This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sarma, H. N. Articles by Padmanabhan, V. Search for Related Content PubMed PubMed Citation Articles by Sarma, H. N. Articles by Padmanabhan, V.

Fetal Programming: Excess Prenatal Testosterone Reduces Postnatal Luteinizing Hormone, But Not Follicle-Stimulating Hormone Responsiveness, to Estradiol Negative Feedback in the Female

Departments of Pediatrics (H.N.S., C.H., M.M., J.D., V.P.), Obstetrics and Gynecology (D.L.F., V.P.), Molecular and Integrative Physiology (V.P.), and Ecology and Evolutionary Biology (D.L.F.), Reproductive Sciences Program (H.S., M.M., C.H., J.D., D.L.F., V.P.), and Center for Statistical Consultation and Research (K.B.W.), University of Michigan, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Vasantha Padmanabhan, Reproductive Sciences Program, 300 North Ingalls Building, Room 1109 SW, Ann Arbor, Michigan 48109-0404. E-mail: vasantha{at}umich.edu.

Exposure of female sheep fetuses to excess testosterone (T) during early to midgestation produces postnatal hypergonadotropism manifest as a selective increase in LH. This hypergonadotropism may result from reduced sensitivity to estradiol (E₂) negative feedback and/or increased pituitary sensitivity to GnRH. We tested the hypothesis that excess T before birth reduces responsiveness of LH and FSH to E₂ negative feedback after birth. Pregnant ewes were treated with T propionate (100 mg/kg in cotton seed oil) or vehicle twice weekly from d 30–90 gestation. Responsiveness to E₂ negative feedback was assessed at 12 and 24 wk of age in the ovary-intact female offspring. Our experimental strategy was first to arrest follicular growth and reduce endogenous E₂ by administering the GnRH antagonist (GnRH-A), Nal-Glu (50 µg/kg sc every 12 h for 72 h), and then provide a fixed amount of exogenous E₂ via an implant. Blood samples were obtained every 20 min at 12 wk and every 10 min at 24 wk before treatment, during and after GnRH-A treatment both before and after E₂ implant. GnRH-A ablated LH pulsatility, reduced FSH by approximately 25%, and E₂ production diminished to near detection limit of assay at both ages in both groups. Prenatal T treatment produced a precocious and selective reduction in responsiveness of LH but not FSH to E₂ negative feedback, which was manifest mainly at the level of LH/GnRH pulse frequency. Collectively, these findings support the hypothesis that prenatal exposure to excess T decreases postnatal responsiveness to E₂ inhibitory feedback of LH/GnRH secretion to contribute to the development of hypergonadotropism.

This article has been cited by other articles:

				R. Homburg Androgen circle of polycystic ovary syndrome Hum. Reprod., July 1, 2009; 24(7): 1548 - 1555. [Abstract] [Full Text] [PDF]

				L. M. Jackson, K. M. Timmer, and D. L. Foster Organizational Actions of Postnatal Estradiol in Female Sheep Treated Prenatally with Testosterone: Programming of Prepubertal Neuroendocrine Function and the Onset of Puberty Endocrinology, May 1, 2009; 150(5): 2317 - 2324. [Abstract] [Full Text] [PDF]

				S. E. Recabarren, P. P. Rojas-Garcia, M. P. Recabarren, V. H. Alfaro, R. Smith, V. Padmanabhan, and T. Sir-Petermann Prenatal Testosterone Excess Reduces Sperm Count and Motility Endocrinology, December 1, 2008; 149(12): 6444 - 6448. [Abstract] [Full Text] [PDF]

				L. M. Jackson, K. M. Timmer, and D. L. Foster Sexual Differentiation of the External Genitalia and the Timing of Puberty in the Presence of an Antiandrogen in Sheep Endocrinology, August 1, 2008; 149(8): 4200 - 4208. [Abstract] [Full Text] [PDF]

				D. H Abbott, D. K Barnett, J. E Levine, V. Padmanabhan, D. A Dumesic, S. Jacoris, and A. F Tarantal Endocrine Antecedents of Polycystic Ovary Syndrome in Fetal and Infant Prenatally Androgenized Female Rhesus Monkeys Biol Reprod, July 1, 2008; 79(1): 154 - 163. [Abstract] [Full Text] [PDF]

				R. Sotomayor-Zarate, M. Dorfman, A. Paredes, and H. E. Lara Neonatal Exposure to Estradiol Valerate Programs Ovarian Sympathetic Innervation and Follicular Development in the Adult Rat Biol Reprod, April 1, 2008; 78(4): 673 - 680. [Abstract] [Full Text] [PDF]

				M. Manikkam, R. C. Thompson, C. Herkimer, K. B. Welch, J. Flak, F. J. Karsch, and V. Padmanabhan Developmental Programming: Impact of Prenatal Testosterone Excess on Pre- and Postnatal Gonadotropin Regulation in Sheep Biol Reprod, April 1, 2008; 78(4): 648 - 660. [Abstract] [Full Text] [PDF]

				A. Veiga-Lopez, W. Ye, D.J. Phillips, C. Herkimer, P.G. Knight, and V. Padmanabhan Developmental Programming: Deficits in Reproductive Hormone Dynamics and Ovulatory Outcomes in Prenatal, Testosterone-Treated Sheep Biol Reprod, April 1, 2008; 78(4): 636 - 647. [Abstract] [Full Text] [PDF]

				T. Steckler, M. Manikkam, E. K. Inskeep, and V. Padmanabhan Developmental Programming: Follicular Persistence in Prenatal Testosterone-Treated Sheep Is Not Programmed by Androgenic Actions of Testosterone Endocrinology, July 1, 2007; 148(7): 3532 - 3540. [Abstract] [Full Text] [PDF]

				R. L. Rosenfield Identifying Children at Risk for Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 787 - 796. [Abstract] [Full Text] [PDF]

				N. B. Ojeda, D. Grigore, L. L. Yanes, R. Iliescu, E. B. Robertson, H. Zhang, and B. T. Alexander Testosterone contributes to marked elevations in mean arterial pressure in adult male intrauterine growth restricted offspring Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R758 - R763. [Abstract] [Full Text] [PDF]

				M. Savabieasfahani, K. Kannan, O. Astapova, N. P. Evans, and V. Padmanabhan Developmental Programming: Differential Effects of Prenatal Exposure to Bisphenol-A or Methoxychlor on Reproductive Function Endocrinology, December 1, 2006; 147(12): 5956 - 5966. [Abstract] [Full Text] [PDF]

				J. Robinson Prenatal programming of the female reproductive neuroendocrine system by androgens. Reproduction, October 1, 2006; 132(4): 539 - 547. [Abstract] [Full Text] [PDF]

				M. Manikkam, T. L. Steckler, K. B. Welch, E. K. Inskeep, and V. Padmanabhan Fetal Programming: Prenatal Testosterone Treatment Leads to Follicular Persistence/Luteal Defects; Partial Restoration of Ovarian Function by Cyclic Progesterone Treatment Endocrinology, April 1, 2006; 147(4): 1997 - 2007. [Abstract] [Full Text] [PDF]

				J. Pielecka, S. D. Quaynor, and S. M. Moenter Androgens Increase Gonadotropin-Releasing Hormone Neuron Firing Activity in Females and Interfere with Progesterone Negative Feedback Endocrinology, March 1, 2006; 147(3): 1474 - 1479. [Abstract] [Full Text] [PDF]