STUDY QUESTION

What is the health-related quality of life (HRQoL) in women with polycystic ovary syndrome (PCOS) undergoing ovulation induction with clomifene citrate (CC) combined with metformin compared with those using CC combined with placebo?

SUMMARY ANSWER

Overall quality of life in women with PCOS treated with CC plus metformin was significantly lower than in women treated with CC plus placebo.

WHAT IS KNOWN ALREADY

There are no data on HRQoL in adult women who receive ovulation induction with the purpose of conceiving. Women with PCOS have higher scores on depression and anxiety scales and lower QoL scores than women without PCOS.

STUDY DESIGN, SIZE AND DURATION

This study was a secondary analysis of a multi-centre RCT completed between June 2001 and May 2004. The randomization was stratified per centre, and the centres received blinded, numbered containers with medication. There were172 women available for the HRQoL assessment: 85 were allocated to metformin and 87 were allocated to placebo.

PARTICIPANTS, SETTING AND METHODS

The Rotterdam Symptom Checklist (RSCL), a standard self-administered questionnaire, was used to assess physical symptoms, psychological distress, activity levels and overall HRQoL.

MAIN RESULTS AND THE ROLE OF CHANCE

In the intention to treat analysis, we found differences between the treatment groups with respect to physical symptoms and overall HRQoL. Physical well-being was significantly impaired in women allocated to metformin but not in women allocated to placebo. The increase in physical symptoms in the metformin group was caused by side-effects typical of metformin, and was most pronounced at Week 1 (mean difference 12 [95% confidence interval (CI): 8–16] and still apparent at Week 16 [mean difference 7 (95% CI 2–12]. Overall well-being was significantly impaired in the metformin group compared with the placebo group [mean difference 13 (95% CI 6–20)].

LIMITATIONS AND REASONS FOR CAUTION

RSCL measurements were available only for three quarters of the participants. Although the number of missing questionnaires and the baseline measurements, were comparable between the treatment groups, some form of selection bias cannot be ruled out.

WIDER IMPLICATIONS OF THE FINDINGS

Our finding that metformin was more burdensome than placebo, strengthens the recommendation that CC only and not CC plus metformin should be the drug of choice in this patient population.

STUDY FUNDING/COMPETING INTEREST(S)

None of the authors declared a conflict of interest. There was no study funding.

Trial Registration Number

ISRCTN55906981.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3273?rss=1

Recommendation and review posted by G. Smith

STUDY QUESTION

Are self-reported menstrual disorders associated with hyperandrogenaemia and metabolic disturbances as early as in adolescence?

SUMMARY ANSWER

Menstrual disorders at the age 16 are a good marker of hyperandrogenaemia, and an adverse lipid profile was associated with higher androgen levels.

WHAT IS KNOWN AND WHAT THIS PAPER ADDS

Hyperandrogenism per se has been suggested to be a significant metabolic risk factor in women and a cause of physical and psychological morbidity in adolescent girls. A weak positive correlation has been described between hyperandrogenaemia and obesity in adolescent girls, but the clinical consequences are still poorly understood. Hyperandrogenism and insulin resistance are also key features of polycystic ovary syndrome (PCOS), and women with PCOS are consequently at an increased risk of developing type 2 diabetes mellitus and/or metabolic syndrome, and may have increased cardiovascular morbidity.

Our findings confirm that the association between menstrual disorders, hyperandrogenism, obesity and metabolic risks is already evident in adolescence.

STUDY DESIGN

This population-based, cross-sectional study used postal questionnaires to targeting 15–16-year-old girls in the Northern Finland Birth Cohort 1986 (n= 4567).

PARTICIPANTS AND SETTING

There were 3669 girls who answered the postal questionnaire and out of 3373 girls who also underwent clinical examinations and blood tests, 2448 were included in the analyses. The questionnaire included one question about the regularity and length of the menstrual cycle: ‘Is your menstrual cycle (the interval from the beginning of one menstrual period to the beginning of the next period) often (more than twice a year) longer than 35 days?’ The girls who answered ‘yes’ to this question were considered to be suffering from menstrual disorders and were classified as ‘symptomatic’. The girls who answered ‘no’ were defined as ‘non-symptomatic’.

MAIN RESULTS AND THE ROLE OF CHANCE

There were 709 (29%) girls who reported menstrual disorders (symptomatic girls) and 1739 who had regular periods (non-symptomatic girls). In the whole population and in both study groups, there were significant correlations between body mass index (BMI) (and waist-to-hip ratio), hyperandrogenaemia and metabolic parameters. Symptomatic girls exhibited significantly higher serum concentrations of testosterone (P= 0.010), lower levels of sex hormone-binding globulin (P =0.042) and higher free androgen indices [FAIs; geometric mean 3.38 (interquartile range (IQR): 2.27, 5.18) versus 3.08 (IQR: 2.15, 4.74), P= 0.002]. The two groups had comparable BMI and insulin sensitivity, and serum levels of glucose, insulin and lipids. There was a significant linear trend towards higher FAI values in the higher BMI quartiles in both symptomatic and non-symptomatic girls. In the whole population, there was a statistically significant linear decrease in high-density lipoprotein concentrations (P < 0.001) and higher triglyceride concentrations (P =0.004) in the upper FAI quartile.

IMPLICATIONS

Information regarding menstrual disorders in adolescence is a good marker of hyperandrogenaemia and may be an early risk factor for the development of PCOS in adulthood. The association between obesity, hyperandrogenism and metabolic risks is already evident in adolescence, which strengthens the importance of noting menstrual disorders at an early stage.

BIAS, LIMITATIONS, GENERALIZABILITY

The cross-sectional nature of the study does not allow us to draw conclusions concerning the metabolic risks of this population in later life. The diagnosis of menstrual disorders was based on a questionnaire, suggesting a risk of information bias in reporting the symptoms. This study was not designed to diagnose PCOS, as ultrasonography was not available and there was no clinical evaluation of hyperandrogenism (i.e. hirsutism). However, we were able to take into account potential confounding factors in the analyses.

STUDY FUNDING/COMPETING INTERESTS

This work was supported by grants from the Finnish Medical Society Duodecim, the North Ostrobothnia Regional Fund, the Academy of Finland (project grants 104781, 120315, 129269, 1114194, SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643) and the Medical Research Council, UK (PrevMetSyn/SALVE). None of the authors have any conflict of interest to declare.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3279?rss=1

Recommendation and review posted by G. Smith

BACKGROUND

For decades androgens have been considered detrimental to follicle maturation. Animal studies now suggest that they are essential for normal folliculogenesis. Especially in women with premature ovarian aging (POA), recent IVF data in humans are supportive. The literature also suggests an association between recently reported ovarian genotypes of the FMR1 gene and ovarian aging patterns. We, therefore, attempted to determine a potential difference in androgen concentrations and androgen interactions in women with POA who do or do not become pregnant while undergoing androgen supplementation, and whether androgen concentrations and pregnancy chances are affected by FMR1 genotypes.

METHODS

We longitudinally assessed androgen metabolism in 91 women with POA, following pre-supplementation with micronized dehydroepiandrosterone (DHEA) prior to IVF. IVF outcomes were assessed based on androgen levels and ovarian FMR1 genotypes.

RESULTS

The mean age of the women was 39.8 ± 4.4 years; the clinical pregnancy rate was 25.3%. Total androgen concentrations were not associated with pregnancy; however, in women with abnormal FMR1 genotypes, but not those with the normal genotype, free testosterone significantly affected clinical pregnancy potential (β = 1.101, SE ± 0.508, P = 0.03). At the start of the IVF cycle, interactions of DHEA with total and free testosterone also significantly affected subsequent pregnancy rates (β = –0.058, SE ± 0.023, P = 0.01 and β = –0.496, SE ± 0.197, P = 0.012).

CONCLUSIONS

Androgen interactions significantly influence IVF pregnancy rates in women with POA, with the impact of total androgens on cycle outcomes varying according to FMR1 genotypes. These observations suggest that the effectiveness of androgen supplementation in women with POA varies based on FMR1 genotypes, and defines androgen deficiency as a subset of diminished ovarian reserve.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3287?rss=1

Recommendation and review posted by G. Smith

STUDY QUESTION

Are anti-Müllerian hormone (AMH) levels lower in women with endometriosis, notably those with endometriomas (OMAs) and deep infiltrating lesions, compared with controls without endometriosis?

SUMMARY ANSWER

Endometriosis and OMAs per se do not result in lower AMH levels. AMH levels are decreased in women with previous OMA surgery independently of the presence of current OMAs.

WHAT IS KNOWN ALREADY

The impact of endometriosis and OMAs per se on the ovarian reserve is controversial. Most previous studies have been conducted in infertile women. The strength of our study lies in the following points: (i) the selection of women undergoing surgery and not only according to the presence of infertility, (ii) the classification of women with endometriosis and controls based on strict surgical and histological criteria.

STUDY DESIGN, SIZE, DURATION

Cross-sectional study using data prospectively collected in all non-pregnant <42-year-old patients, who were surgically explored for a benign gynaecological condition at a university tertiary referral centre between 2004 and 2008. For each patient, a structured questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding surgery. AMH levels were measured in serum samples drawn in the month preceding surgery, without regard to menstrual phase or hormonal therapy.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Operations were done on 1262 women between 2004 and 2008, of which 1133 signed the informed consent. Of the 566 women with a visual diagnosis of endometriosis, 411 had histologically proven endometriosis. Frozen serum samples for the AMH measurement were available in 313 of them. Out of the 554 women without visual endometriosis and without past endometriosis surgery, 413 had a frozen serum sample for the AMH measurement. Univariate analysis examined AMH levels according to baseline patient characteristics, the presence and type of endometriosis (superficial lesion, OMA, deep infiltrating lesion) and previous OMA surgery. Analysis of variance–covariance then examined the effects of co-variables on AMH levels. Finally, logistic regressions were conducted to examine the odds ratio (OR) of having AMH levels <1 ng/ml according to the same co-variables.

MAIN RESULTS AND THE ROLE OF CHANCE

The difference in AMH levels between women with endometriosis and controls did not reach significance (3.6 ± 3.1 versus 4.1 ± 3.4 ng/ml, P = 0.06). Analysis of variance–covariance demonstrated that AMH levels significantly decreased with age (P < 0.001) and in women with prior OMA surgery irrespective of whether OMAs were present or not at the time of study (P < 0.05). Logistic regression revealed that two major factors were related to AMH levels <1 ng/ml: (i) age (compared with <29 years; 30–34 years OR = 3.1, 95% CI: 1.5–6.4, P = 0.01; 35–39 years OR = 7.0, 95% CI: 3.5–14.1, P = 0.001; ≥40 years OR = 20.8, 95% CI: 9.1–47.4, P = 0.001) and (ii) prior OMA surgery (OR = 3.0, 95% CI: 1.4–6.41, P = 0.01).

LIMITATIONS, REASONS FOR CAUTION

The selection of our study population was based on a surgical diagnosis. Women with an asymptomatic form of endometriosis are therefore not included in our study. We cannot exclude that infertile women with OMAs associated with a diminished ovarian reserve, as assessed during their infertility work-up, were less likely to be referred for surgery and might therefore be underrepresented.

WIDER IMPLICATIONS OF THE FINDINGS

Our findings suggest that OMAs per se do not diminish the ovarian reserve reflected by AMH levels but that alterations seen in women with endometriosis are a deleterious consequence of OMA surgery. These findings should be taken into account in the decision to operate OMAs in women with a desire for future pregnancy.

STUDY FUNDING/COMPETING INTERESTS

Study funding: none. Potential competing interests: none.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3294?rss=1

Recommendation and review posted by G. Smith

BACKGROUND

Metformin is a drug used in the treatment of diabetes and of some disorders related to insulin resistance, such as polycystic ovary syndrome. Gestational diabetes can cause complications for both mother and child, and some studies have shown a beneficial effect of metformin during pregnancy without an increase in perinatal complications. However, the effects on the gonads have not been properly studied. Here we investigated the effect of metformin administered during pregnancy on the development and function of the fetal testis.

METHODS

A dual approach in vitro and in vivo using human and mouse models was chosen. Cultures of human and murine organotypic testes were made and in vivo embryonic testes were analysed after oral administration of metformin to pregnant mice.

RESULTS

In human and mouse organotypic cultures in vitro, metformin decreased testosterone secretion and mRNA expression of the main factors involved in steroid production. In vitro, the lowest observed effect concentration (LOEC) on testosterone secretion was 50 µM in human, whereas it was 500 µM in mouse testis. Lactate secretion was increased in both human and mouse organotypic cultures with the same LOEC at 500 µM as observed in other cell culture models after metformin stimulation. In vivo administration of metformin to pregnant mice reduced the testicular size of the fetal and neonatal testes exposed to metformin during intrauterine life. Although the number of germ cells was not affected by the metformin treatment, the number of Sertoli cells, the nurse cells of germ cells, was slightly yet significantly reduced in both periods (fetal period: P = 0.007; neonatal period: P = 0.03). The Leydig cell population, which produces androgens, and the testosterone content were diminished only in the fetal period at 16 days post-coitum.

CONCLUSIONS

This study showed a potentially harmful effect of metformin treatment on the development of the fetal testis and should encourage future human epidemiological studies.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3304?rss=1

Recommendation and review posted by G. Smith