The dark side of random-start ovarian stimulation: ovarian hyperstimulation syndrome due to inadvertent pregnancy.

RESEARCH QUESTION: Can inadvertent pregnancies go unnoticed when initiating random-start ovarian stimulation (RSOS) despite monitoring? DESIGN: Case series at a university-based tertiary care fertility clinic. RESULTS: Between June 2022 and December 2023, two cases of undetected early pregnancy at the onset of RSOS were identified, both leading to severe ovarian hyperstimulation syndrome (OHSS) with hospitalization. CONCLUSION: RSOS protocols add flexibility in fertility clinics when there is no intention of a fresh embryo transfer, but may be associated with insidious risk of OHSS. The authors advocate for comprehensive consultation and serial monitoring of human chorionic gonadotrophin during ovarian stimulation, while cautioning against over-reliance on baseline hormone concentrations when initiating RSOS. If the benefits of RSOS seem limited, healthcare providers should consider delaying ovarian stimulation to avert health, but also medicolegal and financial, complications.

Salivary testosterone across the menstrual cycle.

Testosterone production in women is thought to systematically shift across the menstrual cycle, peaking during the mid-cycle ovulatory window, and potentially influencing women's behavior. Testosterone is a molecular intermediary to the production of estradiol, which is necessary for ovulation to occur, but the amount of testosterone escape and exposure to the peripheral tissues is not fully understood. Salivary testosterone is a common biomarker in behavioral neuroendocrinological studies and is thought to reflect the bioactive portions in serum. In N = 339 women with confirmed ovulation via luteinizing hormone tests, salivary testosterone, assayed with LC-MS/MS, was sampled four times across the mid-cycle ovulatory window the luteal phase. Within-subject analysis revealed a significant but small pattern of a mid-cycle peak and a luteal decrease at the aggregate level. However, at the individual level, there was substantial variability in the direction and magnitude of the testosterone-cycle pattern. We discuss the relevant underlying physiology, background research, issues with assay methodolody, and considerations for researchers studying testosterone levels in women.

Agreement Between the 2- and 3-Step Methods for Identifying Subtle Menstrual Disturbances.

Recent methodological recommendations suggest the use of the "3-step method," consisting of calendar-based counting, urinary ovulation testing, and serum blood sampling, for the identification of subtle menstrual disturbances (SMDs). However, the use of the 3-step method is not always feasible, so a less demanding combination of calendar-based counting and urinary ovulation testing, that is, the 2-step method, may be a viable alternative. PURPOSE: To investigate the agreement between the 2- and 3-step methods for the detection of SMDs. METHODS: Menstrual cycles (MCs, 98) of 59 athletes were assessed using the 2- and 3-step methods. Regular-length MCs (ie, ≥21 and ≤35 d) were classified as either having no SMD (luteal phase length ≥10 d, midluteal progesterone concentration ≥16 nmol·L-1, and being ovulatory) or having an SMD (eg, short luteal phase [<10 d], inadequate luteal phase [midluteal progesterone concentration <16 nmol·L-1], or being anovulatory). Method agreement was assessed using the McNemar test and Cohen kappa (κ). RESULTS: Substantial agreement was observed between methods (κ = .72; 95% CI, .53-.91), but the 2-step method did not detect all MCs with an SMD, resulting in evidence of systematic bias (χ2 = 5.14; P = .023). The 2-step method detected 61.1% of MCs that had an SMD ([51.4, 70.8]), as verified using the 3-step method, and correctly identified 100% of MCs without an SMD. CONCLUSIONS: MCs classified as being disturbed using the 2-step method could be considered valid evidence of SMDs. However, MCs classified without SMDs do not definitively confirm their absence, due to the proven underdetection via the 2-step method.

Luteal phase support with oral progesterone improves live birth rate in intrauterine insemination cycles using letrozole.

RESEARCH QUESTION: Does luteal phase support (LPS) with oral progesterone improve the live birth rate (LBR) in patients undergoing intrauterine insemination (IUI) cycles with letrozole? DESIGN: This retrospective cohort study included 1199 IUI cycles with letrozole between January 2017 and December 2021. A nearest neighbour random matching approach was employed to pair the LPS group and the control group in a 1:2 ratio. Eight variables were chosen for matching in the propensity score matching (PSM) model: age; body mass index; duration of infertility; cause(s) of infertility; antral follicle count; basal concentration of FSH; rank of IUI attempts; and leading follicle size. LBR was selected as the primary outcome. RESULTS: In total, 427 LPS cycles were matched with 772 non-LPS (control) cycles after PSM. The LBR was significantly higher in the LPS group compared with the control group (19.7% versus 14.5%; P = 0.0255). The clinical pregnancy rate (23.2% versus 17.6%; P = 0.0245) and ongoing pregnancy rate (20.6% versus 15.8%; P = 0.0437) were also significantly higher in the LPS group. The biochemical pregnancy rate, ectopic pregnancy rate and miscarriage rate were similar in the two groups (P > 0.05). The intergroup comparison revealed no significant variances in terms of gestational age, mode of delivery, ectopic pregnancy rate or abortion rate. Furthermore, there were no significant differences in birth weight or birth length between the two groups. CONCLUSIONS: Luteal support with oral progesterone significantly improved the LBR in IUI cycles with letrozole, but did not affect neonatal outcomes.

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.

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 Effect of Adding Daily 50 mg Intramuscular Progesterone to 800 mg Progesterone Suppository on The In Vitro Fertilization Success Rate in Women with Low Progesterone Levels: A Clinical Trial Study.

BACKGROUND: A low progesterone level on the embryo transfer (ET) day significantly reduces the pregnancy rate. Therefore, the present study aims to investigate the effect of adding daily 50 mg intramuscular progesterone to a total of 800 mg progesterone suppository on the in vitro fertilization (IVF) success rate in women with low progesterone levels. MATERIALS AND METHODS: This parallel open-label clinical trial was performed on 218 IVF candidate infertile women who had <9.2 ng/ml progesterone levels on the ET day. These women were randomised to the intervention or control group using the randomisation allocation rule. In the intervention group, 50 mg progesterone was prescribed intramuscularly once daily in addition to 400 mg of progesterone suppository every 12 hours from the day of ET. The control group received only 400 mg of progesterone suppositories every 12 hours. In the case of pregnancy, the drugs above were continued until 12 weeks after the ET. RESULTS: Clinical pregnancy occurred in 54 (50.0%) women in the intervention group and in 39 (36.8%) women in the control group, which was significantly different (P=0.035). Ongoing pregnancy occurred in 47 (43.5%) women in the intervention group, and 33 (31.1%) women in the control group, which was significantly different (P=0.042). There were no significant differences in terms of abortion and multiple pregnancy rates between the two groups. CONCLUSION: Intramuscular injection of 50 mg progesterone significantly increases the clinical and ongoing pregnancy rates (registration number: IRCT20150105020558N6).

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.

Low Dose hCG Support in Modified Natural Frozen Embryo Transfer Cycles.

What is the effect of a single low-dose recombinant hCG injection after embryo transfer (ET) in letrozole-induced modified natural frozen embryo transfer cycles (mNC-FET)?. An observational study was conducted in the university-affiliated referral clinic between 2022 and 2024. Women aged 18-42 with at least one vitrified blastocyst obtained from the previous cycle(s) were included. Ovulation induction for endometrial preparation was initiated with oral letrozol (5 mg/day) for five days. Ovulation was triggered using 6500 IU rec hCG sc when the leading follicle > 17 mm, endometrial thickness > 7.5 mm, and serum progesterone (P) < 1.5 ng/ml. All women received 30 mg dydrogesterone/day po for additional five-day luteal support. On the 6th day, ET was performed. Based on a quasi-randomized design, a group of women additionally received a half single bolus of (3250 IU) rec hCG (sc) on the morning of 3rd day of ET (hCG group). Women who did not receive additional hCG were assigned as controls. One hundred fifty-four women were detected to be eligible for the study among 2150 initiated FET cycles during the period. Demographic data of the groups, including mean women's age, BMI, serum AMH, and infertility etiologies, were comparable in terms of variables. Mean serum progesterone values and the number of transferred embryos were also similar. A significantly higher ongoing pregnancy/started cycle was documented in the hCG group than in controls (46.7% vs 33.6% respectively, p = 0.03*). A single low-dose hCG injection after ET may improve the OPRs of women in letrozole mNC-FET cycles.

Undetected, natural conception pregnancies in luteal phase stimulations-case series and review of literature.

STUDY QUESTION: What is the risk of an undetected natural conception pregnancy during luteal phase ovarian stimulation, and how does it impact the pregnancy's course? SUMMARY ANSWER: The risk for an undetected, natural conception pregnancy in luteal phase ovarian stimulation is low and it appears that ovarian stimulation is unlikely to harm the pregnancy. WHAT IS KNOWN ALREADY: Random start ovarian stimulation appears to be similarly effective as early follicular stimulation start; and it allows ovarian stimulation to be started independent of the cycle day and throughout the cycle, in accordance with the patients' and clinics' schedule as long as there is no intention of a fresh embryo transfer in the same cycle. Starting ovarian stimulation in the luteal phase bears the possibility of an-at the timepoint of stimulation start-undetected, natural conception pregnancy that has already occurred. There is scarce data on the incidence of this event as well as on the possible implications of ovarian stimulation on the course of an existing pregnancy. STUDY DESIGN, SIZE, DURATION: This retrospective observational study, performed between June 2017 and January 2024, analyzed luteal phase stimulations, in which a natural conception pregnancy was detected during the ovarian stimulation treatment for IVF/ICSI. Luteal phase stimulation was defined as ovarian stimulation started after ovulation and before the next expected menstrual bleeding, with a serum progesterone (P4) level of >1.5 ng/ml on the day of stimulation start or 1 day before. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who underwent a luteal phase ovarian stimulation in a tertiary referral ART center. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 488 luteal phase stimulation cycles were included in the analysis. Luteal phase stimulation was only started after a negative serum hCG measurement on the day or 1 day before commencement of ovarian stimulation. Ten patients (2.1%) had an undetected natural conception pregnancy at the time of luteal phase stimulation start. Eight of these patients underwent an ovarian stimulation in a GnRH-antagonist protocol and two in a progestin-primed stimulation protocol (PPOS). Recombinant FSH was used as stimulation medication for all patients, the patients with a PPOS protocol received additional recombinant LH. One pregnancy (0.2%) was detected after the oocyte retrieval, the other nine pregnancies were detected either due to persistent high serum progesterone levels or due to an increasing progesterone level after an initial decrease before oocyte retrieval. In the cycles with an undetected natural conception pregnancy, the median number of stimulation days was 8 days (range: 6-11 days) and median serum hCG at detection of pregnancy was 59 IU hCG (range: 14.91-183.1). From 10 patients with a pregnancy, three patients delivered a healthy baby, two patients had ongoing pregnancies at the time of summarizing the data, three patients had biochemical pregnancies (patient age: 30, 39, and 42 years), one patient had an ectopic pregnancy which required a salpingectomy, and one patient (age: 34 years) had an early pregnancy loss. LIMITATIONS, REASONS FOR CAUTION: The retrospective study design and the small sample size can limit the accuracy of the estimates. WIDER IMPLICATIONS OF THE FINDINGS: Overall, there is a small risk of undetected natural conception pregnancies when luteal phase stimulation is undertaken. It appears that there are no adverse effects through either direct effect on the embryo or indirectly through a detrimental effect on the corpus luteum function on the pregnancy in our cohort. STUDY FUNDING/COMPETING INTEREST(S): This study did not receive funding. The authors declare that there is no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Effects of the Menstrual Cycle and Hormonal Contraceptive Use on Metabolic Outcomes, Strength Performance, and Recovery: A Narrative Review.

The effects of female sex hormones on optimal performance have been increasingly recognized as an important consideration in exercise and sport science research. This narrative review explores the findings of studies evaluating the effects of menstrual cycle phase in eumenorrheic women and the use of hormonal contraception (oral contraceptives and hormonal intrauterine devices) on metabolism, muscular strength, and recovery in active females. Ovarian hormones are known to influence metabolism because estrogen is a master regulator of bioenergetics. Importantly, the menstrual cycle may impact protein synthesis, impacting skeletal muscle quality and strength. Studies investigating muscular strength in eumenorrheic women report equivocal findings between the follicular phase and luteal phase with no differences compared to oral contraceptive users. Studies examining recovery measures (using biomarkers, blood lactate, and blood flow) do not report clear or consistent effects of the impact of the menstrual cycle or hormonal contraception use on recovery. Overall, the current literature may be limited by the evaluation of only one menstrual cycle and the use of group means for statistical significance. Hence, to optimize training and performance in females, regardless of hormonal contraception use, there is a need for future research to quantify the intra-individual impact of the menstrual cycle phases and hormonal contraceptive use in active females.

Spontaneous ovulation in the cat: incidence among queens presented at a veterinary teaching facility.

OBJECTIVES: The queen is recognised as an induced ovulator. Ovulation without male contact is generally regarded as spontaneous. The aim of this study was to provide an estimate of the incidence of spontaneous ovulation in a population of intact queens presented to a veterinary care facility for both reproductive and non-reproductive reasons. The secondary objective was to determine the roles of age, breed, body weight, presence of tom cats or other cycling queens, and physical contact with humans on triggering spontaneous ovulation, along with its implications. METHODS: Serum samples from post-pubertal intact queens presented between January 2020 and June 2023 to the Veterinary Teaching Hospital of the University of Padova, Italy, were retrieved and assayed for progesterone (P4) levels. Serum P4 above 2.0 ng/ml without a history of male contact was considered as proof of spontaneous ovulation. RESULTS: In total, 31 serum samples from 29 intact post-pubertal queens were obtained. Of the 31 samples, 14 had a P4 concentration above 2.0 ng/ml and 9/29 (31.0%) queens ovulated spontaneously. The mean age and weight of the nine spontaneously ovulating queens were 4.3 ± 5.7 years and 3.7 ± 0.8 kg, respectively. One queen ovulated spontaneously at her first heat at 6 months of age, which makes it the earliest spontaneous ovulation reported. CONCLUSIONS AND RELEVANCE: As both our findings and previous publications indicate that the incidence of spontaneous ovulation in queens is consistently ⩾30%, cats should not be considered strictly induced ovulators, but as a species in which ovulation can be either spontaneous or induced. Since the risk of progesterone-dependent conditions (cystic endometrial hyperplasia - pyometra complex, feline mammary hypertrophy) is increased in these queens, veterinarians should be aware and advise breeders and clients accordingly.

Female cats ovulate upon vaginal stimulation exerted by the spikes of the male's penis while mating, which makes them induced ovulators. When ovulation occurs without male contact, it is considered spontaneous. There are several factors that are thought to facilitate this non-induced ovulation, but no consensus on their relevance. The aim of this study was to provide an estimate of the rate of spontaneous ovulation in a population of intact female cats of various breeds presented to a veterinary care facility, as well as the influence of factors such as age, breed, body weight, presence of male cats or other cycling females, and physical contact with humans on triggering spontaneous ovulation. In addition, possible implications arising from progesterone exposure were assessed.Progesterone was retrospectively assayed in the serum of adult cycling female cats presented to the Veterinary Teaching Hospital of the University of Padova, Italy, between January 2020 and June 2023. Values above 2.0 ng/ml without a history of male contact were considered proof of spontaneous ovulation. Out of 29 cats, nine (31%) ovulated spontaneously, with one female having done so at puberty (6 months of age), which makes it the first spontaneous ovulation ever reported in a pubertal queen.As spontaneous ovulation has been found to occur at a rate of more than 30% both in our and in previous publications on this topic, we propose that cats should be considered both an induced and a spontaneously ovulating species. Since animals that ovulate spontaneously, and therefore experience additional luteal phases, are at a higher risk of developing progesterone-dependent conditions, veterinarians should be aware and advise breeders and clients accordingly.

Double versus single stimulation in young low prognosis patients followed by a fresh embryo transfer: a randomized controlled trial (DUOSTIM-fresh).

STUDY QUESTION: Does double stimulation, followed by a fresh embryo transfer (DUOSTIM fresh) give a higher number of good-quality blastocysts as compared with a single stimulation in young low prognosis patients? SUMMARY ANSWER: Compared to single stimulation, DUOSTIM fresh leads to a significantly higher number of good quality blastocysts, without hindering fresh embryo transfer outcomes. WHAT IS KNOWN ALREADY: DUOSTIM (ovarian stimulation both in the follicular and luteal phase of the same cycle) is an innovative strategy to retrieve a higher number of oocytes in a shorter time frame, thus it is particularly appealing for poor ovarian responders. Three current limitations of dual stimulation are: (i) it is unclear whether outcomes of the second (luteal) wave result from the second stimulation, or a carry-over effect from previous follicular stimulation; (ii) the desynchronization between endometrium and ovaries and, (iii) lack of robust evidence. No previous studies explored DUOSTIM starting from the luteal phase, and with a fresh embryo transfer (DUOSTIM fresh). STUDY DESIGN, SIZE, DURATION: This study is a randomized, controlled, single-center, superiority clinical trial comparing two different ovarian stimulation protocols: a double stimulation cycle versus a single stimulation cycle followed by fresh embryo transfer. The primary outcome was the number of good quality blastocysts obtained, while secondary outcomes included results from fresh embryo transfer (clinical pregnancy, miscarriage). A total of 120 women were enrolled in this study between October 2020 and October 2022, with a 1:1 allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Only young (<40 years old) low prognosis (anti-Müllerian hormone <1.2 ng/ml) patients were recruited in the Reproductive Medicine Department of Dexeus University Hospital. In the investigational group, DUOSTIM fresh, the first stimulation was initiated in the luteal phase (Day 18-21 cycle) followed by a second stimulation 5 days post first oocyte retrieval, initiated in the follicular phase and a fresh embryo transfer of the best blastocyst generated (first or second cycle). The control group performed a follicular phase single stimulation cycle with a fresh embryo transfer. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 107 patients were analyzed, 53 in the investigational (DUOSTIM fresh) and 54 in the control arm (single stimulation). DUOSTIM fresh resulted in a significantly higher number of good quality blastocysts as compared to single stimulation (difference of mean 0.81, 95% CI 0.12-1.49). The mean percentage of cycles with embryo transfer was comparable (62.3% and 51.9%, respectively for double versus single stimulation). No significant differences were found for clinical outcomes following fresh embryo transfer with an ongoing pregnancy rate of 24.5% for DUOSTIM fresh versus 22.2%, for conventional IVF. Of interest comparisons between different stimulation cycles (A: luteal-phase DUOSTIM fresh, B: follicular-phase DUOSTIM fresh, and C: single stimulation) did not demonstrate any significant difference in terms of ovarian response with the mean (SD) number of mature oocytes being (A: 3.3 (2.9), B: 3.4 (3.4), and C: 3.5 (2.9), respectively). LIMITATIONS, REASONS FOR CAUTION: Study sample size was calculated to detect differences on the mean number of good quality blastocysts. Therefore, results for secondary outcomes (embryo transfer rates and clinical pregnancy rates) should be interpreted with caution as exploratory findings that deserve future investigations. WIDER IMPLICATIONS OF THE FINDINGS: Although DUOSTIM fresh results in a higher number of blastocysts as compared with a single stimulation in young low prognosis patients, the decision of performing dual stim should be evaluated with caution, considering that whether this may improve embryo transfers rate and pregnancy outcomes is still unclear. Results on cumulative-live-birth-rate are warranted. STUDY FUNDING/COMPETING INTEREST(S): The study was an investigator-initiated study supported by an unrestricted grant by Organon. N.P.P. has received grants from Merck Serono, Organon, Ferring Pharmaceutical, Theramex, and Besins Healthcare. N.P.P. has received consulting fees from Merck Serono, Organon, Besins Healthcare, and IBSA. N.P.P. has received honoraria for lectures from Merck Serono, Organon, Theramex, Roche Diagnostics, IBSA, Besins Healthcare, and Ferring. A.R. has received Research grants, honoraria for lectures from Merck Serono, MSD/Organon, Ferring Pharmaceuticals, Besins International, IBSA, Guerbet. The other authors declare that there is no conflict of interest to disclose with respect to the content of this article. TRIAL REGISTRATIO NUMBER: NCT04446845. TRIAL REGISTRATION DATE: 25 June 2020. DATE OF FIRST PATIENT'S ENROLMENT: 30 October 2020.

Effects of exercise on sex steroid hormones (estrogen, progesterone, testosterone) in eumenorrheic females: A systematic to review and meta-analysis.

BACKGROUND: The sex steroid hormones fluctuate during the menstrual cycle, which affects the strength and postural stability of females and leads to injuries and risk of falls. These hormones may be modulated by exercise to impact the overall health of females. OBJECTIVE: To determine the effects of exercise on sex steroid hormones in eumenorrheic females. METHODS: This review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA) guidelines in Lahore, Pakistan. The full-length articles were searched using these databases/search engines (PubMed, Web of Science and Google Scholar, Sci-Hub). Randomized controlled trials along with single group experimental studies were also included. All types of exercises were compared with no exercise in the control group. The Cochrane Risk of Bias assessment tool assessed and screened the articles. The data were then analyzed. The primary outcomes were the levels of estrogen, progesterone and testosterone. RESULTS: Eleven studies were included (5 randomized controlled trials and 6 quasi-experimental studies). The effects of exercise on free estradiol concentration and serum progesterone level were not significant [p = 0.37 (SMD = 0.33, 95% CI = 0.14 to 0.74, I2 = 0%) and p = 0.84 (S.D= -0.65, C.I= -6.92 to 5.62, I2 = 94%)] respectively, whereas, the effects on testosterone levels were significant [p value < 0.00001 (M.D = 0.89, 95% C.I= -2.16 to 3.95, I2 = 94%)]. CONCLUSION: A blinded randomized controlled trial should be conducted in which a structured approach should be followed by women along with warm-ups, cool down and rest intervals. TRIAL REGISTRATION NUMBER: The systematic review was registered prospectively on PROSPERO with registration number CRD42023473767.

PPAR beta/delta regulates the immune response mechanisms in the porcine endometrium during LPS-induced inflammation - An in vitro study.

Inflammation in the reproductive tract has become a serious threat to animal fertility. Recently, the role of peroxisome proliferator-activated receptor gamma (PPARγ) in the context of reproduction and the inflammatory response has been highlighted, but the role of PPARß/δ has not been fully elucidated. The aim of the present study was to investigate the in vitro effect of PPARß/δ ligands (agonist: L-165,041 and antagonist: GSK 3787) on the transcriptome profile of porcine endometrium during LPS-induced inflammation in the mid-luteal and follicular phases of the oestrous cycle (days 10-12 and 18-20, respectively) using the RNA-Seq method. During the mid-luteal phase of the oestrous cycle, the current study identified 145 and 143 differentially expressed genes (DEGs) after treatment with an agonist or antagonist, respectively. During the follicular phase of the oestrous cycle, 55 and 207 DEGs were detected after treatment with an agonist or antagonist, respectively. The detected DEGs are engaged in the regulation of various processes, such as the complement and coagulation cascade, NF-κB signalling pathway, or the pathway of 15-eicosatetraenoic acid derivatives synthesis. The results of the current study indicate that PPARß/δ ligands are involved in the control of the endometrial inflammatory response.

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 ).

Is prolonged luteal phase a problem in lactating Holstein cows?

In this study, the main objective was to assess if long luteal phases could have other causes than pregnancy losses. We enrolled Holstein dairy cows ≥50 d in milk (DIM) from a commercial herd in Brazil from October 2016 to August 2017. All cows received an estradiol-based synchronization protocol, and, on the day of insemination (d 0), were randomly assigned either an artificial insemination (AI) or a placebo insemination (PBO) in a 3:1 ratio. An ultrasound was used to assess the presence of a CL on d17, 24, and 31, which, combined to the information from patches for the detection of estrus, was used to determine the length of the luteal phase following AI or PBO. Pregnancy was assessed by ultrasound on d 31 and cows that were pregnant were excluded from the analyses. The length of the estrous cycles was categorized as short (<17 d), normal (17-23 d), long (24-30 d), and very long (≥31 d). We compared the proportion of cows in each category between the AI and PBO groups using a cumulative ordinal mixed model. We define prolonged luteal phase as estrous cycles ≥24 d and tested its association with potential risk factors (parity, season, DIM, uterine size and position score, milk production, body condition score, and the presence of a corpus luteum (CL) at enrollment to the synchronization protocol) using mixed logistic regression models. Results are presented as odds ratio (OR) and 95% credible intervals (BCI). Data from 876 inseminations (AI: n = 616, PBO: n = 260) was collected. Overall, 12% of estrous cycles were short, 31% were normal, 19% were long, and 38% were very long. There was no difference in the odds of being in longer estrous cycle categories for the AI compared with the PBO group (OR = 0.92, 95% BCI = 0.76-1.10). Season and presence of a CL at enrollment were associated with prolonged luteal phase. In the AI group, there was a possible effect of early pregnancy losses on the lifespan of the CL, but not the PBO group, which led us to conclude that long and very long estrous cycles were not all caused by the embryonic loss. In fact, the high prevalence of cows with an extended CL lifespan in the present study suggests this could be an under- or miss-reported characteristic of high-producing lactating Holstein cows. This finding may have important repercussions in the understanding of the CL function physiology of lactating Holstein cows.

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.

Benefit from luteal phase progestin-primed ovarian stimulation with clomiphene citrate supplementation in young women with diminished ovarian reserve: a retrospective study. / åµæ³¡æœŸå’Œé»„ä½“æœŸé«˜å­•æ¿€ç´ çŠ¶æ€ä¿ƒæŽ’åµæ–¹æ¡ˆåœ¨å¹´è½»åµå·¢å‚¨å¤‡åŠŸèƒ½å‡é€€å¥³æ€§ä¸­çš„åº”ç”¨.

OBJECTIVES: To compare the pregnant outcomes of luteal phase progestin-primed ovarian stimulation (PPOS) protocol with clomiphene citrate supplementation (LPPOS+CC) and follicular phase PPOS+CC protocol (FPPOS+CC) in young women with diminished ovarian reserve (DOR). METHODS: A total of 483 women aged ≤35 years with DOR, who underwent in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI)/embryo transfer (ET) with controlled ovarian stimulation using LPPOS+CC (n=257) or FPPOS+CC (n=226) protocols during June 2018 and December 2021 at the First Affiliated Hospital of Wenzhou Medical University, were included in this retrospective study. The baseline characteristics, ovarian stimulation, endocrinological indicators, clinical outcomes between the two groups, and pregnancy outcomes of women achieved at least one high-quality cleavage-stage embryo or good-morphology blastocyst between the two groups were compared. RESULTS: No statistically significant differences were identified between the groups with respect to number of oocytes retrieved, oocyte maturation rate, high-quality cleavage-stage embryo cycle rate, the percentage of women with profound pituitary suppression, preterm birth rate, and live birth rate (P>0.05). Compared to FPPOS+CC group, the duration of stimulation [11.0 (9.0,12.0) vs. 9.0 (8.0,11.0) d, P<0.01] was significantly longer in the LPPOS+CC group. The LH levels on the day of trigger [4.0 (2.7,5.3) vs. 5.1 (3.2,7.2) IU/L, P<0.01], the percentage of women with LH levels of >10 IU/L on the trigger day (3.13% vs. 10.67%, P<0.01), and the two pronucleate (2PN) rate of ICSI oocytes (72.16% vs. 79.56%, P<0.05) were significantly lower in the LPPOS+CC group than those in the FPPOS+CC group. The consumption of total gonadotropin [2213 (1650,2700) vs. 2000 (1575,2325) IU, P<0.01], the progesterone levels on the day of trigger [1.3 (0.8,2.9) vs. 0.9 (0.6,1.2) ng/mL, P<0.01], the clinical pregnancy rate [61.88% vs. 46.84%, P<0.01], and implantation rate [42.20% vs. 31.07%, P<0.01] in the LPPOS+CC group were significantly higher than those in the FPPOS+CC group. CONCLUSIONS: Compared to FPPOS+CC, the LPPOS+CC protocol appears to have better pregnancy outcomes for young women with DOR undergoing IVF-ICSI-ET.