Is There an Association Between Endometriosis, Early Menopause, and Cardiovascular Disease?

Large-scale studies show endometriosis linked to earlier menopause onset. Recent research targeting women with laparoscopically diagnosed endometriosis found an increase in cases of early natural menopause. Furthermore, recent large-scale cohort studies have found a correlation between endometriosis and an increased risk of cardiovascular disease (CVD). Understanding the causality of early menopause, particularly natural menopause, and cardiovascular risks in women with endometriosis could help medical professionals develop effective strategies for early prevention and new therapies. Endometriosis, early menopause, and cardiovascular risks may be linked by primary or secondary mechanisms. Primary mechanisms involve shared pathways that can lead to all morbidities, while secondary occur due to delayed consequences of management strategies. In these large-scale cohort studies, relevant risk and confounding factors, such as oophorectomy, were considered to refine estimates of associations. However, none of the studies considered endometriotic cystectomy, a globally accepted treatment for endometriosis-associated pelvic pain and infertility, as a mediating factor. There is substantial evidence to indicate that endometriotic cystectomy harms ovarian reserve and may lead to early menopause in cases of multiple surgeries or bilateral cases. Early menopause is a well-established risk factor for CVD. To thoroughly examine the link between endometriosis and early menopause, particularly natural menopause, and their connection with cardiovascular risks, it is imperative to consider all the possible factors that may affect the results, such as endometriotic cystectomy. This will enable us to obtain the most accurate and adjusted hazard ratio.

The impact of ovarian endometrioma and endometriotic cystectomy on anti-Müllerian hormone, and antral follicle count: a contemporary critical appraisal of systematic reviews.

Currently, three crucial questions regarding the reliability of ovarian reserve measures in women with ovarian endometrioma during the reproductive age are being discussed. Firstly, the effects of endometriotic cystectomy on short and long-term ovarian reserve. Secondly, the accuracy of serum anti-Müllerian hormone (AMH) and antral follicle count (AFC) in estimating ovarian reserve in these cases. Thirdly, the impact of endometrioma itself on the ovarian reserve over time in such cases. The purpose of the present review is to critically assess available systematic reviews and meta-analyses that have explored these questions. Nine eligible reviews were found following a systematic search on PubMed.com and similarly assessed. These reviews varied considerably regarding the level of evidence, as per an identical comprehensive scoring system. Moderate to high-quality evidence demonstrates that endometriotic cystectomy, by the stripping technique, adversely affects ovarian reserve in the short and long term, up to 9-18 months post-surgery. Damage to ovarian reserve was considerable but more pronounced in bilateral cases than unilateral cases, equivalent to 39.5% and 57.0%, respectively. Repeat endometriotic cystectomy is detrimental to ovarian reserve. The impact of endometrioma diameter on ovarian reserve before or after surgery is still unclear. Moderate to high-quality evidence, relying on simultaneous assessment of both ovarian reserve measures, shows that AMH is sensitive while AFC is not in cases undergoing ovarian cystectomy. AMH should be the biomarker of choice for counseling and managing women with endometrioma in their reproductive age, especially before surgery. While there is some evidence to show that endometrioma per se may harm ovarian reserve, this evidence is not robust, and there is good-quality evidence to challenge this notion. It is necessary to conduct further targeted RCTs, systematic reviews, and meta-analyses based on solid methodological grounds to increase the level of evidence, refine quantitative estimates, investigate open questions, and decrease heterogeneity.

Low ovarian responders produce more progesterone per follicle than normal and high responders.

OBJECTIVE: Late follicular premature progesterone rise is a complex phenomenon encountered during assisted reproductive technology (ART) treatments; different etiologies can occur in the same patient. Low ovarian responders may be the best example, since higher FSH doses and ovarian aging-related changes may interact and generate a premature progesterone rise. This study aims to explore the correlation between progesterone levels on hCG day and the progesterone-to-follicle index and compare the progesterone-to-follicle index according to ovarian response. METHODS: We performed a retrospective, observational, analytic, cross-sectional, and cohort study at the Reproductive Endocrinology Department at Centro Médico Nacional 20 de November between January 2015 to January 2020. After verifying for normalcy, a Spearman Rho, Principal Component Analysis, and a simple linear regression model were performed. Treatment cycles were classified according to their ovarian response. Low-ovarian responders were classified according to the Bologna Criteria. Then an ANOVA test was performed to compare each group. RESULTS: Our results show that the progesterone-to-follicle index correlates best with progesterone levels on hCG day. Comparing all the ovarian responses, low ovarian responders have the highest progesterone-to-follicle index of the four groups. CONCLUSIONS: Low ovarian responders produce more progesterone per follicle than regular and high responders.

Testicular fine-needle aspiration in infertile men with absolute non-obstructive azoospermia: A single-centre cohort study.

BACKGROUND: The methodology of surgically extracted sperm cells in fertility treatments remains debated, mainly due to the lack of data evaluating its predictive value on treatment outcomes. AIM: To gain insight into the effectiveness of testicular fine-needle aspiration (TEFNA) in a cohort of infertile men with absolute non-obstructive azoospermia and to examine whether the number of retrieved sperm cells affects the fertilisation rate. MATERIALS AND METHODS: A total of 89 infertile men, aged 26-47, meticulously diagnosed with non-obstructive azoospermia, participated in the study. All participants underwent TEFNA. The primary outcome measure was the TEFNA success rate in retrieving mature sperm. The secondary outcome measures included fertilisation rate, clinical pregnancy rates, and live births associated with the retrieved sperm. RESULTS: Sperm cells were successfully retrieved from 40 out of 89 patients (45%) with no significant postoperative complications. Retrieval of up to ten sperm cells occurred in 11 procedures (25%); ten procedures (22.7%) resulted in producing dozens of sperm cells, and 100s to 1000s of sperm cells were obtained from the remainder of 23 procedures (52.3%). Patients whose TEFNA resulted in only a few sperm cells had a much lower fertilisation rate (16.6%) than the other two groups (40.1% and 47.2%, respectively, P = 0.003). CONCLUSIONS: The utilisation of TEFNA for sperm extraction in men with non-obstructive azoospermia is a simple, fast-learning, effective, and safe treatment option. In cases where sperm retrieval was successful, the fertilisation rate was strongly related to the number of sperm cells obtained.

Effects of Probiotics on Glycemic Control and Metabolic Parameters in Gestational Diabetes Mellitus: Systematic Review and Meta-Analysis.

OBJECTIVES: To assess the effects of probiotic supplements on glycemic control and metabolic parameters in women with gestational diabetes mellitus (GDM) by performing a systematic review and meta-analysis of randomized controlled trials. The primary outcome was glycemic control, i.e., serum glucose and insulin levels. Secondary outcomes were maternal weight gain, neonatal birth weight, and lipid parameters. Weighted mean difference (WMD) was used. Cochrane's Q test of heterogeneity and I2 were used to assess heterogeneity. RESULTS: Of the 843 papers retrieved, 14 (n = 854 women) met the inclusion criteria and were analyzed. When compared with placebo, women receiving probiotic supplements had significantly lower mean fasting serum glucose, fasting serum insulin, homeostatic model assessment for insulin resistance (HOMA-IR), triglycerides, total cholesterol, and VLDL levels. Decreased neonatal birth weight was witnessed in supplements containing Lactobacillus acidophilus. CONCLUSION: Probiotic supplements may improve glycemic control and lipid profile and reduce neonatal birth weight in women with GDM.

Should pregnant women be screened for SARS-CoV-2 infection? A prospective multicenter cohort study.

OBJECTIVE: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ranges from asymptomatic to severe infection. We aimed to compare the prevalence of COVID-19 in asymptomatic pregnant versus nonpregnant women in order to establish recommendations for a COVID-19 screening strategy. METHODS: A prospective multicenter cohort study was conducted. Asymptomatic pregnant or nonpregnant women after March 2020 (the time when COVID-19 was first detected in north Israel) were tested for SARS-CoV-2 using nasopharyngeal reverse transcription polymerase chain reaction test, anti-nucleocapsid IgG, and anti-spike IgG. Diagnosis was made if at least one test result was positive. Pregnant women were tested between 34 and 42 weeks, mostly at birth. RESULTS: Among the 297 participating women, 152 were pregnant and 145 were nonpregnant. The prevalence of asymptomatic COVID-19 was similar between the groups (4 [2.6%] and 8 [5.5%], respectively; P = 0.2). All women with COVID-19 delivered healthy appropriate-for-gestational-age babies without malformations, at term. CONCLUSIONS: The rate of asymptomatic COVID-19 in pregnant women is low and comparable to the rate among nonpregnant women. Pregnancy outcomes are favorable. Future screening programs should consider that one of 25 screened asymptomatic women will be positive.

Endometriosis-Associated Ovarian Cancer: What Are the Implications for Women with Intact Endometrioma Planning for a Future Pregnancy? A Reproductive Clinical Outlook.

Endometriosis is a chronic, universal, and prevalent disease estimated to affect up to 1:10 women of reproductive age. Endometriosis-associated ovarian cancer (EAOC) developing at reproductive age is challenging and of concern for women and practitioners alike. This outlook review focuses on the occurrence of EAOC, especially in infertile women or those planning for a future pregnancy, from the perspective of a reproductive endocrinologist, based on recent evidence. Contemporary pathogenesis, genetic profiles, evidence of causality, clinical diagnosis, prognosis, and up-to-date management are discussed. EAOC seems to be merely associated with endometrioma and includes clear-cell and endometrioid ovarian carcinoma. Although endometrioma is frequently found in women of reproductive age (up to 1:18 of women), EAOC appears to be a rare occurrence. These women are of more advanced reproductive age, nulliparous, and hyperestrogenic, with a large-sized unilateral endometrioma (>9 cm) containing solid components and papillary projections. Each case suspected to have EAOC has specific characteristics, and a multidisciplinary discussion and appropriate patient counseling should be conducted to reach an optimal therapeutic plan. Since most of these cases are diagnosed at an early stage with a favorable prognosis, fertility-sparing surgery may be feasible. The pros and cons of fertility preservation techniques should be discussed.

Endometrioma surgery-a systematic review and meta-analysis of the effect on antral follicle count and anti-Müllerian hormone.

OBJECTIVE: Accurate preoperative counseling about whether an endometriotic cystectomy has a detrimental effect on the ovarian reserve has been a considerable challenge, because studies assessing the postoperative antral follicle counts and anti-Müllerian hormone levels have reported conflicting results. Our objective was to explore the impact of endometriotic cystectomy on both the anti-Müllerian hormone levels and antral follicle counts, with focus on prospective studies in which both variables were measured for each woman concurrently (overcoming unmeasured confounding), in the same setting (overcoming surgical technique differences), and at the same 3 postoperative time points, namely early (1-6 weeks), intermediate (2-6 months) and late (9-18 months), to overcome time-sensitive changes. DATA SOURCES: Databases of PubMed, ClinicalTrials.gov, the Cochrane Library, Web of Science, and EBSCO were searched between January 2000 and October 2020. STUDY ELIGIBILITY CRITERIA: Only prospective cohort studies that evaluated the impact of endometriotic stripping cystectomy on anti-Müllerian hormone levels and antral follicle counts in the same women, at matching time points, and in the same setting were eligible. STUDY APPRAISAL AND SYNTHESIS METHODS: Two authors performed the screening and data extraction independently. RESULTS: A total of 14 prospectively designed studies were eligible for the meta-analysis and included 650 women. The included studies had a low risk of bias. The postoperative weighted mean differences in serum anti-Müllerian hormone levels dropped significantly when compared with the preoperative levels by an estimated 1.77 ng/mL (95% confidence interval, 0.77-2.77; P<.001), 1.17 ng/mL (95% confidence interval, 0.66-1.67; P<.001), and 2.13 ng/mL (95% confidence interval, 1.61-2.65; P<.001) at the early (1-6 weeks), intermediate (2-6 months), and late (9-18 months) time points, respectively. This corresponded to a mean reduction in serum anti-Müllerian hormone levels at each of the 3-time points of 44.4%, 35.1%, and 54.2%, respectively. Conversely, the postoperative weighted mean difference in the antral follicle count estimates did not change significantly at any of the 3 time points; the early antral follicle count was 0.70 (95% confidence interval, -2.71 to 3.56; P=.63), the intermediate count was -0.94 (95% confidence interval, -2.53 to 0.65; P=.25), and the late count was 2.58 (95% confidence interval, -0.43 to 5.58; P=.09). Overall, high levels of heterogeneity were encountered (I2 ranging between 92% and 94% for the anti-Müllerian hormone levels and between 94% and 98% for the antral follicle counts at the 3 time points), which were attenuated when similar anti-Müllerian hormone assays were compared, and the meta-regression suggested that age did not contribute to heterogeneity. CONCLUSION: Endometriotic cystectomies are associated with a significant reduction in the serum anti-Müllerian hormone levels but not in the antral follicle counts, with the detrimental effects on the anti-Müllerian hormone levels consistently detectable at the early-, intermediate-, and late-postoperative time points. In women with endometrioma, the anti-Müllerian hormone level may provide a more accurate assessment of the risk for iatrogenic depletion of the ovarian reserve.

Proof of concept use of progesterone/estradiol ratio to investigate late follicular progesterone in women with low number of pre-ovulatory follicles.

BACKGROUND: To investigate late follicular progesterone (P) serum level in women with low number of pre-ovulatory follicles in the assisted reproductive technologies (ART) setting. METHODS: Fifty-five consecutive women having four or less pre-ovulatory follicles of >14 mm on the day of human chorionic gonadotropin (hCG) administration were prospectively evaluated. Spearman correlation tests between serum estradiol (E2) level, serum P level, P/E2 ratio, number of pre-ovulatory follicles, oocytes and embryos were performed. Women enrolled were further divided into two groups in accordance with the P/E2 ratio on the day of hCG administration and compared. RESULTS: Serum E2 level correlated positively with P serum level (rs = 0.36, P < 0.01), number of mature follicles (rs = 0.50, P < 0.01) and number of oocytes retrieved (rs = 0.36, P < 0.05), whereas negatively with P/E2 ratio (rs = - 0.68, P < 0.01). Likewise, number of pre-ovulatory follicles correlated positively with E2 level (rs = 0.50, P < 0.01), P level (rs = 0.27, P < 0.05) and number of oocytes retrieved (rs = 0.33, P < 0.05), while it correlated negatively with P/E2 ratio (rs = - 0.33, P < 0.05). Furthermore, women with P/E2 ratio > 1 on the day of hCG administration received considerably higher total follicular stimulating hormone (FSH) dosage and achieved significantly lower number of oocytes and embryos as compared to controls. CONCLUSIONS: The reverse relationship between number of pre-ovulatory follicles and P/E2 ratio implies that P rise is not only the result of increased steroidogenic activity but other oocytefollicle disrupted mechanisms seems to be involved. An exaggerated FSH stimulation appears to disrupt further these mechanisms.

The Double Edge Sword of Testosterone's Role in the COVID-19 Pandemic.

COVID-19 is a complex disease with a multifaceted set of disturbances involving several mechanisms of health and disease in the human body. Sex hormones, estrogen, and testosterone, seem to play a major role in its pathogenesis, development, spread, severity, and mortalities. Examination of factors such as age, gender, ethnic background, genetic prevalence, and existing co-morbidities, may disclose the mechanisms underlying SARS-CoV-2 infection, morbidity, and mortality, paving the way for COVID-19 amelioration and substantial flattening of the infection curve. In this mini-review, we focus on the role of testosterone through a discussion of the intricate mechanisms of disease development and deterioration. Accumulated evidence suggests that there are links between high level (normal male level) as well as low level (age-related hypogonadism) testosterone in disease progression and expansion, supporting its role as a double-edged sword. Unresolved questions point to the essential need for further targeted studies to substantiate these contrasting mechanisms.

Does large endometrioma per se increase AMH level?

Women with endometriosis, especially those with endometrioma, present a considerable challenge for ovarian reserve appraisal. This diagnostic difficulty arises from several fundamental questions inherently linked to patient management: the potential influence of endometrioma on ovarian reserve; the adverse effect of ovarian surgery on ovarian reserve; and the adequacy of the established ovarian reserve biomarkers, anti-Müllerian hormone and antral follicle count, to appraise ovarian reserve accurately in these women. Until recently, a key argument was that the development and growth of endometriomas is associated with a progressive damage to normal ovarian tissue, resulting in a concomitant reduction in serum AMH levels. Contrary to this widely accepted position; recent studies have reported that, in women with no previous history of ovarian surgery, AMH levels were increased in women with large endometriomas. These findings are surprising and, if replicated, would have substantial clinical implications. In this commentary, we would, however, urge caution before these reports lead to systematic changes in clinical practice, and recommend urgent replication as the finding linking large endometrioma to high serum AMH levels seems to be biologically implausible, and contradicts the existing extensive body of research.

Protein C global assay evaluation in naturally conceived vs. assisted reproduction-achieved twin pregnancies: a prospective longitudinal study.

PURPOSE: Protein C global assay tests the global function of the protein C pathway, the most clinically significant anticoagulant pathway in humans. The objective of this study is to assess the difference in protein C global assay levels, throughout twin gestation, in naturally conceiving and ART-treated women. METHODS: This is a prospective cohort longitudinal study of pregnant women with twin gestation. Protein C Global evaluation was performed on frozen blood samples. Ninety-eight women with twin pregnancy, thirty-eight naturally conceived and sixty following ART, were evaluated on four occasions: during the first, second, and third trimesters, and 6 weeks or later after delivery (baseline). RESULTS: Protein C global assay levels were lower throughout pregnancy as compared to basal levels in both the naturally conceived and ART-conceived groups. However, protein C global assay levels were similar between the ART-conceived and naturally conceived twin pregnancies in all three trimesters. Perinatal complications were associated with decreased protein C global assay levels during the third trimester, although no difference was encountered between naturally conceived and ART-complicated twin pregnancies. CONCLUSION: While protein C global assay levels drop during twin pregnancy, there is no difference between ART-conceived and naturally conceived gestations. Decreased levels of protein C global assay during the third trimester were similarly associated with perinatal complications in both groups. Our results imply that twin pregnancy of itself is a more dominant factor for perinatal complications as compared to other factors, such as subfertility or the exposure to ART per se.

Is there a difference in ovarian reserve biomarkers and ovarian response between the right and left ovaries?

RESEARCH QUESTION: Is there a difference in ovarian reserve biomarkers and ovarian response between the right and left ovaries of infertile women undergoing IVF treatments? DESIGN: A total of 100 infertile women aged 27 to 37 years, diagnosed with either unexplained male factor or mechanical factor infertility, participated in the study. All women had both ovaries intact, and regular menstrual cycles with no previous diagnosis of polycystic ovaries or endometriosis. The data were collected separately for each ovary, and included parameters of basal sonographic ovarian reserve, as well as ovarian response to ovarian stimulation. RESULTS: Basal sonographic ovarian reserve markers were similar between the two ovaries. The right and left ovaries did not differ in their basal antral follicle count (AFC) (6.9 ± 3.9 versus 6.8 ± 3.8, respectively, P = 0.672), nor did they differ in their ovarian volume (10.3 ± 6.7 versus 9.8 ± 8.0 cm3, respectively, P = 0.636). Nevertheless, a superior right-sided ovarian response to ovarian stimulation was observed, with a significantly higher total number of follicles in the right compared with the left ovary (7.8 ± 4.3 versus 6.8 ± 4.2 follicles, respectively, P = 0.006), and a higher number of follicles ≥14 mm on the day of human chorionic gonadotrophin administration (4.9 ± 3.2 versus 3.8 ± 2.4 follicles, respectively, P = 0.002). CONCLUSIONS: Despite comparable basal AFC and ovarian volume, the two ovaries are distinguishable in their response to ovarian stimulation with a clear right-side preference. These findings imply that the superiority of right ovarian response may be derived from local pelvic factors, presumably a more efficient vascularization.

An exome-wide exploration of cases of primary ovarian insufficiency uncovers novel sequence variants and candidate genes.

Primary ovarian insufficiency (POI) implies the cessation of menstruation for several months in women before the age of 40 years and is a major cause of infertility. The study of the contribution of genetic factors to POI has been fueled by the use of whole exome sequencing (WES). Here, to uncover novel causative pathogenic variants and risk alleles, WES has been performed in 12 patients with familial POI (eight unrelated index cases and two pairs of sisters) and six women with early menopause and family history of POI (four index cases and one pair of sisters). Likely causative variants in NR5A1 and MCM9 genes were identified as well as a variant in INHA that requires further investigation. Moreover, we have identified more than one candidate variant in 3 out of 15 familial cases. Taken together, our results highlight the genetic heterogeneity of POI and early menopause and support the hypothesis of an oligogenic inheritance of such conditions, in addition to monogenic inheritance.