Luteal Phase Of Cycle Research Articles

Comparison In Vitro Fertilization Outcomes between DouStim and Minimal Stimulation Protocols in Poor Ovarian Responders: A Randomized Clinical Trial.

Various protocols have been approved to improve the response rate leading to successful fertilization in poor ovarian responders (PORs). The application of double ovarian stimulation (DuoStim) in the follicular and luteal phases of the same ovarian cycle has been shown as an intriguing option to achieve more oocyte retrievals in the shortest time. The aim of the current study is to compare the outcomes of different protocols, minimal stimulation (MS) and Duostim. This randomized clinical trial was performed on 42 in vitro fertilization (IVF) candidates with POR diagnosis. Patients were classified into two equal groups and treated with the DuoStim protocol and MS protocol. The IVF outcomes, including retrieved follicles, oocytes, metaphase II (MII) oocytes and embryos, were compared between these groups. The patients' characteristics including age, anti-mullerian hormone (AMH), follicle stimulating hormone (FSH), luteinizing hormone (LH), and antral follicle count (AFC) were collected and compared. It showed there was no significant difference between the two groups baseline characteristics (P>0.05). We observed that the DuoStim protocol resulted in a significantly higher score in comparison with the MS protocols , including the number of follicles (6.23 ± 2.93 vs. 1.77 ± 1.66, P<0.001), retrieved oocytes (3.86 ± 2.57 vs. 1.68 ± 1.58, P=0.002), MII oocytes (3.36 ± 2.42 vs. 1.27 ± 1.27, P=0.001) and obtained embryos (2.04 ± 1.64 vs. 0.77 ± 0.86, P=0.003). The DuoStim protocol is a favourable and time saving plan that is associated with more oocytes in a single stimulation cycle. The DuoStim protocol significantly can result in more frequent MII oocytes and embryos. We figured that the higher number of oocytes and embryos might have led to a higher rate of pregnancy (registration number: IRCT20200804048303N1).

In-utero exposure to polybrominated biphenyl (PBB) and menstrual cycle function in adulthood

BackgroundThere is evidence that in-utero exposure to PBBs, and similar chemicals, are associated with several adverse reproductive health outcomes including altered pubertal timing. However, less is known about the effects of in-utero exposure to PBBs on menstrual cycle function and reproductive hormone levels in adulthood. MethodsFor this menstrual cycle study, we recruited reproductive-aged women in the Michigan PBB Registry who were not pregnant, lactating, or taking hormonal medications (2004–2014). A total of 41 women who were born after the PBB contamination incident (1973–1974) and were prenatally exposed to PBBs, were included in this analysis. We estimated in-utero PBB exposure using maternal serum PBB measurements taken after exposure and extrapolated to time of pregnancy using a PBB elimination model. Women were followed for up to 6 months during which they provided daily urine samples and completed daily diaries. The urine samples were assayed for estrone 3-glucuronide (E13G), pregnanediol 3-glucuronide (Pd3G), and follicle stimulating hormone (FSH). ResultsWomen in our study were, on average, 27.5 (SD:5.3) years old and contributed 4.9 (SD:1.9) menstrual cycles of follow-up. Compared to women with low in-utero PBB exposure (≤1 ppb), women with medium (>1.0–3.0 ppb) and high (>3.0 ppb) exposure had higher maximum 3-day mean Pd3G levels during the luteal phase. Specifically, the age- and creatinine-adjusted maximum 3-day mean luteal phase Pd3G levels (95% CI) in increasing categories of in-utero PBB exposure were 9.2 (4.6,13.9), 14.8 (11.6,18.0), and 16.1 (12.9,19.3) μg/mg creatinine. There were no meaningful differences in average cycle length, follicular or luteal phase cycle length, bleed length, or creatinine-adjusted E13G or FSH levels by category of in-utero PBB exposure. ConclusionHigher exposure to PBB in-utero was associated with increased progesterone levels across the luteal phase, however, most other menstrual cycle characteristics were largely unassociated with in-utero PBB exposure. Given our modest sample size, our results require cautious interpretation.

Low doses of fluoxetine for the treatment of emotional premenstrual syndrome: a randomized double-blind, placebo-controlled, pilot study

IntroductionThe neuroactive metabolite of progesterone, allopregnanolone (ALLO), has been implicated in premenstrual syndrome (PMS) physiopathology and preclinical studies suggested that low doses of fluoxetine increase the ALLO brain concentration. ObjectivesTo assess which low dose of fluoxetine (2 mg/d, 5 mg/d or 10 mg/d), administered exclusively during the luteal phase of menstrual cycle, has a potential effect for preventing or mitigating emotional PMS symptoms. MethodsIn this randomized, double-blind, placebo-controlled pilot study, we followed 40 women (mean age = 29.7 +/- 7.4 years) with emotional PMS, during two menstrual cycles: cycle 1, without pharmacological intervention; and cycle 2, with pharmacological intervention. Participants took capsules, on average, seven days preceding the likely date of menses. We assessed the severity of PMS symptoms in both cycles using the Daily Record of Severity of Problems scale (DRSP). ResultsThere was an increase in the DRSP scores during the late luteal phase of cycle 1, confirming the diagnosis of emotional PMS. Low doses of fluoxetine (5 mg/d: 33.5%; 10 mg/d: 48.4%) reduced DRSP total score in the day before menses (day-1) at cycle 2 compared with day-1 at cycle 1. Fluoxetine 10 mg/d had the most consistent decline in emotional PMS symptoms; 70% of the participants reported a reduction greater than 40% in the DRSP score. ConclusionsLow doses of fluoxetine, which may have no or few effect on the serotonergic system, but may interfere in the progesterone metabolization, seem to have some potential to mitigate emotional PMS symptoms. While the 10 mg/d of fluoxetine had the best performance on reducing emotional PMS symptoms, the 5 mg/d dose also seems to have some effect on emotional PMS symptoms. Further larger studies will help establish the lowest effective dose of flouxetine for PMS treatment.

Emotion recognition and mood along the menstrual cycle

Previous studies have demonstrated menstrual cycle dependent changes in the recognition of facial emotional expressions, specifically the expression of fear, anger, sadness or disgust. While some studies demonstrate an improvement of emotion recognition performance during the peri-ovulatory phase, when estradiol levels peak, other studies demonstrate a deterioration of emotion recognition performance during the mid-luteal phase, when progesterone levels peak. It has been hypothesized, that these changes in emotion recognition performance mirror mood changes along the menstrual cycle. In the present study, we investigate, whether changes in emotion recognition performance along the menstrual cycle are mediated by mood changes along the menstrual cycle. In a combined cross-sectional and longitudinal study design, two large samples of women completed an emotion recognition task, as well as several mood questionnaires during their menses, peri-ovulatory or mid-luteal cycle phase. 65 women completed the task thrice, once during each cycle phase, order counterbalanced. In order to control for potential learning effects, a sample of 153 women completed the task only once in one of the three cycle phases. In both samples, results demonstrated no significant changes in emotion recognition performance along the menstrual cycle, irrespective of the performance measure investigated (accuracy, reaction time, frequency of emotion classifications) and irrespective of the emotion displayed. Bayesian statistics provided very strong evidence for the null hypothesis, that emotion recognition does not change along the menstrual cycle. There was also no moderation of emotion recognition changes along the menstrual cycle by mood changes along the menstrual cycle. Mood changes along the menstrual cycle followed the expected pattern with highest positive affect and least premenstrual symptoms around ovulation and lowest positive affect, but strongest premenstrual symptoms during menses. Interestingly, premenstrual symptoms were negatively related to estradiol, suggesting a protective effect of estrogen during the luteal cycle phase against mood worsening during the premenstrual phase.

O-224 Effect of intraovarian injection of platelet rich plasma on ovarian response in poor responder women

Abstract Study question Does intraovarian administration of platelet rich-plasma (PRP) increase ovarian response in women with poor ovarian response (POR) undergoing IVF treatment? Summary answer In patients with low ovarian response, the number of oocytes and embryos is higher in the 4 cycles after PRP administration compared to pre-PRP cycles. What is known already The number of oocytes after controlled ovarian stimulation is a crucial factor in IVF outcomes. For this reason, different approaches have been investigated for the management of patients with POR, such as the administration of adjuvant treatments, or the change of protocol, dose or type of gonadotropin. However, none of these strategies has proven to be fully effective in improving oocyte yield. More recently, innovative treatments aimed at activating preantral follicles have emerged, such as intraovarian administration of autologous platelet rich plasma (PRP). Although the evidence is still limited, some studies suggest an improvement in ovarian response following PRP treatment. Study design, size, duration Retrospective study of 83 patients diagnosed with low ovarian reserve according to Bologna criteria who underwent intraovarian PRP between July 2021 and December 2022. 111 stimulation cycles after PRP were compared with the cycles immediately prior to PRP administration. Participants/materials, setting, methods Patients with POR were presented with an oocyte or embryo preservation strategy, which included the option of administering intraovarian platelet-rich plasma (PRP) either during the initial oocyte retrieval or in the follicular phase of the cycle preceding stimulation. A 2 ml dose of PRP was administered into each ovary. The ovarian response was analyzed in terms of the number of oocytes, MII, and embryos, and was further evaluated based on different age groups. Main results and the role of chance 83 women (age: 38,68 ± 3,54, range 28-46 years) underwent a PRP injection. The patients had low ovarian reserve markers (AMH 2,90 ± 2,76 pmol/l, AFC 4,74 ± 2,70). Of the cycles after PRP, 48 were performed in the luteal phase of the same cycle, 28 in the follicular phase of the first post-PRP cycle and 35 between the 2nd and 4th cycle post PRP. The overall mean number of oocytes (2,38 ± 2,09 vs. 3,19 ± 2,70; p = 0,002) and MII (1.84 ± 1.77 vs. 2.54 ± 2.25, p = 0.0008) was significantly higher after PRP. There was also a statistically significant difference in the number of blastocysts pre and post PRP (0,85 ± 1,12 vs. 1,77 ± 1,89; p = 0,0005). There were no differences in the blastulation or euploidy rates. Differences in the number of oocytes were not observed in the luteal phase cycle (2.97 ± 2.35 vs. 3.45 ± 2.66, p = 0.2) compared to the subsequent 1st-4th cycles (1.88 ± 1.77 vs. 2.95 ± 2.73, p = 0.003). Improvement in response was observed in patients younger than 40 years (2 ± 1.52 vs 3.3 ± 2.62 oocytes; p = 0.0002), but not in patients aged ≥ 40 years (2.9 ± 2.58 vs 3.02 ± 2.77 oocytes; p = 0.7). Limitations, reasons for caution The retrospective nature of the study is a significant limitation. As this research is based on real-world clinical practice, the patientś stimulation protocols were diverse which may have impacted the results. To verify our findings, further studies with a uniform control group are required. Wider implications of the findings We observed improved response to intraovarian platelet-rich plasma administration in patients with POR under 40 years of age. This enhancement was observed from the initial follicular cycle following administration. Our findings suggest that intraovarian PRP may be a valuable supplementary treatment for this patient population. Trial registration number not applicable

Ultrasonographic evaluation of canine pyometra

Pyometra is the most common disease found in adult intact female dogs, caused by acute or chronic suppurative bacterial infection of the uterus and is characterized by accumulation of inflammatory exudates in the uterine lumen with diverse clinic-pathological manifestation either locally or systemically. Disease is frequently noticed in adult female dog in luteal phase of estrous cycle during which progesterone level is high (progesterone sensitized uterus) and thus playing key role in pathogenesis. The preliminary diagnosis of pyometra is determined by case history, physical examination findings and laboratory test results in combination with radiography or/and ultrasonography showing a fluid-filled enlarged uterus. A late diagnosis of pyometra, when kidney failure has already occurred, may result in irreversible damage to the kidneys. Effects of sepsis and endotoxaemia can further cause multi-organ dysfunctions, but despite being a potentially life-threatening illness. In this communication, ultrasonography as an accurate procedure for the qualitative and quantitative examination and diagnosis of canine pyometra has been described.

Serum Oestrogen and Progesterone Levels in the Early Luteal Phase as Predictors of Successful In-vitro Fertilisation Outcome: A Prospective Cohort Study

Introduction: The serum levels of oestrogen and progesterone in the luteal phase of In-vitro Fertilisation (IVF) cycles using the long agonist protocol may play a role in predicting the outcome of the cycle. Aim: To determine the levels of oestrogen and progesterone in the early luteal phase of IVF cycles and their association with the pregnancy rate. Materials and Methods: A prospective cohort study was conducted in the IVF centre at Maulana Azad Medical College, Delhi, India, from September 2014 to August 2016. A total of 150 women undergoing IVF were recruited over a period of two years and underwent IVF using the standard long agonist protocol. Luteal phase support was provided according to the Institutional protocol. Blood samples were collected on the day of Ovum Pick Up (OPU) (day 0), the day of embryo transfer (day 3), the day of implantation (day 6), and the day of confirmation of biochemical pregnancy (day 17) to estimate serum Estradiol (E2) and Progesterone (P) levels. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) version 16.0, and a p-value &lt;0.05 was considered significant. Results: The mean age of patients in the study was 31.17±1.09 years, and the mean duration of infertility was 8.2±4.2 years. Serum E2 (day 6, 1403.23±376.67 vs 1258.98±354.31 pg/mL; p=0.02) as well as P4 levels (day 6, 77.82±21.82 vs 68.90±22.17 pg/mL; p=0.01) were significantly higher on the day of implantation and day of confirmation of biochemical pregnancy (day 17, E2 541.80±498.01 vs 289.34±171.94 pg/mL, p&lt;0.001; P4 70.61±121.47 vs 36.17±16.63 pg/mL, p&lt;0.001) among those who conceived compared to those who did not conceive. Conclusion: Serum E2 and P4 levels in the luteal phase may help guide luteal phase support and serve as predictors of a successful cycle outcome in women undergoing IVF using the long agonist protocol.

Frozen-thawed embryo transfer: does the addition of low-dose choriogonadotropin alfa to progesterone in the luteal phase of artificial cycles improve the endometrium and increase the chances of pregnancy?

Primary: To evaluate the effect of low doses of recombinant hCG (choriogonadotropin alfa) in the luteal phase of frozen-thawed embryo transfers (FET) of artificial cycles on the chances of pregnancy in patients aged ≤38years. Secondary: To assess the chances of pregnancy in the FET groups of artificial cycles using micronized vaginal progesterone (VP) versus injectable intramuscular progesterone (IMP) and the chances of pregnancy in type-1 embryo transfers (two top embryos). This retrospective cohort study included 122 cycles of FET and compared two groups of patients aged 38 years or younger, one given hCG in the luteal phase and one not administered hCG. The clinical pregnancy rates (CPR) in the control and hCG groups were 45% and 45.16%, respectively (p=0.9999). The live birth rates (LBR) were 33.33% and 32.25%, respectively, (p=0.99909). The CPR in the VP group (83 patients) was 46.89% versus 41.02% in the IMP group, (p=0.5459). The LBR was 33.73% in the VP group and 30.76% in the IMP group (39 patients), (p=0.7559). The CPR and LBR of patients undergoing FET in groups prescribed and not prescribed low doses of recombinant hCG were similar. No significant difference was found between patients given VP or IMP.

Characterization of the pars tuberalis and hypothalamus transcriptome in female sheep under different reproductive stages

For understanding the molecular events underlying the follicular (F) and luteal (L) phases of estrous cycle, and anestrous (A) phase, the pars tuberalis (PT), and hypothalamus (HT) transcriptomes of 21 ewes were studied. In HT, 72 and 3 differential expression genes (DEGs) were found when comparing F vs. A and L vs. A, respectively. In PT, 6 and 4 DEGs were found in F vs. A and L vs. A comparisons, respectively. Enrichment analysis for DEGs between the F and A phases in the HT revealed significant clusters, mainly associated with actin-binding, and cytoskeleton, that are related to neural plasticity modulated by gonadal steroid hormones, as well as with oxytocin signaling. We found that DEGs in PT had higher differences in expression levels than those found in HT. In this sense, the ITLN was highly upregulated in the F and L vs. A phases, being MRPL57 and IRX4 highly downregulated in L vs. A comparison. The DDC gene in PT, related to LH regulation, was upregulated in the F phase. The gene set enrichment analysis (GSEA) revealed multiple pathways related to neurotransmission and neuronal plasticity. Our study reveals new candidate genes involved in the reproductive stages’ transitions in seasonal sheep.

P-663 Dydrogesterone + progesterone gel vs. subcutaneous aqueous progesterone + progesterone gel for luteal phase supplementation in IVF cycles in women with previous IVF failure

Abstract Study question Does the live birth rate differ between the two regimens for luteal phase supplementation in IVF cycles in women with a history of IVF failure? Summary answer The live birth rate did not differ with dydrogesterone + progesterone gel vs. subcutaneous aqueous progesterone + progesterone gel. What is known already Supplementation of the luteal phase in in vitro fertilization (IVF) cycles is crucial to increase the chance of a live birth. Progesterone is the treatment of choice due to a lower risk of complications compared to human chorionic gonadotropin (hCG) and gonadotropin-releasing hormone (GnRH) analogues. There is no preferred progestogen for use in the general population of women undergoing IVF. The optimal progesterone treatment regimen in the event of previous IVF failure is unknown. Study design, size, duration A prospective randomized tertiary single-center study was conducted. The study included 161 women, aged 25-43 years, with FSH on cycle day 2-4 ≤10 IU/L, with at least one failed IVF cycle, undergoing government-funded IVF in the years 2015-2016. Participants/materials, setting, methods 161 included women were randomized after oocytes retrieval to 2 groups of luteal IVF cycle phase supplementation: dydrogesterone (Duphaston®) + progesterone in vaginal gel (Crinone®) or aqueous progesterone solution in subcutaneous injection (Prolutex®) + progesterone in vaginal gel (Crinone®). At least one blastocyst was obtained in the enrolled women. All women underwent fresh embryo transfer. After viable pregnancy confirmation, treatment was continued until the 12th week of gestation. Main results and the role of chance The indications for IVF were: male factor (51%), tubal factor (27%), endometriosis (24%), decreased ovarian reserve (17%), idiopathic infertility (14%), ovulation disorders (6%), occurring in various combinations. Out of 161 women enrolled in the study, 94 had a history of 1 failed IVF cycle, and 67 had at least 2 failed IVF cycles. Among 94 women with 1 failed IVF, 62 received dydrogesterone + progesterone gel vs. 32 aqueous progesterone + progesterone gel, and the percentages of live births, clinical pregnancies and biochemical pregnancies were: 29 vs. 21% (p = 0.37), 10 vs. 6% (p = 0.53), 5 vs. 12% (p = 0.21). Among 67 women with at least 2 failed IVFs, 24 received dydrogesterone + progesterone gel vs. 43 aqueous progesterone + progesterone gel, and the percentages of live births, clinical pregnancies and biochemical pregnancies were: 17 vs. 32% (p = 0.19), 4 vs. 0% (p = 0.14), 9 vs. 9% (p = 0.95). The results were comparable with both treatment regimens. There were no significant adverse events reported for both treatment regimens. Limitations, reasons for caution The limitations of the study are the small sample size, its single-center character and heterogeneity of indications for IVF. Wider implications of the findings In light of the lack of evidence of greater efficacy of either of the two luteal phase supplementation regimens of the IVF cycle in women with a history of IVF failure, the choice of treatment should be guided by other considerations, i.e. potential side effects, dosing convenience and patient preference. Trial registration number 1072.6120.47.2021

Abstract P5-18-05: Long-acting GnRH agonist ovulation trigger to avoid ovarian hyperstimulation and to combine oocyte cryopreservation with ovarian suppression during chemotherapy

Abstract Background: Oocyte cryopreservation and gonadal suppression during chemotherapy with long-acting GnRH agonists (GnRHa) are standard fertility preservation (FP) methods in women with breast cancer. When both strategies are accepted by the patient, the first injection of GnRHa is frequently administered few days after oocyte retrieval in order to start oncological therapies as soon as possible. GnRHa suppress gonadal function after an initial stimulation phase due to a gonadotropins surge. Consequently, some cases of ovarian hyperstimulation (OHSS) have been described following GnRHa administration during the luteal phase of an oocyte cryopreservation cycle, as a consequence of the initial flare-up effect on recently stimulated ovaries. OHSS is associated with specific complications, such as an increased thromboembolic risk and a possible delay in the start of chemotherapy. These risks may discourage physicians from proposing gonadal suppression in combination with oocyte cryopreservation, denying women a FP opportunity with proven efficacy. However, since the same flare up effect of short-acting GnRHa (e.g. Triptorelin 0.2 mg) is commonly used to trigger ovulation in high responding infertile patients, we propose the initiation of long-acting GnRHa administration at triggering. Our hypothesis is that by inducing ovulation with long-acting GnRHa we meet the last requirement for oocytes maturation and create suppression by the time patients start chemotherapy, without the need of a further injection in the luteal phase. Methods From 2016 to 2020, 70 consecutive ovarian stimulation cycles for oocyte cryopreservation in oncological patients before chemotherapy were performed in a single university centre. Cycle outcomes were evaluated accordingly to the trigger method. Maturation rate was defined as number of cryopreserved mature oocytes/total number of oocytes retrieved. When the long-acting GnRHa was used for triggering, luteal phase hormones were assessed. Results After controlled ovarian stimulation (COS) with standard or random start antagonist protocol, ten women received the long-acting GnRHa trigger (Decapeptyl 3.75 mg, Ipsen. Group A) 36 hours before oocyte retrieval, 37 received highly purified Chorionic Gonadotrophin (Gonasi HP 10000 UI, IBSA. Group B) and 23 the short-acting GnRHa (Decapeptyl 0.2 mg, Ipsen. Group C). The groups were comparable in terms of demographic and clinical parameters. Median number of mature cryopreserved oocytes in group A was 14 (range 8-22) with a maturation rate of 81% (68-100), versus 9 (0-24) with a maturation rate of 78% (43-100) in group B, and 9 (3-34), 78% (38-100) in group C. There was no case of OHSS in Group A. Two patients developed OHSS after administration of long-acting GnRH in the luteal phase after COS, one in Group B and one in Group C. Five days after oocyte retrieval (7 days after trigger), serum FSH median level in group A was 1.28 mUI/ml (0.48-2.50) and LH median level was 1.04 mUI/ml (0.26-2.46). Conclusion We report for the first time the efficacy of long-acting GnRHa in obtaining mature oocytes and, at the same time, in guaranteeing complete suppression by chemotherapy initiation. We are aware that our data should be confirmed by more robust studies and higher numbers. Nevertheless, the feasibility of this strategy is an important step in reducing the risk of OHSS after ovarian stimulation while giving the opportunity to combine oocyte cryopreservation and ovarian suppression during chemotherapy, with proven efficacy as options to preserve fertility and ovarian function, respectively. Citation Format: Claudia Massarotti, Matteo Lambertini, Sara Stigliani, Fausta Sozzi, Paola Scaruffi, Paola Anserini. Long-acting GnRH agonist ovulation trigger to avoid ovarian hyperstimulation and to combine oocyte cryopreservation with ovarian suppression during chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-05.

Gene expression in the amygdala and hippocampus of cyclic and acyclic gilts.

Age at first estrus is the earliest phenotypic indicator of future reproductive success of gilts. Prebreeding anestrus is a major reason for reproductive failure leading to culling of replacement gilts. The two types of prebreeding anestrus are delay in attaining puberty (prepubertal anestrus, PPA) and silent ovulation (behavioral anestrus, BA). Neural tissues such as amygdala and hippocampus play a major role in regulating sexual behavior, social interactions, and receptivity to males. Differences in gene expression in the amygdala and hippocampus of gilts were analyzed in three comparisons: 1) PPA cases and cyclic controls at follicular phase of estrous cycle, 2) BA cases and cyclic controls at luteal phase of estrous cycle, and 3) gilts at different stages of the ovarian cycle (cyclic gilts at follicular phase and luteal phase of estrous cycle) to gain functional understanding of how these rarely studied tissues may differ between pubertal phenotypes and different stages of the estrous cycle of gilts. Differentially expressed genes (DEG) between PPA and BA cases and their respective cyclic controls were involved in neurological and behavioral disorders as well as nervous system functions that could directly or indirectly involved in development of behaviors related to estrus. The comparison between cyclic follicular and luteal phase control gilts identified the greatest number of DEG in the hippocampus and amygdala. These DEG were involved in adult neurogenesis and neural synapse (e.g., GABAergic, dopamine, cholinergic), suggesting that these tissues undergo structural changes and synaptic plasticity in gilts. This is the first report to demonstrate that the stage of estrous cycle is associated with dynamic changes in gene expression within porcine hippocampus and amygdala and indicates a role of gonadal steroids in regulating their biology.

Premenstrual syndrome (PMS) due to allopregnanolone paradoxical effects but possible to treat?

In women with premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD) increased negative mood symptoms are related to progesterone and its metabolite allopregnanolone increase during the luteal phase of ovulatory menstrual cycles. In anovulatory cycles no symptom or sex steroid increase occurs. The negative mood symptoms similar as in PMS reoccur during progesterone/allopregnanolone addition in sequential hormone therapy (HT). The symptoms are not mediated by the classical hormonal progesterone receptor as the progesterone receptor antagonist mefipristone does not inhibit the symptoms. Therefore, one hypothesis is that the symptoms are provoked by progesterone metabolites active on the GABA-A receptor system. GABA-A is the major inhibitory system in the brain. A positive modulator of the GABA-A receptor is the progesterone metabolites allopregnanolone. In certain individuals' positive GABA-A receptor modulators, including allopregnanolone, have biphasic effects. In low physiological concentrations, as during the luteal phase, they paradoxically give strong adverse, anxiogenic effects in 3-8%, and in up to 25% moderates symptoms in premenopausal women. In higher concentrations the compounds show calming properties. Treatments with a GABA-A modulating steroid antagonist (10mg every second day) significantly decreases negative mood symptoms in patients with PMDD, suggesting that this can be a new treatment of PMS/PMDD.

Comparison of Reproductive Outcomes on addition of GnRH agonist for Luteal phase Support in Antagonist IVF cycle

Background: The luteal phase supplementation was reported to be necessary in Controlled Ovarian Hyperstimulation cycles for IVF or ICSI, independently when agonistsor antagonist were used for pituitary desensitization. Theeffectiveness of GnRH agonist in luteal phase supplementation remains controversial.Aims and Objectives: This study aimed at comparing theclinical outcomes of addition of GnRH agonist for lutealphase support in antagonist IVF cycle.Materials and Methods: A cross-sectional study of 150eligible clients who underwent assisted reproduction program in two autonomous IVF centers between 1st January,2017 and 31st December, 2020. Clients were divided intotwo groups; (I) Antagonist stimulation protocol with progesterone and oestradiol valerate and (II) Antagonist Protocol with a single bolus of buserelin in addition to progesterone and oestradiol valerate for luteal phase support. Theprimary outcome was live birth rates while the secondaryoutcomes were clinical pregnancy, miscarriage rates andthe safety for OHSS.Results: There were no statistically significant differencesbetween the number of oocyte received, fertilized, embryosavailability for transfer, duration of infertility, duration ofFSH usage, endometrial thickness and OHSS risk betweenthe groups (p>0.05). The clinical pregnancy and live birthrates were more in group II while the miscarriage rate waslower compared to group I. The differences were statistically significant (p < 0.005).Conclusion: From this study, buserelin addition to the luteal phase of antagonist cycles appears to improve pregnancy outcomes with no associated increase in OHSS risk.Further multi- centered studies with larger sample sizes arerequired to validate these findings.

In-utero exposure to polybrominated biphenyl (PBB) and menstrual cycle function in adulthood

BACKGROUND AND AIM: There is evidence that in-utero exposure to PBBs, and similar chemicals, are associated with several adverse reproductive health outcomes including altered pubertal timing; however, less is known about the effects of in-utero exposure to PBBs on menstrual cycle function and reproductive hormone levels in adulthood. METHODS: For this menstrual cycle study, we recruited reproductive-aged women in the Michigan PBB Registry who were not pregnant, lactating, or taking hormonal medications (2004-2014). A total of 42 women who were born after the PBB contamination incident (1973-1974), who were only exposed in-utero, were included in this analysis. We estimated in-utero PBB exposure using maternal serum PBB measurements taken after exposure and extrapolated to time of pregnancy using a PBB elimination model. Women were followed for up to 6 months during which they provided daily urine samples and completed daily diaries. The urine samples were assayed for estrone 3-glucuronide (E13G), pregnanediol 3-glucuronide (Pd3G), and follicle stimulating hormone (FSH). RESULTS:Women in our study were, on average, 27.5 (SD:5.3) years and contributed 4.9 (SD:1.9) menstrual cycles of follow-up. Compared to women with low in-utero PBB exposure (≤1 ppb), women with medium (1.0-3.0 ppb) and high (3.0 ppb) exposure had significantly higher maximum 3-day mean Pd3G levels during the luteal phase. Specifically, the age- and creatinine-adjusted maximum 3-day mean luteal phase Pd3G levels (95% CI) in increasing categories of in-utero PBB exposure were 9.2 (4.6,13.9), 14.8 (11.6,18.0), and 16.1 (12.9,19.3) μg/mg. There were no significant differences in average cycle length, follicular or luteal phase cycle length, bleed length, or creatinine-adjusted E13G or FSH levels by category of in-utero PBB exposure. CONCLUSIONS:Higher exposure to PBB in-utero was associated with increased progesterone levels across the luteal phase, however, most other menstrual cycle characteristics were largely unassociated with in-utero PBB exposure. Given our modest sample size, our results require cautious interpretation. KEYWORDS: Endocrine disrupting chemicals, Reproductive Outcomes, Chemical exposures, Environmental epidemiology, Long-term exposure

Effects of multiple doses of gonadotropin-releasing hormone agonist on the luteal-phase support in assisted reproductive cycles: A clinical trial study.

BackgroundThe effect of adding gonadotropin-releasing hormone (GnRH) agonist on the luteal phase support in assisted reproductive technique (ART) cycles is controversial.ObjectiveTo determine the effects of adding multiple doses of GnRH agonist to the routine luteal phase support on ART cycle outcomes.Materials and MethodsThis clinical trial study included 200 participants who underwent the antagonist protocol at the Research and Clinical Center for Infertility, Yazd, Iran, between January and March 2020. Of the 200, 168 cases who met the inclusion criteria were equally divided into two groups – the case and the control groups. Both groups received progesterone in the luteal phase, following which the case group received GnRH agonist subcutaneously (0/1 mg triptorelin) zero, three, and six days after the fresh embryo transfer, while the control group did not receive anything. Finally, chemical and clinical pregnancy rates, number of mature oocytes, fertilization rate, total dose of gonadotropin, and the estradiol level were determined.ResultsThe baseline characteristics were similar in both groups. No significant difference was observed between embryo transfer cycles. Clinical results showed that differences between the fertilization rate, chemical and clinical pregnancies were not significant.Conclusion The results showed that receiving multiple doses of GnRH agonist in the luteal phase of ART cycles neither improves embryo implantation nor the pregnancy rates; therefore, further studies are required.

P–682 Serum progesterone level as prognostic factor in frozen-thawed embryo transfer cycles: effect of selected threshold on gestational results. Systematic review, stratified meta-analysis and meta-regression

Abstract Study question Is there an optimum progesterone threshold level below which gestational results are significantly worse in frozen embryo transfer cycles (FET) with hormone replacement therapy (HRT)? Summary answer Low serum progesterone during luteal phase of HRT-FET cycles impairs substantially its gestational outcomes, regardless of threshold level, origin of oocytes and euploidy of embryos. What is known already HRT for endometrial preparation in FET or oocyte donation cycles is widely used. Oestrogen doses are usually patient-tailored varying upon endometrial thickness, whereas the optimal level of progesterone exposure has not been defined. Various studies have found a negative association between serum progesterone levels measured during luteal phase and FET results in terms of pregnancy and miscarriage rates. Most likely there is an optimal level below which results are worse but a standard threshold level is yet to be established, as in almost every study a different threshold has been found. Study design, size, duration Systematic review and stratified meta-analysis with meta-regression following PRISMA guidelines. An electronic search of MEDLINE, EMBASE, Web of Science, Cochrane Gynaecology and Fertility Specialised Register of Controlled Trials and ClinicalTrials.gov was conducted from inception to January 2021. The aim was to identify prospective or retrospective cohort studies measuring serum progesterone levels around frozen embryo transfer date in HRT cycles. A combination of the following key search terms was used: “progesterone”, “serum”, “frozen embryo”, “transfer”, “frozen-thawed”. Participants/materials, setting, methods Studies analyzing association of luteal serum progesterone with FET-HRT outcomes were included. Risk of bias within studies was assessed using the Newcastle-Ottawa Scale (NOS). Clinical/ongoing pregnancy and miscarriage rates (C/OPR,MR) were considered as primary and secondary outcomes respectively. Odds Ratios with 95% Confidence Interval (OR,95%CI) were calculated applying a random effects model meta-analysis. Heterogeneity was assessed using the I2 statistic. A meta-regression was conducted to examine the association of the effect with the threshold level. Main results and the role of chance The systematic search retrieved 792 studies, 494 after duplicates removal of which 343 were screened and 51 assessed for eligibility. 12 studies, reporting 14 threshold levels, were included in the meta-analysis involving 5009 HRT-FET cycles. Two of them were prospective cohort studies while the rest were retrospective. 10 of them have been published in peer review journals and two were conference abstracts. Quality of studies assessed with NOS varied between 5 and 9. The progesterone threshold ranged from 5.0 to 21.94 ng/ml. Low progesterone levels were associated with less C/OPR (OR: 0.52; 95% CI: 0.40 to 0.66; 11 studies, 5009 cycles). Low progesterone was also associated with high MR (OR: 2.01; 95% CI: 1.57 to 2.58; 9 studies, 2560 pregnancies). These effects showed remarkable consistency in specific sub-analyses considering separately studies with progesterone thresholds up to or above 10 mg/mL, and studies carried out in cycles using oocyte donation, autologous oocytes and embryo aneuploidies screening. Meta-regression did not identify significant association between size effect and progesterone threshold, regarding neither C/OPR (regression coefficient: 0.02; CI 95%: –0.02 to 0.06; p: 0.28) nor MR (regression coefficient: 0.11; CI 95%: –0.13 to 0.36; p: 0.32). Limitations, reasons for caution High degree of clinical and statistical heterogeneity was found due to different routes and doses of progesterone administration, date of progesterone analyses and variety of thresholds as well as high diversity of embryo origin. Despite sensibility analysis by embryo origin any of these sources of heterogeneity can preclude the results. Wider implications of the findings: Despite low progesterone levels are significantly associated to lower gestational results, and a threshold of 10 ng/ml constitutes the median value of our distribution, high quality prospective studies are needed to validate the prognostic value of progesterone levels and to establish an standardised threshold level for clinical application. Trial registration number not required

Combined hormonal contraceptives are associated with minor changes in composition and diversity in gut microbiota of healthy women

Recent human and animal studies have found associations between gut microbiota composition and serum levels of sex hormones, indicating that they could be an important factor in shaping the microbiota. However, little is known about the effect of regular hormonal fluctuations over the menstrual cycle or CHC-related changes of hormone levels on gut microbiota structure, diversity and dynamics. The aim of this study was to investigate the effect of CHCs on human gut microbiota composition. The effect of CHC pill intake on gut microbiota composition was studied in a group of 7 healthy pre-menopausal women using the CHC pill, compared to the control group of 9 age-matched healthy women that have not used hormonal contraceptives in the six months prior the start of the study. By analyzing the gut microbiota composition in both groups during one menstrual cycle, we found that CHC usage is associated with a minor decrease in gut microbiota diversity and differences in the abundance of several bacterial taxa. These results call for further investigation of the mechanisms underlying hormonal and hormonal contraceptive-related changes of the gut microbiota and the potential implications of these changes for women's health. This article is protected by copyright. All rights reserved.

Sex hormones modulate sex differences and relate to hemispheric asymmetries in a divided visual field Navon task

Sex differences in functional hemispheric asymmetries (FHA) have been hypothesized as a fundamental mechanism behind sex differences in global-local processing. So far, it has not been assessed how interactive effects of sex and hemifield presentation influence common indicators of global precedence. The current study is the first to investigate the involvement of FHAs by using a divided visual field Navon paradigm and controlling for sex hormone status. Moreover, various factors that have previously shown a reliable influence on global-local processing performance are verified within the context of unilateral presentation. 39 men and 39 naturally cycling women in their luteal cycle phase completed a divided visual field Navon task with the instruction to detect targets either at any level (divided attention) or only at the global or local level (selective attention) in three different spacing conditions. The obtained evidence reveals significant sex differences in the global advantage effect (faster reaction to global vs. local level targets) for densely spaced letter stimuli, as well as significant sex differences in global-local level interference, with findings on both measures being mediated by testosterone. Also, estradiol showed different relationships to the global advantage effect in men and women together with a positive relationship to global advantage for the selective attention condition. Behavioural reaction time results were mirrored by accuracy measures but presented significantly higher global- over local-level accuracy in women compared to men for the divided attention condition. Our results did not show significant sex differences in FHAs but indicate differential relationships between progesterone and FHAs in men and women. In conclusion, sex hormones emerged as central mediators of sex differences in global precedence and possible moderators of hemispheric asymmetries.

The gonadal response to social stress and its relationship to cortisol

The cortisol response to social evaluative stress has been well characterized. However, data regarding changes in gonadal hormones after stress are still scarce and inconsistent. The majority of studies have focused on testosterone reactivity to stress in men, while estradiol responses or gonadal stress responses in women have hardly been investigated. Furthermore, it has not been evaluated whether sex hormone reactivity to stress differs between men and women and the relationship between cortisol and gonadal reactivity to stress is still unclear. To address these questions, we re-analyzed saliva samples collected from 37 men and 30 women in their luteal cycle phase before and repeatedly after social-evaluative stress. Both, testosterone and estradiol levels were assessed. In both men and women, testosterone was significantly reduced after stress. Testosterone levels were at their lowest after 20 minutes, but did not return to baseline until 35 minutes after stress. Across the whole sample, estradiol was significantly increased after stress with two separate peaks after 15 and 30 minutes. Follow-up analyses revealed that 41 participants actually responded with a decrease in estradiol levels to stress, with lowest levels after 20 min, while the remaining participants responded with an increase in estradiol levels. These gonadal stress responses appear to be largely independent of the cortisol response to stress. These results demonstrate that the endocrinological stress response is not restricted to the HPA axis and stress responsivity of gonadal hormones is not simply driven by cortisol. Accordingly, the stress responsivity of gonadal hormones and their association to psychological variables is an additional avenue to explore in both men and women.