Ovulatory Disturbances Research Articles

P-688 Fertility and age at childbirth in polycystic ovary syndrome: results from a longitudinal population-based cohort study

Abstract Study question How does fertility differ between women with and without polycystic ovary syndrome (PCOS), and which factors are associated with advanced maternal age? Summary answer Women with PCOS have less births. PCOS was associated with advanced maternal age, with later diagnosis associated with double the rate of advanced maternal age. What is known already PCOS affects 12% or 140 million women globally. Women with PCOS have broad features including ovulatory disturbances and increased infertility; however, few studies have explored reproductive outcomes in PCOS at the end of reproductive age. In the general population advanced maternal age, defined as giving birth after age 35 years, is associated with increased risk of pregnancy complications and reduced fertility. A recent register-based study found increased risk of advanced maternal age in women with PCOS, yet PCOS prevalence was underreported, and the study did not adjust for important confounders. Study design, size, duration Prospective cohort study. Women with (n = 981) and without (n = 13 266) self-reported PCOS diagnosis were compared during a 25-year follow-up. Participants/materials, setting, methods Women randomly selected from the general population and included in the prospective Australian Longitudinal Study on Women’s Health were assessed with surveys every third year from 1996 (age 18-23 years) to 2021 (age 43-48 years). Main results and the role of chance Overall 9.9% of women reported having PCOS and by 43-48 years, those with PCOS had less births (1.7 ±1.3 vs. 1.9 ±1.2, p < 0.001), and more were nulliparous, 23% vs. 18%, p = 0.003. They were older than women without PCOS at their first, and second childbirth (29.5 ±5.49 vs. 28.8 ±5.48 years and 32.1 ±5.16 vs. 31.1 ±5.00 years, p < 0.001 for both). PCOS was associated with increased odds of advanced maternal age at first childbirth, adjusted odds ratio (aOR) 1.34 (95% confidence interval 1.04-1.75), whereas type 2 diabetes (aOR 0.68 (0.61-1.10)) or hypertension (aOR 0.82 (0.61-1.10)) were not associated with advanced maternal age. Within the PCOS group, a late PCOS diagnosis was associated with increased odds of advanced maternal age, aOR 2.05 (1.24-3.40). Limitations, reasons for caution All outcomes were self-reported. Wider implications of the findings Women with PCOS have lower parity. Later diagnosis is associated with increased odds of advanced maternal age at first childbirth. Given poor reproductive outcomes with increased maternal age, we highlight the importance of earlier diagnosis, patient education and implementation of a reproductive life-plan to optimize attainment of aspirational family size. Trial registration number not applicable

Role of hysteroscopy in categorization of abnormal uterine bleeding in a multispecialty hospital in Bahrain

Background. Abnormal uterine bleeding is a broad term involving various irregularities of the menstrual cycle. Previously various terms were used to define abnormalities in menstrual bleeding. To create a universally accepted system of nomenclature, the Federation of Obstetrics and Gynecology proposed the new terminology PALM-COIEN. The current study is aimed to classify cases of abnormal uterine bleeding as per PALM-COEIN. Materials and Methods. It is a retrospective, observational study using the data from 110 patients, who underwent hysteroscopic evaluation and endometrial biopsy and were categorized based on PALM-COIEN. Patients were grouped under these categories after detailed history, examination, investigations, hysteroscopic findings, and histopathology. Results. Polyp was the commonest group (n=45, 40.9%) in our study, which was followed by leiomyoma (n=30, 27.27%), ovulatory disturbances (n=28, 25.45%), adenomyosis (n=5, 4.54%), malignancy (n=2, 1.81%) respectively. Conclusions. Hysteroscopic evaluation is a simple and useful tool to find out the structural pathologies of PALM-COIEN classification. Further histopathological confirmation of clinical diagnosis can enhance the diagnosis and treatment modalities.

Quantitative Hormone Analysis Reveals Sources of Variability in the Menstrual Cycle

Although the fluctuations of hormones over the menstrual cycle are well recognized, this study investigated the variability in these patterns for individual women. This study examined a set of daily blood hormone results from an underlying data set of previous research. Hormones included follicle-stimulating hormone (FSH), luteinizing hormone, progesterone, and estradiol taken over one menstrual cycle in 20 women of reproductive age (age 20–36 years), with ultrasound-confirmed ovulation. Although every woman’s profile of hormone changes was consistent with the expected physiological sequence of events, there was notable variability in the timing and peak levels. Variability in the length of the follicular phase was greater than in the length of the luteal phase, with the greater part of the variability in the cycle length being explained by variability in the follicular phase. Lower levels of FSH at the beginning of the cycle were associated with a longer follicular phase. Variability in the timing of events around ovulation was relatively consistent across all women. Variability in the length of the luteal phase was associated with the duration of elevated levels of progesterone. Differences were seen in the extent to which FSH increased at the end of the cycle. This study suggests the variability of the first part of the follicular phase may be due to initial FSH changes. Understanding the variability of menstrual cycle hormones is relevant for all women. Identifying subclinical ovulatory disturbances and variability is important to understand female health, across different populations including menstruating women and female athletes.

Free-living competitive racewalkers and runners with energy availability estimates of

The release of luteinising hormone (LH) before ovulation is disrupted during a state of low energy availability (EA). However, it remains unknown whether a threshold EA exists in athletic populations to trigger ovulatory disturbances (anovulation and luteal phase deficiency) as indicated by peak/mid-luteal serum progesterone concentration (Pk-PRG) during the menstrual cycle. We assessed EA and Pk-PRG in 15 menstrual cycles to investigate the relationship between EA and Pk-PRG in free-living, competitive (trained-elite) Guatemalan racewalkers (n = 8) and runners (n = 7) [aged: 20 (14-41) years; post-menarche: 5 (2-26) years; height: 1.53 ± 0.09 m; mass: 49 ± 6 kg (41 ± 5 kg fat-free mass "FFM")]. EA was estimated over 7 consecutive days within the follicular phase using food, training, and physical activity diaries. A fasted blood sample was collected during the Pk-PRG period, 6-8 days after the LH peak, but before the final 2 days of each cycle. Serum progesterone concentration was quantified using electrochemiluminescence immunoassay. Participants that reported an EA of <35 kcal·kg FFM-1·day-1 (n = 7) exhibited ovulatory disturbances (Pk-PRG ≤9.40 ng·mL-1). Athletes with EA ≥36 kcal·kg FFM-1·day-1 (n = 8) recorded "normal"/"potentially fertile" cycles (Pk-PRG >9.40 ng·mL-1), except for a single racewalker with the lowest reported protein intake (1.1 g·kg body mass-1·day-1). EA was positively associated with Pk-PRG [r(9) = 0.79, 95% confidence interval (CI): 0.37-0.94; p = 0.003; 1 - β = 0.99] after excluding participants (n = 4) that likely under-reported/reduced their dietary intake. The result from the linear regression analysis suggests that an EA ≥ 36 kcal·kg FFM-1·day-1 is required to achieve "normal ovulation." The threshold EA associated with ovulatory disturbances in athletes and non-invasive means of monitoring the ovulatory status warrant further research.

Lack of evidence that progesterone in ovulatory cycles causes breast cancer

A recent Perspective article asserted that progesterone secretion during ovulatory cycles is the cause of breast cancer. However, we challenge most of the evidence developed in this publication. First, there is a lack of evidence that progesterone is mutagenic for breast cells. Cause of a cancer should mean initiation by mutation, as opposed to promotion. Second, subclinical ovulatory disturbances occur rather frequently in normal-length menstrual cycles. Third, the authors attribute a potential carcinogenic effect to progesterone secreted during menstrual cycles but not to progesterone during pregnancy. They did not discuss breast cancer evidence from progesterone/progestin therapeutics. They argue that in genetic primary amenorrhea, a hypothetic lower risk of breast cancer could be due to the lack of progesterone, despite the progesterone/progestin in hormone replacements these women receive. Fourth, they advocate a regulatory effect of progesterone on several genes potentially involved in cancer genesis. In particular, they attribute a lower risk of breast cancer in women with Mayer–Rokitansky–Küster–Hauser syndrome to a defect in the progesterone-stimulated Wnt4 gene. However, this defect is only present in a small subset. Thus, the postulated progesterone breast cancer risk is unconvincing, which we discuss point by point in this commentary.

Melatonin Mitigates Cisplatin-Induced Ovarian Dysfunction via Altering Steroidogenesis, Inflammation, Apoptosis, Oxidative Stress, and PTEN/PI3K/Akt/mTOR/AMPK Signaling Pathway in Female Rats.

Ovarian damage and fertility impairment are major side effects of chemotherapy in pre-menopausal cancer patients. Cisplatin is a widely used chemotherapeutic drug. The present study was designed to assess the ameliorative effects of melatonin as an adjuvant for fertility preservation. Thirty-two adult female Wistar rats were divided randomly into four equal groups: Control, Melatonin, Cisplatin (CP) treated, and CP + Melatonin treated. The cisplatin-treated group showed decreased body and ovarian weights, decreased serum E2 and AMH, increased serum LH and FSH, reduced ovarian levels of SOD, CAT, GSH, and TAC, and increased ovarian MDA. The histopathological examination of the cisplatin-treated group showed deleterious changes within ovarian tissue in the form of damaged follicles and corpus luteum, hemorrhage, and inflammatory infiltrates with faint PAS reaction in zona pellucida, increased ovarian collagen deposition, and marked expression of caspase-3 immune reaction in granulosa and theca cells, stroma, and oocytes. Alongside, there was a significant downregulation in the mRNA expression of steroidogenic enzymes, IL10, AMPK, PI3K, AKT, mTOR, and PTEN, while TGF-β1, IL1β, IL6, TNF-α, NF-Kβ, P53, p38-MAPK, JNK, and FOXO3 mRNA expressions were upregulated in cisplatin-treated rats' ovarian tissue. Coadministration of cisplatin-treated rats with melatonin reversed these changes significantly. In conclusion, melatonin's antioxidant, anti-inflammatory, and anti-apoptotic activities could modulate ovarian disturbances induced by cisplatin and preserve fertility.

THE EFFECT OF CIRCADIAN RHYTHM ON FEMALE REPRODUCTIVE HEALTH IN HUMANS: A REVIEW

Circadian clocks are built-in, self-maintaining timekeeping systems that allow organisms to predict changes in their environment and adjust their behaviour and physiology accordingly (Morse and Sassone-Corsi, 2002). Losing circadian clocks is bad for organisms because it makes them less likely to reproduce and live longer in controlled lab settings and less likely to survive in the wild (Vaze et al 2014). Disruptions in the circadian system can throw biological and behavioural cycles out of sync, which can have severe consequences for human health (Bedrosian and Nelson, 2017). This paper offers an in-depth review of the concept of circadian rhythm, the effect of disruption on human systems and diseases linked to such disruption, such as cancer, immunodeciency, sleep disorders, metabolic and cardiovascular system disorders, mental and health problems. It specically focuses on the adverse impact of disruption in circadian rhythm on the female reproductive system in the form of infertility, ovulatory disturbances, frequent miscarriages, birth defects and breast carcinoma. It also discusses some interventions that can be used to mitigate disruptions in circadian rhythm, based on the existing research. This paper adds to the existing literature on impact of circadian rhythm, especially on issues related to female reproductive health and is a useful resource for students, researchers and medical practitioners.

OR15-6 Epidemic of Subclinical Ovulatory Disturbances During SARS-COV2 Pandemic—an Experiment of Nature

Abstract During the SARS-COV2 pandemic (COVID-19) many studies have examined changes in women's stress, depression/anxiety, reproduction, plus post-vaccination cycle/flow changes1. Although there are retrospective basal temperature data2, we lack menstrual cycle and ovulation information during the pandemic. This analysis compared two independent, similar-design, convenience/community-based, single-cycle cohort studies 13 years apart: Menstruation Ovulation Study (MOS3, n=301, 2007-8) and MOS2 (n=112) during the pandemic. With MOS as a control, and given evidence subclinicalovulatory disturbances (SOD; short luteal phase/anovulatory menstrual cycles of normal lengths) occur before changed cycle lengths4 5, we hypothesized MOS2 would have increased SOD but similar cycle lengths as MOS. Methods In both studies, recruitment of menstruating women ages 19-35 years, not using systemic or combined hormonal contraceptives (CHC) used posters/eblasts/social media. In MOS, ovulation was assessed by 3-fold increased follicular (FP)-to-luteal (LP/premenstrual) urinary progesterone (PdG); in MOS2, by validated Quantitative Basal Temperature© (QBT)6 7 (normal LP=10+ days). We performed the same interviewer-administered (CaMos©) questionnaire for demographics, SES, and reproduction, measured anthropomorphic variables, plus collected daily Menstrual Cycle Diary© (Diary) for all. FP and LP/premenstrual PdG or salivary progesterone (Ps) samples were respectively collected. Participants in MOS2 were not different from MOS in: average age 29, menarche age 12.5, BMI 24, living situation and education (≥75% university graduates). Cohorts also differed: MOS2 women were less likely to to be White (56% vs 76%), work fulltime, ever use CHC (68% vs 79%) or to be parous (8% vs 20%); they were younger at starting CHC (17.9 vs 18.6 years). Results MOS2 and MOS had similar cycle (30.3 vs 29.9 days, P =.306) and flow lengths (median 6.0 days; P=.055). MOS2 recorded significantly more SOD cycles (&amp;gt;50% anovulatory) vs MOS3 (63% vs 10%; P&amp;lt;.001). MOS2 Diary analyses by Principal Components Analysis showed significantly increased anxiety/depression/frustration (negative moods) and "outside stresses" plus sleep problems and headaches vs MOS (all P&amp;lt;.001). Discussion This is the first evidence that ovulatory disturbances without cycle length changes may be associated with the multidimensional stresses women experience during the pandemic. Increased SOD may also relate to greater nulliparity, younger CHC teen use and more non-White women in MOS2, as well higher prevalence of negative moods, outside stresses and sleep problems. Salivary progesterone, cortisol and estradiol levels remain pending. Prevalent SOD cycles, if persistent/recurrent, risk increased infertility, bone loss5, early heart attacks, and breast and endometrial cancers8. In this 'experiment of nature,' the pandemic was associated with disturbed ovulation rather than menstrual cycles. 1Edelman AB Ob Gyn 2022; 2Nguyen JK PLOS ONE 2021; 3Prior JC IJERPH 2018; 4Prior JC NEJM 1990; 5Li D Epidiol Rev 2014; 6Prior JC Clin Invest. Med 1990; 7Bedford JL Eur J ObGyn Reprod Biol 2009; 8Prior JC DDDM 2020. Presentation: Sunday, June 12, 2022 12:15 p.m. - 12:30 p.m.

A one-year observational cohort study of menstrual cramps and ovulation in healthy, normally ovulating women

This is a prospective, observational community cohort study with the objective of investigating menstrual cramp occurrence related to ovulatory characteristics. Women reported cramp intensity on daily Menstrual Cycle Diary© records over one year. Ovulation and luteal phase lengths were assessed by validated Quantitative Basal Temperature© (QBT) analysis. Healthy, normal-weight, non-smoking community dwelling premenopausal women ages 21–41 years with two consecutive, normally ovulatory, normal-length menstrual cycles were enrolled. All 53 women, with 13.6 ± 2.8 cycles per woman, reported at least one cramp episode of median intensity 1.5 [0–4 scale; range 1.0–3.5], and 2.2 days’ [range 1.0–10.2] duration. Within the 49 women who experienced all ovulatory cycle types (normal, short luteal length [SLL < 10 days] and anovulatory), median cramp intensity was greater in normal-length cycles having subclinical ovulatory disturbances (SLL and anovulatory; median 1.4 [range 0.0–2.8]) than in normally ovulatory cycles (median 1.2 [range 0.0–2.3]) (P = 0.023). Cramp Scores did not differ by ovulatory status within the 19 women having both normally ovulatory and anovulatory cycles (P = 0.222). Within-woman 1-year Cramp Scores were not different in anovulatory and normally ovulatory menstrual cycles but were more intense with ovulatory disturbances.

Gallic acid reverses ovarian disturbances in mice with letrozole-induced PCOS via modulating Adipo R1 expression

Research questionWomen are increasingly suffering from polycystic ovary syndrome (PCOS). Its pathophysiology is still unknown, though. The purpose of this study was to ascertain how gallic acid affected the pathophysiology of the ovary in an animal model of polycystic ovary syndrome. We also showed the potential mechanism of adiponectin involvement in endocrine metabolic changes in PCOS mice and the function of adiponectin, which appear to be frequent factors in PCOS. DesignEighteen adult female Parkes strain mice (Age: 4–5 weeks) having body weight of 16–21 g were separated into three groups at random with 6 animals in each group as follows: Group I serving the control, received water and normal diet for 81 days; group II received oral gavage administration of letrozole (LETZ)(6 mg/kg b.w.daily), which was dissolved in 0.9 % NaCl solution for 21 days for the induction of PCOS and left untreated for 60 days; Group III received oral gavage administration of LETZ (6 mg/kg) for first 21 days followed by the administration of gallic acid (GA) (75 mg/kg b.w. orally daily) for 60 days. ResultsWe found LETZ-treated mice experienced PCOS-like symptoms, including increased Serum testosterone, LH/FSH ratio, body and ovarian weight, blood glucose, serum insulin levels and inflammatory Cytokines. We also found decreased serum estrogen, oxidant capacity and enzyme activity and altered ovarian cytoarchitecture, with multiple cysts apart from irregular estrous cycle. Furthermore, mRNA expression levels CYP11a, CYP19a1, Kitl, PTGS2 and Adipo R1 were decreased. Furthermore, LETZ-induced PCOS mice when treated with GA we observed decrease in testosterone, LH, LH/FSH ratio, blood glucose, serum insulin and inflammatory cytokines. GA treatment in PCOS mice also increased estrogen levels, and oxidant capacity as well as enzyme activity. Furthermore mRNA expression levels of CYP11a1, CYP19a1, KITL, PTGS2 and Adipo R1 were also increased in LETZ+GA treated mice. These changes were linked to lower levels of circulating adiponectin and were altered when the mice were administered with gallic acid. ConclusionGallic acid might be a potential therapy in treating PCOS by regulating endocrine and metabolic abnormalities that are brought on by a drop in adiponectin levels along with hyperandrogenism. Additionally, adiponectin seems to be a frequent factor in PCOS. In addition to reducing inflammation-related comorbidities linked to LETZ-induced PCOS, GA enhances mRNA expression levels CYP11a, CYP19a1, Kitl and PTGS2 and hence reduces endocrine and metabolic abnormalities.

Ultrasound-guided transvaginal ovarian needle drilling for clomiphene-resistant polycystic ovarian syndrome in subfertile women.

Ovulatory disturbance is a key diagnostic feature of polycystic ovarian syndrome (PCOS), leading to infertility and correspondingly heavy disease burden. Many therapeutic strategies have been used to induce ovulation for women with PCOS who are infertile. Ultrasound-guided transvaginal ovarian needle drilling (UTND) is a novel surgical method used to induce ovulation for women with clomiphene-resistant PCOS at the outpatient clinic. OBJECTIVES: To evaluate the efficacy and safety of UTND for subfertile women with clomiphene-resistant PCOS. We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, and other databases to December 2020. We checked conference abstracts, reference lists, and clinical trials registries. We also contacted experts and specialists in the field for any additional trials . We planned to include randomised controlled trials comparing UTND to laparoscopic ovarian drilling, and UTND combined with gonadotropins to gonadotropins, in women of reproductive age with clomiphene-resistant PCOS and infertility. Two review authors independently screened the trials identified by the search for inclusion, assessed methodological quality and risk of bias, and extracted data. The primary outcomes were live birth rate and incidence of surgical complications (bleeding and infection). Secondary outcomes included pregnancy rate, ovulation rate, and ovarian hyperstimulation syndrome. We planned to calculate odds ratios with 95% confidence intervals for dichotomous data. We would assess overall quality of the evidence by applying the GRADE criteria. We did not identify any trials for inclusion in the review. We were unable to assess the benefit or harm of applying UTND for women with clomiphene-resistant PCOS, as no studies could be included in the current review. We moved the previously included trials to studies awaiting classification due to concerns regarding methodology. Since we did not identify any studies for inclusion, we were unable to assess the benefit or harm of applying UTND for women with clomiphene-resistant PCOS.

The Role of Endometrial Scratching to Improve the Pregnancy Rate Among Infertile Couples

Background: Different technologies have been used in order to improve the endometrial condition as well as the quality of embryos; however, still the implantation process could fail. Endometrial Scratching (ES) has been proposed by many studies and revealed conflicting results. Objective: The study Aims to investigate the effect of ES on improving the Clinical Pregnancy Rate (CPR) and Live Birth Rate (LBR). Methodology: This is a retrospective study was carried out at Libyan National Fertility Centre. 188 Infertile women were included in the study in two different groups. 95 patients who underwent ES and 93 as control group. Cases with male factor infertility, history of surgical sterilization, premature ovarian failure, endometriosis and other hormonal disturbance (thyroid /prolactin) had been excluded from the study. Results: The CPR was positively affected by scratching procedure among infertile women after perform ES (p value 0.022). The secondary infertile patients have got significant benefit after performing ES by improving the CPR (P value 0.045). The ES has improved the CPR on patients with previous history of failed Intra-Cytoplasmic Semen Injection ICSI (P value 0.043). However, there was no statistically significant difference to the effect of ES on LBR. Conclusion: The study found that the ES has a positive role to improve the implantation among specific group of infertile couples. It is recommended to perform ES for couples with secondary infertility and previously failed ICSI cycle.

P–669 “Follitropin”: A retrospective, observational study comparing the efficacy of follitropin alpha biosimilar therapy in different ovarian stimulation protocols: real-world data

Abstract Study question To investigate the therapeutic efficacy of follitropin alpha biosimilar therapy in nonselected patients undergoing IVF. Summary answer This large retrospective study demonstrated similar therapeutic efficacy for follitropin alpha biosimilar therapy in women who underwent ovarian stimulation (OS) using different protocols. What is known already Based on data from the last meta-analyses (Budani et al., 2020), follitropin alpha biosimilars showed similar efficacy and safety in randomized controlled trials aimed at proving the therapeutic equivalence in terms of oocytes retrieved in women undergoing OS. In most cases, normogonadotrophic patients were enrolled in such studies without any endocrine or ovarian disturbances. The absence of real-world data can be compensated by additional post-marketing studies aimed at investigating the efficacy of biosimilars in different OS protocols using antagonists and agonists of GnRH and OS with mixed gonadotropins. Study design, size, duration A retrospective, observational, anonymized cohort study conducted at 35 IVF clinics in Russia, named “FOLLITROPIN”, compared the efficacy of OS in 2020. The OS protocols analysed where follitropin alpha biosimilar (Primapur®) was applied for at least 5 days. All of the analysed subjects underwent OS using GnRH antagonist/agonist protocols, with no restrictions on the OS protocol or food supplements/vitamins. No inclusion or exclusion criteria were applied. Overall, 5484 OS protocols were analysed. Participants/materials, setting, methods The efficacy of 5484 OS protocols was calculated, and two subgroups were extracted: (1) mixed gonadotropin OS protocols (N = 2625) vs monotherapy with Primapur® (N = 2859); (2) GnRH antagonist OS (N = 2183) vs GnRH agonist (N = 676) using only Primapur®. Demographic and clinical characteristics: (1) Age 34.9±4.8 vs 32.9±4.7 (p &amp;lt; 0.001), BMI 23.9±4.7 vs 23.6±4.5 (p &amp;lt; 0.001), IVF attempt 1.4±0.7 vs 1.3±0.6 (p &amp;lt; 0.001); (2) Age 32.9±4.6 vs 33.1±4.9 (p = 0.449), BMI 23.7±4.6 vs 23.1±4.5 (p = 0.019), and IVF attempt 1.2±0.5 vs 1.4±0.9 (p &amp;lt; 0.001). Main results and the role of chance The total efficacy of OS with Primapur®: oocytes retrieved: 9.5±7.2, MII: 6.8±6.6, 2PN: 6.1±5.8, clinical pregnancy per ET (PR) 6 weeks after ET: 38.4%. Subgroup 1 analysis: oocytes retrieved: 8.6±6.8 vs 10.3±7.4 (p &amp;lt; 0.001), MII: 6.7±6.2 vs 7.7±6.9 (p &amp;lt; 0.001), 2PN: 5.8±5.2 vs 7.2±6.2 (p &amp;lt; 0.001). There were statistically significant differences between oocyte yields in mixed vs monotherapy protocols due to subgroup differences, including age, BMI and IVF attempts. No statistically significant differences were found for PR in subgroup 1: 39.3% [95% CI: 36.9–41.7%] vs 37.6% [95% CI: 35.3–39.8%] (p = 0.314). The major accompanying gonadotropin in the mixed protocol was menotropin (75% for mixed OS protocols). Subgroup 2 analysis: oocytes retrieved: 10.5±7.5 vs 9.6±7.0 (p = 0.032), MII: 7.6±6.9 vs 6.7±5.7 (p &amp;lt; 0.001), 2PN: 7.3±6.3 vs 5.7±5.0 (p &amp;lt; 0.001). There were statistically significant differences between oocyte yields in GnRH antagonist vs GnRH agonist monotherapy due to subgroup differences, including BMI and IVF attempts. No statistically significant differences were found for PR in subgroup 2: 37.9% [95% CI: 35.5–40.5%] vs 35.9% [95% CI: 30.8–41.1%] (p = 0.482). All medicines were well tolerated at the injection site, and no serious adverse reactions were reported. This large retrospective cohort study in a nonselected population demonstrated similar clinical efficacy for follitropin alpha biosimilar therapy. Limitations, reasons for caution The real-world patient data analysed in this study were representative, showing the ability of follitropin biosimilars to develop both folliculogenesis and clinical pregnancy in a nonselected population. Additional comparative studies are needed to confirm the efficacy of the biosimilars in patients with classified types of infertility causes, including unexplained infertility. Wider implications of the findings: In this study, we demonstrated the therapeutic efficacy of biosimilars in terms of oocyte yield and clinical pregnancy development in women undergoing different OS protocols. Further large-scale studies with known hormonal levels before and during OS, as well as the micro- and macronutrient status of both parents, are needed. Trial registration number None

Comparison of Ovarian Morphology and Follicular Disturbances between Two Inbred Strains of Cotton Rats (Sigmodon hispidus).

Simple SummaryMulti-oocyte follicles have been reported in several mammals, especially in rabbits and hamsters, although their significance remains unclear. The present study compared ovarian histology, focusing on folliculogenesis, between two inbred cotton rat strains maintained at Hokkaido Institute of Public Health and the University of Miyazaki. Abundant multi-oocyte follicles and double-nucleated oocytes were observed in the Hokkaido strain, whereas Miyazaki had fewer multi-oocyte follicles and lacked double-nucleated oocytes. These findings indicate that early folliculogenesis events such as oocyte nest breakdown and oocyte vitality, rather than proliferation and cell death in each oocyte, affect the unique ovarian phenotypes found in cotton rats, including multi-oocyte follicles or double-nucleated oocytes, and their differences between strains. Therefore, these results can clarify mammalian folliculogenesis and its abnormal processes.Most mammalian ovarian follicles contain only a single oocyte having a single nucleus. However, two or more oocytes and nuclei are observed within one follicle and one oocyte, respectively, in several species, including cotton rat (CR, Sigmodon hispidus). The present study compared ovarian histology, focusing on folliculogenesis, between two inbred CR strains, HIS/Hiph and HIS/Mz. At 4 weeks of age, ovarian sections from both the strains were analyzed histologically. Multi-oocyte follicles (MOFs) and double-nucleated oocytes (DNOs) were observed in all stages of developing follicles in HIS/Hiph, whereas HIS/Mz had MOFs up to secondary stages and lacked DNOs. The estimated total follicles in HIS/Mz were almost half that of HIS/Hiph, but interstitial cells were well developed in HIS/Mz. Furthermore, immunostaining revealed no clear strain differences in the appearance of oocytes positive for Ki67, PCNA, and p63 in MOF or DNOs; no cell death was observed in these oocytes. Ultrastructural analysis revealed more abundant mitochondrial clouds in oocytes of HIS/Hiph than HIS/Mz. Thus, we clarified the strain differences in the CR ovary. These findings indicate that early events during folliculogenesis affect the unique ovarian phenotypes found in CRs, including MOFs or DNOs, and their strain differences.

Obesity alters ovarian folliculogenesis through disrupted angiogenesis from increased IL-10 production

ObjectiveObesity has been reported to have a modulatory effect on the ovulatory functions of patients with polycystic ovary syndrome. The role of adipokines in this obesity-associated ovulatory disturbance has not been extensively explored. In this study, the relationships between obesity, adipokine production from visceral fat, and ovarian folliculogenesis were explored in a mice model of induced obesity. MethodsObesity was induced in female C57BL/6 mice fed ad libitum with high-fat feed and fructose water for 4 weeks. Follicular developments in the ovaries were assessed by histopathology in these diet-induced obese mice. Changes in adipokine expression in the peri-ovarian adipose tissues were screened with an adipokine array. The adipokine with the most significant increase over time was identified. The functions of the adipokine in angiogenic processes were evaluated in a cell model of endothelial proliferation. The in vivo effects of neutralizing this adipokine using specific antibodies were assessed in the same obesity model. ResultsA high-fat and fructose diet induced an accumulation of early ovarian follicles and a reduction in mature follicles and corpus lutea. The number of microvessels in the early follicles also decreased. The adipokine protein array of the peri-ovarian adipose tissues identified a progressive increase in IL-10 expression with the duration of the obesogenic diet. In vitro experiments in the endothelial cell model confirmed IL-10 as a disrupter of VEGF-induced angiogenesis. Administration of anti-IL-10 antibodies prevented the histopathological changes induced by the obesogenic diet and further highlighted the role of IL-10 in disrupting folliculogenesis. ConclusionsObesity may disrupt normal folliculogenesis through increased production of IL-10 in visceral fats. This relationship may help clarify the reported association between obesity and ovulatory dysfunction, which has been found in patients with polycystic ovary syndrome. However, the duration of this study was short, which limited conclusions on the long-term reproductive outcomes.

Implication of some biochemical parameters on normal cyclic and repeat breeding process in Bangladeshi dairy cows

Repeat breeding is one the most common reproductive disorders that hinders favorable productivity in domestic animals. Repeat breeding in dairy cows not only affects the fertility of the cattle to a considerable extent but also incurs great economic loss to the farmer. Biochemical profile can indicate the nutritional status and help in diagnosis and management of infertility in animals. Present study explores the implication of some biochemical parameters (total protein, bilirubin and some macro minerals as calcium, inorganic phosphorus and magnesium) on normal cyclic breeding process of Bangladeshi dairy cows. Current observation indicates that the lower calcium, inorganic phosphorus and magnesium concentrations might be associated with the ovulatory disturbances in repeat breeder cows. On the other hand, total protein and bilirubin do not play a significant role in causing repeat breeding problem in those cows. Thus, this study provides supportive evidence about the importance of calcium, inorganic phosphorus and magnesium in the resumption of repeat breeding condition.&#x0D; Asian J. Med. Biol. Res. June 2020, 6(2): 305-310

Ultrasound-guided transvaginal ovarian needle drilling for clomiphene-resistant polycystic ovarian syndrome in subfertile women.

Ovulatory disturbance is a key diagnostic feature of polycystic ovarian syndrome (PCOS), leading to infertility and correspondingly heavy disease burden. Many therapeutic strategies have been used to induce ovulation for women with PCOS who are infertile. Ultrasound-guided transvaginal ovarian needle drilling (UTND) is a novel surgical method used to induce ovulation for women with clomiphene-resistant PCOS at the outpatients clinic. Nevertheless, the quality in most of the studies seemed low, and the safety and efficacy of UTND is still uncertain. To evaluate the efficacy and safety of UTND for subfertile women with clomiphene-resistant PCOS. We searched the Cochrane Gynaecology and Fertility Group (CGFG) Specialised Register, CENTRAL, MEDLINE, Embase, and six other databases to November 2018. We checked conference abstracts from the 2018 ESHRE, reference lists, and clinical trials registries. We contacted experts and specialists in the field. We included randomised controlled trials (RCTs) comparing UTND to laparoscopic ovarian drilling (LOD), and UTND combined with gonadotropins to gonadotropins alone for women of reproductive age with clomiphene-resistant PCOS and infertility. Two review authors independently screened appropriate trials for inclusion, assessed methodological quality and risk of bias, and extracted data. The primary outcomes were live birth rate and incidence of surgical complications (bleeding and infection). We included ovarian hyperstimulation syndrome (OHSS) as a secondary outcome. Meta-analyses could only be conducted for the secondary outcomes pregnancy rate and ovulation rate in the comparison of UTND versus LOD using a random-effect model. We calculated odds ratios (OR) with 95% confidence intervals (CI) for dichotomous data. We assessed the overall quality of the evidence by applying GRADE criteria. We included five trials involving 639 clomiphene-resistant women with PCOS. Three studies compared UTND with LOD, and two compared UTND combined with gonadotropins with gonadotropins alone. The evidence was of low to very low quality. The main limitations were serious risk of bias due to poor reporting of methods, inconsistency resulting from heterogeneity, imprecision induced by limited sample size, and lack of reporting of clinically relevant outcomes such as live birth and surgical complications.UTND versus LODNo studies reported on the main outcome live birth. One study reported on surgical complications; however, the evidence for this outcome was of very low quality because it was based on one study with small sample size and there were no events in either arm. Thus, we are uncertain whether there is any difference in surgical complications between UTND and LOD.We are also uncertain whether there is any difference in pregnancy rate when comparing UTND with LOD (OR 0.54, 95% CI 0.28 to 1.03; I2 = 56%; 3 RCTs, n = 473; very-low quality evidence). UTND may lead to a slight decrease in ovulation rate when compared to LOD (OR 0.66, 95% CI 0.45 to 0.97; I2 = 0%; 3 RCTs, n = 473; low-quality evidence). This suggests that among clomiphene-resistant women with PCOS using LOD with an expected ovulation rate of 69.5%, the ovulation rate among women using UTND may be between 50.6% and 68.8%No studies reported on the outcomes OHSS and multiple pregnancy. There was also insufficient evidence to reach a conclusion regarding miscarriage as there was only one study of very low quality.UTND combined with gonadotropins versus gonadotropins aloneNo studies reported on the main outcomes live birth and incidence of surgical complications. The evidence for the outcomes OHSS, pregnancy, ovulation, miscarriage, and multiple pregnancy in this comparison was of very low quality. Thus, we are uncertain whether there is any difference in these outcomes for women with clomiphene-resistant PCOS using UTND combined with gonadotropins as compared with gonadotropins. Based on very low-quality evidence, It is uncertain whether there is any difference in pregnancy rate, incidence of surgical complications, and miscarriage rate between UTND and LOD in women with clomiphene-resistant PCOS. UTND may lead to a slight decrease in ovulation rate when compared to LOD. No studies reported on the outcomes live birth rate, incidence of OHSS, and multiple pregnancy rate. No studies reported on the main outcomes live birth and surgical complications for the comparison UTND combined with gonadotrophins versus gonadotrophins alone. The evidence for the outcomes OHSS, pregnancy, ovulation, miscarriage, and multiple pregnancy in this comparison was of very low quality. Thus, it is unclear if there is a difference in any of the outcomes between UTND combined with gonadotrophins versus gonadotrophins alone.

The risk of breast and gynecological cancer in women with a diagnosis of infertility: a nationwide population-based study

Some studies have suggested that infertility is a risk factor for endometrial, ovarian and breast cancer. The study aimed to create a comprehensive picture of the association between infertility and the risk of ovarian, endometrial and breast cancer, and whether any association could be explained by ovulatory disturbances, endometriosis or nulliparity. In a population-based cohort of 2,882,847 women, cox regression analysis was used to investigate cancer incidence among infertile women. Overall, infertility was associated with a higher incidence rate of ovarian (adjusted hazard ratio [aHR] 1.53, 95% confidence interval [CI] 1.38–1.71) and endometrial cancer (aHR 1.25, 95% CI 1.11–1.40), but not of breast cancer (aHR 0.96, 95% CI 0.92–1.01). Ovarian cancer incidence was higher in women diagnosed with endometriosis, and in nulliparous women with ovulatory disturbances, compared to women with none of the diagnoses. Endometrial cancer incidence was higher in women with ovulatory disturbances, but not in women with endometriosis. These findings suggest that infertility could have long-term consequences of importance to physicians and public health workers.

Free Testosterone Reflects Metabolic as well as Ovarian Disturbances in Subfertile Oligomenorrheic Women.

Background Diagnosing polycystic ovary syndrome (PCOS) is based on ovulatory dysfunction, ovarian ultrasound data, and androgen excess. Total testosterone is frequently used to identify androgen excess, but testosterone is mainly bound to sex hormone-binding globulin (SHBG) and albumin. Only 1-2% of nonprotein-bound testosterone (so-called free testosterone) is biologically active and responsible for androgen action. Moreover, automated immunoassays which are frequently used for female testosterone measurements are inaccurate. Objective To assess the clinical usefulness of liquid chromatography-tandem mass spectrometry measured testosterone and calculated free testosterone in subfertile women attending a fertility clinic with oligomenorrhea and suspected PCOS. Methods Hormonal and metabolic parameters were evaluated, and ovarian ultrasound was performed. Total testosterone was measured by liquid chromatography-tandem mass spectrometry. Free testosterone was calculated from total testosterone and SHBG. Results Sixty-six women were included in the study. Total testosterone was associated with ovarian volume and antral follicle count but not with metabolic parameters. However, SHBG and calculated free testosterone were associated with both ovarian ultrasound and metabolic parameters, such as BMI and insulin resistance. Conclusions Assessing SHBG and free testosterone is important in evaluating androgen excess in subfertile women with ovulatory dysfunction and suspected PCOS, as it reflects both ovarian and metabolic disturbances.

Does Molimina Indicate Ovulation? Prospective Data in a Hormonally Documented Single-Cycle in Spontaneously Menstruating Women.

Approximately 33% of normal-length (21–35 days) cycles have subclinical ovulatory disturbances and lack sufficient progesterone, although their normal length ensures enough estrogen. Subclinical ovulatory disturbances are related to significant premenopausal spine bone loss (−0.86%/year). Molimina, non-distressing premenstrual experiences, may detect ovulation within normal-length cycles. This prospective study assessed the relationship between molimina and ovulation. After 1-cycle of daily diary and first morning urine collections, women answered the Molimina Question (MQ): “Can you tell by the way you feel that your period is coming?” and were invited to share (a) predictive premenstrual experience(s). A 3-fold increase in follicular-luteal pregnanediol levels confirmed ovulation. In 610 spontaneously menstruating women (not on hormonal contraception, mean age 31.5 ± 5.3, menarche age 12.7 ± 1.5, cycle length [CL] 29 days, MQ positive in 89%), reported premenstrual experiences which included negative moods (62%), cramps (48%), bloating (39%), and front (26%) or axillary (25%) breast tenderness. Of 432 women with pregnanediol-documented cycles, 398 (92%) were ovulatory (CL: 29 ± 5) and 34 (8%) had ovulatory disturbances (CL: 32 ± 14). Women with/without ovulatory cycles were similar in parity, body mass index, smoking, dietary restraint and the MQ; ovulatory-disturbed cycles were longer. Molimina did not confirm ovulation. A non-invasive, inexpensive ovulation indicator is needed to prevent osteoporosis.