Published 15 April 2023
An integrated meta-analysis and gene variant study demonstrates for the first time the ‘critical role’ of excess childhood/adolescent adiposity on the pathophysiology of adult PCOS. Effective weight maintenance, even from the early years, is likely to reduce the risk.
A complex meta-analysis incorporating data from genome-wide association studies has shown with some conviction what many smaller observational studies had previously indicated - that adiposity and excess body weight in childhood have an adverse impact on the pathophysiology of PCOS in later life.(1) The results, say the authors, ‘clearly favour obesity driving the metabolic, but not reproductive, PCOS phenotype’. Indeed, the risk of PCOS in adolescents with overweight and/or obesity was so great - and associated in a linear relation - that the authors in their conclusion urged control of body weight, ‘even from the early years’, as ‘likely to reduce the risk of this reproductive endocrine disorder’.
The study methodology - meta-analysis combined with ‘Mendelian randomisation’ - was designed to allow synthesis of observational (from 63 studies) and genetic variant data. The latter enabled analysis of the impact of childhood and adult body size, abnormal body composition and metabolic parameters on the odds of incident PCOS. Earlier studies of this type have already shown BMI to have a causal association with PCOS risk, but only in adults. The 63 studies finally identified for meta-analysis included 35 studies from an earlier systematic review.(2) This study too had found that women with PCOS had a greater prevalence of overweight, obesity and central obesity, and had similarly recommended that clinical management of PCOS should include the prevention and management of overweight and obesity.
The international PCOS guidelines, in partnership with ESHRE, has also recommended ‘lifestyle intervention . . . in all those with PCOS and excess weight, for reductions in weight, central obesity and insulin resistance’, adding that ‘achievable goals such as 5% to 10% weight loss in those with excess weight yields significant clinical improvements’.(3) Indeed, the genetic data from this latest study found that for every standard deviation increase in BMI (4.8kg/m2), the odds of PCOS increased by 2.76.
Now, say the authors, their data provide robust evidence in support of a strong causal association between, first, overweight/obesity, and second, metabolic parameters (including hyperinsulinaemia and low levels of sex hormone-binding globulin, SHBG) with incident PCOS. And this, ‘for the first time’, reflects the critical role of excess adiposity in childhood and adolescence in the pathophysiology of adult PCOS. This latter finding was evident in many of the studies selected for meta-analysis, with one of them finding that adolescents with severe obesity (BMI >40 kg/m2) had a 23.1-fold increased odds of PCOS (with overweight OR 3.85, and obese OR 10.25). The genetic data from this latest study implicated early life body size in PCOS risk independent of adult body size. Genetic data also highlighted the role of insulin resistance, with lower level of SHBG (‘a surrogate marker of insulin resistance’) associated with increased risk of PCOS.
The authors highlight the distinctions between two phenotypes of PCOS, explaining their assertion that their results ‘clearly favour obesity driving the metabolic, but not reproductive, PCOS phenotype’. Recent analysis, they note, has proposed the existence of two PCOS phenotypes: metabolic and reproductive - with the latter characterised by less adiposity, a relatively low BMI, normal insulin levels and increased LH and SHBG concentrations, while the former metabolic phenotype is characterised by higher BMI and hyperinsulinaemia but low LH and SHBG.(4)
Such a distinction in the features of PCOS has long been implicit - even if not recognised as two distinct phenotypes - in the arguments behind its diagnosis. Thus, while the Rotterdam criteria for diagnosis (any two from ovarian dysfunction, polycystic ovary morphology and hyperandrogenism) was a joint consensus of ESHRE and the ASRM, the American view had previously (and indeed later) favoured androgen excess as the key diagnostic feature.(5,6) Certainly, metabolic abnormalities, including insulin resistance and reduced levels of SHBG, have long been implicated in PCOS. Studies suggest that around 75% of women with PCOS have insulin resistance.
Findings from the gene variant data in this latest meta-analysis are thus behind its conclusion - that childhood and adulthood overweight and obesity drive this distinct metabolic phenotype of PCOS. In childhood, the implications for early weight maintenance are crucial, to minimise the risk of subsequently developing PCOS and the later cardio-metabolic complications associated with the syndrome.
1. Dobbie LJ, Pittam B, Zhao SS, et al. Childhood, adolescent, and adulthood adiposity are associated with risk of PCOS: a Mendelian randomization study with meta-analysis. Hum Reprod 2023; doi.org/10.1093/humrep/dead053
2. Lim SS, Davies MJ, Norman RJ, Moran LJ. Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 2012; 18: 618–637.
3. See https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Polycystic-Ovary-Syndrome
4. Dapas M, Lin FTJ, Nadkarni GN, et al. Distinct subtypes of polycystic ovary syndrome with novel genetic associations: an unsupervised, phenotypic clustering analysis. PLoS Med 2020; 17: e1003132.
5. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19: 41-47.
6. Azziz R, Carmina E, Dewailly D, et al. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009; 91: 456–488.
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