patients with hypopituitarism, including idiopathic forms, are at risk for hypogonadotropic hypogonadism.
Leptin and leptin receptor defects
Congenital leptin deficiency results from loss of function mutations of the LEP gene, which encodes for the leptin protein. Leptin interacts with the leptin receptor, a member of the interleukin-6 family of receptors. This interaction stimulates the Jak-Stat pathway and leads to activation of downstream target genes. Leptin deficiency acts as a sign of nutritional deprivation and results in the suppression of the reproductive axis. Classic findings in individuals with leptin deficiency include hyperphagia, obesity, and hypogonadotropic hypogonadism. Administration of leptin seemingly rectifies these abnormalities. Leptin receptor (LEPR) abnormalities have a similar phenotype to congenital leptin deficiency. Females with this mutation have hypogonadotropic hypogonadism. These girls present with delayed puberty, lack of a pubertal growth spurt, and reduced expression of secondary sexual characteristics. Some may have irregular menses due to aromatization of subcutaneous fat to estrogen, which then stimulates uterine hyperplasia. Males with leptin receptor mutations have hypogonadotropic hypogonadism and diminished testosterone production.
Syndromes
Numerous syndromes include neuroendocrine dysfunction as a potential feature. Perhaps the best known is Prader-Willi syndrome (PWS), which is caused by a genetic defect involving paternal chromosome 15, usually in the form of a microdeletion within the long arm or maternal unipaternal disomy. Hypothalamic dysfunction is marked in these patients as evidenced by their hypotonia, hyperphagia, and intermittent temperature instability. The hypothalamic dysfunction also leads to hypogonadism and may be attributed to an absence of or abnormal location of GnRH neurons. Early studies in individuals with PWS revealed low circulating serum gonadotropins and in males, attenuated testosterone response to human chorionic gonadotropin. Physical findings in boys include micropenis, scrotal hypoplasia, cryptorchidism, and small testes. Either absent or delayed puberty may ensue. In girls, findings may be less remarkable and include hypoplasia of the clitoris or labia minora, primary amenorrhea, and delayed puberty. However, a wide spectrum of hypogonadism exists in PWS, with some women achieving fertility without hormone replacement therapy.
Acquired Origins
Any significant CNS insult can result in acquired hypogonadotropic hypogonadism. Two of the most common causes in children are traumatic brain injury and CNS tumors.
Traumatic brain injury
Traumatic brain injury (TBI) is an insult to the brain that results in neurologic dysfunction. TBI can have significant neurocognitive, neuropsychological, and neuroendocrine sequelae. Anterior pituitary insufficiency resulting from TBI has been noted in the past, but is garnering more attention as a high prevalence of pituitary hormone insufficiency has been demonstrated. Some retrospective studies indicate that gonadotropin deficiency may be found in 90% to 95% of those with history of TBI, although prospective studies in adults have noted the prevalence to be far less. In one study, hormonal evaluation was conducted on TBI patients at baseline (acute phase) and at 12 months. In the acute phase, approximately 42% of those evaluated had gonadotropin deficiency. At the 12-month follow-up, many of these patients spontaneously recovered reproductive function. The final prevalence of hypogonadism was 7.7%. It is clear that all patients with a history of TBI require ongoing surveillance for pituitary problems, including hypogonadotropic hypogonadism.
Central nervous system tumors
Intracranial injury can also occur as a result of CNS tumors. In children, resultant hypogonadotropic hypogonadism can exist as a result of the primary tumor or due to the therapeutic regimen needed to treat the lesion. In a prospective study of 75 children with various CNS tumors, 13% had an abnormality in gonadotropin secretion before initiation of therapy. In a retrospective study focusing on craniopharyngioma, only 1 out of 64 patients had evidence of hypogonadism before treatment. However, after surgical resection and adjuvant radiotherapy, 80% of those evaluated at a pubertal age had evidence of hypogonadism. Gonadotropin deficiency and delayed puberty are most likely in those who receive 40 Gy or more of radiation. Gonadotropin deficiency may continue to evolve for many years after irradiation, with rates of total incidence ranging from 20% to 50%. Therefore, all children who have CNS lesions should be monitored for gonadotropin deficiency and signs of pubertal delay.
Hypothalamic amenorrhea
Hypothalamic amenorrhea is commonly associated with eating disorders such as anorexia nervosa, and also occurs in elite female athletes. Clinical manifestations include absence of menstrual cycles, increased exercise, and weight loss. In these girls, suppression of GnRH secretion results in attenuation of LH and FSH release, and decreased estrogen production. Several theories have been postulated for this hypothalamic dysfunction, including low circulating energy levels due to high energy expenditure and relative deficiency of nutritional intake. Girls with hypothalamic amenorrhea also have low circulating leptin levels. Administration of recombinant leptin to some women with hypothalamic amenorrhea leads to elevated LH and estradiol, resulting in follicular growth and ovulation.
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