Androgen Signaling in Uterine Diseases: New Insights and New Targets

Abstract

Common uterine diseases include endometriosis, uterine fibroids, endometrial polyps, endometrial hyperplasia, endometrial cancer, and endometrial dysfunction causing infertility. Patients with uterine diseases often suffer from abdominal pain, menorrhagia, infertility and other symptoms, which seriously impair their health and disturb their lives. Androgens play important roles in the normal physiological functions of the uterus and pathological progress of uterine diseases. Androgens in women are synthesized in the ovaries and adrenal glands. The action of androgens in the uterus is mainly mediated by its ligand androgen receptor (AR) that regulates transcription of the target genes. However, much less is known about the signaling pathways through which androgen functions in uterine diseases, and contradictory findings have been reported. This review summarizes and discusses the progress of research on androgens and the involvement of AR in uterine diseases. Future studies should focus on developing new therapeutic strategies that precisely target specific AR and their related signaling pathways in uterine diseases.

Keywords: androgen; androgen receptor; endometrium; uterine diseases.

Figure 1

Schematic of androgen production, metabolism, and classical and nonclassical signaling pathways of AR. The figure was created with https://biorender.com (accessed on 1 September 2022).

Figure 2

The role of androgen in uterine fibroids. (a) Testosterone is converted into E2 under the action of aromatase, thereby promoting the growth of uterine fibroids; (b) AR maintains the stability of IGF-1R protein and triggers the PI3K/AKT and MAPK pathways to promote cell proliferation. AR also mediates anti-apoptotic functions through receptor-dependent and ligand-dependent pathways; (c) Danazol normalizes estrogen metabolism and affects the production of FSH and LH, ultimately inhibiting estrogen production. Danazol can also affect the hemodynamic effects of uterine fibroids.

Figure 3

The role of androgen in endometrial hyperplasia. (a) An IUD containing danazol inhibits estrogen-induced c-fos/jun expression by releasing danazol, thereby inhibiting endometrial hyperplasia; (b) DHEAS and AR are increased in women with PCOS. DHEAS is converted to A4, which increases the expression of VEGF through ERα. VEGF further activates the MAPK and PI3K/AKT pathways, thereby promoting the occurrence of endometrial hyperplasia.

Figure 4

The dual role of androgen signaling in endometrial cancer. High AR expression was positively correlated with a lower grade, early stage, negative lymph node, and lower recurrence rate in EC. Progestin can inhibit tumor growth through AR signaling, and androgen can also bind to PR, thereby enhancing the progestin sensitivity of EC. On the other hand, androgen can promote EC cell proliferation, enhance EMT, and affect the resistance of EC cells to cisplatin.