Rosenfield, R. L., & Ehrmann, D. A. (2016). The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited. Endocrine reviews, 37(5), 467-520. https://doi.org/10.1210/er.2015-1104
Rosenfield RL, Ehrmann DA. The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited. Endocrine reviews. 2016;37(5):467-520. doi:10.1210/er.2015-1104
Rosenfield, Robert L., and David A. Ehrmann. "The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited." Endocrine reviews, vol. 37, no. 5, 2016, pp. 467-520.
For EndNote, Zotero or Mendeley:
Open access
Free to read
No reuse license
Open Access
Free full text on PubMed Central (PMC5045492)
RRM Academy Synopsis
Most PCOS Involves Ovarian Androgen Overproduction, Review Finds
A 2016 expert review ties most PCOS to ovaries that make too much androgen. The authors sum up decades of studies of polycystic ovary syndrome (PCOS), also called polyendocrine metabolic ovarian syndrome (PMOS). Two out of three cases show a typical ovarian pattern.
Key Findings
Insulin resistance with metabolic syndrome affects about half of PCOS patients, and the extra insulin they make worsens androgen excess.
Approximately half of women with polycystic-looking ovaries but normal cycles have mild, hidden ovarian hormone defects tied to functional ovarian hyperandrogenism (FOH).
Among PCOS cases, defined as otherwise unexplained excess androgen with infrequent ovulation, two-thirds have typical FOH: the ovaries overreact to hormonal stimulation.
Of the other third, two-thirds also have FOH, found when testosterone stays high after the adrenal glands are quieted. About 3% of all PCOS cases have isolated functional adrenal hyperandrogenism.
Remaining cases are mild and show no evidence of a steroid secretion problem. Most of these women are obese, which the authors postulate explains their atypical PCOS.
Interpretation
The article is an expert review of mechanisms across many studies, so its conclusions rest on the authors' reading of that literature. Several proportions come from the authors' own studies of small groups. The authors postulate some links, such as obesity accounting for atypical cases. The proportions apply to the review's definition of PCOS, which requires excess androgen and infrequent ovulation with no other explanation. The authors state that more research into the basis of the disorder will be needed.
RRM Context
Restorative reproductive medicine asks what drives a condition before it addresses the signs. The review maps where the excess androgen comes from in PCOS: mainly the ovaries, with the adrenal glands also involved in some. Insulin resistance and obesity add to it in about half. Such a map supports a cause-based look at irregular ovulation.
Our editorial summary of this paper, not the article's abstract.
Abstract
Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989-1995. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis.
