John A. Eden

A systematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome

OBJECTIVE To review the effectiveness of metformin in restoring regular menstrual cycles and ovulation and achieving pregnancy in women with polycystic ovary syndrome (PCOS). DESIGN Systematic review of pertinent studies identified using the bibliographic databases MEDLINE and EMBASE. References of selected articles identified were hand-searched for additional relevant citations. PATIENT(S) Women with PCOS undergoing treatment with metformin alone, metformin combined with other methods of ovulation induction such as clomiphene citrate (CC) or gonadotropin injections, or metformin combined with in vitro fertilization (IVF). RESULT(S) Thirty published studies were included in the overall review. Studies consisted of 12 randomized controlled trials, two cohort studies, and 16 uncontrolled descriptive studies. Due to a strong variability in the use of metformin according to study population, exposure, and outcome of interest, it was not possible to combine the data of the 12 randomized controlled trials to perform a meta-analysis. Limited data on predominately obese PCOS patients demonstrate that metformin alone improves both restoration of regular menses and spontaneous ovulation, but there are no data supporting an improvement in pregnancy rate. The addition of metformin to CC results in an improved ovulation and pregnancy rate in both unselected and CC-resistant PCOS women. There are insufficient data to make any conclusions on the effect of metformin on FSH ovulation induction or IVF. CONCLUSION(S) The effectiveness and role of metformin in the treatment of PCOS anovulatory infertility in clinical practice is difficult to assess from currently available research. Further well-designed prospective, perhaps multicenter, randomized controlled trials with the primary end point of pregnancy or live-birth rate are required.

The effect of Promensil™, an isoflavone extract, on menopausal symptoms

OBJECTIVES The primary aim was to assess whether the use of an isoflavone extract containing 40 mg or 160 mg of total isoflavones affects the frequency of menopausal flushes and other symptoms. The secondary aims were assessments of possible effects on menopause symptom scores and biological measures of estrogen activity. METHODS A randomized, double-blind, placebo-controlled prospective trial of 37 postmenopausal women with symptoms of estrogen deficiency was performed over a 12-week period. The women were randomized to three treatment groups: placebo, 40 mg or 160 mg, delivered in tablet form. RESULTS There was no significant difference in the incidence of flushes between the three groups at trial conclusion. There was no difference between the groups in Greene Menopause Symptom Scores, vaginal pH, levels of follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG) or total cholesterol, liver function or blood parameters. A statistically significant increase in high-density lipoprotein (HDL) cholesterol of 18.1% (p = 0.038) occurred in the 40-mg group. CONCLUSION A large placebo response and inadvertent use of dietary isoflavones in the placebo group may have obscured a significant change in flushing frequency. Previous uncontrolled studies claiming a beneficial effect of foods with a high isoflavone content on menopausal symptoms may have been confounded by a large placebo response.

A Case-control Study of Combined Continuous Estrogen—progestin Replacement Therapy among Women with a Personal History of Breast Cancer

Our objective was to examine the effect on all-cause mortality and tumor recurrence rate of combined continuous estrogen-progestin therapy given to symptomatic menopausal women with a personal history of breast cancer. We performed a nested case-control study in a cohort of women with a personal history of breast cancer. The entire database comprised 901 women with surgically confirmed breast cancer attending one of three teaching hospitals in south-eastern Sydney, Australia. Ninety had taken estrogen for relief of severe menopausal symptoms after their diagnosis and treatment of breast cancer. Most were using combined continuous estrogen-progestin therapy, usually an oral estrogen with a moderate dosage progestin. Controls were matched subjects from the same database who had not taken sex steroids after their diagnosis of cancer. The main outcome measures were all-cause mortality and recurrence of breast cancer (or new contralateral breast cancer). Relative risks (RR) were then calculated comparing sex-hormone users with matched controls. Among the 90 estrogen users, there were no deaths and only 7% developed a recurrence, compared to 17% of the nonusers (using two matched controls); RR = 0.40 (95% CI 0.17–0.93). These results suggest that short-term usage of combined continuous hormone replacement therapy (HRT) by women with a personal history of breast cancer may be safe and might even reduce the risk of recurrence. A formal prospective double-blind controlled study is needed to confirm these results.

A twin study of polycystic ovary syndrome.

OBJECTIVE To examine the role of genetic and environmental factors in polycystic ovary syndrome (PCOS) by using the classic twin model. SETTING Outpatient clinic of the Royal Hospital for Women, Paddington, Sydney, New South Wales, Australia. PATIENTS A group of 19 monozygotic (MZ) and 15 dizygotic (DZ) twin pairs identified from the national twin register. INTERVENTIONS Ultrasound, clinical, and biochemical parameters were used to define PCOS. RESULTS Eleven pairs of twins (5 MZ, 6 DZ pairs) were scan-discordant (i.e., one twin had scan-PCOS and the co-twin did not). Model-fitting analysis suggested that fasting insulin level, androstanediol glucuronide, and body mass index (BMI) were significantly influenced by genetic factors. CONCLUSION This study suggests that PCOS is not the result of a single autosomal genetic defect, but rather environmental factors, perhaps both intrauterine and extrauterine, are involved in the pathogenesis of this disorder or that PCOS may be an X-linked disorder or the result of polygenic factors. However, fasting insulin level, androstanediol glucuronide, and BMI did appear to be under significant genetic influence.

A cohort study of topical vaginal estrogen therapy in women previously treated for breast cancer

Objective: To estimate the risk of recurrence of breast cancer associated with the use of topical vaginal estrogen therapy in the management of vaginal atrophy in women previously treated for breast cancer. Methods: The study group comprised 1472 women with histologically confirmed breast cancer. In 69 of these subjects (4.7%) their only bothersome menopausal problems were vaginal symptoms. In these women, poorly absorbed topical vaginal estrogen cream or tablets were used. The response of these patients was compared with that of the rest of the database. A Cox regression analysis was performed using sex hormone usage after diagnosis as a time-dependent covariate. Disease-free interval was the outcome measured. Results are expressed as a hazard ratio with 95% confidence intervals. The hazard rate is defined as the probability of disease recurrence or of a subject dying from breast cancer over the study period. A second analysis was performed adjusting for factors known to affect breast cancer prognosis. Results: Hormone usage was entered as a time-dependent covariate with disease-free interval as the outcome. Subjects who used a topical estrogen alone for menopausal symptoms had an uncorrected hazard ratio of 0.30 (95% confidence interval (CI) 0.11-0.80, p = 0.02). The corrected hazard ratio was 0.57 (95% CI 0.20-1.58, p = 0.28). The hazard rate for a subject dying was not analyzed, as there were too few numbers. Conclusions: Although the small numbers of this study preclude a definitive result, topical estrogen usage does not appear to be associated with an increased risk of recurrence of breast cancer.

The effects of dietary supplementation with isoflavones from red clover on the lipoprotein profiles of post menopausal women with mild to moderate hypercholesterolaemia

The effects of dietary isoflavone supplementation using a purified extract of red clover containing approximately biochanin A 26 mg, formononetin 16 mg, daidzein 0.5 mg and genistein 1 mg per tablet at doses of one or two tablets per day were compared to placebo in a three-period, randomised, double blind, ascending dose study in 66 post menopausal women with plasma cholesterol levels between 5.0 and 9.0 mmol/l. Each treatment period lasted 4 weeks and a further nine women received placebo for the full 12-week period. All women consumed a low isoflavone diet for 2 weeks preceding the commencement of the study and for the 12-week study period. Urinary isoflavone excretion was very low in subjects receiving placebo but increased in a dose-dependent manner during therapy with one and two of isoflavone tablets. Dietary supplementation with isoflavones did not significantly alter total plasma cholesterol, LDL cholesterol, HDL cholesterol or plasma triglyceride levels. However, inverse correlations were found between urinary genistein excretion and plasma triglyceride levels and between urinary O-DMA excretion (an isoflavone metabolite) and plasma triglyceride levels in subjects receiving one isoflavone tablet, suggesting a weak relationship between isoflavone intake and plasma triglycerides which may be influenced by individual differences in isoflavone absorption or metabolism. The results suggest that isoflavone phytoestrogens from red clover in the proportions and quantities studied do not significantly alter plasma lipids in post menopausal women with moderately elevated plasma cholesterol levels.

Testosterone treatment of HSDD in naturally menopausal women: the ADORE study

Objective To evaluate the efficacy and safety of a transdermal testosterone patch (TTP, 300 μg/day) in naturally menopausal women with hypoactive sexual desire disorder (HSDD). Methods A total of 272 naturally menopausal women, predominantly not using hormone therapy, were randomized in this 6-month, placebo-controlled, double-blind, multicenter study to receive twice weekly either TTP or an identical placebo. Efficacy endpoints measured were the 4-week frequency of satisfying sexual episodes (SSE) using the Sexual Activity Log, the sexual desire domain of the Profile of Female Sexual Function and distress by the Personal Distress Scale. Safety was assessed by adverse events, laboratory parameters and hormone levels. Results The TTP group demonstrated significant improvements in SSE (p = 0.0089) as well as in sexual desire (p = 0.0007) and reduced personal distress (p = 0.0024) versus placebo at 6 months (intent-to-treat analysis, n = 247). The results were significant for all three endpoints in the subgroup (n = 199) not using hormone therapy. Similar numbers of women treated with placebo and TTP discontinued (n = 39, 27.5% vs. n = 26, 20%), reported adverse events (including application site reactions) (n = 101, 71.1% vs. n = 81, 62.3%) and withdrew due to adverse events (n = 20, 14.1% vs. n = 9, 6.9%). No clinically relevant changes were noted in laboratory parameters. Serum free and total testosterone levels increased from baseline in the TTP group (geometric means 5.65 pg/ml and 67.8 ng/dl, respectively, at week 24) within the physiological range; no changes were seen in estradiol and sex hormone binding globulin levels. Conclusions TTP was effective in treating HSDD and improving sexual function in this study of naturally menopausal women with and without concurrent hormone therapy.

Effect of a ginger extract on pregnancy‐induced nausea: A randomised controlled trial

Objective: To investigate the effect of a ginger extract (EV.EXT35) on the symptoms of morning sickness.

Effects on menopausal symptoms and acceptability of isoflavone-containing soy powder dietary supplementation

Objectives: To assess the acceptability of the delivery of an isoflavone supplementation in the form of a powdered drink, and whether the supplementation of dietary isoflavones in this manner decreased the incidence of menopausal flushes. The secondary aims included assessment of other symptoms or parameters of estrogen deficiency and responses to isoflavones. Methods: A randomized, double-blind, placebo-controlled, parallel-group trial comprising 24 postmenopausal women with symptoms of estrogen deficiency was performed over a 12-week period. The women were randomized to receive a dietary beverage containing isoflavones or an isoflavone-free, isocaloric placebo preparation. Results: Although there was a high compliance rate among individual patients, there was a 25% withdrawal rate from the study in the active group. The incidence of complaints of bad taste tended to be higher in the active group (p = 0.07), and the total number of adverse events was significantly higher in this group (p < 0.001). There was no statistically significant difference in the incidence of flushes between the groups. There was no difference between the groups in Greene Menopause Symptom Scores, vaginal maturation value, levels of follicle stimulating hormone (FSH) or sex hormone-binding globulin (SHBG), or bone turnover markers. Conclusions: Powdered energy drinks are not commonly consumed in Australia and were poorly tolerated in this study. The high withdrawal rate and reporting of side-effects suggests that other methods of isoflavone delivery may be more appropriate in this culture, in future trials. At the dose used no benefit was seen in relief from menopausal symptoms, although for the sample size, the study could only have been expected to detect major differences between the groups.

A COMPARISON OF FOLLICULAR FLUID LEVELS OF INSULIN‐LIKE GROWTH FACTOR‐1 IN NORMAL DOMINANT AND COHORT FOLLICLES, POLYCYSTIC AND MULTICYSTIC OVARIES

Fourteen ovulatory patients undergoing diagnostic laparoscopy had at least two samples of clear follicular fluid (FF) collected in the late follicular phase. The cohort concentrations of Insulin‐like Growth Factor‐1 (IGF1) were significantly correlated with serum IGF1 and dominant follicles contained significantly higher concentrations of IGF1 and oestradiol (E2) than their cohorts. After the LH surge, a further significant increase in dominant FF‐IGF1 occurred. FF‐(log)E2 was significantly correlated with both FF‐IGF1 and FF volume. Nine women with the polycystic ovary syndrome (PCOS) and one patient with multicystic ovaries (MCO) associated with weight‐loss related amenorrhoea also had follicular aspiration performed. The mean (SD) FF‐IGF1 in the PCOS group, 0.42 (0.15) U/ml, was not significantly different from that of the cohorts in the control group, 0.39 (0.13) U/ml. The patient with MCO had both serum and FF‐IGF1 concentrations < 10th centile. These results support the hypothesis that IGF1 has a paracrine (and possibly endocrine) role in the regulation of ovarian function in the human female.