The Genetic Basis of the Polycystic Ovary Syndrome: A Literature Review Including Discussion of PPAR-gamma

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of the women of reproductive age. Familial clustering of PCOS has been consistently reported suggesting that genetic factors play a role in the development of the syndrome although PCOS cases do not exhibit a clear pattern of Mendelian inheritance. It is now well established that PCOS represents a complex trait similar to type-2 diabetes and obesity, and that both inherited and environmental factors contribute to the PCOS pathogenesis. A large number of functional candidate genes have been tested for association or linkage with PCOS phenotypes with more negative than positive findings. Lack of universally accepted diagnostic criteria, difficulties in the assignment of male phenotype, obscurity in the mode of inheritance, and particularly small sample size of the study populations appear to be major limitations for the genetic studies of PCOS. In the near future, utilizing the genome-wide scan approach and the HapMap project will provide a stronger potential for the genetic analysis of the syndrome.

Figure 1

PCOS is a complex genetic syndrome. A dysregulation of androgen synthesis plays a key role in the pathogenesis of PCOS. This dysregulation may be triggered by genomic variants related to hyperandrogenism and environmental factors, such as sedentary life-style and dietary habits. The hyperandrogenemic condition causes follicles not to grow as much as dominant follicle and leads oligo/anovulation. The progesterone peak does not occur through luteal phase of menstrual cycle, and the frequency and amplitude of GnRH pulses are increased, which in turn cause the secretion of LH to increase. By means of increasing LH levels, androgen synthesis and secretion are stimulated in the ovaries and adrenals. On the other hand, the inherited insulin resistance leads a hyperinsulinemic condition causing androgen synthesis to increase and SHBG synthesis to decrease. Additionally, obesity that is inherited and/or acquired could cause a chronic inflammation via secreting inflammatory cytokines from adipose tissue, which stimulates androgen sythesis and increases insulin resistance. As a consequence, interactions among ovary, hypothalamus-pituitary, adrenal, adipose tissue, liver, skeletal muscle and $\tilde{\beta }$-cells of pancreas draw the picture of PCOS. Environmental factors and genetic variations constitute the phenotypic variability/colors of the picture.