Hypergonadotropic hypogonadism (ovarian insufficiency)
Hypogonadotropic hypogonadism (hypothalamic-pituitary defects)
Congenital
Congenital
– Turner syndrome
– Kallmann syndrome
– Primary ovarian insufficiency
– Isolated hypogonadotropic hypogonadism (IHH)
– Abnormalities in gonadotropin production or action
– Combined pituitary hormone deficiency
– Galactosemia
– Transcription factor mutations
– Gonadal dysgenesis
– Leptin and leptin receptor defects
– X chromosome abnormalities
– Syndrome (Laurence–Moon–Biedl, CHARGE)
Acquired
Acquired
– Autoimmune destruction
– Traumatic brain injury
– Chemotherapy
– Central nervous system diseases (tumors, infections, autoimmunity, infiltrative diseases)
– Radiation
– Functional hypothalamic amenorrhea (Eating disorders, athletes amenorrhea, stress, obesity)
– Iatrogenic (irradiation, corticosteroids)
– Medical condition (chronic diseases, hypothyroidism, Cushing syndrome, hyperprolactinemia, etc.)
Congenital forms are clinically characterized by absent or partial puberty and infertility. Biologically, HH is characterized by low or normal serum levels of LH and FSH in the setting of low sex steroids. Typically, patients with HH present in adolescence or early adulthood with delayed onset of puberty, primary amenorrhea, poorly developed sexual characteristics, and/or infertility.
4.2.1.1 Congenital Origins
Kallmann syndrome: This syndrome refers to the combination of hypogonadotropic hypogonadism and anosmia. The mutation of KAL1 gene results in a defect in the migration of GnRH and olfactory neurons. Individuals with KS have hypothalamic GnRH-secreting deficiency and aplasia of the olfactory bulb as noted on magnetic resonance imaging (MRI). The inherited mechanism may be X-linked or autosomal.
Isolated hypogonadotropic hypogonadism (IHH): One potential cause is loss of function mutations of the GnRHR, a G-protein coupled receptor (more than 25 loci have been shown and several European centers offer genetic screening, www.orpha.net and www.gnrhnetwork.eu). Genotype–phenotype variations exist even within members of the same kindred. Females typically present with primary amenorrhea. IHH has been noted to be reversible in 10–20% of HH patients.
Combined pituitary hormone deficiency: HH can be present as part of a broader pituitary deficiency disorder (CPHD). It is defined as the presence of two or more pituitary hormonal deficiencies. In some case, neonatal signs such as hypoglycemia can point to a CPHD diagnosis early in life, yet adolescents present for evaluation with absent/partial puberty and short stature.
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 is Prop-1, the prophet of the pituitary transcription factor Pit-1. Prop-1 gene mutations can result in familial combined pituitary hormone deficiency including growth hormone deficiency, central hypothyroidism, and hypogonadotropic hypogonadism. HESX-1 is a transcription factor needed for normal pituitary development; its deficiency can be responsible of septo-optic dysplasia and hypogonadotropic hypogonadism. Other transcription factors implicated in rare causes of hypogonadotropic hypogonadism are LHX4 and SOX2.
Leptin and leptin receptor defects: Leptin deficiency acts as a sign of nutritional deprivation and results in the suppression of the reproductive axis. Classical findings in individual with leptin deficiency include hyperphagia, obesity, and hypogonadotropic hypogonadism. Girls with LEP (leptin) or LEPR (leptin receptor) gene mutations present with delayed puberty, lack of a pubertal growth spurt, and reduced expression of secondary sexual characteristics.
Syndromes: Numerous syndromes include neuroendocrine dysfunction. The best known is Prader–Willi syndrome (PWS), caused by a genetic defect involving paternal chromosome 15 or maternal disomy. In these patients, hypogonadotropic hypogonadism is the expression of the hypothalamic dysfunction also evidenced by their hypotonia, hyperphagia, and intermittent temperature instability.
4.2.1.2 Acquired Origins
Traumatic brain injury: Traumatic brain injury (TBI) is an insult to the brain that results in neurologic dysfunction. TBI can determine anterior pituitary insufficiency and in particular gonadotropin deficiency may be found in 42% in the acute phase, at the 12-month follow-up many of these patients spontaneously recovered reproductive function. The final prevalence of hypogonadism is 7.7%.
Central nervous system diseases: Intracranial tumor is a common cause of acquired hypogonadism in adolescence (e.g., craniopharyngiomas and pituitary adenomas including prolactinoma). HH can result from the compression of pituitary tissue/stalk or secondary to inhibition of GnRH secretion in the case of prolactinoma or Cushing’s disease. Clinically, visual disturbance or headaches may accompany pubertal arrest in these cases. Importantly, all patients with pituitary tumors should have a complete evaluation of anterior and posterior pituitary function.
In children, resultant hypogonadotropic hypogonadism can exist as a result of the primary cerebral tumor or due to the therapeutic regimen needed to treat the lesion (chemotherapy and radiotherapy). 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 radiation, 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. Central hypogonadotropic hypogonadism can be caused by previous central nervous system infection or autoimmune destruction of the pituitary.
Functional hypothalamic amenorrhea: Functional hypothalamic amenorrhea occurs when hypothalamic-pituitary-ovarian axis is suppressed due to an energy deficit stemming from stress, weight loss, excessive exercise, or eating disorders [6, 7]. So, it is commonly associated with eating disorders such as anorexia nervosa and bulimia, and also occurs in elite female athletes. It is characterized by a low estrogen state without other organic or structural disease. Patients with functional amenorrhea may demonstrate the features of the female athlete triad, which consists of insufficient caloric intake with or without an eating disorder, amenorrhea, and low bone density or osteoporosis. Laboratory tests usually reveal low or low-normal levels of serum follicle-stimulating hormone, luteinizing hormone, and estradiol; however these levels can fluctuate, and the clinical context is the discriminating factor. In these girls, suppression of GnRH secretion results in attenuation of LH and FSH release, decreased estrogen production, and low circulating leptin levels.
In addition, chronic, systemic illness can cause HH via deficits in nutritional intake creating a negative energy balance or chronic inflammatory states resulting from immunologic disorders (i.e., inflammatory bowel disease and celiac disease) or psychological stress.
Drugs such as opiates and steroids can also suppress the HPG axis.
4.2.2 Hypergonadotropic Hypogonadism
Delayed onset of puberty or stalled pubertal development can also be caused by gonadal defects that may first become evident in adolescence. In such cases, unresponsive defective gonads lead to increased serum gonadotropin levels that characterize hypergonadotropic hypogonadism [5].
Primary hypogonadism can be due to congenital origins such as chromosomal abnormalities, syndrome, or genetic mutations, but it can also be acquired later in childhood or adolescence due to autoimmunity or exposure to chemotherapy or radiation (Table 4.1).
4.2.2.1 Congenital Origins
Turner syndrome: The most common cause of congenital primary hypogonadism is sex chromosome aneuploidy as is present in Turner syndrome [8]. It occurs in 1:2500 live born females. Diagnosis is suggested by characteristic physical features, including short stature, webbed neck, high palate, renal and cardiac malformations and confirmed by karyotypic analysis showing a partial or complete absence of an X chromosome or a chromosomal mosaicism. In adolescence, key diagnostic features include short disproportionate stature and ovarian insufficiency resulting in absent or incomplete puberty. In some instances, primary amenorrhea is the only presenting symptom. While most TS patients will require pubertal induction, about one-third of girls present with spontaneous initiation of puberty and 5% exhibit menarche and 2% spontaneous pregnancy.
Although intrinsically normal, the ovaries in girls with TS undergo accelerated atresia such that the timing of ovarian failure is variable and can occur anytime between childhood and young adulthood. FSH levels may be very elevated in TS in the first 2 years of life, revealing precocious gonadal insufficiency. Hypogonadism in these patients not only affects puberty and reproductive capacity but also has consequences on metabolic, hepatic, cardiovascular and bone health (density).
Gonadal dysgenesis: The second largest group of young women with primary ovarian insufficiency has a 46, XX karyotype (46, XX gonadal dysgenesis). Some of them have an autosomal recessive form of the disorder, and others have premutation for the fragile X syndrome.
Primary ovarian insufficiency: Primary ovarian insufficiency, a condition characterized by follicle depletion or dysfunction leading to a continuum of impaired ovarian function, is suggested by a concentration of follicle-stimulating hormone in the menopausal range, confirmed on two occasions separated by 1 month, and diagnosed in patients younger than 40 years with amenorrhea or oligomenorrhea [9, 10]. Other terms, including premature ovarian failure, are used synonymously with primary ovarian insufficiency. Up to 1% of women may experience primary ovarian insufficiency. More than 90% of cases unrelated to a syndrome are idiopathic, but they can be attributed to radiation, chemotherapeutic agents, infections, tumors, empty sella syndrome, or an autoimmune or infiltrative process.
Patients with primary ovarian insufficiency should be counseled about possible infertility, because up to 10% of such patients may achieve temporary and unpredictable remission.
There is evidence of genetic predisposition to primary ovarian insufficiency, and patients without evidence of a syndrome should be tested for FMR1 gene mutation [11].
X chromosome abnormalities: Other X chromosome abnormalities, including Xq deletion and Triple X, can cause varying degrees of hypogonadism. The proximal regions of both the p and the q arms of the X chromosomes are most critical for maintenance of the germ cell compliment and also terminal deletions at the telomeric regions of these arms are associated with oocyte depletion. Deletion of these regions is more likely to result in premature ovarian insufficiency after some period of ovarian function rather than a complete loss of germ cells evident at the start of the teenage years as is more commonly seen with the proximal deletions. Early molecular studies have identified two regions of the long arm of the X chromosome within the translocation breakpoints which were felt to harbor important ovarian determinant genes. POF1 (Xq26–q28) contains several candidate genes (HS6ST2, TDPF3, GPC3) and one known to be associated with POI, the Fragile Mental Retardation 1 (FMR1) gene. POF2 (Xq13.3–q22) contains several candidate genes for which one has been disrupted in POI.
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