Increasing LH Pulsatility in Women With Hypothalamic Amenorrhoea Using Intravenous Infusion of Kisspeptin-54
ABSTRACT Hypothalamic amenorrhea (HA) is the one of the most common causes of period loss in women of reproductive age, and is associated with deficient LH pulsatility. High dose kisspeptin-54 acutely stimulates LH secretion in women with HA, but chronic administration causes desensitisation. GnRH has paradoxical effects on reproductive activity; we therefore hypothesised that a dose-dependent therapeutic window exists within which kisspeptin treatment restores the GnRH / LH pulsatility in women with HA.
Determine whether constant intravenous infusion of kisspeptin 54 temporarily increases pulsatile LH secretion in women with HA.
Five patients with HA each underwent six assessments of LH pulsatility. Single-blinded continuous intravenous infusion of vehicle or kisspeptin-54 (0.01, 0.03, 0.10, 0.30 or 1.00nmol/kg/h) was administered. LH pulses were detected using blinded deconvolution.
Kisspeptin increased LH pulsatility in all patients with HA, with peak responses observed at different doses in each patient. The mean peak number of pulses during infusion of kisspeptin-54 was 3-fold higher when compared with vehicle (number of LH pulses per 8h: 1.6±0.4, vehicle; 5.0±0.5, kisspeptin-54, P<0.01 vs. vehicle). The mean peak LH pulse secretory mass during kisspeptin-54 was 6-fold higher when compared with vehicle (LH pulse secretory mass in iU/l: 3.92±2.31, vehicle; 23.44±12.59, kisspeptin-54; P<0.05 vs. vehicle).
Kisspeptin-54 infusion temporarily increases LH pulsatility in women with HA. Furthermore we have determined the dose-range within which kisspeptin-54 treatment increases basal and pulsatile LH secretion in women with HA. This work provides a basis for studying the potential of kisspeptin-based therapies to treat women with HA.
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ABSTRACT: The hypogonadotropic hypogonadism is an easily treatable form of female infertility. The most common cause of hypogonadotropic hypogonadism is functional hypothalamic amenorrhea. The GnRH pump is a simple and effective treatment to restore fertility of patients with hypothalamic amenorrhea: cumulative pregnancy rate is estimated between 70 and 100% after 6 cycles, compared to a low rate of complications and multiple pregnancies. While only 2.8 cycles are on average required to achieve a pregnancy with a pump, this induction of ovulation stays underused in France. The objective of this paper is to propose a practical manual of pulsatile GnRH, in order to improve the accessibility of pulsatile GnRH for patients with hypogonadotropic hypogonadism.Gynécologie Obstétrique & Fertilité 10/2014; DOI:10.1016/j.gyobfe.2014.07.017 · 0.58 Impact Factor
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ABSTRACT: Female reproductive health is noticeably compromised by obesity. The underlying mechanisms remain to be elucidated. Accumulating evidence indicates that the expression level of ovarian Kiss1 peaks in the afternoon during prooestrus, suggesting local regulatory roles for Kiss1 in the ovulatory process. We used a diet-induced model of obesity to evaluate whether the ovarian Kiss1 system is affected by obesity, and, to investigate the association of the Kiss1 system with ovulatory disorders in female rats. Post-weaning, female, Sprague-Dawley rats were randomly fed either a high-fat diet (HFD) or a normal chow diet (NCD) until they reached postnatal day 30 (PND 30), PND 42, or PND 70. The timing of vaginal opening was recorded, and oestrous cyclicity was monitored for 2 consecutive weeks immediately post puberty and again at 8-9 weeks of age. Tissues from the left ovary were collected for determination of the levels of Kiss1 and G protein-coupled receptor 54 (GPR54) mRNA, and tissues from the right ovary were collected for assessment of the immunoreactivity (IR) of the corresponding protein products, kisspeptin and GPR54. The high-fat diet resulted in a significantly higher body weight and an earlier puberty onset. Oestrous cyclicity was disrupted by the HFD with significant reductions in the expression of ovulation-related genes. A marked suppression of ovarian Kiss1 mRNA levels was observed during prooestrus and oestrus at PND 42, and, during prooestrus, oestrus, and metoestrus at PND 70 in the HFD rats compared with the NCD controls. In the HFD group, the immunoreactivity of kisspeptin was significantly lower in theca cells from antral follicles during prooestrus and oestrus at PND 42, and, during prooestrus, oestrus at PND 70. At the prooestrus stage, in the HFD group the immunoreactivity of kisspeptin was also lower in the theca cells of preovulatory follicles at both PND 42 and PND 70. Exposure of female rats to an post-weaning, high-fat diet has long-term deleterious effects on ovulation, that may involve down-regulation of ovarian Kiss1 mRNA and kisspeptin.Reproductive Biology and Endocrinology 12/2014; 12(1):127. DOI:10.1186/1477-7827-12-127 · 2.41 Impact Factor