OR44-1 Kisspeptin advances the menstrual cycle in healthy women

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR44-Female Reproductive Endocrinology
Basic/Translational
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 9:15 AM
Room 256 (Moscone Center)
Alexander N Comninos*1, Channa Nalin Jayasena1, Gurjinder M Nijher1, Ali Abbara1, Akila De Silva1, Johannes D Veldhuis2, Chioma Izzi-Engbeaya1, Risheka Ratnasabapathy1, Adrian Lim3, Daksha Patel3, Mohammad A Ghatei1, Stephen R Bloom1 and Waljit Singh Dhillo1
1Imperial College London, London, United Kingdom, 2Mayo Clinic, Rochester, MN, 3Imperial College Healthcare NHS Trust
The KISS1 gene is a critical regulator of reproductive function and acts via the kisspeptin receptor. In humans, inactivating mutations of the KISS1 gene (1) or its receptor gene (2,3) result in a failure of puberty. In contrast, activating mutations of the KISS1 gene (4) or its receptor gene (5) result in precocious puberty. Administration of kisspeptin induces ovulation in rodents, musk shrews, and sheep (6-8). In women with hypothalamic amenorrhoea, acute administration of kisspeptin leads to potent stimulation of gonadotrophins but chronic administration leads to profound tachyphylaxis (9). It is not known whether exogenous kisspeptin can alter the menstrual cycle in healthy women.

This study examined the effects of acute and chronic kisspeptin administration on the menstrual cycle in healthy women for the first time.

We performed a prospective, single-blinded, one-way crossover study. Five healthy women received twice-daily subcutaneous injections of kisspeptin-54 or saline for 7 consecutive days during days 7-14 of their menstrual cycle. Volunteers underwent serial assessment of basal reproductive hormones, luteinizing hormone (LH) pulsatility, ultrasound parameters of ovarian activity, as well as acute sensitivity to gonadotrophin-releasing hormone (GnRH) and kisspeptin-54 injection.

Kisspeptin treatment shortened the overall menstrual cycle (mean length (days): saline 28.6±1.4 vs. kisspeptin 26.8±3.1, P<0.01), advanced the onset of highest recorded serum LH (mean menstrual day of highest LH: saline 15.2±1.3 vs. kisspeptin 13.0±1.9, P<0.05), and advanced the onset of the luteal phase of menstrual cycle (mean day of progesterone increase: saline 18.0±2.1 vs. kisspeptin 15.8±0.9, P<0.05). On menstrual day 15, the largest ovarian follicle had a significantly larger diameter following 7 days of kisspeptin-54 administration when compared with saline (mean diameter of largest follicle (mm): saline 10.0±2.2 vs. kisspeptin 15.5±1.2, P<0.05). Furthermore, contrary to the effects previously seen in women with hypothalamic amenorrhoea4, chronic kisspeptin-54 administration to healthy women at the very same dose did not abolish acute stimulation of LH following injection of GnRH or kisspeptin-54.

We demonstrate for the first time that exogenous kisspeptin-54 advances the menstrual cycle in healthy women. In addition, we demonstrate that unlike in women with hypothalamic amenorrhoea (9), chronic exogenous kisspeptin administration does not result in tachyphylaxis in healthy women. These findings have novel therapeutic implications for the use of kisspeptin in the treatment of women with reproductive disorders.

(1) Topaloglu AK, Tello JA, Kotan LD, Ozbek MN, Yilmaz MB, Erdogan S, Gurbuz F, Temiz F, Millar RP and Yuksel B. Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med 2012; 366:629-635. (2) Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS,Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG et al. The GPR54 gene as a regulator of puberty. N Engl J Med 2003; 349:1614-1627. (3) de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL and Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA 2003; 100:10972-10976. (4) Silveira LG, Noel SD, Silveira-Neto AP, Abreu AP, Brito VN, Santos MG, Bianco SD, Kuohung W, Xu S, Gryngarten M et al. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab 2010; 95:2276-2280.  (5) Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S, Seminara SB, Mendonca BB, Kaiser UB and Latronico AC. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med 2008; 358:709-715. (6) Matsui H, Takatsu Y, Kumano S, et al. Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem Biophys Res Commun 2004; 320:383-388.   (7) Inoue N, Sasagawa K, Ikai K, Tomikawa J, Oishi S, et al. Kisspeptin neurons mediate reflex ovulation in the musk shrew (Sunsus murinus). Proc Natl Acad Sci USA 2011; 108:17527-17532.   (8) Caraty A, Smith JT, Lomet D, et al. Kisspeptin synchronizes preovulatory surges in cyclical ewes and causes ovulation in seasonally acyclic ewes. Endocrinology 2007; 148:5258-5267.   (9) Jayasena CN, Nijher GM, Chaudhri OB et al. Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis. J Clin Endocrinol Metab 2009; 94:4315-23.

Nothing to Disclose: ANC, CNJ, GMN, AA, AD, JDV, CI, RR, AL, DP, MAG, SRB, WSD

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