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Progesterone is the ovarian steroid produced by the granulosa cells of follicles after the LH peak at mid-cycle. Its role is to sustain embryo endometrial implantation and ongoing pregnancy. Other biological effects of progesterone may exert a protective function in supporting pregnancy up to birth. Luteal phase support (LPS) with progesterone is the standard of care for assisted reproductive technology. Progesterone vaginal administration is currently the most widely used treatment for LPS. Physicians and patients have been reluctant to change an administration route that has proven to be effective. However, some questions remain open, namely the need for LPS in fresh and frozen embryo transfer, the route of administration, the optimal duration of LPS, dosage, and the benefit of combination therapies. The aim of this review is to provide an overview of the uterine and extra-uterine effects of progesterone that may play a role in embryo implantation and pregnancy, and to discuss the advantages of the use of progesterone for LPS in the context of Good Medical Practice.

Research question To determine whether the use of oral dydrogesterone (DYD) in luteal phase support (LPS) during an artificial cycle provides equivalent clinical and ongoing pregnancy, delivery and miscarriage rates as micronized vaginal progesterone (MVP) in oocyte donation recipients. Design This was a retrospective observational study of prospectively collected data from the assisted reproductive technology (ART) Department of Lille University Hospital from July 2018 to July 2022. All recipients underwent endometrial preparation by an artificial cycle. Luteal phase support (LPS) was provided by weekly intramuscular progesterone (IM) (500 mg/2 ml) and either DYD (40 mg/day) or MVP (800 mg/day) for 12 weeks if the pregnancy test was positive. The primary endpoint was the clinical pregnancy rate. Results Our study analysed 372 oocyte donation cycles with embryo transfer: 162 embryo transfers with DYD + IM progesterone and 210 embryo transfers with MVP + IM progesterone. After adjustment for confounding factors, our two groups were comparable in terms of clinical pregnancy rates, with 36.7% in the MVP group versus 30.3% in the DYD group ( p  = 0.55); ongoing pregnancy rates (29,1% versus 25.3%, p  = 0.95); miscarriage rates (7.6% versus 4.9%, p  = 0.35); and live birth rates (26.7% versus 25.3%, p  = 0.86). Conclusion Oral dydrogesterone seems to be a good alternative to vaginal micronized progesterone for LPS treatment during an artificial cycle, especially in combination with a weekly injection of intramuscular progesterone in the course of oocyte donation.

Objective This study aimed to evaluate the impact of adding 4 mg estradiol valerate to progesterone for luteal support on pregnancy rates in IVF cycles following a long protocol with reduced luteal serum estradiol levels post-hCG triggering. Design, setting, and participants The prospective randomized controlled trial was conducted at a public tertiary hospital reproductive center with 241 patients who experienced a significant decrease in serum estrogen levels post-oocyte retrieval. Interventions Participants received either a daily 4 mg dose of estradiol valerate in addition to standard progesterone or standard progesterone alone for luteal support. Results The ongoing pregnancy rate did not show a significant difference between the E2 group and the control group (56.6% vs. 52.2%, with an absolute rate difference (RD) of 4.4%, 95% CI -0.087 to 0.179, P  = 0.262). Similarly, the live birth rate, implantation rate, clinical pregnancy rate, early abortion rate, and severe OHSS rate were comparable between the two groups. Notably, the E2 group had no biochemical miscarriages, contrasting significantly with the control group (0.0% vs. 10.7%, RD -10.7%, 95% CI -0.178 to -0.041, P  = 0.000). In the blastocyst stage category, the clinical pregnancy rate was notably higher in the E2 group compared to the control group (75.6% vs. 60.8%, RD 14.9%, 95% CI 0.012 to 0.294, P  = 0.016). Conclusion Adding 4 mg estradiol valerate to progesterone for luteal support does not affect the ongoing pregnancy rate in embryo transfer cycles using a long protocol with a significant decrease in serum estradiol levels after hCG triggering. However, it may reduce biochemical miscarriages and positively impact clinical pregnancy rates in blastocyst embryo transfer cycles. Trial registration ChiCTR1800020342.

Fluctuating endogenous and exogenous ovarian hormones may influence exercise parameters; yet control and verification of ovarian hormone status is rarely reported and limits current exercise science and sports medicine research. The purpose of this study was to determine the effectiveness of an individualised three-step method in identifying the mid-luteal or high hormone phase in endogenous and exogenous hormone cycles in recreationally-active women and determine hormone and demographic characteristics associated with unsuccessful classification. Cross-sectional study design. Fifty-four recreationally-active women who were either long-term oral contraceptive users (n=28) or experiencing regular natural menstrual cycles (n=26) completed step-wise menstrual mapping, urinary ovulation prediction testing and venous blood sampling for serum/plasma hormone analysis on two days, 6–12days after positive ovulation prediction to verify ovarian hormone concentrations. Mid-luteal phase was successfully verified in 100% of oral contraceptive users, and 70% of naturally-menstruating women. Thirty percent of participants were classified as luteal phase deficient; when excluded, the success of the method was 89%. Lower age, body fat and longer menstrual cycles were significantly associated with luteal phase deficiency. A step-wise method including menstrual cycle mapping, urinary ovulation prediction and serum/plasma hormone measurement was effective at verifying ovarian hormone status. Additional consideration of age, body fat and cycle length enhanced identification of luteal phase deficiency in physically-active women. These findings enable the development of stricter exclusion criteria for female participants in research studies and minimise the influence of ovarian hormone variations within sports and exercise science and medicine research.

Background A normal luteal function is an essential factor for maintaining pregnancy; luteal phase deficiency decreases embryo implantation and pregnancy rate and increases the early miscarriage rate. In stimulated in vitro fertilization-embryo transfer (IVF-ET) patients, luteal phase support (LPS) is achieved by the exogenous supplementation with progesterone to increase endometrial receptivity and pregnancy. While several protocols exist, no commonly accepted protocol has been established for optimal luteal support after IVF-ET to date, the purpose of this study was to investigate the effect of two different luteal phase support protocols in patients undergoing assisted reproductive technologies. Methods In a prospective open, randomized study conducted in a private IVF Unit a total of 700 infertile patients, undergoing in vitro fertilization treatment, were recruited for this study. All patients had a mild ovarian stimulation protocol with GnRH antagonist. The patients were randomized into two groups based on the type of luteal phase support route: Group A, control group ( n  = 310) patients received our routine LPS protocol which consists of the administration of 800 mg of micronized vaginal progesterone and Group B, study group, ( n  = 310) patients received a combination of oral dydrogesterone 20 mg and 90 mg of a gel of vaginal micronized progesterone Pregnancy rate, live birth rate, implantation rate and miscarriage rate were evaluated as primary endpoints. Statistical analysis was performed using JMP software (version 17; SAS, Inc., Cary, NC, USA). A P  ≤  0.05 was considered statistically significant. Results No differences were observed between the two groups in terms of pregnancy rate (Group A 34,9% vs. Group B 35,7%), live birth rate (Group A 30,6% vs. Group B 29,2%), miscarriage rate (Group A 12% vs. Group B 18%) and implantation rate (Group A 18,6% vs. Group B 17,1%). Conclusions The combination of two different formulations of progesterone (vaginal and oral) for luteal phase support does not improve IVF outcomes when compared to the vaginal route of progesterone administration alone. Trial registration The study has been retrospectively registered with the Clinical Trials registry reference number ISRCTN52148405 ( http://isrctn.org/ ).

Background Ovarian stimulation and the use of human chorionic gonadotropin (hCG) for triggering oocyte maturation in women undergoing in vitro fertilisation (IVF) introduces several differences in luteal phase hormone levels compared with natural cycles that may negatively impact on endometrial receptivity and pregnancy rates after fresh embryo transfer. Exogenous luteal phase support is given to overcome these issues. The suitability of a pragmatic approach to luteal phase support is not known due to a lack of data on early phase luteal hormone levels and their association with fertility outcomes during IVF with fresh embryo transfer. This study determined early luteal phase profiles of serum progesterone, 17-hydroxyprogesterone and hCG, and associations between hormone levels/hormone level profile after hCG trigger and the live birth rate in women undergoing IVF with fresh embryo transfer. Methods This prospective single center, cohort study was conducted in Vietnam from January 2021 to December 2022. Women aged 18–38 years with normal ovarian reserve and undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone antagonist protocol were included. Serum hormone levels were determined before trigger, at 12, 24 and 36 h after hCG, and daily from 1 to 6 days after oocyte pick-up. Serum hormone level profiles were classified as lower or upper. The primary outcome was live birth rate based on early luteal phase hormone level profile. Results Ninety-five women were enrolled. Live birth occurred in 19/69 women (27.5%) with a lower progesterone profile and 13/22 (59.1%) with an upper progesterone profile (risk ratio [RR] 2.15; 95% confidence interval [CI] 1.28–3.60), and in 6/31 (19.4%) versus 26/60 (43.3%) with a lower versus upper serum 17-hydroxyprogesterone profile (RR 2.24; 95% CI 1.03–4.86). Nearly 20% of women had peak progesterone concentration on or before day 3 after oocyte pick-up, and this was associated with significantly lower chances of having a life birth. Conclusions These data show the importance of proper corpus luteum function with sufficient progesterone/17-hydroxyprogesterone production for achievement of pregnancy and to maximize the chance of live birth during IVF. Trial Registration NCT04693624 ( www.clinicaltrials.gov ).

Background After ovulation in the cow, the corpus luteum (CL) rapidly develops within a few days with angiogenesis and progesterone production. CL formation resembles an inflammatory response due to the influx of immune cells. Neutrophils play a role in host defense and inflammation, and secrete chemoattractants to stimulate angiogenesis. We therefore hypothesized that neutrophils infiltrate in the developing CL from just after ovulation and may play a role in angiogenesis of the CL. Methods and Results Polymorphonuclear neutrophils (PMN) were detected in CL tissue by Pas-staining, and interleukin-8 (IL-8, a neutrophil-specific chemoattractant) was measured in supernatant of the CL tissue culture: considerable amounts of PMNs and the high level of IL-8 were observed during the early luteal phase (days 1-4 of the estrous cycle). PMNs and IL-8 were low levels in the mid and late luteal phases, but IL-8 was increased during luteal regression. The PMN migration in vitro was stimulated by the supernatant from the early CL but not from the mid CL, and this activity was inhibited by neutralizing with an anti-IL-8 antibody, indicating the major role of IL-8 in inducing active PMN migration in the early CL. Moreover, IL-8 stimulated proliferation of CL-derived endothelial cells (LECs), and both the supernatant of activated PMNs and IL-8 stimulated formation of capillary-like structures of LECs. Conclusion PMNs migrate into the early CL partially due to its major chemoattractant IL-8 produced at high levels in the CL, and PMNs is a potential regulator of angiogenesis together with IL-8 in developing CL in the cow.

This study aimed to investigate the effects of the two pre-ovulatory and mid-luteal phases of the menstrual cycle on cognitive function, as well as possible mediators of metabolism and salivary cortisol, at rest and after an aerobic exercise session. Twelve active young unmarried women aged 22-30 years volunteered to participate in the study. The participants performed a 20-min exercise session on a cycle ergometer at 60-70% of their reserve heart rate twice, during the follicular (pre-ovulation: days 7-10) and luteal (mid-luteal: days 21-24) phases of the menstrual cycle. Saliva samples were collected to measure cortisol. Fat utilization, respiratory exchange ratio (RER), and energy expenditure (during exercise) were measured using a spiroergometer. Cognitive function was assessed using the Stroop test. Cognitive function and cortisol levels were measured before and after each exercise session. The findings of this study indicated no significant differences in variables during the resting follicular and luteal phases. Cortisol levels and cognitive function were increased after exercise compared with before exercise in both the follicular and luteal phases. Cortisol and fat utilization after exercise were significantly higher in the follicular phase than in the luteal phase. There were no significant differences between the follicular and luteal phasesregarding the effects of exercise on cognitive function, energy expenditure, and RER. In general, the follicular and luteal phases of menstruation may not affect cognitive function in response to a single aerobic exercise session, although they change some metabolic factors and cortisol.

Background and Objectives: A similar secretory pattern of prolactin (PRL) and growth hormone (GH) during the menstrual cycle has been reported in response to a high dose of ghrelin in adult healthy women. The present study aimed to assess the pattern of PRL and GH secretions in response to a submaximal dose of ghrelin during different menstrual phases in adult healthy women. Materials and Methods: Eight female subjects with normal cyclicity were enrolled. These subjects were either in the early follicular (EF), late follicular (LF), or mid-luteal (ML) phase of their cycles. Each subject received an IV dose of normal saline (2 mL each time) during the first cycle after enrollment, followed by an IV dose of ghrelin (0.30 μg/kg bw) in the second cycle. The blood samples were collected before and after the IV dosage at −15, 0, 15, 30, 45, 60, 75, 90 and 120 min, where 0 min denotes the time of IV dosage. Results: All the enrolled subjects experienced ovulatory cycles as assessed by increased serum progesterone levels. Serum estradiol levels were significantly higher in the LF than in the EF (p < 0.001) and ML phases (p < 0.01); these levels were also significantly higher in the ML than in the EF phase (p < 0.01). The administration of saline did not affect serum GH or PRL levels. Following the administration of ghrelin, plasma ghrelin levels and serum GH levels increased significantly (p < 0.001). The response amplitude of GH was similar in the three stages of cycle 2. In contrast to GH, the ghrelin injection induced a significant increase in serum PRL levels only in the LF phase (p < 0.05). Conclusions: These results show, for the first time, a different pattern of PRL and GH in response to a submaximal dose of ghrelin during the normal menstrual cycle. It is suggested that the ghrelin threshold for pituitary lactotrophs is higher than for somatotrophs and that, unlike GH, ghrelin-stimulated PRL secretion can be influenced by ovarian steroids.

The optimal endometrial preparation protocol for frozen embryo transfer (FET) remains controversial, with different cycle regimens and luteal phase support strategies across studies yielding conflicting results. This study aimed to compare the pregnancy outcomes of modified natural cycles (mNC) versus hormone replacement therapy (HRT) cycles, both with intensive luteal support using vaginal micronized progesterone and oral dydrogesterone. This retrospective cohort study included 2365 FET cycles (1892 HRT and 473 mNC) in ovulatory women. Both groups received vaginal progesterone (800 mg/day) and oral dydrogesterone (30 mg/day) from the day after ovulation trigger or upon progesterone initiation. Propensity score matching was used to balance baseline characteristics, resulting in 1419 HRT and 473 mNC cycles for analysis. Treatment effect estimates with 95% confidence intervals were estimated using appropriate regression models. The propensity score-matched population had similar live birth rate (34.7% in the mNC group and 34.8% in the HRT group; aRR 1.02, 95% CI 0.80-1.29), pregnancy rate (54.3% vs 51.3%), clinical pregnancy rate (42.9% vs 42.0%), ongoing pregnancy rate (35.5% vs 35.7%), and miscarriage rate (7.8% vs 7.1%). There were no significant differences in multiple pregnancy rates, gestational age at delivery, birthweight, preterm birth rates between the two protocols. In ovulatory women undergoing FET with intensive luteal phase support, the use of HRT or mNC for endometrial preparation yields comparable pregnancy and live birth rates.