Michael F. Costello

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.

Assessment and management of polycystic ovary syndrome: summary of an evidence-based guideline.

Helena J Teede, Marie L Misso, Amanda A Deeks, Lisa J Moran, Bronwyn G A Stuckey, Jennifer L A Wong, Robert J Norman and Michael F Costello on behalf of the Guideline Development Groups

Aromatase inhibitors for PCOS: a systematic review and meta-analysis

BACKGROUND The effectiveness of aromatase inhibitors (AIs) in the treatment of anovulatory polycystic ovary syndrome (PCOS) remains unclear. The objective was to determine whether AIs are effective in improving fertility outcomes in women with PCOS. METHODS Databases were searched until July 2011. Inclusion criteria were women with PCOS, who are infertile, receiving any type, dose and frequency of AI compared with placebo, no other treatment or other infertility treatment. Outcomes were rates of: ovulation, pregnancy, live birth, multiple pregnancies, miscarriage and adverse events, as well as quality of life and cost effectiveness. Data were extracted and risk of bias was assessed. A random-effects model was used for the meta-analyses, using odds ratios (ORs) and rate ratios (RRs). RESULTS The search returned 4981 articles, 78 articles addressed AIs and 13 randomized controlled trials (RCTs) met the inclusion criteria. No RCTs compared AIs versus placebo or no treatment, in therapy naïve women with PCOS. Meta-analyses of six RCTs comparing letrozole with clompihene citrate (CC) demonstrated that letrozole improved the ovulation rate per patient [OR 2.90 (95% confidence interval (CI) 1.72, 4.88), I(2) = 0%, P < 0.0001]; however, there was no statistical difference for the ovulation rate per cycle or the pregnancy, live birth, multiple pregnancy or miscarriage rates. Letrozole also did not improve pregnancy or live birth rates compared with placebo or with CC plus metoformin in women with CC-resistant PCOS. Results of comparisons of letrozole and anastrozole in women with CC-resistant PCOS were conflicting in terms of ovulation and pregnancy rates. CONCLUSIONS In the absence of supportive high-quality evidence, AIs should not be recommended as the first-line pharmacological therapy for infertility in women with PCOS, and further research is needed.

Metformin versus clomiphene citrate for infertility in non-obese women with polycystic ovary syndrome: a systematic review and meta-analysis

UNLABELLED BACKGROUND Recent studies suggest that metformin may be more effective in women with polycystic ovary syndrome (PCOS) who are non-obese. The objective here is to determine and compare the effectiveness of metformin and clomiphene citrate for improving fertility outcomes in women with PCOS and a BMI < 32 kg/m(2) (BMI 32 kg/m(2) was used to allow for international differences in BMI values which determine access to infertility therapy through the public health system). METHODS Databases were searched for English language articles until July 2011. INCLUSION CRITERIA women of any age, ethnicity and weight with PCOS diagnosed by all current criteria, who are infertile; at least 1000 mg of any type of metformin at any frequency, including slow release and standard release, compared with any type, dose and frequency of clomiphene citrate. OUTCOMES rates of ovulation, live birth, pregnancy, multiple pregnancies, miscarriage, adverse events, quality of life and cost effectiveness. Data were extracted and risk of bias assessed. A random effects model was used for meta-analyses of data, using risk ratios (relative risk). RESULTS The search returned 4981 articles, 580 articles addressed metformin or clomiphene citrate and four randomized controlled trials (RCTs) comparing metformin with clomiphene citrate were included. Upon meta-analysis of the four RCTs, we were unable to detect a statistically significant difference between the two interventions for any outcome in women with PCOS and a BMI < 32 kg/m(2), owing to significant heterogeneity across the RCTs. CONCLUSIONS Owing to conflicting findings and heterogeneity across the included RCTs, there is insufficient evidence to establish a difference between metformin and clomiphene citrate in terms of ovulation, pregnancy, live birth, miscarriage and multiple pregnancy rates in women with PCOS and a BMI < 32 kg/m(2). However, a lack of superiority of one treatment is not evidence for equivalence, and further methodologically rigorous trials are required to determine whether there is a difference in effectiveness between metformin and placebo (or no treatment) or between metformin and clomiphene citrate for ovulation induction in women with PCOS who are non-obese. Until then, caution should be exercised when prescribing metformin as first line pharmacological therapy in this group of women.

Transcervical intrauterine topical local anesthetic at hysterosalpingography: a prospective, randomized, double-blind, placebo-controlled trial

OBJECTIVE To assess whether transcervical intrauterine topical instillation of a local anesthetic agent reduces pain at hysterosalpingography. DESIGN Prospective, randomized, double-blind, placebo-controlled study. SETTING Department of reproductive medicine at a university teaching hospital. PATIENT(S) One hundred ten women undergoing hysterosalpingography (HSG). INTERVENTION(S) Subjects were randomized to receive either 2 mL of 2% plain lignocaine or 2 mL of 0.9% sodium chloride solution (placebo) topically into the uterine cavity before the HSG was performed. MAIN OUTCOME MEASURE(S) The degree of lower abdominal pain experienced both during the injection of contrast media at HSG and 10 minutes after the procedure using a 20-cm visual analogue scale (VAS) and a four-point verbal descriptor scale (VDS). RESULT(S) There was no difference in pain scores between lignocaine and placebo during the HSG. However, at 10 minutes after the HSG, subjects receiving lignocaine experienced more pain than those on placebo. CONCLUSION(S) Transcervical intrauterine topical instillation of 2 mL of 2% plain lignocaine does not reduce pain during HSG and may lead to increased pain immediately after the procedure.

The effect of adenomyosis on in vitro fertilisation and intra-cytoplasmic sperm injection treatment outcome ☆

OBJECTIVE To investigate the effect of uterine adenomyosis diagnosed by transvaginal ultrasound on IVF/ICSI treatment outcome. STUDY DESIGN A retrospective cohort study of all women aged ≤ 42 years with infertility who underwent IVF/ICSI treatment at IVF Australia-East between January 2000 and June 2006. Patients were divided into two groups according to findings on a baseline pre-treatment transvaginal pelvic ultrasound: group A consisted of women with adenomyosis and group NA consisted of women without adenomyosis. The primary outcome measure was live birth rate per patient (cycle). RESULTS A total of 201 patients (37 patients in Group A, 164 patients in group NA) undergoing a single stimulated cycle of IVF/ICSI were included in the data analysis. There was no difference in live birth rate per patient (cycle) between the two groups with both raw and logistic regression adjusted data (29.7%V 26.1%; p=0.395; OR 1.45 with 95% CI 0.61-3.43). There were no other differences in ovarian response, embryological parameters or clinical outcomes between the two groups. CONCLUSIONS The presence of transvaginal ultrasound diagnosed adenomyosis did not adversely affect outcome in women undergoing IVF/ICSI treatment at our unit. However, the results are not conclusive and further large, well-designed prospective cohort studies are required in order to confirm our findings.

Systematic review of the treatment of ovulatory infertility with clomiphene citrate and intrauterine insemination

Background:   Controlled ovarian hyperstimulation (COH) with clomiphene citrate (CC) combined with intrauterine insemination (IUI) is often used as treatment for ovulatory infertility which includes unexplained, male, cervical, endometriosis, and tubal infertility.

The treatment of infertility in polycystic ovary syndrome: a brief update

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. Lifestyle change alone is considered the first‐line treatment for the management of infertile anovulatory PCOS women who are overweight or obese. First‐line medical ovulation induction therapy to improve fertility outcomes is clomiphene citrate, whilst gonadotrophins, laparoscopic ovarian surgery or possibly metformin are second line in clomiphene citrate‐resistant PCOS women. There is currently insufficient evidence to recommend aromatase inhibitors over that of clomiphene citrate in infertile anovulatory PCOS women in general or specifically in therapy naive or clomiphene citrate‐resistant PCOS women. IVF/ICSI treatment is recommended either as a third‐line treatment or in the presence of other infertility factors.

No Decline in Semen Quality Among Potential Sperm Donors in Sydney, Australia, Between 1983 and 2001

AbstractPurpose: To determine whether the quality of semen has changed over time in men screened for semen donation. Methods: All 448 men volunteering for semen donation between 1983 and 2001 at a donor insemination clinic in Sydney, Australia, were included in this longitudinal single centre observational analysis of semen parameters. There was no selection for fertility or marital status but all volunteers had to be aged between 18 and 40 years. Results: There was no change in the total sperm count during the study period (r = 0.065, P = 0.17) using a linear regression model. The ejaculate volume did not change (r = 0.002, P = 0.97), while an increase in sperm motility was seen (Spearman R = 0.194, P < 0.001). Conclusion: The semen quality of volunteers for sperm donation presenting to our donor insemination clinic in Sydney between 1983 and 2001 has not declined.

Power doppler ultrasound assessment of the relationship between age and ovarian perifollicular blood flow in women undergoing in vitro fertilization treatment

Purpose: To examine the relationship between age and ovarian perifollicular blood flow (PFBF) in women undergoing IVF.Methods: Serial transvaginal power Doppler ultrasound (PDU) scans to assess ovarian PFBF were performed prospectively throughout the follicular phase of ovarian stimulation in women undergoing IVF. The ultrasound assessment days were categorized according to day of hCG trigger.Results: A total of 1050 ovarian follicles from 34 women undergoing one IVF treatment cycle were used for data analysis. The median age of the women was 38.5 years, ranging from 28 years to 44 years. There was a significant negative correlation between age and ovarian PFBF on the day of hCG trigger or trigger day minus 1, but not beforehand during the follicular phase.Conclusions: There was a significant negative correlation between age and ovarian PFBF in women undergoing IVF which was only observed very late in the follicular phase of ovarian stimulation.