HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sharma, T. P. Articles by Padmanabhan, V. Search for Related Content PubMed PubMed Citation Articles by Sharma, T. P. Articles by Padmanabhan, V. Agricola Articles by Sharma, T. P. Articles by Padmanabhan, V.

Fetal Programming: Prenatal Androgen Disrupts Positive Feedback Actions of Estradiol but Does Not Affect Timing of Puberty in Female Sheep¹

^a Departments of Pediatrics ^b Biostatistics and ^c the Reproductive Sciences Program, University of Michigan, Ann Arbor, Michigan 48109 ^d Laboratory of Neuroendocrinology, Babraham Institute, Cambridge CB2 4AT, United Kingdom

We studied the impact of prenatal androgen exposure on the timing of onset of puberty, maintenance of cyclicity in the first breeding season, and the LH surge mechanism in female sheep. Pregnant sheep were injected with testosterone propionate (100 mg i.m.) twice each week from Day 30 to Day 90 (D30–90) or from Day 60 to Day 90 (D60–90) of gestation (term = 147 days). Concentrations of plasma progesterone and gonadotropins were measured in blood samples collected twice each week from control (n = 10), D60–90 (n = 13), and D30–90 (n = 3) animals. Rate of weight gain and initiation of estrous behavior were also monitored. After the first breeding season, when the animals entered anestrus, competency of the gonadotropin surge system to respond to estradiol positive feedback was tested in the absence or presence of progesterone priming for 12 days. Prenatally androgenized females had similar body weight gain and achieved puberty (start of first progestogenic cycle) at the same time as controls. Duration of the breeding season and the number of cycles that occurred during the first breeding season were similar between control and prenatally androgenized sheep. In contrast, prenatal exposure to androgens compromised the positive feedback effects of estradiol. Onset of LH/FSH surges following the estradiol stimulus was delayed in both groups of androgenized ewes compared with the controls in both the absence and presence of progesterone priming. In addition, the magnitude of LH and FSH surges in the two animals that surged in the D30–90 group were only one third and one half, respectively, of the magnitudes observed in the control and D60–90 groups. The present findings indicate that disruption of the surge system can account for the fertility problems that occur during adulthood in prenatally androgenized sheep.

First decision: 18 September 2001.

¹ Supported by NIH HD 41098 and an educational grant from Parke Davis (Parke Davis merged with Pfizer in June 2000).

² Correspondence: Vasantha Padmanabhan, Reproductive Sciences Program, 300 N. Ingalls Bldg., Rm. 1109 SW, Ann Arbor, MI 48109-0404. FAX: 734 936 8620; vasantha{at}umich.edu

³ Contributed equally to this work

⁴ Current address: Pfizer Global Research and Development, Ann Arbor, MI 48105

⁵ Current address: Department of Reproductive Science and Medicine, Institute of Reproductive and Developmental Biology, Imperial College, Hammersmith Hospital, London W12 ONN, UK

This article has been cited by other articles:

				T. L. Steckler, J. S. Lee, W. Ye, E. K. Inskeep, and V. Padmanabhan Developmental Programming: Exogenous Gonadotropin Treatment Rescues Ovulatory Function But Does Not Completely Normalize Ovarian Function in Sheep Treated Prenatally with Testosterone Biol Reprod, October 1, 2008; 79(4): 686 - 695. [Abstract] [Full Text] [PDF]

				E. K Roberts, V. Padmanabhan, and T. M Lee Differential Effects of Prenatal Testosterone Timing and Duration on Phenotypic and Behavioral Masculinization and Defeminization of Female Sheep Biol Reprod, July 1, 2008; 79(1): 43 - 50. [Abstract] [Full Text] [PDF]

				L. M. Garcia-Segura, B. Lorenz, and L. L DonCarlos The role of glia in the hypothalamus: implications for gonadal steroid feedback and reproductive neuroendocrine output Reproduction, April 1, 2008; 135(4): 419 - 429. [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. A Forsdike, K. Hardy, L. Bull, J. Stark, L. J Webber, S. Stubbs, J. E Robinson, and S. Franks Disordered follicle development in ovaries of prenatally androgenized ewes J. Endocrinol., February 1, 2007; 192(2): 421 - 428. [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]

				K. D. Malcolm, L. M. Jackson, C. Bergeon, T. M. Lee, V. Padmanabhan, and D. L. Foster Long-Term Exposure of Female Sheep to Physiologic Concentrations of Estradiol: Effects on the Onset and Maintenance of Reproductive Function, Pregnancy, and Social Development in Female Offspring Biol Reprod, December 1, 2006; 75(6): 844 - 852. [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]

				C. Guzman, R. Cabrera, M. Cardenas, F. Larrea, P. W. Nathanielsz, and E. Zambrano Protein restriction during fetal and neonatal development in the rat alters reproductive function and accelerates reproductive ageing in female progeny J. Physiol., April 1, 2006; 572(1): 97 - 108. [Abstract] [Full Text] [PDF]

				S. E. Recabarren, V. Padmanabhan, E. Codner, A. Lobos, C. Duran, M. Vidal, D. L. Foster, and T. Sir-Petermann Postnatal developmental consequences of altered insulin sensitivity in female sheep treated prenatally with testosterone Am J Physiol Endocrinol Metab, November 1, 2005; 289(5): E801 - E806. [Abstract] [Full Text] [PDF]

				D.H. Abbott, D.K. Barnett, C.M. Bruns, and D.A. Dumesic Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome? Hum. Reprod. Update, July 1, 2005; 11(4): 357 - 374. [Abstract] [Full Text] [PDF]

				T. Steckler, J. Wang, F. F. Bartol, S. K. Roy, and V. Padmanabhan Fetal Programming: Prenatal Testosterone Treatment Causes Intrauterine Growth Retardation, Reduces Ovarian Reserve and Increases Ovarian Follicular Recruitment Endocrinology, July 1, 2005; 146(7): 3185 - 3193. [Abstract] [Full Text] [PDF]

				E. M. Foecking, M. Szabo, N. B. Schwartz, and J. E. Levine Neuroendocrine Consequences of Prenatal Androgen Exposure in the Female Rat: Absence of Luteinizing Hormone Surges, Suppression of Progesterone Receptor Gene Expression, and Acceleration of the Gonadotropin-Releasing Hormone Pulse Generator Biol Reprod, June 1, 2005; 72(6): 1475 - 1483. [Abstract] [Full Text] [PDF]

				J. L. Zehr, P. E. Van Meter, and K. Wallen Factors Regulating the Timing of Puberty Onset in Female Rhesus Monkeys (Macaca mulatta): Role of Prenatal Androgens, Social Rank, and Adolescent Body Weight Biol Reprod, May 1, 2005; 72(5): 1087 - 1094. [Abstract] [Full Text] [PDF]

				W. P. Unsworth, J. A. Taylor, and J. E. Robinson Prenatal Programming of Reproductive Neuroendocrine Function: The Effect of Prenatal Androgens on the Development of Estrogen Positive Feedback and Ovarian Cycles in the Ewe Biol Reprod, March 1, 2005; 72(3): 619 - 627. [Abstract] [Full Text] [PDF]

				E Zambrano, G. L Rodriguez-Gonzalez, C Guzman, R Garcia-Becerra, L Boeck, L Diaz, M Menjivar, F Larrea, and P. W Nathanielsz A maternal low protein diet during pregnancy and lactation in the rat impairs male reproductive development J. Physiol., February 15, 2005; 563(1): 275 - 284. [Abstract] [Full Text] [PDF]

				M. Savabieasfahani, J. S. Lee, C. Herkimer, T. P. Sharma, D. L. Foster, and V. Padmanabhan Fetal Programming: Testosterone Exposure of the Female Sheep During Midgestation Disrupts the Dynamics of Its Adult Gonadotropin Secretion During the Periovulatory Period Biol Reprod, January 1, 2005; 72(1): 221 - 229. [Abstract] [Full Text] [PDF]

				M. Manikkam, E. J. Crespi, D. D. Doop, C. Herkimer, J. S. Lee, S. Yu, M. B. Brown, D. L. Foster, and V. Padmanabhan Fetal Programming: Prenatal Testosterone Excess Leads to Fetal Growth Retardation and Postnatal Catch-Up Growth in Sheep Endocrinology, February 1, 2004; 145(2): 790 - 798. [Abstract] [Full Text] [PDF]

				A. Rosa-e-Silva, M. A. Guimaraes, V. Padmanabhan, and H. E. Lara Prepubertal Administration of Estradiol Valerate Disrupts Cyclicity and Leads to Cystic Ovarian Morphology during Adult Life in the Rat: Role of Sympathetic Innervation Endocrinology, October 1, 2003; 144(10): 4289 - 4297. [Abstract] [Full Text] [PDF]

				R. A. Birch, V. Padmanabhan, D. L. Foster, W. P. Unsworth, and J. E. Robinson Prenatal Programming of Reproductive Neuroendocrine Function: Fetal Androgen Exposure Produces Progressive Disruption of Reproductive Cycles in Sheep Endocrinology, April 1, 2003; 144(4): 1426 - 1434. [Abstract] [Full Text] [PDF]