An astounding 1 in 6 couples experience infertility, across Australia and New Zealand (FSANZ, 2024). There are a myriad of factors that can contribute to infertility for both males and females, including poor semen quality, ovulation disorders, fallopian tube damage and more (NHS, 2023). Understanding infertility and potential treatments, begins with discerning normal fertility across both sexes. In this article, my aim is to begin to break down the female reproductive cycle. This involves a complex interplay of hormones, relaying signals from the brain to the ovaries. This feedback loop is commonly referred to as the hypothalamic-pituitary-ovarian (HPO) axis, governed by the decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) gonadotropin-releasing hormone (GnRH), that regulates the release of two major gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as small amounts of human chorionic gonadotropin (hCG) (Baba et al, 1971; Casteel & Singh, 2023). I will begin this knowledge journey with GnRH, specifically, its secretion. 

The cell bodies of GnRH neurons are located in the infundibular nucleus, located in the mediobasal hypothalamus, with projections into the median eminence, which contain portal capillaries (Marques et al., 2022; Yin & Gore, 2010; Song & Choi, 2023). The median eminence controls the release of GnRH, which occurs in hourly intervals in mammals (Yin & Gore, 2010). It is believed that GnRH release declines with age (Rubin & Bridges, 1989). The infundibular nucleus is rich in kisspeptin neurons, which secrete kisspeptin, acting on KISS1R on GnRH neurons. KISS1R is a G-protein coupled receptor (GPCR), that activates phospholipase-C (PLC) upon ligand binding, having downstream effects on the recruitment on inositol trisphosphate and diacylglycerol, and resultantly the release of calcium and protein kinase-C (PKC) (Muir et al, 2001). Kisspeptin neurons within the infundibular nucleus co-express neurokinin B and dynorphin (KNDy), that regulate kisspeptin release in an autosynaptic manor (Skorupskaite et al, 2014). Released GnRH from secretory vesicles, is then carried through fenestrated capillaries into the anterior pituitary.  GnRH secretion occurs in an episodic pulsatile manner or during the preovulatory phase surge. The rise of GnRH elicits an accompanying LH release (Marques et al., 2022). During the female menstrual cycle, in the follicular phase, the pulses of LH occur hourly, which develops into an LH surge mid-cycle, followed by a decline in pulse frequency during the luteal phase, to approximately every four hours (Yen & Tsai, 1971). FSH secretion is less regulated by GnRH than LH, which is thought to be attributable to multiple factors, including more sparse storage of FSH compared to LH (Pincus et al, 1998). GnRH has also been shown to regulate the transcription of gonadotropin subunit genes, with dependence on pulse frequency. Rapid pulses increase the gene transcription of LH-⍺ and LH-β, with slow pulse frequency increasing FSH-β (Dalkin et al, 1989).

References:

Baba, Y., Matsuo, H., Schally, A, V. (1971). Structure of the porcine LH- and FSH-releasing hormone. II. Confirmation of the proposed structure by conventional sequential analyses. Biochemical and Biophysical Research Communications. 43(6):1334-9. doi: 10.1016/s0006-291x(71)80019-0

Casteel, C. O., Singh, G. (2023). Physiology, Gonadotropin-Release Hormone. Treasure Island. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK558992/ 

Dalkin, A. C., Haisenleder, D. J., Ortolano, G. A., Ellis, T. R., Marshall, J. C. (1989). The frequency of gonadotropin-releasing-hormone stimulation differentially regulates gonadotropin subunit messenger ribonucleic acid expression. Endocrinology. 125(2):917-24. doi: 10.1210/endo-125-2-917. https://pubmed.ncbi.nlm.nih.gov/2502379/ 

NHS. (2023). Infertility. https://www.nhs.uk/conditions/infertility/ 

FSANZ. (2024). https://www.fertilitysociety.com.au/#:~:text=One%20in%20six%20couples%20in,surgical%20techniques%2C%20or%20lifestyle%20changes. 

Marques, P., Skorupskaite, K., Rozario, K. S., Anderson, R. A. George, J. T. (2022). Physiology of GnRH and Gonadotropin Secretion. Endotext. https://www.ncbi.nlm.nih.gov/books/NBK279070/ 

Mui, A. I., Chamberlain, L., Elshourbagy, N. A., Michalovich, D., Moore, D. J., Calamari, A., Szekeres, P. G., Sarau, H. M., Chambers, J. K., Murdock, P., Steplewski, K., Shabon, U., Miller, J. E., Middleton, S. E., Darker, J. G., Larminie, C. G., Wilson, S. Bergsma, D. J., Emson, P., Faull, R., Philpott, K. L., Harrison, D. C. (2001). AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. Journal of Biological Chemistry. 276(31):28969-75. doi: 10.1074/jbc.M102743200. https://pubmed.ncbi.nlm.nih.gov/11387329/ 

Pincus, S. M., Padmanabhan, V., Lemon, W., Randolph, J., Midgley, A. R. (1998). Follicle-stimulating hormone is secreted more irregularly than luteinizing hormone in both humans and sheep. Journal of Clinical Investigation. 101(6):1318-24. doi: 10.1172/JCI985. https://pubmed.ncbi.nlm.nih.gov/9502773/ 

Rubin, B. S., Bridges, R. S. (1989). Alterations in luteinizing hormone-releasing hormone release from the mediobasal hypothalamus of ovariectomized, steroid-primed middle-aged rats as measured by push-pull perfusion. Neuroendrocinology. 49(3): 225-32. doi: 10.1159/000125121. https://pubmed.ncbi.nlm.nih.gov/2654689/ 

Skorupskaite, K., George, J. T., Anderson, R. A. (2014). The kisspeptin-GnRH pathway in human reproductive health and disease. Human Reproduction Update. 20(4):485-500. doi: 10.1093/humupd/dmu009. https://pubmed.ncbi.nlm.nih.gov/24615662/ 

Song, J., Choi, S-Y. (2023). Arcuate Nucleus of the Hypothalamus: Anatomy, Physiology, and Diseases. Experimental Neurobiology. 32(6): 371-386. doi: 10.5607/en23040 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10789173/ 

Yen, S. S., Tsai, C. C. (1971). The biphasic pattern in the feedback action of ethinyl estradiol on the release of pituitary FSH and LH. The Journal of Clinical Endocrinology and Metabolism. 33(6):882-7. doi: 10.1210/jcem-33-6-882. https://pubmed.ncbi.nlm.nih.gov/5135628/ 

Yin, W., Gore, A. C. (2010). The Hypothalamic Median Eminence and its Role in Reproductive Aging. Annals of the New York Academy of Sciences.1204: 113-122.  doi: 10.1111/j.1749-6632.2010.05518.x https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929984/#:~:text=The%20median%20eminence%20is%20the,vascularizes%20the%20anterior%20pituitary%20gland.