Subfertility and Defective Folliculogenesis in Female Mice Lacking Androgen Receptor

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2004 Jul 28

PMID 15277682

Citations 95

Authors

Yueh-Chiang Hu

Peng-Hui Wang

Shuyuan Yeh

Ruey-Sheng Wang

Chao Xie

Qingquan Xu

Xinchang Zhou

Hsiang-Tai Chao

Meng-Yin Tsai

Chawnshang Chang

Affiliations

Soon will be listed here.

Abstract

The roles of the androgen receptor (AR) in female fertility and ovarian function remain largely unknown. Here we report on the generation of female mice lacking AR (AR(-/-)) and the resulting influences on the reproductive system. Female AR(-/-) mice appear normal but show longer estrous cycles and reduced fertility. The ovaries from sexually mature AR(-/-) females exhibited a marked reduction in the number of corpora lutea. After superovulation treatment, the AR(-/-) ovaries produced fewer oocytes and also showed fewer corpora lutea. During the periovulatory period, an intensive granulosa apoptosis event occurs in the AR(-/-) preovulatory follicles, concurrent with the down-regulation of p21 and progesterone receptor expression. Furthermore, the defective conformation of the cumulus cell-oocyte complex from the AR(-/-) females implies a lower fertilization capability of the AR(-/-) oocytes. In addition to insufficient progesterone production, the diminished endometrial growth in uteri in response to exogenous gonadotropins indicates that AR(-/-) females exhibit a luteal phase defect. Taken together, these data provide in vivo evidence showing that AR plays an important role in female reproduction.

Citing Articles

GGN repeat length of the androgen receptor gene is associated with antral follicle count in Chinese women undergoing controlled ovarian stimulation.

Liu X, Fan Q, Deng M, Xu Y, Guo J, Cao P Nan Fang Yi Ke Da Xue Xue Bao. 2025; 45(2):213-222.

PMID: 40031964 PMC: 11875863. DOI: 10.12122/j.issn.1673-4254.2025.02.01.

Effects of coenzyme q10 supplementation on metabolic and reproductive outcomes in obese rats.

Sarrible G, Bazzano M, Koutsovitis C, Bilbao M, Da Cuna R, Neira M J Ovarian Res. 2025; 18(1):22.

PMID: 39901256 PMC: 11789320. DOI: 10.1186/s13048-025-01604-7.

Searching for the 'X' factor: investigating the genetics of primary ovarian insufficiency.

Knight A, Sugin S, Jurisicova A J Ovarian Res. 2024; 17(1):238.

PMID: 39609914 PMC: 11603650. DOI: 10.1186/s13048-024-01555-5.

An integrated analysis of multiple datasets reveals novel gene signatures in human granulosa cells.

Dhori X, Gioiosa S, Gonfloni S Sci Data. 2024; 11(1):972.

PMID: 39242561 PMC: 11379948. DOI: 10.1038/s41597-024-03715-0.

Androgen Inhibition of Reproductive Neuroendocrine Function in Females and Transgender Males.

Kauffman A Endocrinology. 2024; 165(10).

PMID: 39207217 PMC: 11393496. DOI: 10.1210/endocr/bqae113.

References

Mcgee E, Hsueh A . Initial and cyclic recruitment of ovarian follicles. Endocr Rev. 2000; 21(2):200-14. DOI: 10.1210/edrv.21.2.0394. View

Weil S, Vendola K, Zhou J, Bondy C . Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab. 1999; 84(8):2951-6. DOI: 10.1210/jcem.84.8.5929. View

Yeh S, Hu Y, Rahman M, Lin H, Hsu C, Ting H . Increase of androgen-induced cell death and androgen receptor transactivation by BRCA1 in prostate cancer cells. Proc Natl Acad Sci U S A. 2000; 97(21):11256-61. PMC: 17187. DOI: 10.1073/pnas.190353897. View

Wang H, Andoh K, Hagiwara H, Xiaowei L, Kikuchi N, Abe Y . Effect of adrenal and ovarian androgens on type 4 follicles unresponsive to FSH in immature mice. Endocrinology. 2001; 142(11):4930-6. DOI: 10.1210/endo.142.11.8482. View

Cheng G, Weihua Z, Makinen S, Makela S, Saji S, Warner M . A role for the androgen receptor in follicular atresia of estrogen receptor beta knockout mouse ovary. Biol Reprod. 2001; 66(1):77-84. DOI: 10.1095/biolreprod66.1.77. View

Heinlein C, Chang C . Androgen receptor (AR) coregulators: an overview. Endocr Rev. 2002; 23(2):175-200. DOI: 10.1210/edrv.23.2.0460. View

Paria B, Reese J, Das S, Dey S . Deciphering the cross-talk of implantation: advances and challenges. Science. 2002; 296(5576):2185-8. DOI: 10.1126/science.1071601. View

Zaczek D, Hammond J, Suen L, Wandji S, Service D, Bartke A . Impact of growth hormone resistance on female reproductive function: new insights from growth hormone receptor knockout mice. Biol Reprod. 2002; 67(4):1115-24. DOI: 10.1095/biolreprod67.4.1115. View

Yeh S, Tsai M, Xu Q, Mu X, Lardy H, Huang K . Generation and characterization of androgen receptor knockout (ARKO) mice: an in vivo model for the study of androgen functions in selective tissues. Proc Natl Acad Sci U S A. 2002; 99(21):13498-503. PMC: 129702. DOI: 10.1073/pnas.212474399. View

10.

Durlinger A, Visser J, Themmen A . Regulation of ovarian function: the role of anti-Müllerian hormone. Reproduction. 2002; 124(5):601-9. DOI: 10.1530/rep.0.1240601. View

11.

Ikeda S, Imai H, Yamada M . Apoptosis in cumulus cells during in vitro maturation of bovine cumulus-enclosed oocytes. Reproduction. 2003; 125(3):369-76. View

12.

Ochsner S, Day A, Rugg M, Breyer R, Gomer R, Richards J . Disrupted function of tumor necrosis factor-alpha-stimulated gene 6 blocks cumulus cell-oocyte complex expansion. Endocrinology. 2003; 144(10):4376-84. DOI: 10.1210/en.2003-0487. View

13.

Yeh S, Hu Y, Wang P, Xie C, Xu Q, Tsai M . Abnormal mammary gland development and growth retardation in female mice and MCF7 breast cancer cells lacking androgen receptor. J Exp Med. 2003; 198(12):1899-908. PMC: 2194158. DOI: 10.1084/jem.20031233. View

14.

Heinlein C, Chang C . Androgen receptor in prostate cancer. Endocr Rev. 2004; 25(2):276-308. DOI: 10.1210/er.2002-0032. View

15.

Chang C, Chen Y, Yeh S, Xu Q, Wang R, Guillou F . Infertility with defective spermatogenesis and hypotestosteronemia in male mice lacking the androgen receptor in Sertoli cells. Proc Natl Acad Sci U S A. 2004; 101(18):6876-81. PMC: 406435. DOI: 10.1073/pnas.0307306101. View

16.

Armstrong D, Papkoff H . Stimulation of aromatization of exogenous and endogenous androgens in ovaries of hypophysectomized rats in vivo by follicle-stimulating hormone. Endocrinology. 1976; 99(4):1144-51. DOI: 10.1210/endo-99-4-1144. View

17.

Lyon M, Glenister P . Reduced reproductive performance in androgen-resistant Tfm/Tfm female mice. Proc R Soc Lond B Biol Sci. 1980; 208(1170):1-12. DOI: 10.1098/rspb.1980.0040. View

18.

Daniel S, Armstrong D . Enhancement of follicle-stimulating hormone-induced aromatase activity by androgens in cultured rat granulosa cells. Endocrinology. 1980; 107(4):1027-33. DOI: 10.1210/endo-107-4-1027. View

19.

Chang C, Kokontis J, Liao S . Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science. 1988; 240(4850):324-6. DOI: 10.1126/science.3353726. View

20.

INSLER V . Corpus luteum defects. Curr Opin Obstet Gynecol. 1992; 4(2):203-11. View