Association between serum hormone levels in early pregnancy and risk of hypertensive diseases of pregnancy in women undergoing assisted reproduction.

PURPOSE: We examined the association between progesterone (P4), estradiol (E2), and human chorionic gonadotropin (hCG) levels in early pregnancy and the development of hypertensive diseases of pregnancy among women undergoing assisted reproduction. METHODS: Retrospective study including patients who underwent frozen embryo transfer (FET), ovarian stimulation (OS), or unassisted conception (UC) and had a live singleton birth. The primary outcome was the development of hypertensive diseases of pregnancy (gestational hypertension, preeclampsia, HELLP, or eclampsia). Secondary outcomes were the development of fetal intrauterine growth restriction (IUGR), gestational diabetes mellitus, birth weight, and pre-term birth. Hormone levels and the development of the outcomes were correlated. RESULTS: A total of 681 patients were included; 189 had FET, 193 had OS, and 299 had UC. Patients undergoing FET or OS were not more likely to develop hypertensive diseases of pregnancy compared with UC patients. While median levels of E2 and P4 were significantly different between P-FET and NC-FET patients (E2: 252 vs 317 pg/mL, P4: 64 vs 29 ng/mL, respectively; both p < 0.01), rates of hypertensive diseases of pregnancy did not significantly differ between those two groups. In the multivariate analyses, P4, E2, and hCG were not associated with the development of hypertensive diseases of pregnancy, but progesterone levels were significantly higher among those with IUGR. This remained consistent when the analysis was limited to FET patients. CONCLUSION: P4, E2, and hCG levels did not correlate with the development of hypertensive diseases of pregnancy but elevated progesterone levels did correlate with the development of IUGR.

Obesity and reproduction.

PURPOSE OF REVIEW: The objective of this review is to highlight the recent literature on how obesity affects reproductive capacity in men and women. RECENT FINDINGS: The relationship between fertility and obesity is complex and involves the hypothalamic-pituitary-ovarian axis, neuroendocrine systems and adipose tissue. The exact pathophysiology of how obesity lowers fertility rates is unknown, but is likely multifactorial involving anovulation, insulin resistance and alterations in gonadotropins. In addition, there is controversy on whether oocyte quality or endometrial receptivity plays a larger role in obese infertile women. Data on effects of bariatric surgery and weight loss on obese infertile men and women are mixed. SUMMARY: Obesity alters the hormonal profile, gonadotropin secretion, embryo development and in-vitro fertilization outcomes in both men and women.

Telehealth provider experience in reproductive endocrinology and infertility clinics during the COVID-19 pandemic and beyond.

PURPOSE: To assess telehealth services offered by reproductive endocrinology and infertility specialists and to gauge provider experiences with incorporating telehealth into their practices. METHODS: A 16-question web-based survey on use of telehealth was distributed to Society for Assisted Reproductive Technology (SART) clinics and to Society for Reproductive Endocrinology and Infertility (SREI) members. Clinic demographic data, telehealth descriptive data, and provider satisfaction with use of telehealth were assessed. Results were collected via Survey Monkey. RESULTS: A total of 1160 individuals (330 SART clinic contacts and 830 SREI members) were reached via email with an 18.6% (216) survey response rate. All respondents indicated that they offer telehealth visits. Several telehealth platforms were used, with Zoom (62.7%) and telehealth through the clinic's electronic medical record platform (34.8%) being the most common. The majority of participants (87.0%) anticipate they will offer telehealth visits after the COVID-19 pandemic. Roughly two-thirds (64.4%) of respondents anticipate fewer telehealth visits after the pandemic because of logistics, cost, and patient/provider preference. Nearly all providers are either "very satisfied" (66.2%) or "somewhat satisfied" (31.0%) with telehealth overall. CONCLUSION: Telehealth enabled safe patient-provider interactions throughout the COVID-19 pandemic. While only one-third of survey respondents offered telehealth services before the pandemic, nearly all providers express satisfaction with telehealth and anticipate they will offer telehealth services henceforth.

Reduction in FSH Throughout the Menstrual Cycle After Omega-3 Fatty Acid Supplementation in Young Normal Weight but not Obese Women.

Dietary fish oil restores ovarian function in subfertile rats, which is thought to be associated with decreased transcription of follicle-stimulating hormone (FSH) ß-subunit. We have previously demonstrated a reduction in early follicular serum FSH levels in normal weight but not obese women after treatment with omega-3 polyunsaturated fatty acids (PUFA). Herein, we report the effect of supplementation with omega-3 PUFA on urinary reproductive hormones across the whole menstrual cycle. This interventional study included 17 eumenorrheic women, aged 24-41 years. One month of daily morning urine was collected before and after 1 month of omega-3 PUFA supplementation with 4 g of eicosapentaenoic acid and docosahexaenoic acid daily. Measurements included urinary FSH, luteinizing hormone (LH) and estrogen and progesterone metabolites, plasma fatty acid composition, and markers of endoplasmic reticulum stress. Compliance with dietary supplementation was verified by significantly reduced ratios of omega-6 to omega-3 PUFA for all subjects after treatment (P < .01). After 1 month of omega-3 PUFA supplementation, urinary FSH was significantly decreased in normal weight, but not obese women, in both follicular and luteal phases (-28.4% and -12.6%, respectively, both P = .04). No significant changes were seen in LH or sex steroids for either weight group. The selective and specific decrease in FSH suggests that omega-3 PUFA supplementation merits further investigation in normal weight women with decreased fertility and/or diminished ovarian reserve.

Analysis of Reported Adverse Events with Uterine Artery Embolization for Leiomyomas.

STUDY OBJECTIVE: To analyze and investigate reports associated with uterine artery embolization used for treatment of myomas using this database. DESIGN: A retrospective review of the Manufacturer and User Facility Device Experience (MAUDE) database for events related to uterine artery embolization (Canadian Task Force Classification III). SETTING: The MAUDE database was accessed online. PATIENTS: Patients with myomas undergoing uterine artery embolization. INTERVENTIONS: The MAUDE database was accessed online and searched for events related to uterine artery embolization reported between 1998 and 2018. These reports were reviewed and analyzed, reported events were categorized, and other relevant information was collected and tabulated. MEASUREMENTS AND MAIN RESULTS: A total of 193 reports published during the study period were identified. Pain was the most frequently reported event (68 events; 35.2%), followed by vaginal discharge (45 events; 23.3%), operational misfire (37 events; 19.2%), and fever or infectious complications (36 events; 18.7%). A surgical procedure was required in 27 events (14.0%), with hysterectomy reported in 7.8% of the events. Death following this procedure was mentioned in 5 events (2.6%). CONCLUSION: The MAUDE database may be useful for clinicians using a Food and Drug Administration-approved medical device to identify the occurrence of adverse events and complications. A variety of adverse events associated with the use of uterine artery embolization were reported to the MAUDE database related to its use in the treatment of uterine myomas. We encourage physicians to review the MAUDE database when using medical devices, because this is an important tool to assess uncommon but major problems that could be associated with a medical device.

Multiple Myeloma 1 Transcription Factor Is Superior to CD138 as a Marker of Plasma Cells in Endometrium.

Chronic endometritis is characterized by plasma cell (PC) infiltration of endometrial stroma. Identification of PCs can be challenging by routine hematoxylin and eosin (H&E) stain due to the low numbers of PCs or to their being obscured by other cells in the stroma. CD138 is widely used as an ancillary immunohistochemistry stain to identify PCs; however, it has a high background reaction. In this study, multiple myeloma 1 (MUM1) transcription factor is introduced as an alternative PC marker in endometrial tissues. In this study, 311 endometrial biopsies, submitted to rule out chronic endometritis, were selected. They were divided into Group I (n = 87) and Group II (n = 224). Both had MUM1 and H&E while Group I also had accompanying CD138 stains. In both groups combined, MUM1 detected plasma cells in 48% of the cases, while CD138 and H&E identified the cells in 23% and 15% of the biopsies, respectively. In addition to having a clean background, MUM1 is a more sensitive stain than CD138 for detection of PCs in endometrium.

Cornual uterine diverticulum following a failed pregnancy.

The discovery of a uterine diverticulum is a rare event. Diverticula can lead to outcomes including pelvic pain, ectopic pregnancy, and diverticula rupture and should be considered in cases of uterine cystic masses. We report a case of a 32-year-old G3P0030 with a complicated pregnancy and surgical history who presented to us following an abnormal laparoscopy for severe pelvic pain four years after salpingectomy for a tubal pregnancy. This laparoscopy reported a cornual uterine cystic structure. Saline infusion sonohysterography was performed with fluid filling a uterine cornual cystic mass. On hysteroscopy, no outpouching was identified. With chromopertubation on laparoscopy, methylene blue filled the diverticulum. The diverticulum was laparoscopically removed. Pathology examination was consistent with a diverticulum containing a placental implantation site and necrotic chorionic villi.

The impact of infertility diagnosis on embryo-endometrial dialogue.

Initial stages of implantation involve bi-directional molecular crosstalk between the blastocyst and endometrium. This study investigated an association between infertility etiologies, specifically advanced maternal age (AMA) and endometriosis, on the embryo-endometrial molecular dialogue prior to implantation. Co-culture experiments were performed with endometrial epithelial cells (EEC) and cryopreserved day 5 blastocysts (n = 41 ≥ Grade 3BB) donated from patients presenting with AMA or endometriosis, compared to fertile donor oocyte controls. Extracellular vesicles isolated from co-culture supernatant were analyzed for miRNA expression and revealed significant alterations correlating to AMA or endometriosis. Specifically, AMA resulted in 16 miRNAs with increased expression (P ≤ 0.05) and strong evidence for negative regulation toward 206 target genes. VEGFA, a known activator of cell adhesion, displayed decreased expression (P ≤ 0.05), validating negative regulation by 4 of these increased miRNAs: miR-126; 150; 29a; 29b (P ≤ 0.05). In endometriosis patients, a total of 10 significantly altered miRNAs displayed increased expression compared to controls (miR-7b; 9; 24; 34b; 106a; 191; 200b; 200c; 342-3p; 484) (P ≤ 0.05), targeting 1014 strong evidence-based genes. Three target genes of miR-106a (CDKN1A, E2F1 and RUNX1) were independently validated. Functional annotation analysis of miRNA-target genes revealed enriched pathways for both infertility etiologies, including disrupted cell cycle regulation and proliferation (P ≤ 0.05). These extracellular vesicle-bound secreted miRNAs are key transcriptional regulators in embryo-endometrial dialogue and may be prospective biomarkers of implantation success. One of the limitations of this study is that it was a stimulated, in vitro model and therefore may not accurately reflect the in-vivo environment.

Evidence for disruption of normal circadian cortisol rhythm in women with obesity.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis may play a role in the pathogenesis of comorbidities encountered in obesity, including the relative hypogonadotropic hypogonadism that we and others have observed. We sought to examine serum cortisol profiles throughout the day and evening in a sample of normal weight women and women with obesity. In this cross-sectional study, regularly cycling obese (n = 12) and normal weight (n = 10) women were recruited. Mean serum cortisol was measured by frequent blood sampling for 16 h (8am-midnight) in the luteal phase of the menstrual cycle. Women with obesity had significantly higher overall cortisol levels when compared to normal weight women (6.2 [4.3, 6.6] vs. 4.7 [3.7, 5.5] ug/dl, p = .04). Over the two-hour postprandial period, obese women displayed an almost two-fold greater (7.2 [6.5, 8.6] ug/dl) rise in cortisol than normal weight controls (4.4 [3.7, 6.2] ug/dl, p < .01). In addition, obese women demonstrated a sustained evening cortisol elevation compared to normal weight women, who displayed the typical decline in cortisol (3.2 [2.3, 4] vs. 2 [1.5, 3.2] ug/dl, p < .05). Changes in the HPA axis in the setting of obesity may be related to risks of obesity-associated metabolic comorbidities and reproductive dysfunction often seen in these women.

Use of fertility medications and cancer risk: a review and update.

PURPOSE OF REVIEW: There is increasing use of fertility medications for ovulation induction and ovarian stimulation for in-vitro fertilization in the treatment of female infertility. In this review, recent literature regarding the association between fertility medication and cancer risk is reviewed. RECENT FINDINGS: Several important publications have recently addressed the relationship between use of fertility medications and cancer risk. There are methodological limitations to many of these studies, including unique challenges in studying rare cancers that often develop several years after the time of fertility medication exposure. Although infertility per se is a risk factor for some female cancers, including breast, endometrial and ovarian cancer, most studies do not show a significant risk of these cancers with the use of fertility medications. Some studies, however, have shown a possible increased relative risk of borderline ovarian cancer, although the increased absolute risk is small without a clear causal relationship. SUMMARY: The collective data regarding the risk of developing cancer from use of fertility medications are reassuring, although several methodological issues in these studies limit definitive conclusions.

Omega-3 Fatty Acid Supplementation Lowers Serum FSH in Normal Weight But Not Obese Women.

CONTEXT: Dietary omega-3 fatty acids delay ovarian aging and promote oocyte quality in mice. OBJECTIVE: To test whether dietary supplementation with omega-3 polyunsaturated fatty acids (PUFA) modulates reproductive hormones in reproductive-age women. DESIGN: Prospective interventional study. SETTING: Academic center. PARTICIPANTS: Fifteen obese and 12 normal-weight (NW) eumenorrheic women, ages 28-34 years. INTERVENTION: Two frequent blood-sampling studies were performed before and after 1 month of omega-3 PUFA supplementation with 4 g of eicosapentaenoic acid and docosahexaenoic acid daily. MAIN OUTCOME MEASURES: Serum LH and FSH (basal and after GnRH stimulation). RESULTS: The ratio of omega-6 to omega-3 PUFA was significantly reduced in plasma and red blood cell components for both groups after treatment (both P < .01). Omega-3 PUFA supplementation resulted in reduction of FSH and FSH response to GnRH by 17% on average (P = .06 and P = .03, respectively) in NW but not obese women. Serum levels of IL-1ß and TNF-α were reduced after omega-3 PUFA supplementation (-72% for IL-1ß; -56% for TNF-α; both, P < .05) in obese but not in NW women. This reduction, however, was not associated with a hormonal change in obese women. CONCLUSIONS: Dietary administration with omega-3 PUFA decreased serum FSH levels in NW but not in obese women with normal ovarian reserve. This effect is intriguing and is directionally consistent with murine data whereby higher dietary omega-3 PUFA extends reproductive lifespan. Our results imply that this nutritional intervention should be tested in women with diminished ovarian reserve in an attempt to delay ovarian aging.

Estradiol Priming Improves Gonadotrope Sensitivity and Pro-Inflammatory Cytokines in Obese Women.

CONTEXT: Obesity is associated with a pro-inflammatory state and relative hypogonadotropic hypogonadism. Estrogen (E2) is a potential link between these phenomena because it exhibits negative feedback on gonadotropin secretion and also inhibits production of pro-inflammatory cytokines. OBJECTIVE: We sought to examine the effect of estrogen priming on the hypothalamic-pituitary-ovarian axis in obesity. DESIGN, SETTING, AND PARTICIPANTS: This was an interventional study at an academic center of 11 obese and 10 normal-weight (NW) women. INTERVENTION: A frequent blood-sampling study and one month of daily urinary collection were performed before and after administration of transdermal estradiol 0.1 mg/d for one entire menstrual cycle. MAIN OUTCOME MEASURES: Serum LH and FSH before and after GnRH stimulation, and urinary estrogen and progesterone metabolites were measured. RESULTS: E2 increased LH pulse amplitude and FSH response to GnRH (P = .048, and P < .03, respectively) in obese but not NW women. After E2 priming, ovulatory obese but not NW women had a 25% increase in luteal progesterone (P = .01). Obese women had significantly higher baseline IL-6, IL-10, TGF-ß, and IL-12 compared with NW (all P < .05); these levels were reduced after E2 (-6% for IL-1ß, -21% for IL-8, -5% for TGF-ß, -5% for IL-12; all P < .05) in obese but not in NW women. CONCLUSIONS: E2 priming seems to improve hypothalamic-pituitary-ovarian axis function and systemic inflammation in ovulatory, obese women. Reducing chronic inflammation at the pituitary level may decrease the burden of obesity on fertility.

Joint MiRNA/mRNA expression profiling reveals changes consistent with development of dysfunctional corpus luteum after weight gain.

Obese women exhibit decreased fertility, high miscarriage rates and dysfunctional corpus luteum (CL), but molecular mechanisms are poorly defined. We hypothesized that weight gain induces alterations in CL gene expression. RNA sequencing was used to identify changes in the CL transcriptome in the vervet monkey (Chlorocebus aethiops) during weight gain. 10 months of high-fat, high-fructose diet (HFHF) resulted in a 20% weight gain for HFHF animals vs. 2% for controls (p = 0.03) and a 66% increase in percent fat mass for HFHF group. Ovulation was confirmed at baseline and after intervention in all animals. CL were collected on luteal day 7-9 based on follicular phase estradiol peak. 432 mRNAs and 9 miRNAs were differentially expressed in response to HFHF diet. Specifically, miR-28, miR-26, and let-7b previously shown to inhibit sex steroid production in human granulosa cells, were up-regulated. Using integrated miRNA and gene expression analysis, we demonstrated changes in 52 coordinately regulated mRNA targets corresponding to opposite changes in miRNA. Specifically, 2 targets of miR-28 and 10 targets of miR-26 were down-regulated, including genes linked to follicular development, steroidogenesis, granulosa cell proliferation and survival. To the best of our knowledge, this is the first report of dietary-induced responses of the ovulating ovary to developing adiposity. The observed HFHF diet-induced changes were consistent with development of a dysfunctional CL and provide new mechanistic insights for decreased sex steroid production characteristic of obese women. MiRNAs may represent novel biomarkers of obesity-related subfertility and potential new avenues for therapeutic intervention.

Obesity and menopause.

Over the recent decades, the prevalence of obesity in the United States has increased to epidemic proportions to more than 35% of adults, along with an increased risk of a number of health conditions, including hypertension, adverse lipid concentrations, and type 2 diabetes. The relationships between menopausal transition, weight gain, and obesity are reported but incompletely understood. The association between menopause and these measures has been the subject of many studies, along with examining their effect on reproductive hormones and menopausal symptoms. The purpose of this review is to summarize what is published in the literature on this subject and examine it through: (1) the possible impact of obesity on the timing of menopause; (2) the effect of obesity on menopausal symptoms and reproductive hormones around the time of menopause; and (3) the effect of menopause on obesity, weight gain, and body composition.

Fertility preservation in a patient with benign multicystic peritoneal mesothelioma.

Benign multicystic peritoneal mesothelioma (BMPM) is a rare peritoneal tumor. Surgery is the only effective treatment for BMPM, and affected tissues occasionally must be sacrificed to achieve adequate debulking. A 25-year-old female was diagnosed with BMPM. She was counseled on fertility preservation and had oocyte cryopreservation prior to her debulking. Fertility preservation through embryo or oocyte cryopreservation is a valuable option for patients at risk of losing reproductive tissues during extensive surgery and chemotherapy.

Menopausal hormone therapy and menopausal symptoms.

A majority of women will experience bothersome symptoms related to declining and/or fluctuating levels of estrogen during their menopausal transition. Vasomotor symptoms, vaginal dryness, poor sleep, and depressed mood have all been found to worsen during the menopausal transition. While vasomotor symptoms gradually improve after menopause, the time course can be many years. Vaginal dryness does not improve without treatment, while the long-term course of sleep and mood deterioration is not clearly defined at this time. A small minority of women have vasomotor symptoms that persist throughout the remainder of their lives. These common menopausal symptoms all improve with estrogen treatment. Over the last 10 years, we have witnessed a dramatic reduction in enthusiasm for menopausal hormone therapy, despite its high efficacy relative to other treatments. We have also seen the emergence of sound, evidence-based clinical trials of non-hormonal alternatives that can control the common menopausal symptoms. Understanding the natural history of menopausal symptoms, and the risks and benefits of both hormonal and non-hormonal alternatives, helps the clinician individualize management plans to improve quality of life.

Analysis of adverse events with Essure hysteroscopic sterilization reported to the Manufacturer and User Facility Device Experience database.

STUDY OBJECTIVE: The Manufacturer and User Facility Device Experience database may be useful for clinicians using a Food and Drug Administration-approved medical device to identify the occurrence of adverse events and complications. We sought to analyze and investigate reports associated with the Essure hysteroscopic sterilization system (Conceptus Inc., Mountain View, CA) using this database. DESIGN: Retrospective review of the Manufacturer and User Facility Device Experience database for events related to Essure hysteroscopic sterilization from November 2002 to February 2012 (Canadian Task Force Classification III). SETTING: Online retrospective review. PATIENTS: Online reports of patients who underwent Essure tubal sterilization. INTERVENTION: Essure tubal sterilization. MEASUREMENTS AND MAIN RESULTS: Four hundred fifty-seven adverse events were reported in the study period. Pain was the most frequently reported event (217 events [47.5%]) followed by delivery catheter malfunction (121 events [26.4%]). Poststerilization pregnancy was reported in 61 events (13.3%), of which 29 were ectopic pregnancies. Other reported events included perforation (90 events [19.7%]), abnormal bleeding (44 events [9.6%]), and microinsert malposition (33 events [7.2%]). The evaluation and management of these events resulted in an additional surgical procedure in 270 cases (59.1%), of which 44 were hysterectomies. CONCLUSION: Sixty-one unintended poststerilization pregnancies were reported in the study period, of which 29 (47.5%) were ectopic gestations. Thus, ectopic pregnancy must be considered if a woman becomes pregnant after Essure hysteroscopic sterilization. Additionally, 44 women underwent hysterectomy after an adverse event reported to be associated with the use of the device.

Adenomyosis within a uterine septum in a patient with secondary infertility.

BACKGROUND: Adenomyosis is a benign infiltration of endometrial stroma and glands into the myometrium. Until the advent and advancement of imaging techniques such as transvaginal ultrasound scan (TVUS) and magnetic resonance imaging (MRI), the diagnosis of adenomyosis could only be made with confidence using histology following hysterectomy. CASE: The patient is a 37-year-old woman, with a long history of secondary infertility. A hysterosalpingogram (HSG) and a pelvic MRI showed two separate uterine cavities. The patient underwent laparoscopy and hysteroscopy revealing a bicornuate appearance of the uterus and a uterine septum. Resection of the septum showed adenomyosis on histologic examination. COMMENT: Adenomyosis of uterine septum should be considered if MRI shows features of adenomyosis elsewhere in the uterus with thickened junctional zone. Further research is needed to investigate this association with the pathogenesis of adenomyosis.

Comparative analysis of different laparoscopic hysterectomy procedures.

PURPOSE: To compare the antecedent gynecological characteristics, indications for, and complications associated with, the different laparoscopic approaches to hysterectomy, in women with benign gynecological conditions. METHODS: A retrospective cohort study of 957 patients who underwent laparoscopic supracervical (LSH), total (TLH), and assisted vaginal (LAVH) hysterectomies between January 2003 and December 2009. RESULTS: Among 957 LH, 799 (83.5%) were LSH, 62 (6.4%) TLH, and 96 (10.1%) LAVH. Demographic characteristics were not different among the groups. Antecedent gynecologic conditions that were associated with the type of laparoscopic hysterectomy (LH) performed were: postmenopausal bleeding [LAVH vs. LSH, odds ratio (OR) 2.20; 95% confidence interval (CI) 1.04-4.65], previous pelvic surgery (TLH vs. LSH, OR 1.92; CI 1.05-3.52), previous cesarean delivery (LAVH vs. LSH, OR 0.39; CI 0.21-0.76), and prior hysteroscopy (LAVH vs. LSH, OR 0.29; CI 0.16-0.50). Preoperative diagnoses that were associated with the choice of LH were: menometrorrhagia (LAVH vs. LSH, OR 0.23; CI 0.14-0.38; TLH vs. LSH, OR 0.50; CI 0.26-0.98), uterine fibroids (LAVH vs. LSH, OR 0.25; CI 0.15-0.41), endometrial hyperplasia (TLH vs. LSH, OR 5.5; CI 2.04-14.84), and cervical dysplasia (TLH vs. LSH, OR 17.1; CI 6.83-42.79; LAVH vs. LSH, OR 8.05; CI 3.05-22.06). Estimated blood loss, operating time, and length of hospital stay were significantly reduced with LSH. CONCLUSION: Antecedent gynecological history and the indications for surgery were associated with the type of LH performed in our institution. LSH was the most common approach and was associated with significantly less morbidity.