Individualized luteal phase support in frozen-thawed embryo transfer after intramuscular progesterone administration might rectify live birth rate.

Background: The serum P concentrations are suggested to have an impact on pregnancy outcome. However there is no consensus about the optimal progesterone cut-off during the luteal phase. Few studies evaluated the effectiveness of a "rescue protocol" for low serum P concentrations and most of these studies used vaginal progesterone administration. There is paucity of data on the effectiveness of rescue protocol using intramuscular progesterone (IM-P) in frozen-thawed embryo transfer (FET). Methods: This study is a retrospective cohort study included 637 single or double blastocyst FETs with artificially prepared endometrium receiving 100 mg IM progesterone (P) after incremental estrogen treatment. Serum P concentrations were evaluated using blood samples obtained 117-119 hours after the first IM-P administration and 21 ± 2 hours after the last IM-P administration. Patients with serum P concentrations <20.6 ng/ml on the ET day were administrated 400 mg vaginal progesterone for rescue. Results: Demographic and cycle characteristics were similar between patients receiving rescue vaginal P (embryo transfer (ET)-day P concentration < 20.6 ng/ml) and patients who did not need rescue vaginal P (ET-day P concentration ≥ 20.6 ng/ml). Clinical pregnancy, miscarriage, and live birth rates were similar between two groups: 52.9%(45/85) vs 59.6%(326/552), p=0.287; 11.1%(5/45) vs 14.1%(46/326), p=0.583; and 47.1%(40/85) vs 50.7%(280/552), p=0.526, respectively. Logistic regression analysis revealed that the female age (p = 0.008, OR=0.942, 95% CI = 0.902-0.984) and embryo quality (ref: good quality for moderate: p=0.02, OR=0.469, 95% CI =0.269-0.760; for poor: p=0.013, OR= 0.269, 95% CI = 0.092-0.757) were independent variables for live birth. Following rescue protocol implementation, ET-day P concentration was not a significant predictor of live birth. Conclusions: Rescue vaginal P administration for low ET day serum P concentrations following IM-P yields comparable live birth rates.

Rectal versus vaginal progesterone administration for luteal phase support in the hormone replacement therapy frozen embryo transfer (HRT-FET) cycle: protocol for a non-inferiority randomised controlled trial.

INTRODUCTION: This study compares rectal administration with vaginal administration of progesterone as luteal phase support in hormone replacement therapy frozen embryo transfer (HRT-FET) cycles. The reason for comparing the two routes of administration is that rectal administration has been suggested to be more patient friendly. METHODS AND ANALYSIS: This study is a randomised controlled trial comparing the ongoing pregnancy rate (OPR) at week 12 in HRT-FET cycles after rectal administered progesterone as the only administered progesterone compared with a vaginal luteal phase support regimen. All patients are enrolled from a Danish public fertility clinic and randomised to one of two groups, with 305 patients receiving embryo transfer assigned to each group. Endometrial preparation includes 6 mg oestradiol daily. The intervention group receives rectally administered progesterone (400 mg/12 hours) and the control group receives vaginally administered progesterone (400 mg/12 hours). If P4 is <35 nmol/L on blastocyst transfer day an additional rectal luteal phase rescue regimen is started (control group). Thawing and transferring of a single autologous vitrified blastocyst is scheduled on the sixth day of progesterone administration in both groups. The power calculation is based on a non-inferiority analysis with an expected OPR in both groups of 44% and the upper limit of a one-sided 95% CI will exclude a difference in favour of the control group of more than 10.0%. An interim analysis will be conducted once half of the study population has been enrolled. ETHICS AND DISSEMINATION: The trial was approved on 21 November 2023 by the Danish National Ethical Committee and the Danish Medicines Agency and is authorised by the Clinical Trials Information System (EUCT number 2023-504616-15-02). All patients will provide informed consent before being enrolled in the study. The results will be published in an international journal. TRIAL REGISTRATION NUMBER: EUCT number: 2023-504616-15-02.

Effect of occupational exposure to vat-textile dyes on follicular and luteal hormones in female dye workers in Abeokuta, Nigeria.

Background: Some synthetic dyes used mainly in textile industries have been associated with endocrine disruption, resulting in infertility, among other disorders. It is unknown if occupational exposure to Vat textile dyes among premenopausal dyers alters hormonal levels. Objectives: We aimed at determining the probable effects of occupational exposure to Vat dyes on reproductive hormones of female textile dyers in the follicular and luteal phases while relating this to age categories and duration of exposure. Methods: Thirty-three premenopausal Vat textile dyers at "Itoku", Abeokuta, Nigeria, among a population of about 80 female dyers were age and sex-matched with 55 non-exposed (control) female participants. Using semi-structured questionnaires, socio-demographic, occupational details and the LMP of participants were obtained. Serum samples were collected in follicular and luteal phases and assayed for female sex hormones using Enzyme Immunoassay. Mann-Whitney U and Z- statistic were used for comparison of the two groups. P-value < 0.05 was considered to be significant. Results: In the follicular phase, the result showed a lower mean FSH ranking (in age category ≤20 years) and higher (p<0.05) Estradiol ranking (in age category 31-40 years) in the exposed than the unexposed. Mean ranks of Progesterone and Estradiol in the luteal phase (age category 31-40 years) were higher (p<0.05) in the exposed, while Estradiol (age category ≥41years) ranked lower (p<0.05). Prolactin demonstrated a significant inverse relationship with the duration of exposure. Conclusion: Occupational exposure to Vat dye among female dyers in Abeokuta is associated with some sex hormone disruption which appears to be age and duration of exposure-related.

The natural menstrual cycle revisited - can natural cycle be trusted.

BACKGROUND: The serum progesterone (P4) level during the luteal phase (LP) plays a crucial role in the initiation and maintenance of pregnancy. However, it is unclear whether the natural cycle consistently provides the best endocrine profile and whether mid-luteal serum P4 levels are always sufficient to support implantation and early pregnancy. The question has become more relevant in relation to fertility treatment, as more frozen embryo transfer cycles are performed in the natural cycle. Moreover, can serum hormone levels and covariates measured during the follicular phase (FP), such as Follicle Stimulation Hormone (FSH), Luteinizing Hormone (LH), Estradiol (E2), Anti-Mullerian Hormone (AMH) and Antral Follicle Count (AFC), be used to predict P4 levels during the luteal phase (LP)? RESULTS: This observational prospective cohort study analysed 26 healthy women with a cycle length between 21-35 days and a body mass index (BMI) < 30 kg/m2. Blood sampling started on the fifth day of the menstrual cycle and continued every fifth day until the next cycle. The procedure was repeated for a total of three cycles. The study found that only ten women had a P4 level greater than 30 nmol/L on cycle day 20 or 25 in all three cycles. In total, only 45 cycles out of 77 cycles had serum P4 levels ≥ 30 nmol/L. The E2 level ≥ 345 pmol/L on cycle day 10 proved to be predictive of a P4 level of ≥ 30 nmol/L on either day 20 or day 25 with a sensitivity of 57% and a specificity of 89%. No other covariates, including the FSH level cycle day 5, LH levels during the follicular phase, age, weight, AFC and AMH cycle day 5 correlated with LP P4 levels. CONCLUSIONS: A significant correlation between FP E2 levels cycle day 5 (> 131pmol/L) and cycle day 10 (> 345pmol/L) and a LP P4 level ≥ 30 nmol/l was found; thus, the FP E2 level is a predictor of corpus luteum competence. Our findings highlight the existence of suboptimal P4 levels during the LP and a significant inter-individual and intra-cycle variation in P4 levels during the LP in regular menstruating women.

Comparison of luteal support protocols in fresh IVF/ICSI cycles: a network meta-analysis.

Despite the proven superiority of various luteal phase support protocols (LPS) over placebo in view of improved pregnancy rates in fresh cycles of IVF (in vitro fertilization) and ICSI (intracytoplasmic sperm injection) cycles, there is ongoing controversy over specific LPS protocol selection, dosage, and duration. The aim of the present study was to identify the optimal LPS under six core aspects of ART success, clinical pregnancy, live birth as primary outcomes and biochemical pregnancy, miscarriage, multiple pregnancy, ovarian hyperstimulation syndrome (OHSS) events as secondary outcomes. Twelve databases, namely Embase (OVID), MEDLINE (R) (OVID), GlobalHealth (Archive), GlobalHealth, Health and Psychosocial Instruments, Maternity & Infant Care Database (MIDIRS), APA PsycTests, ClinicalTrials.gov, HMIC Health Management Information Consortium, CENTRAL, Web of Science, Scopus and two prospective registers, MedRxiv, Research Square were searched from inception to Aug.1st, 2023, (PROSPERO Registration: CRD42022358986). Only Randomised Controlled Trials (RCTs) were included. Bayesian network meta-analysis (NMA) model was employed for outcome analysis, presenting fixed effects, odds ratios (ORs) with 95% credibility intervals (CrIs). Vaginal Progesterone (VP) was considered the reference LPS given its' clinical relevance. Seventy-six RCTs, comparing 22 interventions, and including 26,536 participants were included in the present NMA. Overall CiNeMa risk of bias was deemed moderate, and network inconsistency per outcome was deemed low (Multiple pregnancy χ2: 0.11, OHSS χ2: 0.26), moderate (Clinical Pregnancy: χ2: 7.02, Live birth χ2: 10.95, Biochemical pregnancy: χ2: 6.60, Miscarriage: χ2: 11.305). Combinatorial regimens, with subcutaneous GnRH-a (SCGnRH-a) on a vaginal progesterone base and oral oestrogen (OE) appeared to overall improve clinical pregnancy events; VP + OE + SCGnRH-a [OR 1.57 (95% CrI 1.11 to 2.22)], VP + SCGnRH-a [OR 1.28 (95% CrI 1.05 to 1.55)] as well as live pregnancy events, VP + OE + SCGnRH-a [OR 8.81 (95% CrI 2.35 to 39.1)], VP + SCGnRH-a [OR 1.76 (95% CrI 1.45 to 2.15)]. Equally, the progesterone free LPS, intramuscular human chorionic gonadotrophin, [OR 9.67 (95% CrI 2.34, 73.2)] was also found to increase live birth events, however was also associated with an increased probability of ovarian hyperstimulation, [OR 1.64 (95% CrI 0.75, 3.71)]. The combination of intramuscular and vaginal progesterone was associated with higher multiple pregnancy events, [OR 7.09 (95% CrI 2.49, 31.)]. Of all LPS protocols, VP + SC GnRH-a was found to significantly reduce miscarriage events, OR 0.54 (95% CrI 0.37 to 0.80). Subgroup analysis according to ovarian stimulation (OS) protocol revealed that the optimal LPS across both long and short OS, taking into account increase in live birth and reduction in miscarriage as well as OHSS events, was VP + SCGnRH-a, with an OR 2.89 [95% CrI 1.08, 2.96] and OR 2.84 [95% CrI 1.35, 6.26] respectively. Overall, NMA data suggest that combinatorial treatments, with the addition of SCGnRH-a on a VP base result in improved clinical pregnancy and live birth events in both GnRH-agonist and antagonist ovarian stimulation protocols.

In vitro fertilization outcome based on the detailed early luteal phase trajectory of hormones: a prospective cohort study.

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 ).

Safety profiles of offspring born from early-follicular long-acting GnRH agonist protocol and daily mid-luteal GnRH agonist protocol: a retrospective study.

BACKGROUND: The gonadotropin hormone-releasing hormone agonists (GnRH-a) have been widely used for controlled ovarian stimulation in assisted reproductive technology (ART). The early-follicular long-acting GnRH-a long protocol (EFL) and the luteal phase short-acting GnRH-a long protocol (LPS) are commonly used GnRH agonist protocols. We conducted a retrospective analysis to assess and compare the rates of congenital abnormalities and safety profiles in offspring born from the EFL and LPS protocols. METHODS: We conducted a retrospective cohort study to analyze and compare neonatal data from patients who using EFL or LPS protocols at our center between January 1, 2014, and June 30, 2017. The study ultimately included 1810 neonates from 1401 cycles using the EFL protocol and 2700 neonates from 2129 cycles using the LPS protocol.The main outcome measures are gestational age at delivery, birth weight, and congenital anomaly rate.To assess the influence of various factors on congenital abnormalities, a random-effects logistic regression model was employed. RESULTS: The EFL and LPS protocols led to similar congenital anomaly rates (1.64% vs. 2.35%, P = 0.149). No significant differences were found between the two groups regarding birth weight and its categories, newborn gender and congenital anomaly rate. The results of the multivariate logistic regression model indicated no association between congenital anomaly and BMI, duration of infertility, treatment protocol, fertilization method, or embryo transfer stage. Compared with singleton pregnancies, the probability of congenital defects in multiple pregnancies was 2.64 times higher (OR: 2.64, 95% CI: 1.72-4.05, P < 0.0001). Newborns with congenital defects were born with a lower gestational age compared with full-term pregnancies. CONCLUSION: In conclusion, the EFL protocol is considered a safe option for ensuring offspring safety, comparable with the LPS protocol; however, multiple pregnancies represent an independent risk factor for congenital abnormalities. This approach can be widely adopted; however, prioritizing single embryo transfers is strongly recommended to minimize the potential risks associated with multiple pregnancies in offspring.

Correlation of sex hormone levels with orthodontic tooth movement in the maxilla: a prospective cohort study.

BACKGROUND: Sex hormones secreted during the menstrual cycle and the application of orthodontic forces to teeth can affect the metabolism of periodontal ligaments. This study aimed to determine whether there are any differences in orthodontic tooth displacement during the menstrual cycle and when using hormonal contraceptives and whether the amount of female sex hormones influences the efficiency of tooth displacement. METHODS: A total of 120 women aged between 20 and 30 years with Angle Class II requiring transpalatal arch (TPA) to derotate teeth 16 and 26 were included in this study. The participants were divided into two groups: group A, which included women with regular menstruation, and control group B, which included women taking monophasic combined oral contraceptives. Group A was divided into subgroups according to the moment of TPA activation: menstruation (A1), ovulation phase (A2), and luteal phase (A3) (examination I). On intraoral scans, measurement points were marked on the proximal mesial cusps of teeth 16 and 26, and the intermolar distance (M1) was determined. The change in the position of the measurement points 6 weeks after activation (examination II) made it possible to determine the derotating extent of teeth 16 (O16) and 26 (O26) and the widening of the intermolar distance (M2-M1). In examinations I and II, tooth mobility in the alveoli was assessed using Periotest based on the periotest values (PTV) PTV1 and PTV2, respectively. RESULTS: A significant difference in all parameters was observed among groups A1, A2, and A3 (P < 0.001). Group A3 showed the highest values of parameters O16, O26, and M2-M1, and group A2 showed the lowest values, which did not differ from the control group (P = 0.64). PTV2 and PTV1 were the highest in group A3 and the lowest in groups A1 and B. Intergroup differences were statistically significant (P < 0.001). CONCLUSIONS: With the quantification of changes in tooth mobility in the alveoli during the menstrual cycle in women undergoing orthodontic treatment, it was possible to determine that female sex hormones affect the effectiveness of orthodontic treatment, and the optimal moment for TPA activation is the luteal phase of the menstrual cycle.

Midluteal serum estradiol levels are associated with live birth rates in hormone replacement therapy frozen embryo transfer cycles: a cohort study.

OBJECTIVE: To study whether midluteal serum estradiol (E2) levels are associated with the live birth rate in hormone replacement therapy frozen embryo transfer (HRT-FET) cycles in patients with optimal midluteal serum progesterone (P4) levels. DESIGN: Observational prospective cohort study. SETTING: Public fertility clinic. PATIENTS: A total of 412 women had an HRT-FET cycle single blastocyst transfer from January 2020 to November 2022. INTERVENTION: The HRT-FET cycle priming regimen included oral E2 (6mg/24 h) administered in the evening, followed by vaginal P4 (400mg/12 h). Serum E2 and P4 levels were measured using a standardized method, 2-4 hours after the latest P4 administration and 9-14 hours after E4 administration on the day of blastocyst transfer, day 6 of P4 administration. Patients with serum P4 levels (<11 ng/mL [35 nmol/L]) on the day of transfer received additional rectal P4 (400mg/12 h). No additional E2 dose was administered. MAIN OUTCOME MEASURES: The primary outcome was the live birth rate (LBR) in relation to E2 levels at blastocyst transfer day. RESULTS: The optimal serum E2 levels correlating with ongoing pregnancy were ≥292 pg/mL and <409 pg/mL (≥1,070 pmol/L and <1,500 pmol/L). The LBR was 59% (60/102) when E2 levels were within this range, whereas a significantly lower LBR of 39% (101/260) was seen in patients when E2 levels were <292 pg/mL (<1,070 pmol/L) and of 28% (14/50) when E2 levels were ≥409 pg/mL (≥1,500 pg/mL). In a logistic regression analysis, adjusting for serum P4 level ≥11 ng/mL or <11 ng/mL (≥35 nmol or <35 nmol/L) on the day of transfer, body mass index, age at oocyte retrieval, day 5 or 6 vitrified blastocysts, and blastocyst score, the adjusted risk difference of live birth was -0.21 (-0.32; -0.10) when the E2 level was <292 pg/mL (<1,070 pmol/L) and -0.31 (-0.45; -0.18) when the E2 level was ≥409 pg/mL (≥1,500 pmol/L) compared with E2 levels ≥292 pg/mL and <409 pg/mL (≥1,070 and <1,500 pmol/L). Importantly, only 25% of patents had optimal levels. CONCLUSION: The study shows a significant association between serum E2 levels and reproductive outcomes in an HRT-FET cohort in which optimal serum P4 levels were secured. Midluteal serum E2 levels are associated with the LBR in HRT-FET cycles, and E2 levels should neither be too high nor too low. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT No.: 2019-001539-29.

Influence of female sex hormones on proactive behavioral and physiological immune parameters.

Women may be more susceptible to infections in the luteal phase, supposedly as a consequence of the hormone progesterone and its immunosuppressive action. While immunosuppression may be important for successful oocyte implantation and pregnancy, it makes women more vulnerable to pathogens. According to theory, to compensate for reduced immunocompetence, women in the luteal phase exhibit proactive behavioral responses, such as disgust and avoidance of disease-associated stimuli, to minimize contagion risk. However, previous studies yielded inconsistent results, and did not account for accompanying proactive immune responses, like the increase of secretory immunoglobin A (sIgA). Here, we assessed the proactive immune response and feelings of disgust associated with disease cues in the comparison of 61 woman with a natural menstrual cycle (31 in the follicular and 30 in the luteal phase) and 20 women taking hormonal contraception (HC). Women rated disease vulnerability and disgust propensity, watched a video displaying people with respiratory symptoms, which was evaluated for its disgust-evoking potential and contagiousness, and provided saliva samples for hormone and sIgA analysis. Women with HC reported a heightened vulnerability to disease compared to naturally cycling women, whereas both the feeling of disgust and the sIgA increase elicited by the disease video were similar across groups, regardless of progesterone. We found a u-shaped relationship between progesterone and baseline sIgA in naturally cycling women, with its nadir during ovulation. Overall, our data do not support a compensatory relationship between the proposed progesterone-induced immunosuppression and heightened disgust or a proactive sIgA response.

Changes on corpus luteum structure and progesterone synthesis pathway after hCG or GnRH treatment during the early luteal phase in sheep.

This study investigated the effect of hCG or GnRH on structural changes of the corpora lutea (CL) and the regulation of the expression of steroidogenic enzymes involved in P4 secretion in post-ovulatory (po-CL) and accessory CL (acc-CL). Sixty-four ewes were assigned to three groups receiving: 300 IU of hCG (hCG) or 4 µg Buserelin (GnRH) or 1 mL of saline solution (Control) on Day (d) 4 post artificial insemination (FTAI). Laparoscopic ovarian were performed on d 4, 14 and, 21 post-FTAI to determine the numbers of CL. Blood samples were collected for serum LH and P4 analysis. On d 14 post-FTAI, both CL were removed from the ovary to determine large luteal cell (LLC) number and to evaluate the expression of steroidogenic enzymes (HSD3B1, STAR, CYP11A1). Only hCG and GnRH treated ewes generated acc-CL. The LLC in both po- and acc-CL were significantly greater in the hCG group compared to GnRH and Control groups (P<0.05). Overall, hCG group showed the greatest immunodetection of HSD3B1and STAR in both po- and acc-CL (P<0.05). rnRNA expression of HSD3B1, STAR and CYP11A1 in the acc-CL tended to be greater in hCG group than in GnRH group (P<0.1). The LH concentration was increased in GnRH group (P<0.05) and P4 concentration was greater in hCG group compared to the other groups (P<0.05). In conclusion, administration of hCG has a notably impact on acc-CL development and the expression of steroidogenic enzymes compared to GnRH treatment in ewes. This leads to elevated P4 concentration and improved luteal function.

Menstrual cycle phases and dosage of synthetic hormonal contraceptives influence diurnal rhythm characteristics of distal skin temperature.

This study aimed to explore how natural menstrual cycle phases and dosage of oral hormonal contraceptives (OC) influence the diurnal rhythm of distal skin temperature (DST) under real-life conditions. Participants were 41 healthy females (23.9 ± 2.48 y), comprising 27 females taking monophasic hormonal oral contraceptives (OC users) and 14 females with menstrual cycles (non-OC users). Wrist DST was continuously recorded and averaged over two consecutive 24-hour days during (pseudo)follicular and (pseudo)luteal menstrual phases. Diurnal rhythm characteristics, i.e. acrophase and amplitude, describing timing and strength of the DST rhythm, respectively, were calculated using cosinor analysis. Results show that non-OC users experienced earlier diurnal DST maximum (acrophase, p = 0.019) and larger amplitude (p = 0.016) during the luteal phase than during the follicular phase. This was observed in most (71.4%) but not all individuals. The OC users showed no differences in acrophase or amplitude between pseudoluteal and pseudofollicular phases. OC users taking a higher dosage of progestin displayed a larger amplitude for DST rhythm during the pseudoluteal phase (p = 0.009), while estrogen dosage had no effect. In conclusion, monophasic OC cause changes in diurnal DST rhythm, similar to those observed in the luteal phase of females with menstrual cycles, suggesting that synthetic progestins act in a similar manner on skin thermoregulation as progesterone does.

Different Dosages of Progesterone in Luteal Phase Support Reflect Varying Endometrial microRNA Expression in Frozen Embryo Transfer Cycles.

Despite serum progesterone being a widely accepted method for luteal phase support during embryo transfer cycles, debates persist regarding the optimal strategy for guiding clinical decisions on progesterone dosages to maximize reproductive outcomes. This retrospective study explored the utility of microRNA (miRNA) biomarkers in guiding personalized progesterone dosage adjustments for frozen embryo transfer (FET) cycles in 22 in vitro fertilization (IVF) patients undergoing hormone replacement therapy. Utilizing MIRA, an miRNA-based endometrial receptivity test, we analyzed patients' miRNA expression profiles before and after progesterone dosage adjustments to determine suitable dosages and assess endometrial status. Despite patients receiving identical progesterone dosages, variations in miRNA profiles were observed in the initial cycle, and all patients presented a displaced window of implantation. Following dosage adjustments based on their miRNA profiles, 91% of patients successfully transitioned their endometrium towards the receptive stages. However, two patients continued to exhibit persistent displaced receptivity despite the adjustments. Given the evident variation in endometrial status and serum progesterone levels among individuals, analyzing miRNA expression profiles may address the challenge of inter-personal variation in serum progesterone levels, to deliver more personalized dosage adjustments and facilitate personalized luteal phase support in IVF.

Investigation of luteal HCG supplementation in GnRH-agonist-triggered fresh embryo transfer cycles: a randomized controlled trial.

RESEARCH QUESTION: Does splitting the human chorionic gonadotrophin (HCG) support in IVF cycles triggered by a gonadotrophin-releasing hormone agonist result in a better progesterone profile? DESIGN: Randomized controlled three-arm study, performed at the Fertility Clinic, Odense University Hospital, Denmark. Patients with 12-25 follicles ≥12 mm were randomized into three groups: Group 1 - ovulation triggered with 6500 IU HCG; Group 2 - ovulation triggered with 0.5 mg GnRH agonist, followed by 1500 IU HCG on the day of oocyte retrieval (OCR); and Group 3 - ovulation triggered with 0.5 mg GnRH agonist, followed by 1000 IU HCG on the day of OCR and 500 IU HCG on OCR + 5. All groups received 180 mg vaginal progesterone. Progesterone concentrations were analysed in eight blood samples from each patient. RESULTS: Sixty-nine patients completed the study. Baseline and laboratory data were comparable. Progesterone concentration peaked on OCR + 4 in Groups 1 and 2, and peaked on OCR + 6 in Group 3. On OCR + 6, the progesterone concentration in Group 2 was significantly lower compared with Groups 1 and 3 (P = 0.003 and P < 0.001, respectively). On OCR + 8, the progesterone concentration in Group 3 was significantly higher compared with the other groups (both P<0.001). Progesterone concentrations were significantly higher in Group 3 from OCR + 6 until OCR + 14 compared with the other groups (all P ≤ 0.003). Four patients developed ovarian hyperstimulation syndrome in Group 3. CONCLUSION: Sequential HCG support after a GnRH agonist trigger provides a better progesterone concentration in the luteal phase.

Psychophysiological Responses to High-Intensity Interval Training Exercise over Menstrual Cycle Phases: An Exploratory Study.

INTRODUCTION: Although there is potential for the menstrual cycle to impact psychophysiological responses to exercise, there has been a paucity of studies investigating this aspect, specifically in the context of high-intensity interval training (HIIT). PURPOSE: This exploratory study aimed to examine the psychophysiological responses to HIIT over the menstrual cycle. METHODS: Twenty-three healthy and physically active young women were recruited. Each woman completed a cycle ergometer HIIT session in the menstrual, follicular, and luteal phases of the menstrual cycle in a random order. Psychophysiological variables of interest were collected at baseline, and during and after exercise. Primary variables of interest were anxiety, mood, motivation, enjoyment, arousal, affect, and menstrual distress. RESULTS: Higher pain, water retention, behavior change (related to social interactions, eating habits, and self-performance), and autonomic reactions (consisting of nausea, dizziness, hot flashes, and cold sweats) were observed before HIIT during the menstrual phase compared with the follicular phase ( P < 0.05). Participants exhibited worse psychological responses to HIIT sessions during the menstrual phase, followed by the luteal phase. Findings also noted participants arrived to the laboratory with lower motivation to initiate HIIT sessions during the luteal and menstrual phases compared with the follicular phase. This difference was observed before and during HIIT. Motivation and depressive symptoms showed a significant reduction from pre-HIIT to post-HIIT ( P < 0.05), regardless of menstrual phase. CONCLUSIONS: The findings revealed that the menstrual cycle had a significant impact on psychophysiological responses. Moreover, HIIT could be adopted to improve motivation and depressive symptoms; however, further research is needed to explore the effects of HIIT across the menstrual cycle in women with clinical depression.

Predicting risk of endometrial failure: a biomarker signature that identifies a novel disruption independent of endometrial timing in patients undergoing hormonal replacement cycles.

OBJECTIVE: To propose a new gene expression signature that identifies endometrial disruptions independent of endometrial luteal phase timing and predicts if patients are at risk of endometrial failure. DESIGN: Multicentric, prospective study. SETTING: Reproductive medicine research department in a public hospital affiliated with private fertility clinics and a reproductive genetics laboratory. PATIENTS: Caucasian women (n = 281; 39.4 ± 4.8 years old with a body mass index of 22.9 ± 3.5 kg/m2) undergoing hormone replacement therapy between July 2018 and July 2021. Endometrial samples from 217 patients met RNA quality criteria for signature discovery and analysis. INTERVENTION(S): Endometrial biopsies collected in the mid-secretory phase. MAIN OUTCOME MEASURE(S): Endometrial luteal phase timing-corrected expression of 404 genes and reproductive outcomes of the first single embryo transfer (SET) after biopsy collection to identify prognostic biomarkers of endometrial failure. RESULTS: Removal of endometrial timing variation from gene expression data allowed patients to be stratified into poor (n = 137) or good (n = 49) endometrial prognosis groups on the basis of their clinical and transcriptomic profiles. Significant differences were found between endometrial prognosis groups in terms of reproductive rates: pregnancy (44.6% vs. 79.6%), live birth (25.6% vs. 77.6%), clinical miscarriage (22.2% vs. 2.6%), and biochemical miscarriage (20.4% vs. 0%). The relative risk of endometrial failure for patients predicted as a poor endometrial prognosis was 3.3 times higher than those with a good prognosis. The differences in gene expression between both profiles were proposed as a biomarker, coined the endometrial failure risk (EFR) signature. Poor prognosis profiles were characterized by 59 upregulated and 63 downregulated genes mainly involved in regulation (17.0%), metabolism (8.4%), immune response, and inflammation (7.8%). This EFR signature had a median accuracy of 0.92 (min = 0.88, max = 0.94), median sensitivity of 0.96 (min = 0.91, max = 0.98), and median specificity of 0.84 (min = 0.77, max = 0.88), positioning itself as a promising biomarker for endometrial evaluation. CONCLUSION(S): The EFR signature revealed a novel endometrial disruption, independent of endometrial luteal phase timing, present in 73.7% of patients. This EFR signature stratified patients into 2 significantly distinct and clinically relevant prognosis profiles providing opportunities for personalized therapy. Nevertheless, further validations are needed before implementing this gene signature as an artificial intelligence (AI)-based tool to reduce the risk of patients experiencing endometrial failure.

Luteal phase support using micronized vaginal progesterone as pessaries or capsules in artificial cycles: is there any difference?

RESEARCH QUESTION: Is there a difference between the proportion of patients with serum progesterone <8.8 ng/ml on the day of embryo transfer when micronized vaginal progesterone (MVP) for luteal phase support (LPS) is given as pessaries versus capsules? DESIGN: This retrospective, matched-cohort, single-centre study compared pessaries (Cyclogest) versus capsules (Utrogestan, Progeffik) for LPS in hormone replacement treatment-embryo transfer (HRT-ET) cycles. Patients under 50 years old with a triple-layer endometrial thickness of ≥6.5 mm underwent transfer of one or two blastocysts. Serum progesterone concentrations were measured on the day of transfer; patients with concentrations <8.8 ng/ml received a single 'rescue' dose of additional progesterone by subcutaneous injection. RESULTS: In total 2665 HRT-ET cycles were analysed; 663 (24.9%) used pessaries for LPS and 2002 (75.1%) used capsules. Mean serum progesterone concentrations with standard deviations on the day of embryo transfer were significantly higher in the group using MVP pessaries compared with those using capsules (14.5 ± 5.1 versus 13.0 ± 4.8 ng/ml; P = 0.000). The percentage of participants with suboptimal serum progesterone concentrations on the day of embryo transfer (<8.8 ng/ml) was significantly lower in the pessary group than the capsule group (10.3%, 95% confidence interval [CI] 7.9-12.6% versus 17.9%, 95% CI 16.2-19.6%; adjusted odds ratio 0.426, 95% CI 0.290-0.625; P = 0.000). No differences in pregnancy outcome were observed between the groups. CONCLUSIONS: Using MVP pessaries rather than capsules for LPS resulted in significantly fewer patients having suboptimal serum progesterone concentrations on the day of embryo transfer. Consequently, almost 50% fewer patients in the pessary group needed rescue treatment.

Cortical morphology variations during the menstrual cycle in individuals with and without premenstrual dysphoric disorder.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) is hypothesized to stem from maladaptive neural sensitivity to ovarian steroid hormone fluctuations. Recently, we found thinner cortices in individuals with PMDD, compared to healthy controls, during the symptomatic phase. Here, we aimed at investigating whether such differences illustrate state-like characteristics specific to the symptomatic phase, or trait-like features defining PMDD. METHODS: Patients and controls were scanned using structural magnetic resonance imaging during the mid-follicular and late-luteal phase of the menstrual cycle. Group-by-phase interaction effects on cortical architecture metrics (cortical thickness, gyrification index, cortical complexity, and sulcal depth) were assessed using surface-based morphometry. RESULTS: Independently of menstrual cycle phase, a main effect of diagnostic group on surface metrics was found, primarily illustrating thinner cortices (0.3 < Cohen's d > 1.1) and lower gyrification indices (0.4 < Cohen's d > 1.0) in patients compared to controls. Furthermore, menstrual cycle-specific effects were detected across all participants, depicting a decrease in cortical thickness (0.4 < Cohen's d > 1.7) and region-dependent changes in cortical folding metrics (0.4 < Cohen's d > 2.2) from the mid-follicular to the late luteal phase. LIMITATIONS: Small effects (d = 0.3) require a larger sample size to be accurately characterized. CONCLUSIONS: These findings provide initial evidence of trait-like cortical characteristics of the brain of individuals with premenstrual dysphoric disorder, together with indications of menstrual cycle-related variations in cortical architecture in patients and controls. Further investigations exploring whether these differences constitute stable vulnerability markers or develop over the years may help understand PMDD etiology.

Comparison of luteal phase and follicular phase in-vitro maturation in women with oocyte maturation abnormalities.

RESEARCH QUESTION: Are there differences in immature oocyte retrieval following luteal phase in-vitro maturation (IVM) compared with follicular phase IVM in women with oocyte maturation abnormalities (OMAs). DESIGN: From January 2019 to May 2023, a retrospective cohort study at a private IVF centre included 36 women with 53 IVM cycles in Group 1 (follicular phase) and 24 women with 32 IVM cycles in Group 2 (luteal phase). Additionally, nine women had both follicular and luteal phase IVM cycles for intracycle variability analysis. RESULTS: There were no differences in oocyte maturation stages between the groups at collection. Group 1 and Group 2 exhibited comparable median metaphase II oocyte rates per patient at 48 h after collection [40.0%, interquartile range (IQR) 0.0-66.7% versus 22.5%, IQR 0.0-52.9%] (P = 0.53). The median fertilization rate in Group 1 (66.7%, IQR 50.0-66.7%) was found to be comparable with that in Group 2 (66.7%, IQR 50.0-66.7%). There were no significant differences in the yielded embryo grades and pregnancy rates between the groups. Comparing follicular and luteal phase IVM within the same menstrual cycle in nine patients, no differences were observed in metaphase II oocyte maturation rates (P > 0.05). CONCLUSIONS: This study found no significant differences in oocyte maturation, fertilization rate, embryo quality or pregnancy outcomes between luteal phase and follicular phase IVM in women with OMAs. These findings suggest that luteal phase IVM can be used similarly to follicular phase IVM, offering a potential avenue to enhance embryo yield for women with OMAs.