Polycystic ovary syndrome (PCOS) is a prevalent heterogeneous disorder linked with disturbances of reproductive, endocrine and metabolic function. The definition and aetiological hypotheses of PCOS are continually developing to incorporate evolving evidence of the syndrome, which appears to be both multifactorial and polygenic. The pathophysiology of PCOS encompasses inherent ovarian dysfunction that is strongly influenced by external factors including the hypothalamic–pituitary axis and hyperinsulinaemia. Neuroendocrine abnormalities including increased gonadotrophin-releasing hormone (GnRH) pulse frequency with consequent hypersecretion of luteinising hormone (LH) affects ovarian androgen synthesis, folliculogenesis and oocyte development. Disturbed ovarian–pituitary and hypothalamic feedback accentuates the gonadotrophin abnormalities, and there is emerging evidence putatively implicating dysfunction of the Kiss 1 system. Within the follicle subunit itself, there are intra-ovarian paracrine modulators, cytokines and growth factors, which appear to play a role. Adrenally derived androgens may also contribute to the pathogenesis of PCOS, but their role is less defined.
Highlights
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Ovarian dysfunction is key to the pathophysiology in polycystic ovary syndrome.
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Theca cells of PCOS patients have a generalised overactive steroidogenesis.
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Hyperinsulinaemia plays an important role in the increased androgen production.
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Neuroendocrine dysfunction affects the hypothalamic–pituitary–ovarian axis.
Introduction
In order to understand the multifactorial and polygenic pathophysiology of polycystic ovary syndrome (PCOS), it is important to consider both the nature of the dysfunction within the ovary and the external influences modifying ovarian behaviour, including hypothalamic–pituitary and adrenal contributions. PCOS features a vast range of endocrine and metabolic abnormalities, culminating in a heterogeneous picture of anovulation with associated infertility, hyperandrogenism, obesity, insulin resistance and other metabolic disturbance, including hypertension, dyslipidaemia and hyperhomocystinaemia . Insulin resistance per se plays an important role in the pathogenesis of the syndrome. It acts in combination with luteinising hormone (LH) to promote ovarian androgen synthesis. Furthermore, insulin suppresses the hepatic production of sex hormone-binding globulin (SHBG), with subsequent elevated levels of free testosterone . A further feature of PCOS is increased gonadotrophin-releasing hormone (GnRH) pulsatility, resulting in higher LH levels combined with a relative deficiency of follicle-stimulating hormone (FSH) . The excessive ovarian androgen biosynthesis and ovulatory dysfunction generates a self-perpetuating cycle of endocrine dysfunction.
Normal ovarian function
Whilst women with clinical manifestations of hyperandrogenism, oligo-/amenorrhoea and polycystic ovaries typically have the highest levels of androgens, women with polycystic ovaries and mild or absent symptoms have mean serum testosterone concentrations above those with normal ovaries . The ovary is considered to be the source of excess androgens, as a consequence of dysregulation of steroidogenesis ; thus, the ovary is central to PCOS. An understanding of normal ovarian function and steroidogenesis is required to understand the disordered folliculogenesis and ovarian activity apparent in PCOS.
Steroidogenesis
In a normal, premenopausal woman, the theca interna layer of the ovarian follicle and the zona fasciculata of the adrenal cortex contribute equally to the majority of the circulating concentrations of androgens, secreting significantly greater levels of androstenedione than testosterone. LH and adrenocorticotrophic hormone (ACTH) are responsible for controlling the enzymes involved in the formation of androstenedione from its initial substrate, cholesterol, in the ovary and adrenal glands, respectively . Peripheral metabolism of androstenedione, primarily in the lung, liver, adipose tissue and skin, is responsible for almost half of the circulating testosterone in normal adult women. Adipose tissue also converts androstenedione into oestrone, hence the hyperoestrogenic state seen in obese women. Almost all the dihydrotestosterone (DHT) in the circulation is produced in the periphery by the action of 5α-reductase on predominantly androstenedione. Androgen secretion undergoes approximately twofold episodic, diurnal and cyclic variation .
Steroidogenesis initially commences with the conversion of cholesterol to pregnenolone in two stages, involving initially the cholesterol side-chain cleavage enzyme (P450scc) and then the acute steroidogenic regulatory protein. The resultant pregnenolone is converted to dehydroepiandrosterone (DHEA) in a two-step process catalysed by cytochrome P450c17α, along the Δ 5 -steroid pathway. The gene expression of P450c17 is dependent on trophic hormones (LH in the ovary and ACTH in the adrenal cortex). The Δ 4 -steroid pathway, which occurs in parallel, is responsible for the conversion of progesterone, which is derived from pregnenolone, firstly to 17-hydroxyprogesterone (17-OHP) and then to androstenedione. In the adrenal gland, 17-OHP is converted to either androstenedione or cortisol. Androstenedione requires 17β-hydroxydehydrogenase for conversion to testosterone, DHT and oestradiol ( Fig. 1 ) .
