H PRIZANT and others Androgen actions in the ovary 222:3 R141–R151 Review Androgen actions in the ovary: balance is key Correspondence 1 2 1,2 Hen Prizant , Norbert Gleicher and Aritro Sen should be addressed to A Sen 1Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine Email and Dentistry, 601 Elmwood Avenue, PO Box 693, Rochester, New York 14642, USA aritro_sen@urmc. 2Center for Human Reproduction, New York, New York 10021, USA rochester.edu Abstract For many decades, elevated androgens in women have been associated with poor Key Words reproductive health. However, recent studies have shown that androgens play a crucial " androgen role in women’s fertility. The following review provides an overall perspective about " androgen receptor how androgens and androgen receptor-mediated actions regulate normal follicular " female reproduction development, as well as discuss emerging concepts, latest perceptions, and controversies " ovary regarding androgen actions and signaling in the ovary. Journal of Endocrinology (2014) 222, R141–R151 Introduction Journal of Endocrinology Recently, there has been a lot of interest towards the role ovarian insufficiency (POI), thereby negatively impacting of androgens in the regulation of follicular development female fertility. Many studies (Kimura et al. 2007, Walters and female fertility. In fact, over the years our under- et al. 2008, 2010, Gleicher et al. 2011, Sen & Hammes 2011, standing of the effects of androgens on follicular develop- Lebbe & Woodruff 2013) in the past 5 years have addressed ment and female fertility has undergone considerable androgen actions in the ovary. In this review, we change. Androgens have traditionally been considered summarize what currently is known about the direct detrimental to ovarian function and are often associated physiological actions of androgens in the regulation of with infertility. However, development of different types normal follicular development, and provide the molecular of androgen receptor (AR) knockout mouse models, along and/or signaling basis of these androgen actions. We also with various in vivo and in vitro studies, as well as clinical highlight the ranging controversy regarding the use of reports, has established a new concept that sufficient androgens as a treatment option in LFOR/POI patients. androgen actions through the AR is necessary for normal follicle development and function. Consequently, it is AR expression and regulation now increasingly realized that, likely, a critical balance exists between the essentiality of androgens in normal The idea that androgens might regulate follicular develop- follicular development and their detrimental effects in ment initially started with studies in the mid- and late hyper-androgenic conditions that regulate female fertility. 1990s looking at AR expression in the ovary. Studies across While androgen excess enhances follicular development species reported that ARs are expressed in theca cells, and dysfunctional formation of antral follicles leading granulosa cells (GCs), and the oocyte of the follicle and to polycystic ovary syndrome (PCOS), low androgen levels throughout most stages of follicular development (Horie may be associated with abnormalities of follicular growth, et al. 1992, Chadha et al. 1994, Hirai et al. 1994, Suzuki et al. low functional ovarian reserve (LFOR) and primary 1994, Tetsuka & Hillier 1996, Hillier et al. 1997, Szoltys & http://joe.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-14-0296 Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 07:11:01PM via free access Review H PRIZANT and others Androgen actions in the ovary 222:3 R142 Slomczynska 2000, Slomczynska & Tabarowski 2001, Gill of androgens in monkey (Abbott et al. 1998, Vendola et al. et al. 2004, Hampton et al. 2004, Juengel et al. 2006). 1998) and ewes (Smith et al. 2009) demonstrated initiation However, their expression patterns may differ between of follicular recruitment, stimulation of early stages of ovarian cell types (Tetsuka & Hillier 1996, Szoltys & follicular growth, and increase in the number of growing Slomczynska 2000) and in most species, AR is abundant in follicles. Importantly, in all these studies, it was demon- the preantral/antral stages of follicular development but strated that the observed androgenic effects could be declines as follicles mature to the preovulatory stage blocked by anti-androgens (Peluso et al. 1981, Murray et al. (Horie et al. 1992, Chadha et al. 1994, Suzuki et al. 1994, 1998, Yang & Fortune 2006). Despite all of these studies, the Hillier et al. 1997, Weil et al. 1998, Duffy et al. 1999, question still remained whether these reported androgen Slomczynska et al. 2001, Cardenas & Pope 2002, Hampton actions are the consequence of direct androgen actions via et al. 2004, Juengel et al. 2006). In fact, AR is expressed in the AR or due to aromatization of androgens to estrogen. cell-specific regions of human ovarian follicles at all stages of follicular development beyond the primordial phase AR knockout mouse models (Rice et al. 2007). Based on these AR expression pattern studies, it was suggested that androgens through an Earlier, it was believed that androgens affect ovarian autocrine and/or paracrine effect might differentially function either by acting as a precursor of steroidogenesis regulate various stages of follicular development. What (specifically by aromatization to estrogen) or by indirect exactly regulates AR expression in the follicle is not yet effects mediated by the hypothalamus–pituitary axis or clear. Studies in primates (Weil et al. 1998) demonstrate metabolic tissues. The development of the global AR that androgens (testosterone) in a positive feedback loop knockout (ARKO) female mouse models in the mid- and increases AR expression in the theca and GCs of preantral late 2000 established the importance of direct androgen follicles, while studies in rats have shown that AR action through ARs in normal female reproduction. The expression is developmentally regulated (Tetsuka et al. first Ar-null model (Lyon & Glenister 1974)carried 1995). The general sense is that, as follicles grow from the homozygous mutation in the testicular feminization pre-antral to the antral/preovulatory phase, the AR (Tfm) Ar gene on the X chromosome (Artfm/Artfm). expression decreases, and the dominant steroid receptor Artfm/Artfm mice ovulated, mated, and maintained preg- shifts from AR to estrogen receptor. nancies, but demonstrated significantly reduced repro- ductive performance (Lyon & Glenister 1980). As the Ar Journal of Endocrinology Stimulatory effects of androgens in follicular gene is located on the X chromosome and males lacking Ar development functional are infertile, homozygous female offspring lacking functional Ar were difficult to generate. Looking at different aspects of follicular development Later, however, using the Cre/LoxP system, three following androgen stimulation in various species, in vivo different global ARKO models were, nevertheless, gener- K/K and in vitro studies in the late 1990s and early 2000s first ated by targeting deletion of exons 1 (Ar1 )(Shiina et al. K/K K/K demonstrated direct androgen effects in folliculogenesis. 2006), exon 2 (Ar2 )(Hu et al. 2004), or exon 3 (Ar3 ) In rodents, androgen treatment enhances pre-antral (Walters et al. 2007) of the AR, leading to either the loss of K/K K/K follicular development and improves ovulatory response AR protein (in AR1 and AR2 ) or to a nonfunctional K/K by increasing GC proliferation and attenuating follicular AR protein (in AR3 ). All of these Ar-null female mice atresia (Mori et al. 1977, Ware 1982, Wang et al. 2001, were demonstrated to have normal ovarian and oviductal K/K K/K Sen et al. 2014). Moreover, in vitro culture of whole mouse morphology but reduced fertility, with Ar1 and Ar2 K/K follicles in presence of androgens significantly increases exhibiting a mildly more severe phenotype than Ar3 . the diameter of immature follicles and enhances the All three models are, however, distinctively sub-fertile, development of preantral follicles (Murray et al. 1998, with smaller litter size, less corpora lutea, higher atretic Wang et al. 2001, Sen et al. 2014). In large farm animals, follicle rates, and development of POI. in vivo administration of testosterone was shown to Given that ARs are expressed in all three components stimulate the transition of follicles from primary to of the hypothalamus–pituitary–ovarian axis (Sullivan secondary stage (Hampton et al. 2004, Yang & Fortune & Moenter 2004, Dart et al. 2013), two cell-specific 2006) and to increase the number of ovulatory follicles (oocyte- and GC targeted) ARKO mice have been and corpora lutea (Cardenas & Pope 1994, Cardenas et al. generated by crossing Ar (exon 2)-floxed mice with 2002, Hickey et al. 2004, 2005). Finally, administration either growth-differentiation factor 9 (GDF9)-Cre or http://joe.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-14-0296 Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 07:11:01PM via free access Review H PRIZANT and others Androgen actions in the ovary 222:3 R143 anti-Mu¨llerian hormone receptor type 2 (AMHR2)-Cre pups. In addition, these animals show decreased cumulus mice, respectively, to determine whether ovarian andro- cell expansion and lower rates of fertilization,