Effect of estrogen and progesterone on nerve conduction studies during ovarian cycle

Objectives: This study aims to investigate the effects of estrogen and progesterone on nerve conduction studies (NCSs) in three different hormonal phases of the ovarian cycle. Patients and methods: Between April 2008 and July 2008, a total of 40 healthy volunteer women (mean age: 24.1±5.1 years; range 21 to 43 years) with regular menstrual cycles were included in this prospective study. The participants were regularly menstruating for at least one year, without any hormonal disease and without taking any medication that could lead to hormonal dysregulation. Motor and sensory conduction velocities, amplitudes, and distal latencies were analyzed at the dominant extremities within the early follicular phase (EFP), late follicular phase (LFP), and the midluteal phase (MLP). Results: Except for the median nerve motor conduction velocity (MCV), there were no statistically significant differences between the peripheral NCS results in the three ovarian cycle phases (p=0.033). After adjusting for multiple comparisons, a significant difference was found between the EFP and LFP (p=0.004). Conclusion: Our study results showed that only median nerve MCV was affected in the menstrual cycle. However, this would be an incidental finding, or an increased sensibility of the median nerve motor fibers to ovarian steroids by an unknown mechanism. Further studies are warranted.

Heparin Effects on Serum Gonadotropins

Introduction Studies using lipid infusions to raise fatty acid levels require heparin to release lipoprotein lipase (LPL), thus calling into question the appropriate control infusion for this type of study: saline alone or saline plus heparin. We aimed to evaluate whether the addition of heparin alone, in doses needed to release LPL, would alter circulating free fatty acids (FFA) and/or affect gonadotropins. Materials and Methods This was a secondary analysis using combined data from eumenorrheic normal-weight women subjected to ‘control’ conditions in one of two separate studies. In one study, participants received saline alone (Group 1) as a control, and in the other study participants received saline alone and/or saline plus heparin (Groups 2-3) as a control. Both studies performed early follicular phase, frequent blood sampling. FSH and LH were compared across groups and in conditions with and without heparin. Linear mixed models were used to analyze the data. Results LH did not differ across any of the 3 groups. Estimated means (SE) for FSH differed between groups but this difference was marginal (p=0.05) after adjusting for AMH and unrelated to heparin infusion [Group 1: 4.47IU/L (SE 1.19), Group 2: 8.01IU/L (SE 1.14), Group 3: 7.94IU/L (SE 1.13)]. Conclusions Heparin does not exert major effects on gonadotropins when infused in quantities sufficient to release LPL. However, because it can release other vascular membrane bound proteins, heparin should be considered part of the control infusions in lipid infusion studies where increased FFA levels are the goal.

Evidence that pubertal status impacts KNDy neurons in the gilt

Puberty onset is a complex physiological process which enables the capacity for reproduction through increased gonadotropin-releasing hormone (GnRH), and subsequently luteinizing hormone (LH), secretion. While cells that coexpress kisspeptin, neurokinin B (NKB), and dynorphin in the hypothalamic arcuate nucleus (ARC) are believed to govern the timing of puberty, the degree to which KNDy neurons exist and are regulated by pubertal status remains to be determined in the gilt. Hypothalamic tissue from prepubertal and postpubertal, early follicular phase gilts was used to determine the expression of kisspeptin, NKB, and dynorphin within the ARC. Fluorescent in situ hybridization revealed that the majority (> 74%) of ARC neurons that express mRNA for kisspeptin coexpressed mRNA for NKB and dynorphin. There were fewer ARC cells that expressed mRNA for dynorphin in postpubertal gilts compared to prepubertal gilts (P < 0.05), but the number of ARC cells expressing mRNA for kisspeptin or NKB was not different between groups. Within KNDy neurons, mRNA abundance for kisspeptin, NKB, and dynorphin of postpubertal gilts was the same as, less than, and greater than, respectively, prepubertal gilts. Immunostaining for kisspeptin did not differ between prepubertal and postpubertal gilts, but there were fewer NKB immunoreactive fibers in postpubertal gilts compared to prepubertal gilts (P < 0.05). Together, these data reveal novel information about KNDy neurons in gilts and supports the idea that NKB and dynorphin play a role in puberty onset in the female pig.

Early Follicular Phase Human Chorionic Gonadotropin Addition May Improve the Outcomes of In Vitro Fertilization/Intracytoplasmic Sperm Injection in Patients With “Unpredictable” Poor Response to Gonadotropin-Releasing Hormone Antagonist Protocol

PurposeTo compare the effects of early and mid-late follicular phase administration of 150 IU of human chorionic gonadotropin (hCG) on gonadotropin-releasing hormone (GnRH) antagonist protocol in “unpredictable” poor ovarian response (POR) women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment.MethodsA retrospective single-center cohort study was conducted on 67 patients with “unpredictable” POR in their first IVF/ICSI cycle receiving GnRH antagonist protocol. Patients were treated with a second IVF/ICSI cycle using the same GnRH antagonist protocol with the same starting dose of recombinant follicle-stimulating hormone (rFSH) as the first cycle; a daily dose of 150 IU of hCG was administrated on either stimulation day 1 (Group A, n = 35) or day 6 (Group B, n = 32). The number of oocytes retrieved, number of usable embryos, serum level of estradiol (E2) on day of hCG trigger, and clinical pregnant outcomes were studied.ResultsThe addition of 150 IU of hCG on either the first day or sixth day of stimulation increases the serum level of E2, luteinizing hormone (LH), and hCG on the day of hCG trigger. Only the use of 150 IU of hCG on the first stimulation day improved the number of oocytes retrieved, mature of oocytes, and usable embryos, but not the addition of hCG on stimulation day 6. Implantation rate, clinical pregnancy rate, and ongoing pregnancy rate showed an increasing trend in patients receiving 150 IU of hCG in the early phase compared with mid-late phase, even thought there was no statistically significant difference.ConclusionsOur study demonstrated that adding 150 IU of hCG in subsequent GnRH antagonist cycle in “unpredictable” poor responders is associated with the improvement of response to stimulation. Furthermore, early follicular phase addition of 150 IU of hCG significantly increased the number of oocytes retrieved and usable embryos than did the mid-late addition of the same dose.

Pretreatment With a Long-acting GnRH Agonist in Early Follicular Phase Increases Clinical Pregnancy Rate in Frozen-thawed Embryo Transfer Cycles

Background: It is controversial whether gonadotropin-releasing hormone agonist (GnRHa) pretreatment can benefit the pregnancy outcomes in frozen-thawed embryo transfer (FET) cycles. In most of studies, GnRHa was administered during the mid-luteal phase for pretreatment. Few studies focus on FET cycles with GnRHa administered in early follicle phase.Methods: The retrospective cohort study was conducted in a university-affiliated IVF center. 630 patients in the GnRHa FET group and 1141 patients in the hormone replacement treatment (HRT) FET without GnRHa group from October 2017 to March 2019 were included. The menstruation cycle of these patients was irregular. Results: There were no differences observed between the two groups in patient’s characteristics. However, the GnRHa FET group showed a higher percentage of endometrium with triple line pattern (94.8% vs 89.6%, p<0.001) on the day of progesterone administration, and an increased implantation rate (34.7% vs 30%, p<0.01), biochemical pregnancy rate (60.6% vs 54.3%, p = 0.009), and clinical pregnancy rate (49.8% vs 43.3%, p = 0.008), as compared to that in the HRT FET cycles with similar endometrial thickness, ectopic pregnancy rate, and early miscarriage rate. Binary logistic regression analysis showed the GnRHa FET group to be associated with an increased chance of clinical pregnancy rate compared with HRT FET without GnRHa group (P=0.014, odds ratio [OR] 1.30, 95% confidence interval [CI] 1.06-1.61).Conclusions: Pretreatment with a long-acting GnRHa in early follicular phase can improve the clinical outcome of the FET cycles. However, further randomized control trials (RCTs) will be needed to verify these results.

Clinical and perinatal outcomes of fresh single-blastocyst-transfer cycles under an early follicular phase prolonged protocol according to day of trigger estradiol levels

Backgroud This study’s objectives were to compare the clinical, perinatal, and obstetrical outcomes of patients with different estradiol (E2) levels in fresh single-blastocyst-transfer (SBT) cycles under an early follicular phase prolonged regimen on the day of trigger. Methods We recruited patients in fresh SBT cycles (n = 771) undergoing early follicular phase prolonged protocols with β-hCG values above 10 IU/L between June 2016 and December 2018. Patients who met the inclusion and exclusion criteria were divided into four groups according to their serum E2 level percentages on the day of trigger: <25th, 25th–50th, 51st–75th, and >75th percentile groups. Results Although the rates of clinical pregnancy (85.57% (166/194)), embryo implantation 86.60% (168/194), ongoing pregnancy (71.13% (138/194)), and live birth (71.13% (138/194)) were lowest in the >75th percentile group, we did not observe any significant differences (all P > 0.05). We used this information to predict the rate of severe ovarian hyperstimulation syndrome (OHSS) area under the curve (AUC) = 72.39%, P = 0.029, cut off value of E2 = 2,893 pg/ml with the 75% sensitivity and 70% specificity. The 51st–75th percentile group had the highest rates of low birth weight infants (11.73% (19/162), P = 0.0408), premature delivery (11.43% (20/175), P = 0.0269), admission to the neonatal intensive care unit (NICU) (10.49% (17/162), P = 0.0029), twin pregnancies (8.57% (15/175), P = 0.0047), and monochorionic diamniotic pregnancies (8.57% (15/175); P = 0.001). We did not observe statistical differences in obstetrics complications, including gestational diabetes mellitus (GDM), gestational hypertension, placenta previa, premature rupture of membranes (PROM), and preterm premature rupture of membranes (PPROM). Conclusion We concluded that serum E2 levels on the day of trigger were not good predictors of live birth rate or perinatal and obstetrical outcomes. However, we found that high E2 levels may not be conducive to persistent pregnancies. The E2 level on the day of trigger can still be used to predict the incidence of early onset severe OHSS in the fresh SBT cycle.

Influence of Ischemia-reperfusion Injury on Endothelial Function in Men and Women with Similar Serum Estradiol Concentrations

Prior data suggest that relative to the early follicular phase, women in the late follicular phase are protected against endothelial ischemia-reperfusion (I/R) injury when estradiol concentrations are highest. In addition, endothelial I/R injury is consistently observed in men with naturally low endogenous estradiol concentrations that are similar to women in the early follicular phase. Therefore, the purpose of this study was to determine if the vasodeleterious effect of I/R injury differs between women in the early follicular phase of the menstrual cycle and age-matched men. We tested the hypothesis that I/R injury would attenuate endothelium-dependent vasodilation to the same extent in women and age-matched men with similar circulating estradiol concentrations. Endothelium-dependent vasodilation was assessed via brachial artery flow-mediated dilation (duplex ultrasound) in young healthy men (N = 22) and women (N = 12) before (pre-I/R) and immediately after I/R injury (post-I/R), which was induced via 20 min of arm circulatory arrest followed by 20 min reperfusion. Serum estradiol concentrations did not differ between sexes (men, 115.0 ± 33.9 pg ml-1 vs. women, 90.5 ± 40.8 pg ml-1; P = 0.2). The magnitude by which I/R injury attenuated endothelium-dependent vasodilation did not differ between men (pre-I/R, 5.4 ± 2.4 % vs. post-I/R 3.0 ± 2.7 %;) and women (pre-I/R, 6.1 ± 2.8 % vs. post-I/R 3.7 ± 2.7 %; P = 0.9). Our data demonstrate that I/R injury similarly reduces endothelial function in women in the early follicular phase of the menstrual cycle and age-matched men with similar estradiol concentrations.

P–599 random antral follicle count, performed at any day of the menstrual cycle, demonstrates the same predictive value for ovarian response in in vitro fertilization cycles

Study question Does antral follicle count (AFC) retains its predictive value for ovarian response to stimulation for in vitro fertilization (IVF) throughout the whole menstrual cycle? Summary answer AFC is strongly correlated to anti-mullerian hormone (AMH) and highly predictive of good ovarian response whatever the day of cycle the ultrasound is performed. What is known already Usually performed in the early follicular phase (at day 2–3 of the menstrual cycle), AFC and AMH are the most accurate markers of ovarian reserve. They are routinely used to predict ovarian response to ovarian stimulation for IVF and eventually to individualize the gonadotropin starting dose. Study design, size, duration Retrospective cohort study performed between January, 2017 and December, 2019. Participants/materials, setting, methods 410 consecutive women aged 20 to 42 years were included. Random AFC (r-AFC) was performed during the fertility workup whatever the day of their menstrual cycle was: early follicular phase i.e. day 1 to day 6 (eFP-AFC), mid follicular phase i.e. day 7 to 12 (mFP-AFC) and luteal phase i.e. day 13 or after (LP-AFC). A second AFC was performed before the start of the stimulation (SD1-AFC). AMH was measured in the early follicular phase. Main results and the role of chance Random AFC (r-AFC) was correlated to AMH (r = 0.692; p &lt; 0.001), SD1-AFC (r = 0.756; p &lt; 0.001) and number of oocytes retrieved (r = 0.491; p &lt; 0.001). When regarding AFC depending on the cycle day group, the correlation with AMH was significantly higher for the LP-AFC, (LP-AFC) (r = 0.853) than for the eFP-AFC (r = 0.657; p &lt; 0.001) and for the mFP-AFC (r = 0.668). The correlation with SD1-AFC was similar regardless of the time of performance of r-AFC (r = 0.739, 0.783, 0.733, respectively for eFP, mFP and LP-AFC). Moreover, the ROC analysis showed the same predictive value for good ovarian response (more than 6 oocytes retrieved) for the eFP-AFC, mFP-AFC and LP-AFC (AUC 0.73, 0.75 and 0.84 respectively) as well as for AMH and SD1-AFC (AUC 0.74 and 0.74, respectively). Limitations, reasons for caution This is a retrospective analysis, however data were prospectively collected and the method for ultrasound acquisition of AFC was standardized. Wider implications of the findings: The absence of significant variation of AFC across the menstrual cycle allows to its random performance. Ultrasound performed besides early follicular phase discloses informations on ovaries, the uterus and the endometrium. It is more comfortable and convenient for women and physicians by limiting targeted appointment during menstruation and reiterated examination. Trial registration number Not applicable

Oral Progestins in Hormonal Contraception: Importance and Future Perspectives of a New Progestin Only-Pill Containing 4 mg Drospirenone

Hormonal contraceptives are an effective and safe method for preventing pregnancy. Progestins used in contraception are either components of combined hormonal contraceptives (tablets, patches or vaginal rings) or are used as a single active ingredient in progestin mono-preparations (the progestin-only pill (POP), implants, intrauterine systems or depot preparations). Progestins are highly effective in long-term contraception when used properly, and have a very good safety profile with very few contraindications. A new oestrogen-free ovulation inhibitor (POP) has recently been authorised in the USA and the EU. This progestin mono-preparation contains 4 mg of drospirenone (DRSP), which has anti-gonadotropic, anti-mineralocorticoidic and anti-androgenic properties. The hormone administration regimen of 24 days followed by a 4-day hormone-free period was chosen to improve bleeding control and to maintain oestradiol concentrations at early follicular-phase levels, preventing oestrogen deficiency. Clinical trials have demonstrated a high contraceptive effectiveness, a very low risk of cardiovascular side effects and a favourable menstrual bleeding pattern. Due to the long half-life of DRSP (30 – 34 hours), the effectiveness of the preparation is maintained even if a woman forgets to take a pill on a single occasion. Studies involving deliberate 24-hour delays in taking a pill have demonstrated that ovulation inhibition is maintained if a single pill is missed. Following a summary of the current status of oestrogen-free contraception, this review article will describe the clinical development programme of the 4 mg DRSP mono-preparation and the resulting data on the effectiveness and safety of this new oestrogen-free oral hormonal contraceptive.