The Hypothalamic-Pituitary Axis in Reproduction

Lisa M. Halvorson, M.D.

As is well-known by this audience, normal reproductive function requires the complex interaction of hypothalamic, pituitary, and gonadal factors. During the last decade, clinical, translational, and bench research programs have provided remarkable new insights into the mechanisms by which normal reproductive cyclicity is achieved and maintained at the level of the hypothalamic-pituitary axis. These studies also have also improved our understanding of the pathophysiology of various reproductive disorders, such as hypogonadotropic hypogonadism, pubertal abnormalities, and polycystic ovarian syndrome (PCOS), as well as the development of reproductive senescence. These advances provide groundwork for future investigations and suggest potential sites for the development of improved clinical treatments.

In this issue, Schwarting, Wierman, and Tobet elegantly describe migration of the gonadotropin-releasing hormone (GnRH) neurons from the olfactory placode to specific nuclei within the hypothalamus. Disturbances in this developmental process results in hypogonadotropic hypogonadism, including Kallmann syndrome. In a substantial subset of patients, hypogonadotropic hypogonadism has been linked to mutations in the Kal-1 and FGFR1 genes. Additional genes with critical importance for normal development of the GNRH neuronal system undoubtedly will be identified in the future.

Once appropriately located within the hypothalamus, GnRH-expressing neurons are regulated by a wide variety of neuronal and hormonal inputs. Studies of GNRH gene regulation have been hampered by the relatively small number of GnRH neurons as well as their dispersal throughout several hypothalamic nuclei, rather than discrete localization within a specific nucleus. The development of transgenic animal models and immortalized GnRH cell lines has provided significant insight into the molecular mechanisms that translate physiologic stimuli into altered GnRH transcription. Of interest, these studies have identified expression of GnRH and its receptor in an array of reproductive tissues, including the ovary, testis, placenta, and breast. In two separate articles, Kim et al detail current understanding of the regulation of GnRH gene expression in both hypothalamic and nonhypothalamic tissues.

Puberty has been ascribed to an awakening of the GnRH neurons; however, the factors that mediate this process are poorly understood. As described by Seminara, the peptide factor, kisspeptin-1/metastin, recently has been identified as a potent activator of GnRH neuronal function. Mutations in kisspeptin or its receptor, Gpr54, have been shown to result in either delayed or precocious puberty as determined in both human disease and animal models. Kisspeptin expression in the hypothalamus is upregulated by the adipose-derived factor, leptin, suggesting that kisspeptin provides a link between metabolic and reproductive function.

Reproductive aging in females is associated with the progressive decline and ultimate cessation of ovarian function. Accumulating evidence from both women and animal models suggests that this decline may partially be due to changes at the hypothalamic-pituitary level of the reproductive axis in addition to the better appreciated intrinsic failure of the ovary. Hall presents current data supporting the presence of abnormalities in hypothalamic-pituitary function that occur during reproductive aging in women.

PCOS is a common gynecologic disorder affecting ~5 to 10% of women. These patients have a constellation of signs and symptoms, including oligo-anovulation and hyperandrogenemia with resultant hirsutism and/or acne. In their article, Blank, McCartney, Helm, and Marshall propose a mechanism for the development of PCOS. In this model, elevated androgen levels during puberty reduce the sensitivity of GnRH neurons to sex-steroid inhibition, thereby enhancing GnRH pulsatility. Increased GnRH pulse frequency preferentially stimulates the biosynthesis and secretion of luteinizing hormone (LH) over follicle-stimulating hormone (FSH), thereby exacerbating thecal-derived androgen production as well as inhibiting normal follicular development-both hallmarks of this syndrome.

The second group of articles focuses on the anterior pituitary gland. As just described, elevated levels of serum LH are believed to be involved in the pathogenesis of PCOS. In support of this concept, chronic LH overexpression in transgenic mouse models has been found to result in increased serum testosterone levels, cystic ovaries, and chronic anovulation, as described by Sutton and Keri. Depending on the model system, animals overexpressing LH or the related human chorionic gonadotropin have been noted to develop granulosa cell tumors, mammary adenocarcinomas, and pituitary adenomas, as well as obesity, increased adrenal steroidogenesis, and anomalies of the urinary system. These observations suggest the presence of previously unappreciated LH targets.

As described by Bédécarrats and Kaiser, a subset of patients with hypogonadotropic hypogonadism have been found to have mutations in the GnRH receptor. Characterization of these mutations has provided important insight into the structure-function relationships of this receptor, including precise characterization of the functional domains required for membrane localization, ligand binding, and signal transduction.

Gonadotropin biosynthesis and secretion is modulated by the complex integration of signals from the hypothalamus (primarily GnRH), as well as gonadally derived steroids and peptides. These classic hormonal effects are modulated critically by several autocrine and paracrine factors within the pituitary gland, including activin, inhibin, follistatin, and PACAP. In their article, Winters and Moore describe the elegant coordination of LH and FSH biosynthesis and secretion by these pituitary-derived peptides.

In the final article, Beshay and I outline the diagnosis and management of pituitary adenomas, with a focus on the impact of these tumors on reproductive function.

In summary, modern genetic and molecular approaches are providing powerful tools for improving our understanding of the mechanisms by which the hypothalamus and anterior pituitary gland contribute to both normal and abnormal reproductive physiology. The articles in this issue of Seminars in Reproductive Medicine have been chosen to exemplify these recent advances.