Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders.

BACKGROUNDKisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders.METHODSWe conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1R-mediated inositol monophosphate (IP1) and Ca2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices.RESULTSIn healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU∙h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012).CONCLUSIONTaken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders.TRIAL REGISTRATIONInternational Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.FUNDINGNational Institute for Health Research and NIH.

GnRH pulse frequency-dependent differential regulation of LH and FSH gene expression.

The pituitary gonadotropin hormones, FSH and LH, are essential for fertility. Containing an identical α-subunit (CGA), they are comprised of unique ß-subunits, FSHß and LHß, respectively. These two hormones are regulated by the hypothalamic decapeptide, GnRH, which is released in a pulsatile manner from GnRH neurons located in the hypothalamus. Varying frequencies of pulsatile GnRH stimulate distinct signaling pathways and transcriptional machinery after binding to the receptor, GnRHR, on the cell surface of anterior pituitary gonadotropes. This ligand-receptor binding and activation orchestrates the synthesis and release of FSH and LH, in synergy with other effectors of gonadotropin production, such as activin, inhibin and steroids. Current research efforts aim to discover the mechanisms responsible for the decoding of the GnRH pulse signal by the gonadotrope. Modulating the response to GnRH has the potential to lead to new therapies for patients with altered gonadotropin secretion, such as those with hypothalamic amenorrhea or polycystic ovarian syndrome.

Nocturnal oxytocin secretion is lower in amenorrheic athletes than nonathletes and associated with bone microarchitecture and finite element analysis parameters.

OBJECTIVE: Preclinical data indicate that oxytocin, a hormone produced in the hypothalamus and secreted into the peripheral circulation, is anabolic to bone. Oxytocin knockout mice have severe osteoporosis, and administration of oxytocin improves bone microarchitecture in these mice. Data suggest that exercise may modify oxytocin secretion, but this has not been studied in athletes in relation to bone. We therefore investigated oxytocin secretion and its association with bone microarchitecture and strength in young female athletes. DESIGN: Cross-sectional study of 45 females, 14-21 years (15 amenorrheic athletes (AA), 15 eumenorrheic athletes (EA), and 15 nonathletes (NA)), of comparable bone age and BMI. METHODS: We used high-resolution peripheral quantitative CT to assess bone microarchitecture and finite element analysis to estimate bone strength at the weight-bearing distal tibia and non-weight-bearing ultradistal radius. Serum samples were obtained every 60  min, 2300-0700  h, and pooled for an integrated measure of nocturnal oxytocin secretion. Midnight and 0700  h samples were used to assess diurnal variation of oxytocin. RESULTS: Nocturnal oxytocin levels were lower in AA and EA than in NA. After controlling for estradiol, the difference in nocturnal oxytocin between AA and NA remained significant. Midnight and 0700  h oxytocin levels did not differ between groups. At the tibia and radius, AA had impaired microarchitecture compared with NA. In AA, nocturnal oxytocin correlated strongly with trabecular and cortical microarchitecture, particularly at the non-weight-bearing radius. In regression models that include known predictors of microarchitecture in AA, oxytocin accounted for a substantial portion of the variability in microarchitectural and strength parameters. CONCLUSIONS: Nocturnal oxytocin secretion is low in AA compared with NA and associated with site-dependent microarchitectural parameters. Oxytocin may contribute to hypoestrogenemic bone loss in AA.

Eating disorders in adolescence: what is the role of hormone replacement therapy?

PURPOSE OF REVIEW: To review the diagnostic criteria and clinical presentation of eating disorders in adolescence, to outline an approach to treatment, and examine evidence for prescribing hormone replacement therapy to increase bone mineral density in anorexia nervosa. RECENT FINDINGS: Eating disorders are prevalent in adolescents and can present with amenorrhea and menstrual disturbances. Reduced bone mineral density leading to osteoporosis and increased fracture risk is a frequent, severe, and potentially irreversible complication of anorexia nervosa. The degree of bone mineral density reduction depends on the duration of amenorrhea and degree of malnutrition. Limited evidence supports the use of hormone replacement therapy to increase bone mineral density in adolescents with anorexia nervosa. SUMMARY: In adolescents with amenorrhea or menstrual disturbances, the gynecologist should consider the possibility of an eating disorder. The diagnosis can be made on history and physical examination. If an eating disorder is suspected, the patient should be referred for evaluation and treatment. Support for the use of hormone replacement therapy to increase bone mineral density in adolescents with anorexia nervosa is limited, and its routine use should be discouraged. Weight restoration, calcium and vitamin D supplementation and the resumption of spontaneous menses is the mainstay of treatment.

Treating primary infertility due to pituitary atrophy with Chinese herbs: a case report.

In the report a patient who suffered from secondary amenorrhea for 6 years and primary infertility for 2 years due to pituitary atrophy was successfully cured with Chinese herbs. After orally administered Chinese herbs for 1 month, the patient menstruated once and became pregnant later.

The ovarian markers of the FSH insufficiency in functional hypothalamic amenorrhoea.

BACKGROUND: The purpose of this work was to revisit the gonadotrophin insufficiency of functional hypothalamic amenorrhoea (FHA) with the use of relevant ovarian markers. METHODS: Serum anti-Mullerian hormone (AMH), estradiol (E2), inhibin B, LH and FSH were immunoassayed in 31 women with FHA and in 30 healthy women in early follicular phase. The ovarian antral follicle number (FN) was determined within two distinct diameter ranges (2-5 and 6-9 mm) by ultrasound in real time, the same day as the blood sampling. RESULTS: The 2-5 mm FN was similar between the two groups, while the 6-9 mm FN was significantly less in FHA than in controls, in relation with lower serum FSH levels (r=0.428; P<0.024). Nine (29%) FHA patients had a low serum basal FSH level (i.e. <4.5 IU/l, 5th percentile of control values). In the 22 (71%) patients with apparently normal FSH, the mean 6-9 mm FN was similar to controls. However, in this sub-group, the mean AMH serum level and the AMH:2-5 mm FN ratio were significantly higher and the mean inhibin B serum level was significantly lower than in controls. No significant relationship was found between the serum LH levels and the FN, AMH or inhibin B values. CONCLUSION: Only a minority of patients with FHA have a low serum basal FSH level, and we show that this is associated with fewer 6-9 mm follicles at the ovarian level. Despite a normal serum FSH level and 6-9 mm FN in the majority of patients with FHA, the functional follicle markers are abnormal. This suggests that the FSH action on the ovary is incomplete and is not properly reflected by its serum level nor by FN at ultrasound.

[Effect of Yangxue bushen tablet on ovarian function in animal model of Yang deficiency].

OBJECTIVE: To study the therapeutic mechanism of Yangxue Bushen tablet (tablet for nourishing blood and tonifying Kidney) on the Kidney deficiency type of functional amenorrhea and infrequent menstruation. METHODS: Applied with orimeten, models of Yang deficiency in female rabbits were made, ikaclomine was taken as the control drug. Group I was the group of animal model of Yang deficiency; Group II was the ikaclomine treatment group; Group III was the high dosage treatment group; Group IV was the low dosage group; Group V normal rabbit treated with distilled water. The functional effect of gonadal axis was evaluated by the changes of the signs of animal histomorphology of ovary and uterus, and the level of beta-endorphin. RESULTS: The animals of Yang deficiency in Group II, III and IV recovered as a whole, and the changes of different levels of folliculi, morphosis of endometria and deciduous vaginal epithelial cell in group II, III and IV were more obviously than those in group I and V (P < 0.05). The content of beta-endorphin in blood plasma in group I was 106.6 pg/ml, which was lower than those in the other groups (P < 0.05), and the contents of beta-endorphin in blood plasma, in group III, IV and II were similar to that in group V (P < 0.05). CONCLUSION: Yangxue Bushen tablet has the effect on regulating menstruation by regulating the function of gonadal axis, regulating and promoting the ovarian function.

Evidence of luteinizing hormone secretion in hypothalamic amenorrhea associated with weight loss.

The lack of plasma luteinizing hormone (LH) pulsatile pattern or episodic LH secretory bursts during night have been demonstrated in hypothalamic amenorrhea. The availability of both sensitive and specific immunofluorimetric assay and algorithm for pulse detection enabled us to reanalyze the question of whether or not patients with hypothalamic amenorrhea secrete LH in a pulsatile fashion. Seven women with secondary amenorrhea associated with weight loss and four normally cycling women were studied, sampling every 5 minutes for 8 hours. Control subjects were studied during four different phases of the menstrual cycle. In all amenorrheic patients, a frequent LH pulsatile secretion, with pulses of low amplitude, was found (10.7 +/- 1.4 peaks/8 h; mean +/- SEM). The pulse frequency was significantly higher (P less than 0.05) than any phases of the control group (early follicular: 7 +/- 0.4 peaks/8 h; late follicular: 6.8 +/- 0.6 peaks/8 h; early luteal: 4.3 +/- 0.4 peaks/8 h; late luteal: 7 +/- 0.3 peaks/8 h). The LH pulsatile release in amenorrheic patients showed a mean pulse duration and amplitude shorter than in any phase of the menstrual cycle of the controls. In conclusion, in weight-loss-related-amenorrhea, the major change was not the absence of the LH pulsatile release but its increased frequency with reduced pulse amplitude.

The immature HPO axis.

One cause or anovulation may be an immature hypothalamic-pituitary-ovarian axis. The fact that initial menstrual cycles are usually irregular and often anovulatory implies that a maturation process is taking place in the HPO axis and that cyclic ovulatory menstruation begins only when adequate maturation occurs. Moreover, the external appearance of the ovary of a severely oligomenorrheic or amenorrheic female frequently is similar to that of a prepubertal female--this is, the ovary appears normal in size of slightly smaller, has a smooth, glistening surface without convolutions, and its capsule-like outer surface reveals few, if any, underlying follicles. A reasonable assumption is that there is inadequate gonadotropin stimulation of these ovaries possibly as a result of an immature HPO axis. The studies by radioimmunoassay of FSH and LH levels in prepubertal and pubertal females offer no statistical data by which to measure the maturity of the HPO axis, although consistently low FSH and LH levels may prove meaningful. Studies of FSH and LH in patients exhibiting gonadal dysgenesis neither support or disprove the immature HPO axis theory, but studies of idiopathic sexual precocity tend to support it. Studies using LH-RF in prepubertal and pubertal females indicate a pattern of response which may give useful information in the area.

PIP: The theory of an immature hypothalamic-pituitary-ovarian (HPO) axis was evaluated by turning to radioimmunoassay studies of follicle stimulating hormone (FSH) and luteinizing hormone (LH) in prepubertal and pubertal females. FSH and LH levels in prepubertal and pubertal females offered no statistical data by which to measure the maturity of the HPO axis, although consistently low levels may be meaningful. Data support the concept that idiopathic sexual precocity is a premature maturation of the HPO axis. Gonadal dysgenesis studies suggest no relevant conclusions about maturation of the HPO axis. Results of several studies with LH-releasing factor (RF) showed that pubertal children respond to LH-RF cannot be so clearly defined. It is concluded that a poorly stimulated ovary, similar in appearance to a prepubertal ovary, found in the oligomenorrheic pubertal female indirectly supports the theory of the immature HPO axis.