Summary
A recent systematic review and meta-analysis [1] aimed to assess the pathophysiology, clinical manifestations, diagnosis, prognosis and treatment of polycystic ovary syndrome (PCOS) in peri- or postmenopausal women. The study compared peri- and postmenopausal women aged ≥ 45 years with or without PCOS regarding outcomes including: age at menopause, hormonal, metabolic, cardiac and breast cancer. Following PRISMA reporting criteria, multiple databases were searched for cross-sectional and prospective studies published to 15 April 2023. Accepted definitions for PCOS (NIH, Rotterdam, AE-PCOS) were used in addition to histopathology, self-report using validated scales, or self-report alone. Meta-analysis was conducted where ≥ 3 studies were available and heterogeneity, random effects, sensitivity analysis and publication bias were assessed. Quality assessment included risk of bias and GRADE evaluation. From 1,400 studies identified, 37 studies were included with 28 studies undergoing meta-analysis. The risk of bias was high or very high for all studies and GRADE quality of evidence ranged from very low to moderate. Studies involved predominately European or US women with one study from China. Meta-analysis indicated: (i) no difference in age at natural menopause; (ii) increased serum total testosterone, free androgen index and androstenedione in women with PCOS, whereas sex hormone binding globulin levels were decreased; (iii) increased body mass index (BMI), waist circumference and waist/hip ratio in women with PCOS; (iv) increased insulin resistance, fasting insulin, fasting glucose and 3 fold risk of diabetes in women with PCOS; (iv) decreased HDL cholesterol and increased triglyceride levels; (v) increased systolic blood pressure and odds for hypertension (odds ratio 1.79); (vi) increased odds for myocardial infarction and stroke (odds ratio 2.51 and 1.75 respectively; (vii) no increased risk of breast cancer. Similar findings were obtained when restricting analysis to studies that included standard definitions of PCOS, population-based studies, or excluded women with ovarian surgery. No difference in diabetes, hypertension, blood pressure, fasting glucose and indices of insulin resistance were seen after restricting analyses to only postmenopausal women. When restricting the meta-analyses to studies which compared women with similar BMI, only decreased HDL-C levels in women with PCOS remained statistically significant; differences in glucose/ insulin resistance indices, triglyceride levels, blood pressure, risk of hypertension and diabetes between the groups were no longer observed (hormonal levels were not analysed due to an inadequate number of studies).
Narrative review indicated that hirsutism was more prevalent in peri/postmenopausal women with PCOS versus controls and ovarian volume was larger. Climacteric symptoms were only addressed in three reports with mixed findings. Mixed findings were reported in the few studies regarding psychological health and health related quality of life. The authors conclude that (i) clinical and biochemical hyperandrogenism persist into menopause in women with PCOS; and (ii) most cardiometabolic consequences co-morbidities were associated with the co-existence of excess weight. The overall low quality of evidence highlights the need for further research.
Commentary
Polycystic ovary syndrome (PCOS) is a common condition in reproductive age women, affecting up to 15% [2]. PCOS is characterised by hyperandrogenism, menstrual irregularity, polycystic ovarian morphology and is associated with adverse cardiometabolic, psychological and fertility outcomes [2]. However, the consequences of the menopause transition and menopause in regard to PCOS is less clear. This comprehensive systematic review and meta-analysis [1] is timely given the recent release of the updated international PCOS guidelines [2] which was published just prior. The key question in the PCOS guideline for the section regarding “Menopause life stage” was “What is the post-menopausal phenotype of PCOS and how elevated should androgens be to indicate PCOS”? [2]. Only consensus and conditional recommendations could be made on the basis of the included evidence in the narrative review. These include: “17.1 A diagnosis of PCOS should be considered as lifelong; 17.2 Healthcare professionals could consider that both clinical and biochemical hyperandrogenism persist in the postmenopause for women with PCOS; 17.3 PCOS diagnosis could be considered postmenopause. If there is a past diagnosis, or long-term history of oligomenorrhoea with hyperandrogenism and/or polycystic ovarian morphology, during the younger reproductive years (age 20-40); 17.4 Further investigations should be considered to rule out androgen-secreting tumours and ovarian hyperthecosis in postmenopausal women presenting with new-onset, severe or worsening hyperandrogenism including hirsutism” [2]. The findings of this meta-analysis [1] provide additional data to answer this question and support these recommendations, although the low quality of evidence evaluated and some methodological issues of the systematic review limit the conclusions that can be drawn. Observational studies of women aged 45 years or older were included with varying proportions of postmenopausal women with PCOS (13-100% where reported) and may have involved late reproductive age women. PCOS diagnosis was assigned retrospectively according to varying criteria. A number of sensitivity analyses were conducted reducing the number of included studies (although a minimum of three studies was required for meta-analysis) and potentially reducing statistical power to detect significant differences.
The findings of this systematic review suggest that menopause age does not differ in women with PCOS and, in support of the PCOS guideline, indicates that clinical and biochemical hyperandrogenism persist after menopause in women with PCOS. As observed in younger women [2], increased BMI, adiposity indices and adverse cardiometabolic changes were observed in peri- and postmenopausal women with PCOS compared to controls in the overall meta-analysis.
The menopausal transition is associated with adverse cardiometabolic changes including increased insulin resistance, increased fat mass, dyslipidemia, diabetes risk and increased blood pressure [3]. No difference was observed between PCOS and controls in regard to insulin resistance, fasting glucose, hypertension, diabetes risk and lipid profile when restricting the meta-analysis to postmenopausal women of similar age. This finding may reflect decreased statistical power with lower number of included studies or the worsening of cardiometabolic health in control women rather than potential beneficial changes in PCOS with cessation of ovarian function. Additionally, after including only studies with women of similar BMI, no difference in fasting glucose, indices of insulin resistance, and diabetes, hypertension or dyslipidemia risk was observed between peri- and postmenopausal women with PCOS or controls. This is in contrast to younger women with PCOS where diabetes risk is increased compared to controls regardless of BMI [2]; this current finding may reflect the lower number of women included in the sensitivity studies contributing to loss of statistical power. Thus, the conclusion of the authors that most cardiometabolic co-morbidities in peri-and postmenopausal women were related to the co-existence of excess weight needs caution and further research is needed to refute or confirm. Regardless of this, these findings emphasize the importance of maintenance of a healthy weight range and prevention of weight gain in all women during the menopausal transition and postmenopause. The PCOS guideline has recommendations regarding lifestyle management [2]. This systematic review and the PCOS guideline highlight the knowledge gaps and need for further research regarding the long-term natural history of PCOS, manifestations of this disorder after menopause and optimal management in postmenopausal women.
Amanda Vincent, MBBS, B Med Sci (Hons), PhD, FRACP
Head, Early Menopause Research, Monash Centre for Health Research and Implementation (MCHRI), School of Public Health and Preventive Medicine, Monash University, Australia
Endocrinologist, Department of Endocrinology, Monash Health, Clayton, Victoria, Australia
Board member of the International Menopause Society
References
- Millán-de-Meer M, Luque-Ramírez M, Nattero-Chávez L, Escobar-Morreale HF. PCOS during the menopausal transition and after menopause: a systematic review and meta-analysis. Hum Reprod Update. 2023;29(6):741-772.
https://pubmed.ncbi.nlm.nih.gov/37353908/ - Teede HJ, Tay CT, Laven JJE, et al. Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2023;108(10):2447-2469.
https://pubmed.ncbi.nlm.nih.gov/37580314/ - Nappi RE, Chedraui P, Lambrinoudaki I, Simoncini T. Menopause: a cardiometabolic transition. Lancet Diabetes Endocrinol. 2022;10(6):442-456.
https://pubmed.ncbi.nlm.nih.gov/35525259/
If you would like to add a comment or contribute to a discussion based on this issue, please contact Menopause Live Editor, Peter Chedraui, at peter.chedraui@cu.ucsg.edu.ec.
