Abstract
The concept that androgens are atretogenic, derived from murine ovary studies, is difficult to reconcile with the fact that hyperandrogenic women have more developing follicles than normal-cycling women. To evaluate androgen's effects on primate follicular growth and survival, normal-cycling rhesus monkeys were treated with placebo-, testosterone-(T), or dihydrotestosterone-sustained release implants, and ovaries were taken for histological analysis after 3-10 d of treatment. Growing preantral and small antral follicles up to 1 mm in diameter were significantly and progressively increased in number and thecal layer thickness in T-treated monkeys from 3-10 d. Granulosa and thecal cell proliferation, as determined by immunodetection of the Ki67 antigen, were significantly increased in these follicles. Preovulatory follicles (> 1 mm), however, were not increased in number in androgen-treated animals. Follicular atresia was not increased and there were actually significantly fewer apoptotic granulosa cells in the T-treated groups. Dihydrotestosterone treatment had identical effects, indicating that these growth-promoting actions are mediated by the androgen receptor. These findings show that, over the short term at least, androgens are not atretogenic and actually enhance follicular growth and survival in the primate. These new data provide a plausible explanation for the pathogenesis of "polycystic" ovaries in hyperandrogenism.
Full Text
The Full Text of this article is available as a PDF (827.9 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Billig H., Furuta I., Hsueh A. J. Estrogens inhibit and androgens enhance ovarian granulosa cell apoptosis. Endocrinology. 1993 Nov;133(5):2204–2212. doi: 10.1210/endo.133.5.8404672. [DOI] [PubMed] [Google Scholar]
- Buyalos R. P., Lee C. T. Polycystic ovary syndrome: pathophysiology and outcome with in vitro fertilization. Fertil Steril. 1996 Jan;65(1):1–10. doi: 10.1016/s0015-0282(16)58017-0. [DOI] [PubMed] [Google Scholar]
- De Leo V., Lanzetta D., D'Antona D., la Marca A., Morgante G. Hormonal effects of flutamide in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1998 Jan;83(1):99–102. doi: 10.1210/jcem.83.1.4500. [DOI] [PubMed] [Google Scholar]
- Donesky B. W., Adashi E. Y. Surgically induced ovulation in the polycystic ovary syndrome: wedge resection revisited in the age of laparoscopy. Fertil Steril. 1995 Mar;63(3):439–463. doi: 10.1016/s0015-0282(16)57408-1. [DOI] [PubMed] [Google Scholar]
- Dunaif A. Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus. Am J Med. 1995 Jan 16;98(1A):33S–39S. doi: 10.1016/s0002-9343(99)80057-6. [DOI] [PubMed] [Google Scholar]
- Dunaif A., Scully R. E., Andersen R. N., Chapin D. S., Crowley W. F., Jr The effects of continuous androgen secretion on the hypothalamic-pituitary axis in woman: evidence from a luteinized thecoma of the ovary. J Clin Endocrinol Metab. 1984 Sep;59(3):389–393. doi: 10.1210/jcem-59-3-389. [DOI] [PubMed] [Google Scholar]
- Faiman C., Reyes F. I., Dent D. W., Fuller G. B., Hobson W. C., Thliveris J. A. Effects of long-term testosterone exposure on ovarian function and morphology in the rhesus monkey. Anat Rec. 1988 Nov;222(3):245–251. doi: 10.1002/ar.1092220305. [DOI] [PubMed] [Google Scholar]
- Futterweit W., Deligdisch L. Histopathological effects of exogenously administered testosterone in 19 female to male transsexuals. J Clin Endocrinol Metab. 1986 Jan;62(1):16–21. doi: 10.1210/jcem-62-1-16. [DOI] [PubMed] [Google Scholar]
- Gerdes J., Li L., Schlueter C., Duchrow M., Wohlenberg C., Gerlach C., Stahmer I., Kloth S., Brandt E., Flad H. D. Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67. Am J Pathol. 1991 Apr;138(4):867–873. [PMC free article] [PubMed] [Google Scholar]
- Gougeon A. Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev. 1996 Apr;17(2):121–155. doi: 10.1210/edrv-17-2-121. [DOI] [PubMed] [Google Scholar]
- Hild-Petito S., West N. B., Brenner R. M., Stouffer R. L. Localization of androgen receptor in the follicle and corpus luteum of the primate ovary during the menstrual cycle. Biol Reprod. 1991 Mar;44(3):561–568. doi: 10.1095/biolreprod44.3.561. [DOI] [PubMed] [Google Scholar]
- Hillier S. G., Ross G. T. Effects of exogenous testosterone on ovarian weight, follicular morphology and intraovarian progesterone concentration in estrogen-primed hypophysectomized immature female rats. Biol Reprod. 1979 Mar;20(2):261–268. doi: 10.1095/biolreprod20.2.261. [DOI] [PubMed] [Google Scholar]
- Hillier S. G., Tetsuka M., Fraser H. M. Location and developmental regulation of androgen receptor in primate ovary. Hum Reprod. 1997 Jan;12(1):107–111. doi: 10.1093/humrep/12.1.107. [DOI] [PubMed] [Google Scholar]
- Hughesdon P. E. Morphology and morphogenesis of the Stein-Leventhal ovary and of so-called "hyperthecosis". Obstet Gynecol Surv. 1982 Feb;37(2):59–77. doi: 10.1097/00006254-198202000-00001. [DOI] [PubMed] [Google Scholar]
- KASE N., KOWAL J., PERLOFF W., SOFFER L. J. IN VITRO PRODUCTION OF ANDROGENS BY A VIRILIZING ADRENAL ADENOMA AND ASSOCIATED POLYCYSTIC OVARIES. Acta Endocrinol (Copenh) 1963 Sep;44:15–19. doi: 10.1530/acta.0.0440015. [DOI] [PubMed] [Google Scholar]
- Koering M. J., Danforth D. R., Hodgen G. D. Early follicle growth in the juvenile macaca monkey ovary: the effects of estrogen priming and follicle-stimulating hormone. Biol Reprod. 1994 Mar;50(3):686–694. doi: 10.1095/biolreprod50.3.686. [DOI] [PubMed] [Google Scholar]
- MacDougall M. J., Tan S. L., Balen A., Jacobs H. S. A controlled study comparing patients with and without polycystic ovaries undergoing in-vitro fertilization. Hum Reprod. 1993 Feb;8(2):233–237. doi: 10.1093/oxfordjournals.humrep.a138029. [DOI] [PubMed] [Google Scholar]
- Pache T. D., Chadha S., Gooren L. J., Hop W. C., Jaarsma K. W., Dommerholt H. B., Fauser B. C. Ovarian morphology in long-term androgen-treated female to male transsexuals. A human model for the study of polycystic ovarian syndrome? Histopathology. 1991 Nov;19(5):445–452. doi: 10.1111/j.1365-2559.1991.tb00235.x. [DOI] [PubMed] [Google Scholar]
- Pache T. D., Hop W. C., Wladimiroff J. W., Schipper J., Fauser B. C. Transvaginal sonography and abnormal ovarian appearance in menstrual cycle disturbances. Ultrasound Med Biol. 1991;17(6):589–593. doi: 10.1016/0301-5629(91)90029-v. [DOI] [PubMed] [Google Scholar]
- Pache T. D., Hop W. C., de Jong F. H., Leerentveld R. A., van Geldorp H., Van de Kamp T. M., Gooren L. J., Fauser B. C. 17 beta-Oestradiol, androstenedione and inhibin levels in fluid from individual follicles of normal and polycystic ovaries, and in ovaries from androgen treated female to male transsexuals. Clin Endocrinol (Oxf) 1992 Jun;36(6):565–571. doi: 10.1111/j.1365-2265.1992.tb02266.x. [DOI] [PubMed] [Google Scholar]
- SMITH B. D., BRADBURY J. T. Ovarian weight response to varying doses of estrogens in intact and hypophysectomized rats. Proc Soc Exp Biol Med. 1961 Aug-Sep;107:946–949. doi: 10.3181/00379727-107-26805. [DOI] [PubMed] [Google Scholar]
- Schmitz G. G., Walter T., Seibl R., Kessler C. Nonradioactive labeling of oligonucleotides in vitro with the hapten digoxigenin by tailing with terminal transferase. Anal Biochem. 1991 Jan;192(1):222–231. doi: 10.1016/0003-2697(91)90212-c. [DOI] [PubMed] [Google Scholar]
- Spinder T., Spijkstra J. J., van den Tweel J. G., Burger C. W., van Kessel H., Hompes P. G., Gooren L. J. The effects of long term testosterone administration on pulsatile luteinizing hormone secretion and on ovarian histology in eugonadal female to male transsexual subjects. J Clin Endocrinol Metab. 1989 Jul;69(1):151–157. doi: 10.1210/jcem-69-1-151. [DOI] [PubMed] [Google Scholar]
- Takayama K., Fukaya T., Sasano H., Funayama Y., Suzuki T., Takaya R., Wada Y., Yajima A. Immunohistochemical study of steroidogenesis and cell proliferation in polycystic ovarian syndrome. Hum Reprod. 1996 Jul;11(7):1387–1392. doi: 10.1093/oxfordjournals.humrep.a019405. [DOI] [PubMed] [Google Scholar]
- Van Der Meer M., Hompes P. G., De Boer J. A., Schats R., Schoemaker J. Cohort size rather than follicle-stimulating hormone threshold level determines ovarian sensitivity in polycystic ovary syndrome. J Clin Endocrinol Metab. 1998 Feb;83(2):423–426. doi: 10.1210/jcem.83.2.4585. [DOI] [PubMed] [Google Scholar]
- Wallach E. E., Noriega C. Effects of local steroids on follicular development and atresia in the rabbit. Fertil Steril. 1970 Mar;21(3):253–267. doi: 10.1016/s0015-0282(16)37393-9. [DOI] [PubMed] [Google Scholar]