Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause.

INTRODUCTION: Estrogens used in women's healthcare have been associated with increased risks of venous thromboembolism (VTE) and breast cancer. Estetrol (E4), an estrogen produced by the human fetal liver, has recently been approved for the first time as a new estrogenic component of a novel combined oral contraceptive (E4/drospirenone [DRSP]) for over a decade. In phase 3 studies, E4/DRSP showed good contraceptive efficacy, a predictable bleeding pattern, and a favorable safety and tolerability profile. AREAS COVERED: This narrative review discusses E4's pharmacological characteristics, mode of action, and the results of preclinical and clinical studies for contraception, as well as for menopause and oncology. EXPERT OPINION: Extensive studies have elucidated the properties of E4 that underlie its favorable safety profile. While classical estrogens (such as estradiol) exert their actions via both activation of nuclear and membrane estrogen receptor α (ERα), E4 presents a specific profile of ERα activation: E4 binds and activates nuclear ERα but does not induce the activation of membrane ERα signaling pathways in specific tissues. E4 has a small effect on normal breast tissue proliferation and minimally affects hepatic parameters. This distinct profile of ERα activation, uncoupling nuclear and membrane activation, is unique.

Ospemifene: A Novel Oral Therapy for Vulvovaginal Atrophy of Menopause.

Vulvovaginal atrophy (VVA) resulting from estrogen deprivation at menopause often results in distressing vaginal dryness and dyspareunia. Fewer than 25% of affected women seek help for this condition citing embarrassment, cultural values, an aging or unavailable partner and concerns about use of estrogens following the Women's Health Initiative. Available non-hormonal treatments, such as moisturizers, while affording some relief can be messy to apply and do not prevent disease progression. A new oral selective estrogen receptor modulator, ospemifene, has been found to have strong estrogenic activity in vaginal tissues without adverse estrogenic effects at other sites.

Number of motile spermatozoa inseminated and pregnancy outcomes in intrauterine insemination.

PURPOSE: To determine whether age modifies the effect of the number of motile spermatozoa inseminated (NMSI) as a predictor of success in Intrauterine Insemination (IUI). METHODS: This retrospective cohort study included all patients who underwent IUI at an academic infertility center between October 2004 and June 2018. The primary outcome was clinical pregnancy (CP; a gestational sac and fetal heartbeat on ultrasound). Results were analyzed by patient factors including age, NMSI, duration of infertility, and cause of infertility, along with treatment factors such as number of follicles and ovulation induction protocol. Factors associated with the odds of achieving a clinical pregnancy were analyzed using binary logistic generalized estimating equations to control for clustering effects by couple. Female age was categorized as <35 years vs. ≥35 years. RESULTS: Seven hundred thirty-seven couples that underwent 2062 IUI cycles for heterogeneous indications were included. The overall CP rate was 15.1% per cycle, and the cumulative CP rate per couple was 35.9%. For females < 35 years, the odds of CP per cycle were reduced for NMSI categories (× 106) of < 5.0 vs. ≥10.0 (OR = 0.49; 95% CI 0.29-0.83); the odds of CP per cycle did not differ for NMSI 5.0-9.9 vs. ≥10.0 (OR = 0.66; 0.37-1.18). For those ≥35 years, no difference was seen in the odds of CP per cycle for NMSI categories < 5.0 vs. ≥10.0 (OR = 1.55; 95% CI 0.72-3.31) or 5.0-9.9 vs. ≥10.0 (OR = 1.04; 95% CI 0.48-2.27). CONCLUSIONS: These results suggest that the NMSI can be used as a predictor of success in IUI in couples with women who are < 35 years of age; these patients should be counselled about their lower pregnancy rates when the NMSI is < 5.0 × 106. In patients ≥35 years, the NMSI does not appear to be a useful predictor of success. Further studies with larger sample size should be conducted.

Hormone Therapy in Breast Cancer Survivors and Those at High Risk for Breast Cancer.

Women and health care providers are often fearful of using hormone therapy to deal with distressing menopausal symptoms in circumstances where there is a perceived or real increased risk of breast cancer. This paper examines the evidence for and against hormone therapy use in 3 common clinical situations: the woman with a positive family history in a first-degree relative, the woman who has undergone risk-reducing salpingo-oophorectomy due to a known genetic mutation, and the woman in whom treatment of breast cancer has induced premature menopause.

SCUBA Diving in Pregnancy.

OBJECTIVE: Obstetrical care providers may occasionally encounter women with questions about the safety of Self-Contained Underwater Breathing Apparatus (SCUBA) diving in pregnancy. This article provides an overview of safety issues associated with basic SCUBA diving and offers guidance to practitioners about how to evaluate and counsel pregnant women about the associated maternal and fetal risks. Basic diving physiology is reviewed and the implications of SCUBA diving during pregnancy are discussed. A literature review examined available animal and human data about the potential adverse effects of the physiological changes of pregnancy on divers, the impact of pressure changes during diving, and possible consequences of hyperbaric gas exposure and rapid decompression on mother and fetus. DATA SOURCES: Studies were found by searching the terms "scuba diving," "pregnancy," "fetus," "decompression illness," "hyperbaric medicine," and "animal studies" in the databases Medline, Pubmed, and Embase. Reference lists from existing articles and reports from identified diving magazines were also reviewed. Studies were limited to the English language and included publications until 2016. STUDY SELECTION: All relevant human studies were selected. Five retrospective studies and one prospective study assessing the antenatal and postnatal outcomes of women who participated in SCUBA diving while pregnant were reviewed. DATA SYNTHESIS: Published data was limited in both quantity and quality. The authors' experience with SCUBA diving together with a background in obstetrics allowed themes to be explored and recommendations developed. CONCLUSIONS: In addition to established risks of SCUBA diving, pregnant women are at increased risk due to changes in body habitus (affecting equipment fitting and balance). Animal data suggest possible adverse fetal effects due to fetal decompression illness (DCI) and hyperbaric oxygen exposure. Human data, though generally reassuring, are of poor quality and thus do not completely exclude adverse outcomes. In general, women should be cautioned to avoid diving during pregnancy, but inadvertent exposure to recreational diving in early pregnancy is not a reason for pregnancy termination.

Premenstrual Dysphoric Disorder: Contemporary Diagnosis and Management.

Most ovulatory women experience premenstrual symptoms (premenstrual syndrome, molimina) which indicate impending menstruation and are of little clinical relevance because they do not affect quality of life. A few women, however, experience significant physical and/or psychological symptoms before menstruation that, if left untreated, would result in deterioration in functioning and relationships. The precise etiology remains elusive, although new theories are gaining support in pre-clinical and early clinical trials. Refined diagnostic criteria allow better discrimination of this condition from other psychiatric diagnoses and the selection of symptom appropriate therapies that afford relief for most women. Pharmacotherapies (particularly selective serotonin reuptake inhibitors and SNRIs) represent the first-line treatment for premenstrual dysphoric disorder and severe, mood-related premenstrual syndrome. Continuous combined oral contraceptives have limited evidence for usefulness in premenstrual dysphoric disorder, whereas medical ovarian suppression is often recommended for patients who fail to respond or cannot tolerate first-line treatments (e.g., selective serotonin reuptake inhibitors). The use of cognitive behavioural therapies is promising, but it remains limited by sparse data and restricted access to trained professionals. A proper diagnosis (particularly the distinction from other underlying psychiatric conditions) is crucial for the implementation of effective therapy and alleviation of this impairing condition.

Testosterone in Women: Measurement and Therapeutic Use.

Androgens, both in excessive and depleted states, have been implicated in female reproductive health disorders. As such, serum testosterone measurements are frequently ordered by physicians in cases of sexual dysfunction and in women presenting with hirsutism. Commercially available androgen assays have significant limitations in the female population. Furthermore, the measurements themselves are not always informative in patient diagnosis, treatment, or prognosis. This article reviews the limitations of serum androgen measurements in women suspected to have elevated or reduced androgen action. Finally, we consider when therapeutic use of androgen replacement may be appropriate for women with sexual interest/arousal disorders.

Ten Challenges in Contraception.

Despite the introduction of promising products into the contraceptive market, the rate of unintended pregnancies remains high. Women with underlying medical conditions should have access to safe and effective contraceptive methods for various reasons, including the potential deleterious effect of the disease on the pregnancy or the effect of the pregnancy on the disease process. Healthcare providers are often confronted with cases in which contraception counseling is problematic due to controversial evidence and persistent myths. This review will examine a number of medical conditions that often create contraception counseling challenges. It should in no way be considered as an extensive review of all contraceptive options for a given medical condition. The following topics will be explored: depression, immunosuppression, inflammatory bowel diseases, past bariatric surgery, liver diseases, family history of breast cancer, migraines, polycystic ovarian syndrome, perimenopausal state, and sickle cell disease. We advocate for improved information and accessibility to contraception as a means of decreasing the rate of unintended pregnancies.

Optimizing Participation of Pregnant Women in Clinical Trials: Factors Influencing Decisions About Participation in Medication and Vaccine Trials.

OBJECTIVE: To obtain information on women's attitudes and opinions about participation in vaccine and medication trials during pregnancy. METHODS: A quantitative, cross-sectional survey was administered to 110 consenting women over a four-week period in the waiting room of an ambulatory obstetrics and gynaecology clinic in Ontario. RESULTS: The final response rate was 74.8%, with the majority of participants agreeing with statements about the importance of obtaining safety data about products in pregnancy and the importance of a woman having the ability to choose whether to participate in such research. Of all participants, 16.3% indicated they would consider participating in vaccine research during pregnancy and 20.0% would consider participating in medication research during pregnancy. Factors relating to maternal or fetal/child health were the most frequently cited factors influencing willingness to participate, with lack of trust in researchers and pharmaceutical companies as factors that would discourage participation. CONCLUSION: A minority of pregnant women were willing to consider participating in medication or vaccine research during pregnancy. Optimizing participation requires providing women (and if appropriate, their partners) with detailed, multidisciplinary education about the maternal and fetal benefits and risks of such trials. Education about the principles of research ethics, including the limits of involvement of pharmaceutical companies, would be beneficial.

Recombinant human oviductin regulates protein tyrosine phosphorylation and acrosome reaction.

The mammalian oviduct synthesizes and secretes a major glycoprotein known as oviductin (OVGP1), which has been shown to interact with gametes and early embryos. Here we report the use of recombinant DNA technology to produce, for the first time, the secretory form of human OVGP1 in HEK293 cells. HEK293 colonies stably expressing recombinant human OVGP1 (rHuOVGP1) were established by transfecting cells with an expression vector pCMV6-Entry constructed with OVGP1 cDNA. Large quantities of rHuOVGP1 were obtained from the stably transfected cells using the CELLSPIN cell cultivation system. A two-step purification system was carried out to yield rHuOVGP1 with a purity of >95%. Upon gel electrophoresis, purified rHuOVGP1 showed a single band corresponding to the 120-150 kDa size range of human OVGP1. Mass spectrometric analysis of the purified rHuOVGP1 revealed its identity as human oviductin. Immunofluorescence showed the binding of rHuOVGP1 to different regions of human sperm cell surfaces in various degrees of intensity. Prior treatment of sperm with 1% Triton X-100 altered the immunostaining pattern of rHuOVGP1 with an intense immunostaining over the equatorial segment and post-acrosomal region as well as along the length of the tail. Addition of rHuOVGP1 in the capacitating medium further enhanced tyrosine phosphorylation of sperm proteins in a time-dependent manner. After 4-h incubation in the presence of rHuOVGP1, the number of acrosome-reacted sperm induced by calcium ionophore significantly increased. The successful production of rHuOVGP1 can now facilitate the study of the role of human OVGP1 in fertilization and early embryo development.

Evaluating Acquisition of Knowledge about Infertility Using a Whiteboard Video.

OBJECTIVE: Myths about fertility are commonplace in society. Few studies have investigated educational approaches to bridge gaps in knowledge among consumers. We evaluated the effectiveness of an animated, 15-minute whiteboard video to effect change in knowledge about infertility. METHODS: We recruited medical students in their first or second year of training for participation. The students completed the study before their formal lectures on infertility issues. Participants completed questionnaires assessing infertility knowledge immediately before and one week after watching the educational video. Before and after scores (maximum = 50 points) were compared using paired t tests. RESULTS: The study cohort included 101 medical students; 69% (70/101) were female and 31% (31/101) were male. Overall, students increased their score by 4.0/50 (95% CI 3.2 to 4.8, P < 0.001) from 36.5/50 to 40.5/50. Female students improved slightly more in their responses than did male students (mean improvement 4.7/50 vs. 2.5/50). CONCLUSION: A whiteboard video presentation on infertility resulted in short-term improvement in medical students' knowledge of basic reproductive biology, infertility risk factors, treatments, and common myths associated with infertility.

Confronting the challenges of the menopausal transition.

Canada's Generation X is now entering the menopausal transition and pursuing effective therapy for bothersome vasomotor symptoms. They do so at a time when confusion about the safe and appropriate use of menopausal hormone therapy (MHT) has never been greater. Misplaced fears among women and their health care providers about MHT have, in many circumstances, led them to abandon this most effective therapy. This review discusses the physiology of the menopausal transition, the nature of symptoms related to withdrawal of ovarian estrogen production, and the potential benefits and risks of MHT. It is now clear that for most recently menopausal women the benefits of MHT outweigh the risks. The rationale for choosing different dosages, formulations, and regimens is reviewed.

Glucose-induced inhibition of the appetitive brain response to visual food cues in polycystic ovary syndrome patients.

We postulate that insulin regulation of food intake is compromised when insulin resistance is present. In order to investigate the effect of insulin sensitivity on appetitive brain responses, we conducted functional magnetic resonance imaging studies in a group of women diagnosed with polycystic ovary syndrome (PCOS) in which insulin sensitivity ranged from normal to resistant. Subjects (n=19) were imaged while viewing pictures of high calorie (HC) foods and low calorie (LC) foods after ingesting either 75 g glucose or an equivalent volume of water. The insulin sensitive group showed reduced blood oxygen level dependent (BOLD) signal in response to food pictures following glucose ingestion in numerous corticolimbic brain regions, whereas the insulin resistant group did not. There was a significant interaction between insulin sensitivity (sensitive vs resistant) and condition (water vs glucose). The largest clusters identified included the left insula, bilateral limbic/parahippocampal gyrus/culmen/midbrain, bilateral limbic lobe/precuneus, and left superior/mid temporal gyrus/parietal for HC and LC stimuli combined, the left parahippocampal gyrus/fusiform/pulvinar/midbrain for HC pictures, and the left superior/mid temporal gyrus/parietal and middle/inferior frontal gyrus/orbitofrontal cortex for LC pictures. Furthermore, BOLD signal in the anterior cingulate, medial frontal gyrus, posterior cingulate/precuneus, and parietal cortex during a glucose challenge correlated negatively with insulin sensitivity. We conclude the PCOS women with insulin resistance have an impaired brain response to a glucose challenge. The inability of postprandial hyperinsulinemia to inhibit brain responsiveness to food cues in insulin resistant subjects may lead to greater non-homeostatic eating.

In vitro development of human primordial follicles to preantral stage after vitrification.

PURPOSE: The aim was to culture primordial follicles in vitro to reach preantral stage in vitrified human ovarian tissue. METHODS: Ovarian tissue samples were obtained from six women. Tissue strips were vitrified by infiltration with a cryoprotectant followed by mounting on a stainless steel carrier. After culturing for 7 days the morphology and developmental stages of follicles enclosed in fresh and vitrified groups were analyzed. RESULTS: High proportion of viable follicles in vitrified ovarian strips was obtained. After culturing for 7 days the percentage of secondary and preantral follicles increased significantly (P < 0.05) whereas primordial and transitory follicles showed a significant decrease (P < 0.05) compared to their respective counterparts at day 0 of culture. CONCLUSIONS: Vitrification of ovarian strips with an improved carrier device and culturing of follicles in ovarian strips after warming yielded developed follicles with high viability and morphological integrity that may be suitable for use in fertility preservation among cancer patients.