In 2000, a study conducted by Japanese researchers on quail brains reported the existence of a gonadotropin-inhibitory hormone (GnIH), the first hypothalamic peptide noted in a vertebrate that directly blocks the synthesis and release of gonadotropins from the pituitary gland. Although several subsequent studies have identified the presence of the hormone in mice and sheep models, the existence of a similar hypothalamic gonadotropin-inhibiting system in humans was unclear. Now, in a groundbreaking study published in the recent issue of the journal PLoS One, researchers report the identification of human homologs of the GnIH hormone: RFamide-related peptide-1 (RFRP-1) and RFRP-3, in the human hypothalamus. The discovery of the new reproductive hormone mandates the revision of our current understanding of the central control mechanisms that regulate human reproductive functions.
In addition to the existence of the GnIH hormone analogs, the study led by Takayoshi Ubuka from the Department of Integrative Biology, University of California, Berkeley, characterized the distribution and biological activity of these analogs in human hypothalamus. Using mass spectrometry, the researchers identified the peptide sequences of RFRP-1 and RFRP-3 as MPHSFANLPLRF-NH2 and VPNLPQRF-NH2, respectively. Further, immunocytochemistry analysis demonstrated the presence of GnIH-immunoreactive neuronal cell bodies in the hypothalamic dorsomedial region with the axonal projections extending to the GnRH neurons present in the preoptic area and the median eminence.
Another recent study conducted by Clarke and colleagues (Endocrinology, 2008) showed the ability of the human RFRP-3 in blocking the production of the gonadotropin hormone in sheep pituitary cell culture via the inhibition of Ca2+ mobilization. The study also demonstrated the expression of the GnIH receptor mRNA in the pituitary and hypothalamus; specifically in the luteinizing hormone producing cells (gonadotropes) present in the anterior pituitory.
Another research group from the University of Berkeley (PNAS, 2009) reported that the stress-induced increase in adrenal glucocorticoids contributes to increase in RFRP, which in turn causes a hypothlamic suppression of reproductive functions. The direct association noted by the researchers between stress and RFRP may aid in gaining better insight into stress-related reproductive dysfunction and infertility.
Analogs of luteinizing-hormone-releasing hormone (LHRH), with the potential to modulate the hypothalamic-pituitary-gonadal axis, have already been recognized as effective agents to treat diverse sex-steroid-dependent, benign and malignant disorders. Now, the novel GnIH hormones, having the ability to inhibit the action of gonadotropes, hold greater therapeutic implications as alternative or adjunct agents for treating:
• Various hormone-dependent diseases, such as endometriosis, precocious puberty, uterine fibroids, and benign prostatic hyperplasia
• Cancerous conditions, including prostatic and breast cancers.
The researchers also anticipate that the recent findings could pave the way for developing new contraceptive strategies.
References
1. New human reproductive hormone could lead to novel contraceptives. Press Release. University of California. Last accessed December 30, 2009.
2. Ubuka T, Morgan K, Pawson AJ, et al. Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis. PLoS One. 2009 Dec 22;4(12):e8400.
3. Clarke IJ, Sari IP, Qi Y, et al. Potent action of RFamide-related peptide-3 on pituitary gonadotropes indicative of a hypophysiotropic role in the negative regulation of gonadotropin secretion. Endocrinology. 2008 Nov;149(11):5811-21.
4. Kirby ED, Geraghty AC, Ubuka T, Bentley GE, Kaufer D. Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats. Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11324-9.
