Removal of DHT can relieve polycystic ovarian but not metabolic abnormalities in DHT-induced hyperandrogenism in mice
Li-Feng Sun
A B * , Ya-Li Yang A * , Tian-Xia Xiao A , Meng-Xia Li A and Jian V. Zhang A C D
+ Author Affiliations
- Author Affiliations
A Research Laboratory for Reproductive Health, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
B University of Chinese Academy of Sciences, Beijing 100049, China.
C Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.
D Corresponding author. Email: jian.zhang@siat.ac.cn
Reproduction, Fertility and Development 31(10) 1597-1606 https://doi.org/10.1071/RD18459
Submitted: 23 August 2018 Accepted: 24 April 2019 Published: 30 May 2019
Abstract
Polycystic ovary syndrome (PCOS) is an endocrine disorder with a high prevalence in women of childbearing age. To date, there is no method of efficiently diagnosing PCOS and curing it completely because its pathomechanism remains unclear. Here, we investigated whether metabolic abnormalities maintain the hyperandrogenism and PCOS-like ovaries and whether the symptoms induced by excess androgen are treatable. We ceased the abnormal dihydrotestosterone (DHT) stimulation to determine changes in PCOS-like mice. After ceasing DHT stimulation, the ovarian morphology and gene expression recovered from the DHT-stimulated status. However, after cessation of DHT stimulation, the hypertrophy of adipose tissues and hepatic steatosis were not significantly restored, and fat accumulation-related gene expression and serum metabolic markers in the mice were altered. These findings showed that the reproductive dysfunction was obviously relieved, but because the metabolic abnormalities were not relieved after the cessation of excess androgen for 30 days, it appears that the latter may not maintain the former.
Additional keywords: adipose tissues, lipid, liver, ovary, PCOS.
References
Abbott, D. H., Nicol, L. E., Levine, J. E., Xu, N., Goodarzi, M. O., and Dumesic, D. A. (2013). Nonhuman primate models of polycystic ovary syndrome. Mol. Cell. Endocrinol. 373, 21–28.| Nonhuman primate models of polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 23370180PubMed |
Amiri, M., Golsorkhtabaramiri, M., Esmaeilzadeh, S., Ghofrani, F., Bijani, A., Ghorbani, L., and Delavar, M. A. (2014). Effect of metformin and flutamide on anthropometric indices and laboratory tests in obese/overweight PCOS women under hypocaloric diet. J. Reprod. Infertil. 15, 205.
| 25473629PubMed |
Azziz, R., Carmina, E., Dewailly, D., Diamanti-Kandarakis, E., Escobar-Morreale, H. F., Futterweit, W., Janssen, O. E., Legro, R. S., Norman, R. J., Taylor, A. E., Witchel, S. F., Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen Excess and PCOS Society (2009). The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil. Steril. 91, 456–488.
| The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report.Crossref | GoogleScholarGoogle Scholar | 18950759PubMed |
Becerra-Fernández, A., Pérez-López, G., Román, M. M., Martín-Lazaro, J. F., Lucio Pérez, M. J., Asenjo Araque, N., Rodríguez-Molina, J. M., Berrocal Sertucha, M. C., and Aguilar Vilas, M. V. (2014). Prevalence of hyperandrogenism and polycystic ovary syndrome in female to male transsexuals. Endocrinol. Nutr. 61, 351–358.
| 24680383PubMed |
Blank, S. K., McCartney, C. R., Helm, K. D., and Marshall, J. C. (2007). Neuroendocrine effects of androgens in adult polycystic ovary syndrome and female puberty. Semin. Reprod. Med. 25, 352–359.
| Neuroendocrine effects of androgens in adult polycystic ovary syndrome and female puberty.Crossref | GoogleScholarGoogle Scholar | 17710731PubMed |
Brennan-Speranza, T. C., Henneicke, H., Gasparini, S. J., Blankenstein, K. I., Heinevetter, U., Cogger, V. C., Svistounov, D., Zhang, Y., Cooney, G. J., Buttgereit, F., Dunstan, C. R., Gundberg, C., Zhou, H., and Seibel, M. J. (2012). Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism. J. Clin. Invest. 122, 4172–4189.
| Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism.Crossref | GoogleScholarGoogle Scholar | 23093779PubMed |
Brothers, K. J., Wu, S., DiVall, S. A., Messmer, M. R., Kahn, C. R., Miller, R. S., Radovick, S., Wondisford, F. E., and Wolfe, A. (2010). Rescue of obesity-induced infertility in female mice due to a pituitary-specific knockout of the insulin receptor. Cell Metab. 12, 295–305.
| Rescue of obesity-induced infertility in female mice due to a pituitary-specific knockout of the insulin receptor.Crossref | GoogleScholarGoogle Scholar | 20816095PubMed |
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 | GoogleScholarGoogle Scholar | 24877633PubMed |
Caldwell, A. S. L., Edwards, M. C., Desai, R., Jimenez, M., Gilchrist, R. B., Handelsman, D. J., and Walters, K. A. (2017). Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome. Proc. Natl Acad. Sci. USA 114, E3334–E3343.
| Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar |
Fauser, B. C., Tarlatzis, B. C., Rebar, R. W., Legro, R. S., Balen, A. H., Lobo, R., Carmina, E., Chang, J., Yildiz, B. O., Laven, J. S., Boivin, J., Petraglia, F., Wijeyeratne, C. N., Norman, R. J., Dunaif, A., Franks, S., Wild, R. A., Dumesic, D., and Barnhart, K. (2012). Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil. Steril. 97, 28–38.e25.
| Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group.Crossref | GoogleScholarGoogle Scholar | 22153789PubMed |
Foretz, M., Pacot, C., Dugail, I., Lemarchand, P., Guichard, C., Le Lièpvre, X., Berthelier-Lubrano, C., Spiegelman, B., Kim, J. B., Ferré, P., and Foufelle, F. (1999). ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose. Mol. Cell. Biol. 19, 3760–3768.
| ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose.Crossref | GoogleScholarGoogle Scholar | 10207099PubMed |
Gambineri, A., Pagotto, U., Tschöp, M., Vicennati, V., Manicardi, E., Carcello, A., Cacciari, M., De Iasio, R., and Pasquali, R. (2003). Anti-androgen treatment increases circulating ghrelin levels in obese women with polycystic ovary syndrome. J. Endocrinol. Invest. 26, 629–634.
| Anti-androgen treatment increases circulating ghrelin levels in obese women with polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 14594113PubMed |
Gorry, A., White, D. M., and Franks, S. (2006). Infertility in polycystic ovary syndrome. Endocrine 30, 27–33.
| Infertility in polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 17185789PubMed |
Horton, J. D., Shimomura, I., Brown, M. S., Hammer, R. E., Goldstein, J. L., and Shimano, H. (1998). Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2. J. Clin. Invest. 101, 2331–2339.
| Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2.Crossref | GoogleScholarGoogle Scholar | 9616204PubMed |
Hu, M., Richard, J. E., Maliqueo, M., Kokosar, M., Fornes, R., Benrick, A., Jansson, T., Ohlsson, C., Wu, X., Skibicka, K. P., and Stener-Victorin, E. (2015). Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring. Proc. Natl. Acad. Sci. USA 112, 14348–14353.
| Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring.Crossref | GoogleScholarGoogle Scholar | 26578781PubMed |
Hussain, M. M., Rava, P., Walsh, M., Rana, M., and Iqbal, J. (2012). Multiple functions of microsomal triglyceride transfer protein. Nutr. Metab. (Lond.) 9, 14.
| Multiple functions of microsomal triglyceride transfer protein.Crossref | GoogleScholarGoogle Scholar | 22353470PubMed |
Kar, S. (2012). Clomiphene citrate or letrozole as first-line ovulation induction drug in infertile PCOS women: a prospective randomized trial. J. Hum. Reprod. Sci. 5, 262–265.
| Clomiphene citrate or letrozole as first-line ovulation induction drug in infertile PCOS women: a prospective randomized trial.Crossref | GoogleScholarGoogle Scholar | 23531705PubMed |
Karoli, R., Fatima, J., Chandra, A., Gupta, U., Islam, F. U., and Singh, G. (2013). Prevalence of hepatic steatosis in women with polycystic ovary syndrome. J. Hum. Reprod. Sci. 6, 9.
| Prevalence of hepatic steatosis in women with polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 23869143PubMed |
Lai, H., Jia, X., Yu, Q., Zhang, C., Qiao, J., Guan, Y., and Kang, J. (2014). High-fat diet induces significant metabolic disorders in a mouse model of polycystic ovary syndrome. Biol. Reprod. 91, 127.
| High-fat diet induces significant metabolic disorders in a mouse model of polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 25100714PubMed |
Liu, G., Shi, F., Blas-Machado, U., Duong, Q., Davis, V. L., Foster, W. G., and Hughes, C. L. (2005). Ovarian effects of a high lactose diet in the female rat. Reprod. Nutr. Dev. 45, 185–192.
| Ovarian effects of a high lactose diet in the female rat.Crossref | GoogleScholarGoogle Scholar | 15954229PubMed |
Lujan, M. E., Chizen, D. R., and Pierson, R. A. (2008). Diagnostic criteria for polycystic ovary syndrome: pitfalls and controversies. J. Obstet. Gynaecol. Can. 30, 671–679.
| Diagnostic criteria for polycystic ovary syndrome: pitfalls and controversies.Crossref | GoogleScholarGoogle Scholar | 18786289PubMed |
Mannerås, L., Cajander, S., Holmäng, A., Seleskovic, Z., Lystig, T., Lönn, M., and Stener-Victorin, E. (2007). A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome. Endocrinology 148, 3781–3791.
| A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 17495003PubMed |
Nasiri, N., Moini, A., Eftekhari-Yazdi, P., Karimian, L., Salman-Yazdi, R., Zolfaghari, Z., and Arabipoor, A. (2015). Abdominal obesity can induce both systemic and follicular fluid oxidative stress independent from polycystic ovary syndrome. Eur. J. Obstet. Gynecol. Reprod. Biol. 184, 112–116.
| Abdominal obesity can induce both systemic and follicular fluid oxidative stress independent from polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 25498475PubMed |
Nisenblat, V., and Norman, R. J. (2009). Androgens and polycystic ovary syndrome. Curr. Opin. Endocrinol. Diabetes Obes. 16, 224–231.
| Androgens and polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 19390322PubMed |
Padmanabhan, V., and Veiga-Lopez, A. (2013). Sheep models of polycystic ovary syndrome phenotype. Mol. Cell. Endocrinol. 373, 8–20.
| Sheep models of polycystic ovary syndrome phenotype.Crossref | GoogleScholarGoogle Scholar | 23084976PubMed |
Paradisi, R., Fabbri, R., Battaglia, C., and Venturoli, S. (2013). Ovulatory effects of flutamide in the polycystic ovary syndrome. Gynecol. Endocrinol. 29, 391–395.
| Ovulatory effects of flutamide in the polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 23327685PubMed |
Pignatelli, D. (2013). Non-classic adrenal hyperplasia due to the deficiency of 21-hydroxylase and its relation to polycystic ovarian syndrome. Front. Horm. Res. 40, 158–170.
| Non-classic adrenal hyperplasia due to the deficiency of 21-hydroxylase and its relation to polycystic ovarian syndrome.Crossref | GoogleScholarGoogle Scholar | 24002412PubMed |
Pradeep, P. K., Li, X., Peegel, H., and Menon, K. M. J. (2002). Dihydrotestosterone inhibits granulosa cell proliferation by decreasing the cyclin D2 mRNA expression and cell cycle arrest at G1 phase. Endocrinology 143, 2930–2935.
| Dihydrotestosterone inhibits granulosa cell proliferation by decreasing the cyclin D2 mRNA expression and cell cycle arrest at G1 phase.Crossref | GoogleScholarGoogle Scholar | 12130558PubMed |
Radavelli-Bagatini, S., Blair, A. R., Proietto, J., Spritzer, P. M., and Andrikopoulos, S. (2011). The New Zealand obese mouse model of obesity insulin resistance and poor breeding performance: evaluation of ovarian structure and function. J. Endocrinol. 209, 307–315.
| The New Zealand obese mouse model of obesity insulin resistance and poor breeding performance: evaluation of ovarian structure and function.Crossref | GoogleScholarGoogle Scholar | 21429962PubMed |
Rittmaster, R. S. (1999). Antiandrogen treatment of polycystic ovary syndrome. Endocrinol. Metab. Clin. North Am. 28, 409–421.
| Antiandrogen treatment of polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 10352926PubMed |
Sang, J., Wang, Z., Li, M., Cao, J., Niu, G., Xia, L., Zou, D., Wang, F., Xu, X., Han, X., Fan, J., Yang, Y., Zuo, W., Zhang, Y., Zhao, W., Bao, Y., Xiao, J., Hu, S., Hao, L., and Zhang, Z. (2018). ICG: a wiki-driven knowledgebase of internal control genes for RT-qPCR normalization. Nucleic Acids Res. 46, D121–D126.
| ICG: a wiki-driven knowledgebase of internal control genes for RT-qPCR normalization.Crossref | GoogleScholarGoogle Scholar | 29036693PubMed |
Sullivan, S. D., and Moenter, S. M. (2004). Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder. Proc. Natl Acad. Sci. USA 101, 7129–7134.
| Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder.Crossref | GoogleScholarGoogle Scholar | 15096602PubMed |
The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. (2004). Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil. Steril. 81, 19–25.
| Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 15126094PubMed |
van Houten, E. L., Kramer, P., McLuskey, A., Karels, B., Themmen, A. P., and Visser, J. A. (2012). Reproductive and metabolic phenotype of a mouse model of PCOS. Endocrinology 153, 2861–2869.
| Reproductive and metabolic phenotype of a mouse model of PCOS.Crossref | GoogleScholarGoogle Scholar | 22334715PubMed |
Walters, K. A., Allan, C. M., and Handelsman, D. J. (2012). Rodent models for human polycystic ovary syndrome. Biol. Reprod. 86, 149.
| Rodent models for human polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 22337333PubMed |
Yu, S., Matsusue, K., Kashireddy, P., Cao, W. Q., Yeldandi, V., Yeldandi, A. V., Rao, M. S., Gonzalez, F. J., and Reddy, J. K. (2003). Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor γ1 (PPARγ1) overexpression. J. Biol. Chem. 278, 498–505.
| Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor γ1 (PPARγ1) overexpression.Crossref | GoogleScholarGoogle Scholar | 12401792PubMed |
Zeleznik, A. J., Little-Ihrig, L., and Ramasawamy, S. (2004). Administration of dihydrotestosterone to rhesus monkeys inhibits gonadotropin-stimulated ovarian steroidogenesis. J. Clin. Endocrinol. Metab. 89, 860–866.
| Administration of dihydrotestosterone to rhesus monkeys inhibits gonadotropin-stimulated ovarian steroidogenesis.Crossref | GoogleScholarGoogle Scholar | 14764806PubMed |
