Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype–phenotype relationships

Abstract

Congenital hypogonadotropic hypogonadism (CHH) results from abnormal gonadotropin secretion, and it is characterized by impaired pubertal development. CHH is caused by defective GNRH release, or by a gonadotrope cell dysfunction in the pituitary. Identification of genetic abnormalities related to CHH has provided major insights into the pathways critical for the development, maturation, and function of the reproductive axis. Mutations in five genes have been found specifically in Kallmann's syndrome, a disorder in which CHH is related to abnormal GNRH neuron ontogenesis and is associated with anosmia or hyposmia.In combined pituitary hormone deficiency or in complex syndromic CHH in which gonadotropin deficiency is either incidental or only one aspect of a more complex endocrine disorder or a nonendocrine disorder, other mutations affecting GNRH and/or gonadotropin secretion have been reported.Often, the CHH phenotype is tightly linked to an isolated deficiency of gonadotropin secretion. These patients, who have no associated signs or hormone deficiencies independent of the deficiency in gonadotropin and sex steroids, have isolated CHH. In some familial cases, they are due to genetic alterations affecting GNRH secretion (mutations in GNRH1, GPR54/KISS1R and TAC3 and TACR3) or the GNRH sensitivity of the gonadotropic cells (GNRHR). A minority of patients with Kallmann's syndrome or a syndromic form of CHH may also appear to have isolated CHH, but close clinical, familial, and genetic studies can reorient the diagnosis, which is important for genetic counseling in the context of assisted reproductive medicine.This review focuses on published cases of isolated CHH, its clinical and endocrine features, genetic causes, and genotype-phenotype relationships.

Parental Consanguinity in Infertile Males

“…The reason might be the low prevalence of this syndrome complex (1/4000 -10.000 in males) [8]. There are many mutations in either sporadic or familial form [9]. In our group non of the infertile males had consanguinity with another.…”

Menstrual Cycle Disturbances at Reproductive Age

“…The prevalence of IHH has been estimated at 1/4000 to 1/10 000 in males. It is reported to be between 2 and 5 times less frequent in females (Brioude, 2009). The classification of IHH has recently been made on the basis of genetic and pathophysiological features.…”

“…These attenuated forms have also been described as having conceived spontaneously. Retarded bone maturation, osteopenia and osteoporosis are frequent when the gonadotropin deficiency is discovered in adulthood (Brioude, 2009). …”

“…This therapy offers a clear advantage over treatment with exogenous gonadotropins, which involves higher rates of both multiple gestation and ovarian hyperstimulation syndrome. For either approach, however, the rate of conception is approximately 30% per ovulation cycle (Brioude, 2009). Recently, in nIHH women in order to stimulate ovulation recombinant FSH is commonly used.…”

Primary and Secondary Amenorrhea

“…Idiopathic hypogonadotropic hypogonadism has been suggested to be the result of isolated functional anomalies of the neuroendocrine signals for release of gonadotropin-releasing hormone or gonadotropins. In fact, in these subjects no developmental or anatomical alterations of the hypothalamus-pituitarygonadotropin axis have been described; the affected patients present a normal olfaction in presence of a phenotype deriving from pre-and postnatal gonadotropins and sex steroid deficiency (Brioude et al, 2010). Hypogonadotropic hypogonadism may be also due to mutations in gonadotropin-releasing hormone receptor genes (Layman et al, 2001 …”