Abstract
The pituitary is an organ of dual provenance: the anterior lobe is epithelial in origin, whereas the posterior lobe derives from the neural ectoderm. The pituitary gland is a pivotal element of the axis regulating reproductive function in mammals. It collects signals from the hypothalamus, and by secreting gonadotropins (FSH and LH) it stimulates the ovary into cyclic activity resulting in a menstrual cycle and in ovulation. Pituitary organogenesis is comprised of three main stages controlled by different signaling molecules: first, the initiation of pituitary organogenesis and subsequent formation of Rathke’s pouch; second, the migration of Rathke’s pouch cells and their proliferation; and third, lineage determination and cellular differentiation. Any disruption of this sequence, e.g., gene mutation, can lead to numerous developmental disorders. Gene mutations contributing to disordered pituitary development can themselves be classified: mutations affecting transcriptional determinants of pituitary development, mutations related to gonadotropin deficiency, mutations concerning the beta subunit of FSH and LH, and mutations in the DAX-1 gene as a cause of adrenal hypoplasia and disturbed responsiveness of the pituitary to GnRH. All these mutations lead to disruption in the hypothalamic–pituitary–ovarian axis and contribute to the development of primary amenorrhea.
Highlights
Pituitary organogenesis is comprised of three main stages controlled by different signaling molecules: first, the initiation of pituitary organogenesis and the subsequent formation of Rathke’s pouch; second, the migration of Rathke’s pouch cells and their proliferation; and third, lineage determination and cellular differentiation
Gene mutations contributing to the disruption of pituitary development can themselves be classified: mutations affecting transcriptional determinants of pituitary development, mutations causal to gonadotropin deficiency, mutations affecting the beta subunit of FSH and LH, and mutations in the DAX-1 gene as a cause of adrenal hypoplasia and of disturbed responsiveness of the pituitary to gonadotropin-releasing hormone (GnRH) (Table 1)
On the other hand, inactivating mutations cause a lack of kisspeptin action and prevent the activation of GnRH neurons, which leads to isolated hypogonadotropic hypogonadism (IHH) with or without anosmia [34,38,39,40,41,42]
Summary
Both pituitary gonadotropins (follicle-stimulating hormone (FSH) and Luteinizing Hormone (LH)) are composed of 2 subunits (alpha and beta). In 1993, an FSH-β subunit mutation was identified by Matthews et al [3] as a homozygous 2-bp deletion in codon 61 (Val 61) of the FSHβ gene This patient presented with primary amenorrhea and infertility [3]. The typical presenting phenotype of a patient with an FSH-β subunit mutation is primary amenorrhea and complete absence of pubertal development [5]. Molecular analysis revealed one nonsense mutation (c.343C>T:p Arg115Stop) in exon 3 Both sisters presented with undetectable serum FSH and estradiol, high serum LH, primary amenorrhea, and the absence of breast development. Zhu et al [8] identified a novel FSH-β subunit mutation (mutation Arg 97X) in a 29-year-old women suffering from primary amenorrhea, impaired pubertal development, and infertility. Documenting an accurate genetic background and clinical phenotype in patients with FSH-β mutation is helpful in understanding the basis for this complicated abarrency of female reproduction
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