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.

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.

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.

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.

Effect of insulin sensitivity on corticolimbic responses to food picture in women with polycystic ovary syndrome.

OBJECTIVE: Insulin is one of several molecules that transmit information about energy balance to the brain. It has been hypothesized that insulin resistance fosters non-homeostatic eating. The objective of the current study was to characterize corticolimbic brain responses to appetitive stimuli in subjects with insulin sensitivities ranging from resistant to normal. DESIGN AND METHODS: Sixteen women diagnosed with polycystic ovary syndrome (PCOS) underwent functional magnetic resonance imaging (fMRI) while viewing pictures of high calorie (HC) foods, low calorie (LC) foods, and control (C) pictures. RESULTS: A region of interest analysis of the blood oxygen level dependent (BOLD) signal revealed widespread activation within corticolimbic regions in response to food pictures. Activated regions included the dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (mPFC) , insula, nucleus accumbens (NAc), pallidum, ventral tegmental area (VTA), putamen, amygdala, caudate, substantia nigra, hippocampus, pulvinar, and midbrain. Activation of the anterior cingulate, dorsolateral prefrontal cortex (DLPFC), and midbrain by HC food pictures (HC - C) and activation of the lateral orbitofrontal cortex (OFC), pallidum, substantia nigra, ventral tegmental area (VTA), pulvinar, and midbrain by LC food pictures (LC - C) was negatively correlated with insulin sensitivity. In contrast, activation of the OFC, DLPFC, insula, hypothalamus, pallidum, substantia nigra, VTA, pulvinar, and midbrain by the HC - LC contrast was positively correlated with insulin sensitivity, whereas activation of the caudate was negatively correlated. CONCLUSIONS: The association between insulin sensitivity and corticolimbic responses to food pictures may reflect abnormal brain responses to insulin feedback that contribute to the development and or perpetuation of obesity in PCOS.

Favorable survival observed after carboplatin, paclitaxel, and concurrent accelerated hyperfractionated radiotherapy for treatment of locally advanced head and neck carcinoma.

PURPOSE: Several trials have demonstrated the superiority of simultaneous chemoradiotherapy compared with radiation alone for patients with locally advanced head and neck cancers. However, the optimal regimen remains to be defined. This study assessed the safety and activity of combined carboplatin (C), paclitaxel (P), and twice-daily radiotherapy (RT) in a community based, multicenter, phase II trial. MATERIALS AND METHODS: Eligible patients (N = 52) had ECOG PS 0-2 and previously untreated, stage III or IV (M0), unresectable, squamous cell cancers of the head and neck. Treatment consisted of 6 weekly courses of C (AUC = 1), P (40 mg/m(2)/1-h) and twice-daily radiation (120 cGy BID; total dose of 6,960 cGy). Subsequently, patients with N2/N3 disease were permitted neck dissection. RESULTS: Median follow-up was 61 months. Sixty-seven percent (67%) of patients had stage IV (M0) disease at baseline. Fifty-five percent (55%) of treated patients experienced NCI Grade 3-4 dysphagia, stomatitis, or mucositis; 80% had > or = Grade 3 toxicity of any organ system. Median weight loss was 7.1 lbs; 35% of patients experienced 10% or more weight loss. Of 43 patients evaluable for response, responses were: 29 CR (67%), 7 PR (16%), 1 MR (2%), 4 SD (9%), and 2 PD (5%); the overall response rate (CR+PR) was 84%. For the entire cohort of 52 patients, the estimated overall survival at 36 months was 60%; progression-free survival was 50%. CONCLUSIONS: We conclude that weekly C + P and concurrent twice-daily hyperfractionated radiotherapy is tolerated and highly active in patients with unresectable, locally advanced squamous cell carcinoma of the head and neck.

Developing a model of nutritional amenorrhea in rhesus monkeys.

Nutritional amenorrhea is defined as cessation of menstrual cycles resulting from a chronic negative energy balance. Although it is agreed that nutritional amenorrhea results from reduced secretion of GnRH, the neuroendocrine mechanisms leading to GnRH inhibition are poorly defined. Because the invasiveness of many neuroendocrine experimental approaches precludes its use in the clinical setting, we set out to establish a model of nutritional amenorrhea in rhesus monkeys. Studies were conducted in four normal-weight and one obese female rhesus monkey. Dietary intake was gradually reduced with the goal of achieving a 15-20% weight reduction. Dietary restriction inhibited ovulation in all animals. The weight loss required to inhibit ovulation ranged from 2-11% in the four normal-weight animals and was achieved with a 23% reduction in dietary intake. The time of initiating reduced food intake to first missed ovulation was 62 +/- 13 d. Greater weight loss (46% reduction) over a longer period (10 months) was required to inhibit ovulation in the obese monkey. The onset of anovulation was not preceded by changes in menstrual cycle length or progesterone secretion. Realimentation initiated ovulation at a weight that approximated the animal's weight at the time of the last ovulatory cycle during dietary restriction. By contrast, caloric intake at the return of ovulation during realimentation was 28% greater. This is the first demonstration that chronic dietary restriction can inhibit ovulation in rhesus monkeys. This model will be useful for studying the neuroendocrine mechanisms involved in diet-induced anovulation in primates.

Caloric restriction inhibits steroid-induced gonadotropin surges in ovariectomized rhesus monkeys.

We recently reported that caloric restriction inhibited ovulation in rhesus monkeys. The objective of the current study was to determine if caloric restriction affected the positive feedback response to ovarian steroids in non-human primates. Studies were conducted in four long-term ovariectomized rhesus monkeys. Animals were given an estrogen/progesterone challenge while maintained on a normal diet and on a diet that reduced body weight by approx 20%. In all cases, animals were maintained at the desired weight [based on a calculation of body mass index (BMI)] for a minimum of 4 wk before initiating the steroid challenge. Caloric restriction reduced BMI from 23.3 +/- 0.3 to 18.9 +/- 0.2 kg/m2. The estrogen/progesterone challenge elicited an LH and FSH surge in each animal maintained at a normal BMI. By contrast, gonadotropin surges were significantly compromised when monkeys were challenged at a low BMI. In addition to affecting the reproductive axis, caloric restriction stimulated cortisol release and suppressed T3 secretion. These endocrine effects of caloric restriction are consistent with our findings in ovary-intact monkeys. In summary, our previous reports in ovary-intact animals confirmed an effect of caloric restriction on tonic gonadotropin secretion leading to anovulation. Our current results suggest the effects of caloric restriction on the reproductive axis extend beyond inhibition of tonic gonadotropin secretion to include a disturbance of phasic gonadotropin secretion.

What women believe about oral contraceptives and the effect of counseling.

OBJECTIVES: To evaluate Canadian women' s knowledge of the risks, benefits and side effects of oral contraceptives (OCs) and the effect of counseling. STUDY DESIGN: Six-hundred and forty-nine Canadian women filling an OC prescription at Shopper's Drug Mart stores completed the survey. Respondents recorded whether or not they had discussed 12 separate issues about OC use with their healthcare provider. Optimal responses to multiple-choice questions were compared between those reporting counseling to those reporting no counseling, using Fisher's Exact Tests. Women were also questioned on what they were told about associated cancer risks. RESULTS: Eighty percent or more of the women selected the optimal response for the questions relating to dysmenorrhea, leg pain and co-medication. Less than half of survey respondents identified the optimal response for nausea, breakthrough bleeding, breast tenderness, acne, headaches and weight change. Counseling made a significant impact on selection of the optimal response for 7 of the 12 questions (p < 0.004, adjusted significance level). Fifty-two percent indicated that they did not know what they were told about the risk of uterine and ovarian cancer when on the pill. A significant proportion of women said they would phone their physician for relatively minor problems such as breakthrough bleeding (65%), breast tenderness (55%) and acne (54%). CONCLUSIONS: The knowledge level of Canadian women on the pill regarding risks, benefits and side effects of the pill remains deficient in several key areas. Adequate counseling by healthcare providers can help women recognize the pill's positive health benefits, and may result in fewer unnecessary physician contacts and unwanted pregnancies.

A survey of recommendations by gynecologists in Canada regarding oral contraceptive use in the perioperative period.

OBJECTIVE: This survey was conducted to determine the practice patterns of gynecologists in Canada regarding the discontinuation of oral contraceptives before gynecologic surgical procedures. STUDY DESIGN: In May and June of 1997, surveys were sent to all obstetricians and gynecologists on the mailing list of the Society of Obstetricians and Gynaecologists of Canada. RESULTS: Of the 1472 surveys that were sent, 702 of the surveys were completed and returned, for a response rate of 48%. More than 90% of the gynecologists who were surveyed would advise their patients to continue using oral contraceptives before relatively minor surgical procedures and <1% of them would use low-dose heparin before these procedures. Rates of oral contraceptive discontinuation increased as the extent of the surgical intervention increased: Prolonged laparoscopy (39.8%), vaginal repairs and hysterectomy (54.7%), and abdominal hysterectomy or adnexectomy (56.1%). Just over one half of the gynecologists (56.1%) indicated that they would advise discontinuation > or =4 weeks before the surgical procedure, which is the minimum time required for the prothrombotic changes that are associated with oral contraceptive use to return to baseline. Less than 10% of the surgeons indicated that they would use low-dose heparin even when the patient was advised to continue taking oral contraceptives before major surgical procedures. CONCLUSION: The controversy over whether young healthy women should discontinue oral contraceptive use before major surgical procedures that are associated with immobility is reflected by a lack of consensus among gynecologists in Canada.