Androgen excess: a hallmark of polycystic ovary syndrome

Abstract

Polycystic ovarian syndrome (PCOS) is a metabolic, reproductive, and psychological disorder affecting 6-20% of reproductive women worldwide. However, there is still no cure for PCOS, and current treatments primarily alleviate its symptoms due to a poor understanding of its etiology. Compelling evidence suggests that hyperandrogenism is not just a primary feature of PCOS. Instead, it may be a causative factor for this condition. Thus, figuring out the mechanisms of androgen synthesis, conversion, and metabolism is relatively important. Traditionally, studies of androgen excess have largely focused on classical androgen, but in recent years, adrenal-derived 11-oxygenated androgen has also garnered interest. Herein, this Review aims to investigate the origins of androgen excess, androgen synthesis, how androgen receptor (AR) signaling mediates adverse PCOS traits, and the role of 11-oxygenated androgen in the pathophysiology of PCOS. In addition, it provides therapeutic strategies targeting hyperandrogenism in PCOS.

Keywords: Hyperandrogenism; androgen receptor; insulin resistance; polycystic ovarian syndrome; steroidogenesis.

Figure 1

The major clinical manifestations of PCOS. These symptoms can be divided into four categories: reproductive, endocrine, metabolic, and psychological comorbidities. (1) Reproductive features: the dysregulated hypothalamus-pituitary-gonadal (HPG) axis and neuroendocrine factors contribute to menstrual irregularities, anovulation, infertility, and increased risks of pregnancy complications. (2) Endocrine features: hormonal imbalances (ovarian and adrenal hyperandrogenemia). Symptoms like hirsutism, acne, and androgenic alopecia are induced by high levels of circulating androgens. (3) Metabolic features: 30% of lean and 70% of obese patients exhibit insulin resistance. Additionally, women with PCOS suffer from abdominal obesity, dyslipidemia, and non-alcoholic fatty liver disease (NAFLD). These metabolic abnormalities can result in long-term cardiometabolic sequelae, including type 2 diabetes, hypertension, and atherosclerotic disease. (4) Psychological features: PCOS is associated with an increased prevalence of depression, anxiety, and poor quality of life. Created with BioRender.com.

Figure 2

Ovarian-derived androgen biosynthesis in PCOS women (the classical and backdoor pathway). A series of steroidogenic enzymes, including CYP11A1, CYP17A1, and HSD3B2 in the theca cells and CYP19A1 in granulosa cells, are reported to increase in PCOS patients. It is demonstrated that circulating A4 was preferentially elevated in women with PCOS. Furthermore, globally higher SRD5A1 activity is observed, resulting in increased downstream androstanedione and DHT activation from A4 and T, respectively. The backdoor pathway, which involves the production of DHT bypassing the formation from T, is enhanced. In detail, 17OHP4 is the starting point of the backdoor pathway. Because 17OH-Allo is more efficiently metabolized by CYP17A1 than 17OH-Preg, it preferentially synthesizes DHT through the backdoor pathway rather than the classic pathway. The red arrows represent the enhanced pathways. SRD5A1, 5a-reductase type I; A4, androstenedione; T, testosterone; DHT, dihydrotestosterone; 17OHP4, 17ahydroxy-progesterone; 17OH-Allo, 17-hydroxy-allopregnanolone.

Figure 3

Adrenal-derived androgen synthesis in PCOS women (the classical and backdoor pathway). The levels of adrenal-derived A4, DHEA, and its sulfated metabolite DHEAS were significantly higher in PCOS patients. AKR1C3, also known as HSD17B5, is primarily expressed in peripheral tissues and only minimally distributed in the adrenal gland, which explains the negligible contents of T in the adrenal gland. Hence, 11OHA4 has the highest content of 11-oxygenated androgen content in the adrenal cortex. As for PCOS patients, the 11-oxygenated androgens 11-OHA-4, 11-KA4, 11-OH-T, and 11-KT are all elevated. Moreover, 11-KT is the predominant 11-oxygenated androgen in circulation. The red arrows represent the enhanced pathways. A4, Androstenedione; DHEA, dehydroepiandrosterone; 11-OH-A4, 11-OH-androstenedione; 11-KA4, 11-ketoandrostenedione; 11OH-T, 11OH-testosterone; 11-KT, 11-ketotestosterone.