Endocrine Responses to Triptorelin in Healthy Women, Women With Polycystic Ovary Syndrome, and Women With Hypothalamic Amenorrhea.

CONTEXT: Limited data exist regarding whether the endocrine response to the gonadotropin-releasing hormone receptor agonist (GnRHa) triptorelin differs in women with polycystic ovary syndrome (PCOS) compared with healthy women or those with hypothalamic amenorrhea (HA). OBJECTIVE: We compared the gonadotropin response to triptorelin in healthy women, women with PCOS, or those with HA without ovarian stimulation, and in women with or without polycystic ovaries undergoing oocyte donation cycles after ovarian stimulation. METHODS: The change in serum gonadotropin levels was determined in (1) a prospective single-blinded placebo-controlled study to determine the endocrine profile of triptorelin (0.2 mg) or saline-placebo in healthy women, women with PCOS, and those with HA, without ovarian stimulation; and (2) a retrospective analysis from a dose-finding randomized controlled trial of triptorelin (0.2-0.4 mg) in oocyte donation cycles after ovarian stimulation. RESULTS: In Study 1, triptorelin induced an increase in serum luteinizing hormone (LH) of similar amplitude in all women (mean peak LH: healthy, 52.3; PCOS, 46.2; HA, 41.3 IU/L). The AUC of change in serum follicle-stimulating hormone (FSH) was attenuated in women with PCOS compared with healthy women and women with HA (median AUC of change in serum FSH: PCOS, 127.2; healthy, 253.8; HA, 326.7 IU.h/L; P = 0.0005). In Study 2, FSH levels 4 hours after triptorelin were reduced in women with at least one polycystic morphology ovary (n = 60) vs normal morphology ovaries (n = 91) (34.0 vs 42.3 IU/L; P = 0.0003). Serum anti-Müllerian hormone (AMH) was negatively associated with the increase in FSH after triptorelin, both with and without ovarian stimulation. CONCLUSION: FSH response to triptorelin was attenuated in women with polycystic ovaries, both with and without ovarian stimulation, and was negatively related to AMH levels.

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.

Endocrine Requirements for Oocyte Maturation Following hCG, GnRH Agonist, and Kisspeptin During IVF Treatment.

Objective: The maturation of oocytes to acquire competence for fertilization is critical to the success of in vitro fertilization (IVF) treatment. It requires LH-like exposure, provided by either human chorionic gonadotropin (hCG), or gonadotropin releasing hormone agonist (GnRHa). More recently, the hypothalamic stimulator, kisspeptin, was used to mature oocytes. Herein, we examine the relationship between the endocrine changes following these agents and oocyte maturation. Design: Retrospective cohort study. Methods: Prospectively collected hormonal data from 499 research IVF cycles triggered with either hCG, GnRHa, or kisspeptin were evaluated. Results: HCG-levels (121 iU/L) peaked at 24 h following hCG, whereas LH-levels peaked at ~4 h following GnRHa (140 iU/L), or kisspeptin (41 iU/L). HCG-levels were negatively associated with body-weight, whereas LH rises following GnRHa and kisspeptin were positively predicted by pre-trigger LH values. The odds of achieving the median mature oocyte yield for each trigger were increased by hCG/LH level. Progesterone rise during oocyte maturation occurred precipitously following each trigger and strongly predicted the number of mature oocytes retrieved. Progesterone rise was positively associated with the hCG-level following hCG trigger, but negatively with LH rise following all three triggers. The rise in progesterone per mature oocyte at 12 h was greater following GnRHa than following hCG or kisspeptin triggers. Conclusion: The endocrine response during oocyte maturation significantly differed by each trigger. Counter-intuitively, progesterone rise during oocyte maturation was negatively associated with LH rise, even when accounting for the number of mature oocytes retrieved. These data expand our understanding of the endocrine changes during oocyte maturation and inform the design of future precision-triggering protocols.

A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial.

STUDY QUESTION: Can increasing the duration of LH-exposure with a second dose of kisspeptin-54 improve oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS)? SUMMARY ANSWER: A second dose of kisspeptin-54 at 10 h following the first improves oocyte yield in women at high risk of OHSS. WHAT IS KNOWN ALREADY: Kisspeptin acts at the hypothalamus to stimulate the release of an endogenous pool of GnRH from the hypothalamus. We have previously reported that a single dose of kisspeptin-54 results in an LH-surge of ~12-14 h duration, which safely triggers oocyte maturation in women at high risk of OHSS. STUDY DESIGN, SIZE, DURATION: Phase-2 randomized placebo-controlled trial of 62 women at high risk of OHSS recruited between August 2015 and May 2016. Following controlled ovarian stimulation, all patients (n = 62) received a subcutaneous injection of kisspeptin-54 (9.6 nmol/kg) 36 h prior to oocyte retrieval. Patients were randomized 1:1 to receive either a second dose of kisspeptin-54 (D; Double, n = 31), or saline (S; Single, n = 31) 10 h thereafter. Patients, embryologists, and IVF clinicians remained blinded to the dosing allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Study participants: Sixty-two women aged 18-34 years at high risk of OHSS (antral follicle count ≥23 or anti-Mullerian hormone level ≥40 pmol/L). Setting: Single centre study carried out at Hammersmith Hospital IVF unit, London, UK. Primary outcome: Proportion of patients achieving an oocyte yield (percentage of mature oocytes retrieved from follicles ≥14 mm on morning of first kisspeptin-54 trigger administration) of at least 60%. Secondary outcomes: Reproductive hormone levels, implantation rate and OHSS occurrence. MAIN RESULTS AND THE ROLE OF CHANCE: A second dose of kisspeptin-54 at 10 h following the first induced further LH-secretion at 4 h after administration. A higher proportion of patients achieved an oocyte yield ≥60% following a second dose of kisspeptin-54 (Single: 14/31, 45%, Double: 21/31, 71%; absolute difference +26%, CI 2-50%, P = 0.042). Patients receiving two doses of kisspeptin-54 had a variable LH-response following the second kisspeptin dose, which appeared to be dependent on the LH-response following the first kisspeptin injection. Patients who had a lower LH-rise following the first dose of kisspeptin had a more substantial 'rescue' LH-response following the second dose of kisspeptin. The variable LH-response following the second dose of kisspeptin resulted in a greater proportion of patients achieving an oocyte yield ≥60%, but without also increasing the frequency of ovarian over-response and moderate OHSS (Single: 1/31, 3.2%, Double: 0/31, 0%). LIMITATIONS, REASONS FOR CAUTION: Further studies are warranted to directly compare kisspeptin-54 to more established triggers of oocyte maturation. WIDER IMPLICATIONS OF THE FINDINGS: Triggering final oocyte maturation with kisspeptin is a novel therapeutic option to enable the use of fresh embryo transfer even in the woman at high risk of OHSS. STUDY FUNDING/COMPETING INTEREST(S): The study was designed, conducted, analysed and reported entirely by the authors. The Medical Research Council (MRC), Wellcome Trust & National Institute of Health Research (NIHR) provided research funding to carry out the studies. There are no competing interests to declare. TRIAL REGISTRATION NUMBER: Clinicaltrial.gov identifier NCT01667406. TRIAL REGISTRATION DATE: 8 August 2012. DATE OF FIRST PATIENT'S ENROLMENT: 10 August 2015.

Efficacy of Kisspeptin-54 to Trigger Oocyte Maturation in Women at High Risk of Ovarian Hyperstimulation Syndrome (OHSS) During In Vitro Fertilization (IVF) Therapy.

CONTEXT: In vitro fertilization (IVF) treatment is an effective therapy for infertility, but can result in the potentially life-threatening complication, ovarian hyperstimulation syndrome (OHSS). OBJECTIVE: This study aimed to investigate whether kisspeptin-54 can be used to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS. SETTING AND DESIGN: This was a phase 2, multi-dose, open-label, randomized clinical trial of 60 women at high risk of developing OHSS carried out during 2013-2014 at Hammersmith Hospital IVF unit, London, United Kingdom. INTERVENTION: Following a standard recombinant FSH/GnRH antagonist protocol, patients were randomly assigned to receive a single injection of kisspeptin-54 to trigger oocyte maturation using an adaptive design for dose allocation (3.2 nmol/kg, n = 5; 6.4 nmol/kg, n = 20; 9.6 nmol/kg, n = 15; 12.8 nmol/kg, n = 20). Oocytes were retrieved 36 h after kisspeptin-54 administration, assessed for maturation, and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. Women were routinely screened for the development of OHSS. MAIN OUTCOME MEASURE: Oocyte maturation was measured by oocyte yield (percentage of mature oocytes retrieved from follicles ≥ 14 mm on ultrasound). Secondary outcomes include rates of OHSS and pregnancy. RESULTS: Oocyte maturation occurred in 95% of women. Highest oocyte yield (121%) was observed following 12.8 nmol/kg kisspeptin-54, which was +69% (confidence interval, -16-153%) greater than following 3.2 nmol/kg. At all doses of kisspeptin-54, biochemical pregnancy, clinical pregnancy, and live birth rates per transfer (n = 51) were 63, 53, and 45%, respectively. Highest pregnancy rates were observed following 9.6 nmol/kg kisspeptin-54 (85, 77, and 62%, respectively). No woman developed moderate, severe, or critical OHSS. CONCLUSION: Kisspeptin-54 is a promising approach to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS.

Adenomyosis reduces pregnancy rates in infertile women undergoing IVF.

High-resolution transvaginal ultrasound has facilitated the diagnosis of adenomyosis. This study determined the prevalence of this finding in infertile women and its effect on the outcome of IVF/intracytoplasmic sperm injection (ICSI). This prospective study evaluated 275 consecutive women, commencing IVF/ICSI for the first time. Inclusion criteria were adequate ovarian reserve. Women with fibroids or a previous myomectomy were excluded. All women were screened for adenomyosis by transvaginal ultrasound on three separate occasions. The control group included 256 women and the adenomyosis group included 19 women. There was no significant difference in the ages of women, FSH, cause of infertility, body mass index, total dose of gonadotrophin used and number of oocytes collected between the two groups. However, women with adenomyosis had a higher mean antral follicle count (P=0.006). The clinical pregnancy rate (22.2% versus 47.2%) and ongoing pregnancy rate (11.1% versus 45.9%) were significantly lower in women with adenomyosis and the miscarriage rate (50.0% versus 2.8%) was significantly higher in women with adenomyosis (all P<0.001). Ultrasound evidence of adenomyosis is found in a significant number of women presenting with infertility and has a negative impact on the outcome of IVF/ICSI. This paper suggests that a common condition known as adenomyosis is associated with a reduced success following fertility treatment such as IVF. The diagnosis of adenomyosis has been greatly facilitated by the advent of high-resolution transvaginal ultrasound. This was a study including 275 consecutive women who were commencing IVF for the first time. Comparing women who did not have adenomyosis and those that did, the clinical and ongoing pregnancy rates were both lower in women with adenomyosis (22.2% versus 47.2% and 11.1% versus 45.9%, respectively). So, fewer women with adenomyosis became pregnant and had an ongoing pregnancy. The miscarriage rate was higher in women with adenomyosis compared with those without (50.0% versus 2.8%). We conclude that ultrasound evidence of adenomyosis is found in a significant number of women presenting with infertility and has a negative impact on the outcome of IVF.

The value of pre-operative treatment with GnRH analogues in women with submucous fibroids: a double-blind, placebo-controlled randomized trial.

BACKGROUND: Submucous fibroids are common benign tumours responsible for menorrhagia, subfertility and miscarriage. They can be readily removed by hysteroscopic transcervical resection of myoma (TCRM). To facilitate resection, pre-operative GnRH analogues have been suggested, but the value of this treatment is uncertain. Our aim was to assess the value of pre-operative GnRH analogues for the resection of submucous fibroids. METHODS: This was a prospective, double-blind, placebo-controlled, randomized trial. Women found to have submucous fibroids on three-dimensional saline infusion sonohysterography (3D SIS) were randomized to receive GnRH or placebo. Following treatment patients underwent TCRM by a single operator blinded to the group allocation. Women were followed up 6 weeks after their operation to ascertain resolution of symptoms. The primary outcome measure of the study was completeness of fibroid resection. Secondary outcome measures included the duration of the TCRM, the fluid deficit recorded at TCRM, the resolution of symptoms post-operatively and the number of subsequent fibroid related operations. RESULTS: Forty-seven women were randomized to GnRH or placebo. On the basis of intention-to-treat analysis, there was no significant difference in the number of complete fibroid resections between women who received GnRH analogues [14/24, 58.3% (95% CI 38.6-78.1)] and those who received placebo [16/23, 69.6% (50.8-88.4)] (RR 0.84, 95% CI 0.54-1.29; P = 0.43). Similarly there was no significant difference between the groups in any of the secondary outcome measures. CONCLUSIONS: Our study does not support routine administration of GnRH analogues before transcervical resection of fibroid as we did not identify any benefit in such treatment.

The value of ultrasound visualization of the ovaries during the routine 11-14 weeks nuchal translucency scan.

OBJECTIVE: To investigate the feasibility and possible value of routine screening for ovarian pathology in asymptomatic pregnant women at 11-14 weeks' gestation. STUDY DESIGN: A policy of routine ovarian visualization was implemented in 2925 pregnant women attending for a nuchal translucency scan at 11-14 weeks' gestation. In all cases, an attempt was made to visualize the ovaries on transabdominal ultrasound scan. Simple cysts were defined as unilocular cysts with regular internal walls and no solid components, which contained clear anechoic fluid. All other cysts were classified as complex. Simple cysts<5 cm in diameter were all managed expectantly with no further follow-up. All women with large simple cysts>or=5 cm in diameter or complex cysts had further detailed follow-up scans. Surgical intervention during pregnancy was offered to women with clinical symptoms suggestive of cyst complications or those with ultrasound features suggestive of malignancy. All other women were managed expectantly until after delivery. RESULTS: Adnexal cysts were found in 728/2925 (24.9%) pregnant women. 400/728 (55%) women had simple cysts<5 cm in diameter, whilst 328/728 (45%) women had large simple or complex cysts requiring follow-up. On subsequent scans, cysts resolved spontaneously in 278/328 (84.8%) women. A total of 33/728 (4.5%) women with ultrasound evidence of adnexal cyst underwent surgery. In one woman the intervention was required because of pain, one woman had suspected cancer on ultrasound scan and the remaining 31/33 (94%) of operations were performed at patients' requests. All the cysts were found to be benign on histological examination. The overall intervention rate was 1.1/100 screened pregnant women or 4.5/100 cysts detected on ultrasound scan. CONCLUSION: Asymptomatic adnexal cysts detected in the first trimester of pregnancy are unlikely to be malignant or to cause clinical symptoms antenatally. The policy of routine ultrasound visualization of the ovaries in pregnancy cannot be justified.