Genetics of the HPA Axis & PCOS
The molecular basis of genetic variation in the HPA axis activity relates to adrenal production of glucocorticoids, their binding to corticosteroid-binding globulin (CBG) and consequently their bioavailability and their efficacy on the transduction mechanisms. Numerous molecular polymorphisms have been described to contribute to physiological as well as to HPA axis-related variations. Unfortunately, the genetic imprinting of the HPA axis in PCOS has been poorly investigated, in spite of the intensive research of genetic factors involved in the development of androgen excess and metabolic alterations. On the other hand, the few available studies suggest that genetic factors may play some potential role in the expression of the HPA axis activity in this disorder. One study investigated the sibling correlation of ACTH hormone-stimulated steroid hormone levels between probands with PCOS and their sisters and found that ACTH log-transformed DHEA and cortisol values were significantly correlated between siblings, which supports a potential genetic basis of the adrenal androgen excess observed in PCOS. Another study found that, in a large cohort of women with hirsutism, including 45% women with PCOS, approximately 20% of women with idiopathic hirsutism and PCOS had increased 17-hydroxyprogesterone and cortisol response to ACTH (1–24) stimulation, supporting the concept that CYP21-carrier status could not explain the observed high prevalence of abnormal ACTH-stimulated adrenal hormone levels. A third study assessed the influence of known functional polymorphisms in genes involved in the production, metabolism and signal transduction of steroid hormones in a large cohort of women with or without PCOS. This study found that the genotype-frequencies were similar in PCOS cases and population-based controls, although a possible association between glucocorticoid receptor genotype and LH levels was suggested. In fact, the data showed lower LH levels in association with glucocorticoid receptor alleles that are known to increase receptor sensitivity (rs6195 and rs41423247) and higher LH levels in glucocorticoid receptor variants that may inhibit receptor sensitivity (rs6190 and rs6198), supporting the concept that these variants may influence gonadotrophin levels in women with anovulatory PCOS, through modulation of the function of the hypothalomo–pituitary–gonadal axis. Finally, there are no studies on the genetics of CBG in PCOS, although stress-induced falls in CBG levels may heighten HPA axis responses and CBG:tissue interactions may allow targeted cortisol delivery. There are only preliminary data of altered CBG levels in hypertension and in the metabolic syndrome, but the nature of these associations is uncertain. The genetics of enzymes involved in the metabolism of cortisol in peripheral tissues is discussed in the specific following paragraphs.
Expert Rev Endocrinol Metab. 2012;7(5):555-566. © 2012 Expert Reviews Ltd.