Self-managed dietary changes and functional gut symptoms in endometriosis: A qualitative interview study.

Objective: Endometriosis is a chronic gynaecological condition, often causing gastrointestinal symptoms and misdiagnosed as irritable bowel syndrome (IBS). Endometriosis guidelines do not formally endorse dietary changes and little is known about how they are self-managed. The objective of this study is to understand nutritional practices and management of gut symptoms in people with endometriosis. Study design: Participants were recruited as part of a larger survey study via endometriosis support groups on social media. Eligibility criteria were: a self-reported physician-led diagnosis of endometriosis, over 18 years old and residing in the United Kingdom (UK). Semi-structured interviews were undertaken virtually via Zoom using a predefined interview guide. All interviews were transcribed and analysed using thematic analysis. Results: 10 people with endometriosis were interviewed. All had made individual dietary changes to manage their gut-related endometriosis symptoms. Dietary changes were made based on advice from social media support, books, websites or professionals other than dietitians. Changes included the restriction and exclusion of multiple essential food groups, including dairy, grains (primarily gluten), vegetables, fruits, and animal products. These changes impacted participants' weight, nutritional status and relationship with food. Four strong themes were identified: 1) impact of pain 2) severe and unpredictable gut symptoms 3) dietary changes and their impact 4) seeking support for dietetic intervention. A common thread underlying and linking these four main themes was the feeling of being dismissed, care being delayed and lack of support. Overall the long delay waiting for a diagnosis, surgery and, at times, the re-occurrence of symptoms post-surgery led to unsupported trial and error with modifiable lifestyle factors, including diet. Conclusion: Overall, participants demonstrated some patterns of restrictive eating behaviour and wanted more professional support to help manage their endometriosis-related gut symptoms. This highlights the need for dietitians to be involved in endometriosis care to help alleviate gut symptoms, whilst ensuring nutritional adequacy and offering weight management support where required.

Socioeconomic status and fertility treatment outcomes in high-income countries: a review of the current literature.

The association between socioeconomic status and fertility is a subject that has received much attention. Yet, little is known as to whether the socioeconomic status has an impact on the outcomes of fertility treatment. This systematic review aims to assess any possible relationship between socioeconomic deprivation and treatment outcomes. A database search was conducted of all publications in this field up to March 2021. Eleven studies were identified and six of these specifically investigated the impact of socioeconomic status on fertility treatment outcomes. Children conceived following assisted conception are more likely to be born to mothers of a higher socioeconomic status than those conceived naturally. Of the few studies investigating the impact of socioeconomic status on fertility treatment outcomes and the results are conflicting, making it difficult to draw robust conclusions as to its effect. It is unknown which, if any, marker of socioeconomic status is the most significant for fertility patients: whether it is the characteristics of the individual or that of their surroundings. Further research is urgently needed.

Is the clinician an independent variable in embryo transfer outcomes under standardized direct and indirect supervision? A 5-year observational cohort study.

Objective: To compare the cumulative pregnancy rate (CPR) for experienced clinicians and trainees naive to the skill of embryo transfer (ET) during an assisted reproductive treatment (ART) cycle. To establish the minimum number of procedures required to achieve consistent outcomes. Method: A non-interventional retrospective observational cohort study looking at all consecutive ETs undertaken over a 5-year study period. The CPR was determined by a self-reported urinary home pregnancy test undertaken 16 days after oocyte retrieval. Results: The CPR did not differ between an experienced clinician (39%) and trainee (45%) for the first 50 (p=0.41) and last 50 (40.7% versus 42.7%) (p=0.81) ET procedures. The CPR for the individuals remained consistent with their peaks and troughs mirroring the overall success rate of the unit. This pattern continued when the data was further stratified for co-variables (age [≤37 years of age], catheter type [soft] and embryo quality [expanded blastocyst of grade ≥2]): CPRs for experienced clinicians was 65.7% (first 50 transfers) and 40.9% (last 50 transfers); CPR for trainees was 66.7% (first 50 transfers) and 53.6% (last 50 transfers); p=0.95 and p=0.37, respectively. The trainees, however, were more likely to use a stylet catheter with a 2-step transfer technique, with a cost over clinical implication. Furthermore, patients expressed a preference for an experienced clinician to perform their procedure, despite being informed that the grade of the clinician had no impact on the cycle outcome after an analysis of the unit's data. Conclusion: The clinician's grade and duration of service have not been shown to significantly impact the outcome of the ART cycle. The findings, however, should be interpreted with caution, as they reflect the culture of training in the unit, where there is a strong emphasis on adequate direct and indirect supervision. Furthermore, the relationship between the volume of work and outcomes is established in postgraduate medical education, with the exact number required to achieve clinical competence being dependent on the procedure and intensity of the workload.

A cross-sectional national questionnaire survey assessing the clinical attitudes of members of the British Menopause Society to the management of women with premature ovarian insufficiency.

OBJECTIVE: To explore the current clinical attitudes of members of the British Menopause Society to the management of premature ovarian insufficiency. DESIGN: An electronic cross-sectional questionnaire survey. SETTING: Members of the British Menopause Society. POPULATION: All members of the British Menopause Society with a valid email address. METHOD: Completion of an electronic survey. MAIN OUTCOME MEASURES: Investigations and treatment options and preferences for the management of women with premature ovarian insufficiency. RESULTS: A total of 130 questionnaires were returned and analysed. The majority of responses were from Hospital Consultants (n = 55/130; 42.3%). A total of 53/124 (42.7%) clinicians routinely performed a bone density scan. A total of 73/130 (56.2%) clinicians would prescribe hormone replacement therapy in preference to combined ethinyl estradiol and progesterone (COC; 27/130, 20.8%). A total of 44/108 (40.7%) routinely prescribed oral estradiol in preference to transdermal administration (62/108, 57.4%). A total of 26/128 (20.3%) prescribed oral micronised progesterone, 31/128 (24.2%) oral progestogens, while 42/128 (32.8%) preferred the intra-uterine system. Fertility concerns remain an important aspect of care, with 33.9% (n = 39/115) of clinicians indicating that more than 50% of their patients had a concern regarding their fertility. CONCLUSION: The majority of clinicians indicated a preference for hormone replacement therapy instead of the COC as their choice of hormone replacement in women with premature ovarian insufficiency. However, there was a significant variation in practices. This information can be useful in counselling women and in guiding clinical practitioners. The results highlight the need for further research to determine the optimal regimens for the management of women with premature ovarian insufficiency.

Fertility desires, choice of hormone replacement and the effect of length of time since menopause on bone density in women with premature ovarian insufficiency: a review of 223 consecutive new referrals to a tertiary centre.

Premature ovarian insufficiency can have significant implications for the affected women. This review assesses the fertility desires, choice of hormone replacement, and the effect of time since menopause on the bone density of these women. This is a retrospective analysis of 223 consecutive new referrals. The average age (mean [± standard deviation]) of the women was 37.35 (± 5.88) years, with 24.1% (n = 19/79) presenting within 12 months of the onset of symptoms, most commonly, vasomotor type symptoms (n = 98/223; 43.9%). Of the women included, 58.7% (n = 131/223) took hormone replacement therapy (HRT), most commonly, an oral (n = 90/131; 68.7%) sequential preparation (n = 91/131; 69.5%), with a significant number of women >40 years of age preferring the transdermal route (n = 26/54; 48.1%; p<0.01). A total of 37.7% (n = 84/223) of the women expressed concerns regarding their future fertility, more notable in women ≤ 40 years (n = 72/142; 50.7%; p < 0.01). Of these, 41.7% (n = 35/84) took HRT, most commonly, a sequential regimen (n = 26/35; 74.3%) with oral estradiol (n = 30/35; 85.7%); 69.5% (n = 155/223) of the women had had a bone densitometry scan performed, with 66.5% (n = 103/155) showing normal bone mineral density (BMD), but a greater likelihood of having reduced BMD the greater the time delay in presentation. No difference was seen for the three broad categories of BMD when further analysed for the cause of premature ovarian insufficiency, but a significant difference was noted for the spinal Z-scores, whereby women who underwent a surgically induced menopause were noted to have lower BMD compared with the other causes (p < 0.01). These findings can be useful in counselling women and guiding clinicians in their management of women with premature ovarian insufficiency.

A randomised controlled trial comparing the effects of micronized progesterone to medroxyprogesterone acetate on cardiovascular health, lipid metabolism and the coagulation cascade in women with premature ovarian insufficiency: study protocol and review of the literature.

Premature ovarian insufficiency (POI) can have significant health implications for the affected patient population, but remains a largely under researched area. There is lack of evidence from randomised controlled trials to guide clinical practice, regarding the optimal hormone replacement therapy regimens, dose and route of administration. Furthermore, little research has addressed the effect of the various progestogens used on health parameters in women with POI. Here we describe an ongoing randomised clinical trial looking at the effects of micronized progesterone and medroxyprogesterone acetate, both used in combination with transdermal oestradiol on the cardiovascular system, lipid profile and coagulation cascade in women with POI as a step towards better understanding of the implications of hormone treatment in this cohort of women.

See-and-treat outpatient hysteroscopy: an analysis of 1109 examinations.

The aim of this study was to assess the feasibility of diagnostic and therapeutic outpatient hysteroscopy. Data were collected prospectively from 1109 consecutive hysteroscopy examinations. The main outcome measure was success and failure of diagnostic and therapeutic outpatient hysteroscopy examination. The mean age (sd) was 47.7 (11.8) years and 53.3% and 39.5% of subjects were post-menopausal and nulliparous, respectively. The most common indications for referral were post-menopausal bleeding (39.8%), menorrhagia (25.7%) and irregular periods (14.5%). Hysteroscopy examination was successfully completed in 96.2% (1067/1109) of the subjects. Success was negatively influenced by age and menopausal status but not parity, although the differences between the age groups and pre- versus post-menopausal groups were minimal. The most common abnormalities were intrauterine polyps (425/1109, 38.3%) and submucous fibroids (142/1109, 12.8%). Of these two groups, respectively, 285/425 (67.1%) and 23/142 (16.2%) subjects had complete polyp and fibroid resection in the outpatient setting and 116/425 (27.3%) and 63/142 (44.4%) underwent polyp and fibroid resection under general anaesthesia. In conclusion, diagnostic and therapeutic hysteroscopy is feasible and highly successful in an outpatient setting. The majority of subjects with endometrial polyps and intrauterine adhesions are amenable to a see-and-treat approach.

Changes in vaginal morphology, steroid receptor and natural antimicrobial content following treatment with low-dose mifepristone.

BACKGROUND: We have previously shown that the antigestagen mifepristone is contraceptive when given in a daily dose of 5 mg, po. Epidemiological studies suggest that gestagen-only contraceptives may increase the risk of transmission of human immunodeficiency virus (HIV) due to effects on the vaginal defenses to infection. We investigate the effects of mifepristone on vaginal thickness, steroid receptor and natural antimicrobial content and pharmacokinetics of mifepristone. METHODS: In a pilot study, eight women were given mifepristone 5 mg/day for an average of 33 days. Ovarian function was assessed by measurement of estradiol and progesterone in blood and their metabolites in urine and by serial ultrasound of their ovaries. Vaginal biopsies were collected before (late proliferative) and after taking mifepristone. RESULTS: All subjects showed a similar pattern of descending serum concentrations of mifepristone. The elimination phase half-life was 18+/-5.1 h (mean+/-SD). Mean Cmax measured at 1 h was 641.7 nmol/L (range, 502-740 nmol/L). All eight women reported amenorrhea for the duration of treatment and seven of eight women showed biochemical and ultrasound evidence of anovulation. There was no significant change in vaginal thickness following treatment [342+/-40 microm pretreatment, 303+/-69 microm posttreatment (mean+/-SEM); p>.05]. Estrogen (ERalpha, ERbeta) and androgen receptor were expressed in both vaginal epithelium and subepithelial stroma, whereas progesterone receptor was expressed predominantly in the subepithelial stroma. There was no change in receptor content and distribution following mifepristone treatment. Natural antimicrobial mRNA [secretory leukocyte protease inhibitor, human beta defensins mRNA (HBD1, HBD2, HBD3, HBD5), granulysin and elafin] was extracted from the vaginal tissues, and the content was unaffected by mifepristone treatment. CONCLUSION: The absence of changes in vaginal thickness, steroid receptor and natural antimicrobial content and its distribution in this preliminary study suggests that in contrast to other estrogen-free contraceptives, mifepristone is unlikely to be associated with the increased risk of transmission of HIV and other sexually transmitted infections.

Toward developing a once-a-month pill: a double-blind, randomized, controlled trial of the effect of three single doses of mifepristone given at midcycle on the pattern of menstrual bleeding.

OBJECTIVE: To test the feasibility of timing the administration of mifepristone as a once-a-month contraceptive pill on the 12th day before the next menses, as calculated from the length of the previous menstrual cycles. DESIGN: Double-blind, randomized, controlled trial. SETTING: Five family planning centers across the world. PATIENT(S): Three hundred ninety-nine women attending family planning clinics. INTERVENTION(S): Randomized to receive 10, 25, or 200 mg of mifepristone or a placebo. MAIN OUTCOME MEASURE(S): Lengthening or shortening of the normal menstrual cycle length following administration of the drug by at least 5 days. RESULT(S): The menstrual period came within 5 days of the predicted date in 88% of women receiving the placebo, 84% of women receiving 10 mg, 72% of women receiving 25 mg of mifepristone, and only 48% of women treated with 200 mg of mifepristone. Increasing the dose of mifepristone was associated with an increased chance of having a delayed period (P<.001). Only 45% of women were in the peri-ovulatory phase of the cycle according to LH and P measurements on the day of drug administration. Women treated before ovulation were more likely to have delayed menses with all three doses of mifepristone. CONCLUSION(S): Because of the disruption in cycle length, it appears unlikely that mifepristone administered once a month, at a calendar-based time, would provide a reliable method of contraception.

Mifepristone-induced amenorrhoea is associated with an increase in microvessel density and glucocorticoid receptor and a decrease in stromal vascular endothelial growth factor.

BACKGROUND: We have previously shown that the progesterone antagonist mifepristone is a contraceptive when given in a dose of 2 or 5 mg per day. The majority of women experience amenorrhoea rather than the irregular break through bleeding usually occurring with other estrogen-free contraceptive pills, such as progestogen-only pill (POP). We investigated the effects of low-dose mifepristone on endometrial parameters which may be associated with changes in endometrial function, such as microvasculature, vascular endothelial growth factor (VEGF) and glucocorticoid receptor (GR) content. METHODS AND RESULTS: Endometrial biopsies were collected from 16 women before (late proliferative phase) and 60 and 120 days after taking 2 or 5 mg mifepristone daily for 120 days. Seven of the eight women who received 2 mg mifepristone and all eight women who received 5 mg were amenorrhoeic during the study. Mean estradiol (E(2)) concentrations remained in the mid-proliferative range, and the majority (9/16) of women showed proliferative endometrial histology at 60 and 120 days following treatment. There was a significant increase in the density of the endometrial stroma (P < 0.05) and microvessels (P < 0.01) following 120 days of treatment. Immunocytochemistry showed that GR, hitherto localized specifically in endometrial stroma, was up-regulated in the nuclei of glands (P < 0.05) and surface (luminal) epithelium (P < 0.01) by 60 days and maintained at 120 days. There was a significant reduction in stromal VEGF protein expression by day 120 of treatment (P < or = 0.01). CONCLUSION: The high incidence of amenorrhoea in women taking mifepristone may be related to changes in the regulation of vascular function.

Low-dose mifepristone inhibits endometrial proliferation and up-regulates androgen receptor.

Mifepristone in daily low doses has contraceptive potential by inhibiting ovulation. Follicular development is maintained, and although the endometrium is exposed to unopposed estrogen, there are no signs of hyperplasia or atypia. The mechanism of this antiestrogenic action is unknown. We have investigated the effect of daily low-dose mifepristone on proliferation markers and steroid receptors in surface epithelium, glands, and stroma of the endometrium. Endometrial biopsies were collected from 16 women before (late proliferative) and 60 and 120 d after taking 2 or 5 mg mifepristone daily for 120 d. Endometrial proliferation (H3 mitosis marker) and steroid (estrogen, progesterone, and androgen) receptor content were studied using standard immunocyotchemistry techniques. There was a significant decrease in the expression of H3 mitosis marker (P

Effects of onapristone on postmenopausal endometrium.

The progesterone antagonist mifepristone (RU486, Exelgyn) has been shown to exert a paradoxical agonist effect on postmenopausal endometrium. We conducted a study to investigate the effects of the 'pure' antiprogestin onapristone (ZK 98 299, Schering AG) on postmenopausal endometrium. Seventeen postmenopausal subjects (45-62 years), took 2 mg of oestradiol and either placebo, 1 mg onapristone or 10 mg of onapristone, daily for 56 days. An endometrial biopsy was performed during the final week of treatment and assessed for histology and immunohistochemistry for oestrogen receptors (ER), progesterone (PR), androgen receptors (AR) and the cell proliferation marker Ki 67. FSH fell in all 14 subjects who completed the study, consistent with the effect of oestradiol treatment. There was a dose-dependent additive effect of onapristone on suppression of gonadotrophins. All endometrial biopsies showed proliferative endometrium. A similar pattern and intensity of immunostaining of ER, PR and Ki 67 was observed in all groups, with positive immunoreactivity in both glands and stroma. AR immunostaining was observed in both glands and stroma from all subjects, but there was an increase in intensity of immunostaining within the glandular epithelium of women receiving 10 mg onapristone. The antiprogestin onapristone, in contrast to mifepristone, is not agonistic on postmenopausal endometrium and does not exert obvious antiproliferative effects. It does however cause a dose dependent suppression of FSH and LH release.

Mifepristone: a novel estrogen-free daily contraceptive pill.

When the first synthetic progesterone antagonist (mifepristone) was synthesized over 20 years ago, it was clear that it had a potential as an antifertility agent. Research into the use of antiprogestogens for contraception have concentrated on three general approaches: (1) inhibition of ovulation, (2) inhibition of implantation and (3) disruption of implantation or "menstrual induction". The effect of mifepristone on the ovarian and endometrial cycle depends on dose, timing and frequency of administration. Doses of 10 mg per day or more suppress follicular development and estradiol levels. Ovulatory cycles are maintained in the dose of less than 2 mg although there is increased variability in cycle length. The endometrium shows some minor asynchronous changes, although these are not sufficient to prevent pregnancy. We have chosen to investigate daily doses between 2 and 5 mg which inhibit ovulation and menstruation in over 90% of cycles while still maintaining follicular development and levels of estradiol within the range found during the follicular phase. The endometrium shows proliferative or cystic changes lined by a layer of inactive glandular epithelium set in densely packed stroma. There is, however, an absence of proliferative activity as reflected by a reduced mitotic index and Ki67 staining. These unusual histological appearances are associated with downregulation of PR but a massive upregulation of AR in particularly glandular epithelium. The antiproliferative effect of mifepristone is reassuring suggesting that the risk of atypical hyperplasia due to the effect of prolonged exposure to estrogen unopposed by progesterone is low. In a pilot study, there were no pregnancies in 200 months of exposure in 50 women who used this method as their sole method of contraception. Daily mifepristone could provide a novel contraceptive method which should be devoid of the risks associated with estrogen containing combined oral contraceptive (COC), e.g. venous thromboembolism. The health benefits of avoiding the morbidity associated with menstruation are considerable. Recent surveys suggest that amenorrhoea would be popular with many women.

Medical management of late intrauterine death using a combination of mifepristone and misoprostol.

OBJECTIVE: To assess the efficacy and safety of mifepristone in combination with misoprostol in the management of late fetal death. DESIGN: Observational study. SETTING: Aberdeen Maternity Hospital, Aberdeen. METHODS: A consecutive series of 96 women with intrauterine death after 24 weeks of gestation were studied. Each woman received a single dose of 200 mg mifepristone orally, following which a 24-48 hour interval was recommended before administration of misoprostol. For gestations of 24-34 weeks, 200 microg of intravaginal misoprostol was administered, followed by four oral doses of 200 microg at three hourly intervals. Gestations over 34 weeks were given a similar regimen but a reduced dose of 100 microg misoprostol. RESULTS: The average induction to delivery interval was 8.5 hours. Ninety-five women (98.9%) were delivered within 72 hours of administration of first dose of misoprostol, with 66.7%, 87.5%, 92.7% and 95.8% women delivering within 12, 24, 36 and 48 hours, respectively. No significant correlation was found between mean induction to delivery interval and maternal age, parity, Bishop's score, birthweight and mifepristone/ misoprostol interval. The induction to delivery interval was shorter with increasing gestation (P = 0.04). Mild side effects were noted in eight (8.3%) women. Three (3.1%) women had treatment for presumed or proven pelvic sepsis. No cases of uterine tachysystole, haemorrhage or coagulopathy were recorded. CONCLUSION: The combination of mifepristone and misoprostol for induction of labour following late fetal death is an effective and safe regimen. The induction to delivery interval with this regimen appears shorter than studies using mifepristone or misoprostol.