Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Subfertility in androgen-insensitive female mice is rescued by transgenic FSH

K. A. Walters A B , M. C. Edwards A , M. Jimenez A , D. J. Handelsman A and C. M. Allan A

A ANZAC Research Institute, Andrology Laboratory, University of Sydney, Concord Hospital, Hospital Road, Concord, NSW 2139, Australia.

B Corresponding author. Email: k.walters@unsw.edu.au

Reproduction, Fertility and Development - https://doi.org/10.1071/RD16022
Submitted: 12 January 2016  Accepted: 30 May 2016   Published online: 22 June 2016

Abstract

Androgens synergise with FSH in female reproduction but the nature of their interaction in ovarian function and fertility is not clear. In the present study, we investigated this interaction, notably whether higher endogenous FSH can overcome defective androgen actions in androgen receptor (AR)-knockout (ARKO) mice. We generated and investigated the reproductive function of mutant mice exhibiting AR resistance with or without expression of human transgenic FSH (Tg-FSH). On the background of inactivated AR signalling, which alone resulted in irregular oestrous cycles and reduced pups per litter, ovulation rates and antral follicle health, Tg-FSH expression restored follicle health, ovulation rates and litter size to wild-type levels. However, Tg-FSH was only able to partially rectify the abnormal oestrous cycles observed in ARKO females. Hence, elevated endogenous FSH rescued the intraovarian defects, and partially rescued the extraovarian defects due to androgen insensitivity. In addition, the observed increase in litter size in Tg-FSH females was not observed in the presence of AR signalling inactivation. In summary, the findings of the present study reveal that FSH can rescue impaired female fertility and ovarian function due to androgen insensitivity in female ARKO mice by maintaining follicle health and ovulation rates, and thereby optimal female fertility.

Additional keywords: androgen receptor, female fertility, ovarian function.


References

Allan, C. M., Haywood, M., Swaraj, S., Spaliviero, J., Koch, A., Jimenez, M., Poutanen, M., Levallet, J., Huhtaniemi, I., Illingworth, P., and Handelsman, D. J. (2001). A novel transgenic model to characterize the specific effects of follicle-stimulating hormone on gonadal physiology in the absence of luteinizing hormone actions. Endocrinology 142, 2213–2220.
| 1:CAS:528:DC%2BD3MXjvFGgur8%3D&md5=052dbb38462db00327e093ead21419d2CAS | 11356665PubMed | open url image1

Balasch, J., Fabregues, F., Penarrubia, J., Carmona, F., Casamitjana, R., Creus, M., Manau, D., Casals, G., and Vanrell, J. A. (2006). Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH. Hum. Reprod. 21, 1884–1893.
Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH.CrossRef | 1:CAS:528:DC%2BD28Xms1Ontrg%3D&md5=398d28ef9f822c94b9eef867d5c19508CAS | 16517559PubMed | open url image1

Bosdou, J. K., Venetis, C. A., Kolibianakis, E. M., Toulis, K. A., Goulis, D. G., Zepiridis, L., and Tarlatzis, B. C. (2012). The use of androgens or androgen-modulating agents in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Hum. Reprod. Update 18, 127–145.
The use of androgens or androgen-modulating agents in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis.CrossRef | 1:CAS:528:DC%2BC38XjtFKrtb4%3D&md5=fd9e66d470be391f69ed6c3462a11f5aCAS | 22307331PubMed | open url image1

Caldwell, A. S., Middleton, L. J., Jimenez, M., Desai, R., McMahon, A. C., Allan, C. M., Handelsman, D. J., and Walters, K. A. (2014). Characterization of reproductive, metabolic, and endocrine features of polycystic ovary syndrome in female hyperandrogenic mouse models. Endocrinology 155, 3146–3159.
Characterization of reproductive, metabolic, and endocrine features of polycystic ovary syndrome in female hyperandrogenic mouse models.CrossRef | 1:CAS:528:DC%2BC2cXhs1egsrbF&md5=f87c8fb6501ea8e158ae09c50d4b3f87CAS | 24877633PubMed | open url image1

Cárdenas, H., Herrick, J. R., and Pope, W. F. (2002). Increased ovulation rate in gilts treated with dihydrotestosterone. Reproduction 123, 527–533.
Increased ovulation rate in gilts treated with dihydrotestosterone.CrossRef | 11914115PubMed | open url image1

Cheng, X. B., Jimenez, M., Desai, R., Middleton, L. J., Joseph, S. R., Ning, G., Allan, C. M., Smith, J. T., Handelsman, D. J., and Walters, K. A. (2013). Characterizing the neuroendocrine and ovarian defects of androgen receptor-knockout female mice. Am. J. Physiol. Endocrinol. Metab. 305, E717–E726.
Characterizing the neuroendocrine and ovarian defects of androgen receptor-knockout female mice.CrossRef | 1:CAS:528:DC%2BC3sXhs1Sqsb7F&md5=fc8ce0cc192201c6462fd10ff5bdda3fCAS | 23880317PubMed | open url image1

Davison, S. L., Bell, R., Donath, S., Montalto, J. G., and Davis, S. R. (2005). Androgen levels in adult females: changes with age, menopause, and oophorectomy. J. Clin. Endocrinol. Metab. 90, 3847–3853.
Androgen levels in adult females: changes with age, menopause, and oophorectomy.CrossRef | 1:CAS:528:DC%2BD2MXmtlCisLk%3D&md5=f66732605c41d2780a518f381100b902CAS | 15827095PubMed | open url image1

Fábregues, F., Peñarrubia, J., Creus, M., Manau, D., Casals, G., Carmona, F., and Balasch, J. (2009). Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: a randomized, clinical trial. Hum. Reprod. 24, 349–359.
Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: a randomized, clinical trial.CrossRef | 19054777PubMed | open url image1

Harwood, D. T., and Handelsman, D. J. (2009). Development and validation of a sensitive liquid chromatography–tandem mass spectrometry assay to simultaneously measure androgens and estrogens in serum without derivatization. Clin. Chim. Acta 409, 78–84.
Development and validation of a sensitive liquid chromatography–tandem mass spectrometry assay to simultaneously measure androgens and estrogens in serum without derivatization.CrossRef | 1:CAS:528:DC%2BD1MXht1aju7%2FI&md5=b09661ffb4d5a4e05e296c25027618bbCAS | 19747904PubMed | open url image1

Hickey, T. E., Marrocco, D. L., Gilchrist, R. B., Norman, R. J., and Armstrong, D. T. (2004). Interactions between androgen and growth factors in granulosa cell subtypes of porcine antral follicles. Biol. Reprod. 71, 45–52.
Interactions between androgen and growth factors in granulosa cell subtypes of porcine antral follicles.CrossRef | 1:CAS:528:DC%2BD2cXltFKktLg%3D&md5=62fe4fe7c3b574dfad9f3ad7430daf1fCAS | 14973257PubMed | open url image1

Hillier, S. G., and De Zwart, F. A. (1981). Evidence that granulosa cell aromatase induction/activation by follicle-stimulating hormone is an androgen receptor-regulated process in-vitro. Endocrinology 109, 1303–1305.
Evidence that granulosa cell aromatase induction/activation by follicle-stimulating hormone is an androgen receptor-regulated process in-vitro.CrossRef | 1:CAS:528:DyaL3MXls1anurg%3D&md5=89fd19de19243a7966be49535a8e5b96CAS | 6793349PubMed | open url image1

Hillier, S. G., and Tetsuka, M. (1997). Role of androgens in follicle maturation and atresia. Baillieres Clin. Obstet. Gynaecol. 11, 249–260.
Role of androgens in follicle maturation and atresia.CrossRef | 1:STN:280:DyaK1c7pslaksA%3D%3D&md5=ce41b9a18d917d2a9049eb6a0a2ce473CAS | 9536210PubMed | open url image1

Hillier, S. G., Whitelaw, P. F., and Smyth, C. D. (1994). Follicular oestrogen synthesis: the ‘two-cell, two-gonadotrophin’ model revisited. Mol. Cell. Endocrinol. 100, 51–54.
Follicular oestrogen synthesis: the ‘two-cell, two-gonadotrophin’ model revisited.CrossRef | 1:CAS:528:DyaK2cXktVWisLk%3D&md5=964804330efbf989330e820888f68a5dCAS | 8056158PubMed | open url image1

Howles, C. M., Loumaye, E., Giroud, D., and Luyet, G. (1994). Multiple follicular development and ovarian steroidogenesis following subcutaneous administration of a highly purified urinary FSH preparation in pituitary desensitized women undergoing IVF: a multicentre European Phase III study. Hum. Reprod. 9, 424–430.
| 1:STN:280:DyaK2c3nsVygtA%3D%3D&md5=e5840a33b9fcba6f494ce3d3218d720fCAS | 8006130PubMed | open url image1

Hu, Y. C., Wang, P. H., Yeh, S., Wang, R. S., Xie, C., Xu, Q., Zhou, X., Chao, H. T., Tsai, M. Y., and Chang, C. (2004). Subfertility and defective folliculogenesis in female mice lacking androgen receptor. Proc. Natl Acad. Sci. USA 101, 11 209–11 214.
Subfertility and defective folliculogenesis in female mice lacking androgen receptor.CrossRef | 1:CAS:528:DC%2BD2cXmvVKgtro%3D&md5=9126af48d860538b00e57a3e1ad5674bCAS | open url image1

Kumar, T. R., Wang, Y., Lu, N., and Matzuk, M. M. (1997). Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility. Nat. Genet. 15, 201–204.
Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility.CrossRef | 1:CAS:528:DyaK2sXhtVOks7c%3D&md5=58f02df0e142e59b8b605437a8fa48d8CAS | 9020850PubMed | open url image1

Massin, N., Cedrin-Durnerin, I., Coussieu, C., Galey-Fontaine, J., Wolf, J. P., and Hugues, J. N. (2006). Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique: a prospective, randomized, double-blind study. Hum. Reprod. 21, 1204–1211.
Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique: a prospective, randomized, double-blind study.CrossRef | 1:CAS:528:DC%2BD28XjsFWjtLk%3D&md5=d0a59b0d86546a828a579f92350a4710CAS | 16476678PubMed | open url image1

McGee, E. A., and Hsueh, A. J. (2000). Initial and cyclic recruitment of ovarian follicles. Endocr. Rev. 21, 200–214.
| 1:STN:280:DC%2BD3c3ksVahsw%3D%3D&md5=8f84e11125e8971773b1655663a30badCAS | 10782364PubMed | open url image1

McNamara, K. M., Harwood, D. T., Simanainen, U., Walters, K. A., Jimenez, M., and Handelsman, D. J. (2010). Measurement of sex steroids in murine blood and reproductive tissues by liquid chromatography–tandem mass spectrometry. J. Steroid Biochem. Mol. Biol. 121, 611–618.
Measurement of sex steroids in murine blood and reproductive tissues by liquid chromatography–tandem mass spectrometry.CrossRef | 1:CAS:528:DC%2BC3cXpvFKqt7c%3D&md5=f153fa49c36f5457994e251123d36510CAS | 20144714PubMed | open url image1

McTavish, K. J., Jimenez, M., Walters, K. A., Spaliviero, J., Groome, N. P., Themmen, A. P., Visser, J. A., Handelsman, D. J., and Allan, C. M. (2007). Rising follicle-stimulating hormone levels with age accelerate female reproductive failure. Endocrinology 148, 4432–4439.
Rising follicle-stimulating hormone levels with age accelerate female reproductive failure.CrossRef | 1:CAS:528:DC%2BD2sXpslCnurk%3D&md5=61ac5733af2d3d23f774210a7d57023eCAS | 17540727PubMed | open url image1

Myers, M., Britt, K. L., Wreford, N. G., Ebling, F. J., and Kerr, J. B. (2004). Methods for quantifying follicular numbers within the mouse ovary. Reproduction 127, 569–580.
Methods for quantifying follicular numbers within the mouse ovary.CrossRef | 1:CAS:528:DC%2BD2cXkvFOqu78%3D&md5=4d558d79990170bcf8931596982bad38CAS | 15129012PubMed | open url image1

Notini, A. J., Davey, R. A., McManus, J. F., Bate, K. L., and Zajac, J. D. (2005). Genomic actions of the androgen receptor are required for normal male sexual differentiation in a mouse model. J. Mol. Endocrinol. 35, 547–555.
Genomic actions of the androgen receptor are required for normal male sexual differentiation in a mouse model.CrossRef | 1:CAS:528:DC%2BD28XivVGntw%3D%3D&md5=4deb0c28383ea5c1f40131a9d0fe3053CAS | 16326839PubMed | open url image1

Oktem, O., and Urman, B. (2010). Understanding follicle growth in vivo. Hum. Reprod. 25, 2944–2954.
Understanding follicle growth in vivo.CrossRef | 20937745PubMed | open url image1

Schwenk, F., Baron, U., and Rajewsky, K. (1995). A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res. 23, 5080–5081.
A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells.CrossRef | 1:CAS:528:DyaK28XlsVCrsA%3D%3D&md5=50023ca086b4710c523b52b6c0738ba9CAS | 8559668PubMed | open url image1

Sen, A., and Hammes, S. R. (2010). Granulosa cell-specific androgen receptors are critical regulators of ovarian development and function. Mol. Endocrinol. 24, 1393–1403.
Granulosa cell-specific androgen receptors are critical regulators of ovarian development and function.CrossRef | 1:CAS:528:DC%2BC3cXpt1CntrY%3D&md5=8ed3798239df8981b23ed05ba7117c8eCAS | 20501640PubMed | open url image1

Sen, A., Prizant, H., Light, A., Biswas, A., Hayes, E., Lee, H. J., Barad, D., Gleicher, N., and Hammes, S. R. (2014). Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression. Proc. Natl Acad. Sci. USA 111, 3008–3013.
Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression.CrossRef | 1:CAS:528:DC%2BC2cXjtVKhsrY%3D&md5=09648f0f7b10580267acee06be343cc5CAS | 24516121PubMed | open url image1

Shiina, H., Matsumoto, T., Sato, T., Igarashi, K., Miyamoto, J., Takemasa, S., Sakari, M., Takada, I., Nakamura, T., Metzger, D., Chambon, P., Kanno, J., Yoshikawa, H., and Kato, S. (2006). Premature ovarian failure in androgen receptor-deficient mice. Proc. Natl Acad. Sci. USA 103, 224–229.
Premature ovarian failure in androgen receptor-deficient mice.CrossRef | 1:CAS:528:DC%2BD28Xms12huw%3D%3D&md5=c1d10f4fddddbe4765a2fbca5ac71985CAS | 16373508PubMed | open url image1

Simanainen, U., Gao, Y. R., Walters, K. A., Watson, G., Desai, R., Jimenez, M., and Handelsman, D. J. (2012). Androgen resistance in female mice increases susceptibility to DMBA-induced mammary tumors. Horm. Cancer 3, 113–124.
Androgen resistance in female mice increases susceptibility to DMBA-induced mammary tumors.CrossRef | 1:CAS:528:DC%2BC38XmsF2ms78%3D&md5=b8819e3676c33cfca3e53fcef72c1c77CAS | 22370991PubMed | open url image1

Sipe, C. S., Thomas, M. R., Stegmann, B. J., and Van Voorhis, B. J. (2010). Effects of exogenous testosterone supplementation in gonadotrophin stimulated cycles. Hum. Reprod. 25, 690–696.
Effects of exogenous testosterone supplementation in gonadotrophin stimulated cycles.CrossRef | 1:CAS:528:DC%2BC3cXitFeisbc%3D&md5=51ba027ca9a1d9378e4260c4d725b4c4CAS | 20031956PubMed | open url image1

Tetsuka, M., and Hillier, S. G. (1996). Androgen receptor gene expression in rat granulosa cells: the role of follicle-stimulating hormone and steroid hormones. Endocrinology 137, 4392–4397.
| 1:CAS:528:DyaK28XlvVSmsLk%3D&md5=1ef34cd20faac7be6507fb7d547abac2CAS | 8828500PubMed | open url image1

Walters, K. A. (2015). Role of androgens in normal and pathological ovarian function. Reproduction 149, R193–R218.
Role of androgens in normal and pathological ovarian function.CrossRef | 1:CAS:528:DC%2BC2MXns1Srtr0%3D&md5=b9789194f00411ff3047f193f2d4886aCAS | 25516989PubMed | open url image1

Walters, K. A., Allan, C. M., Jimenez, M., Lim, P. R., Davey, R. A., Zajac, J. D., Illingworth, P., and Handelsman, D. J. (2007). Female mice haploinsufficient for an inactivated androgen receptor (AR) exhibit age-dependent defects that resemble the AR null phenotype of dysfunctional late follicle development, ovulation, and fertility. Endocrinology 148, 3674–3684.
Female mice haploinsufficient for an inactivated androgen receptor (AR) exhibit age-dependent defects that resemble the AR null phenotype of dysfunctional late follicle development, ovulation, and fertility.CrossRef | 1:CAS:528:DC%2BD2sXot1Oisbk%3D&md5=87047093c2591926b12e46f81a3d9f4aCAS | 17463055PubMed | open url image1

Walters, K. A., Allan, C. M., and Handelsman, D. J. (2008). Androgen actions and the ovary. Biol. Reprod. 78, 380–389.
Androgen actions and the ovary.CrossRef | 1:CAS:528:DC%2BD1cXisFSltb8%3D&md5=64e206397e1e89ee44560ac97746493aCAS | 18003945PubMed | open url image1

Walters, K. A., McTavish, K. J., Seneviratne, M. G., Jimenez, M., McMahon, A. C., Allan, C. M., Salamonsen, L. A., and Handelsman, D. J. (2009). Subfertile female androgen receptor knockout mice exhibit defects in neuroendocrine signaling, intraovarian function, and uterine development but not uterine function. Endocrinology 150, 3274–3282.
Subfertile female androgen receptor knockout mice exhibit defects in neuroendocrine signaling, intraovarian function, and uterine development but not uterine function.CrossRef | 1:CAS:528:DC%2BD1MXotlCrsLg%3D&md5=f25394de1a517144e97df37827d1c1c2CAS | 19359383PubMed | open url image1

Walters, K. A., Middleton, L. J., Joseph, S. R., Hazra, R., Jimenez, M., Simanainen, U., Allan, C. M., and Handelsman, D. J. (2012). Targeted loss of androgen receptor signaling in murine granulosa cells of preantral and antral follicles causes female subfertility. Biol. Reprod. 87, 151.
Targeted loss of androgen receptor signaling in murine granulosa cells of preantral and antral follicles causes female subfertility.CrossRef | 23115271PubMed | open url image1

Wang, H., Andoh, K., Hagiwara, H., Xiaowei, L., Kikuchi, N., Abe, Y., Yamada, K., Fatima, R., and Mizunuma, H. (2001). Effect of adrenal and ovarian androgens on type 4 follicles unresponsive to FSH in immature mice. Endocrinology 142, 4930–4936.
Effect of adrenal and ovarian androgens on type 4 follicles unresponsive to FSH in immature mice.CrossRef | 1:CAS:528:DC%2BD3MXnslGqu7s%3D&md5=a5694cc491612bc4a3c24f679526660cCAS | 11606461PubMed | open url image1

Weil, S., Vendola, K., Zhou, J., and Bondy, C. A. (1999). Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J. Clin. Endocrinol. Metab. 84, 2951–2956.
Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development.CrossRef | 1:CAS:528:DyaK1MXltFCltbk%3D&md5=7ecafdf4bc2cbea28531d1c352a9e858CAS | 10443703PubMed | open url image1

Wiser, A., Gonen, O., Ghetler, Y., Shavit, T., Berkovitz, A., and Shulman, A. (2010). Addition of dehydroepiandrosterone (DHEA) for poor-responder patients before and during IVF treatment improves the pregnancy rate: a randomized prospective study. Hum. Reprod. 25, 2496–2500.
Addition of dehydroepiandrosterone (DHEA) for poor-responder patients before and during IVF treatment improves the pregnancy rate: a randomized prospective study.CrossRef | 1:CAS:528:DC%2BC3cXhtFyltLjE&md5=a7c84d5ae8d4a96999a8129de2bca818CAS | 20729538PubMed | open url image1

Wu, S., Chen, Y., Fajobi, T., DiVall, S. A., Chang, C., Yeh, S., and Wolfe, A. (2014). Conditional knockout of the androgen receptor in gonadotropes reveals crucial roles for androgen in gonadotropin synthesis and surge in female mice. Mol. Endocrinol. 28, 1670–1681.
Conditional knockout of the androgen receptor in gonadotropes reveals crucial roles for androgen in gonadotropin synthesis and surge in female mice.CrossRef | 25157703PubMed | open url image1

Yeung, T. W. Y., Chai, J., Li, R. H. W., Lee, V. C. Y., Ho, P. C., and Ng, E. H. Y. (2014). A randomized, controlled, pilot trial on the effect of dehydroepiandrosterone on ovarian response markers, ovarian response, and in vitro fertilization outcomes in poor responders. Fertil. Steril. 102, 108–115.e1.
A randomized, controlled, pilot trial on the effect of dehydroepiandrosterone on ovarian response markers, ovarian response, and in vitro fertilization outcomes in poor responders.CrossRef | 1:CAS:528:DC%2BC2cXnsFCjtrc%3D&md5=1f49a78840fb201f3b47f2b2a32541f5CAS | open url image1



Export Citation