3. Polycystic ovarian syndrome
Polycystic ovary syndrome (PCOS) is a true syndrome, being a heterogeneous collection of signs and symptoms that gathered together form a spectrum of a disorder with a mild presentation in some, whilst in others there is a severe disturbance of reproductive, endocrine and metabolic function. There has been much debate about phenotype and, more recently, genotype. There has also been scepticism in some quarters, with a feeling that we may be looking at one end of a spectrum that is in reality 'normal', or perhaps a consequence of the modern disease of obesity. Whilst the polycystic ovary is at the centre of the syndrome, it is external effects such as hyperinsulinism, that influence its expression. There is no consensus on the definition of PCOS and so studies that compare epidemiology and treatments often have very different starting points, and so cannot be compared. In this debate we wish to re-explore our current thinking on PCOS, with a particular emphasis on the British and European perspective and invite others to contribute to the discussion which could form the basis for an international consensus.
The existing literature provides a strong basis for arguing that PCOS clusters in families. However, the mode of inheritance of the disorder is still uncertain, although the majority of studies are consistent with an autosomal dominant pattern, modified perhaps by environmental factors. In addition, studies on PCOS cells (theca, muscle, and adipocytes) in culture have documented a persistent biochemical and molecular phenotype that distinguishes them from normal cells. Although several loci have been proposed as PCOS genes including CYP11A, the insulin gene, and a region near the insulin receptor, the evidence supporting linkage is not overwhelming. The strongest case can be made for the region near the insulin receptor gene, as it has been identified in two separate studies. However, the responsible gene at chromosome 19p13.3 remains to be identified. Association studies have provided a number of potential loci with genetic variants that may create or add to a PCOS phenotype, including Calpain 10, IRS-1 and -2, and SHBG. Collectively, these findings are consistent with the concept that a gene or several genes are linked to PCOS susceptibility. Because the mutations/genotypes associated with PCOS are rare, and their full impact on the phenotype incompletely understood, routine screening of women with PCOS or stigmata of PCOS for these genetic variants is not indicated at this time. Currently the treatment implications for individually identified genetic variants is uncertain and must be addressed on a case by case basis.
Insulin resistance is a prominent feature of polycystic ovarian syndrome (PCOS), and women with the disorder are at increased risk for the development of other diseases that have been linked to insulin resistance-namely, type 2 diabetes and cardiovascular disease. The recognition of insulin resistance as a principal factor in the pathogenesis of polycystic ovarian syndrome (PCOS) has led to the use of insulin-lowering agents, also called 'insulin-sensitizing drugs', for its treatment. The most extensively studied insulin-lowering agent in the treatment of PCOS is metformin: an oral antihyperglycaemic agent used initially in the treatment of type 2 diabetes mellitus. Metformin is effective in the treatment of PCOS-related anovulation and infertility. Moreover, preliminary evidence indicates that metformin may also be effective in decreasing the risk of early spontaneous miscarriage in women with PCOS. Metformin also appears to induce cardioprotective effects on serum lipids as well as plasminogen activator inhibitor (PAI)-1 and may decrease the risk of development of type 2 diabetes. The highly promising therapeutic profile of metformin is related to the role of this agent in controlling an important aetiologic factor in the pathogenesis of PCOS: hyperinsulinaemia. Limited evidence exists to suggest that oral contraceptive pills-the currently standard therapy for PCOS-may actually decrease insulin sensitivity and induce impaired glucose tolerance in women with PCOS. Hence, PCOS should be regarded as a general health issue and the use of insulin-sensitizing drugs such as metformin should be considered for the prevention of type 2 diabetes.
Reference
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Nestler JE. Should patients with polycystic ovarian syndrome be treated with metformin?: An enthusiastic endorsement. Hum Reprod 2002 Aug;17(8):1950-3.
Seli E, Duleba AJ. Should patients with polycystic ovarian syndrome be treated with metformin?
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