Women with polycystic ovary syndrome (PCOS) suffer symptoms associated with excess androgen (hirsutism, acne, and central adiposity), reproductive dysfunction (infertility, menstrual irregularity, miscarriage, and pregnancy complications), metabolic complications, depression and anxiety. Remarkably, for such a complex and major health issue, we still understand little as to the underlying pathological mechanisms of PCOS. However, PCOS is known to have a genetic predisposition, as well as a fetal origin, implying that fetal development is perturbed either directly or via the mother. We recently published the following conclusion (Azumah et al, 2022) namely that ‘…TGFβ signalling could be involved in the fetal predisposition to PCOS or at least in the development of polycystic ovaries….’. This was based on the following observations:
(1) TGFβ is linked to the development of fibrous stroma, which is a hallmark of polycystic ovaries.
(2) In fetal ovarian fibroblasts TGFβ1 can regulate 7 genes genetically associated with PCOS.
(3) In fetal ovarian fibroblasts TGFβ1 can alter the expression of AR (androgen receptor) and an AR cofactor. Androgen signalling has been shown to be very likely involved in the fetal development of an adult PCOS phenotype.
(4) In fetal ovarian fibroblasts TGFβ1 can regulate expression of COL1A1 (collagen) and COL3A1, thus regulating collagen synthesis.
(5) Many of the components of TGFβ signalling are dynamically expressed in fetal ovaries across gestation, as are the PCOS candidate genes.
We have additionally identified relationships in expression of TGFβ signalling molecules and PCOS candidate genes not only in the fetal ovary, but also in other human fetal tissues. Thus, mis-regulation of stromal development in many organs of a developing fetus may predispose that person to developing PCOS in later life.