This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart 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 Robinson, J. E. Articles by Taylor, J. A. Search for Related Content PubMed PubMed Citation Articles by Robinson, J. E. Articles by Taylor, J. A.

In Utero Exposure of Female Lambs to Testosterone Reduces the Sensitivity of the GnRH Neuronal Network to Inhibition by Progesterone

Laboratory of Neuroendocrinology, The Babraham Institute, Babraham Hall, Cambridge CB2 4AT, United Kingdom

Address all correspondence and requests for reprints to: Jane Robinson, Laboratory of Neuroendocrinology, The Babraham Institute, Cambridge CB2 4AT, United Kingdom. E-mail: jane.robinson{at}bbsrc.ac.uk

Exposure of the female ovine fetus to exogenous androgens during early gestation permanently masculinizes the reproductive anatomy, physiology, and behavior of the adult ewe. In utero testosterone exposure has been shown to act centrally on the GnRH neuronal network to alter the response to both the stimulatory and inhibitory actions of estrogen. It is currently unknown whether fetal androgens alter other mechanisms that are critical for the regulation of GnRH release and, specifically, other important regulatory steroid feedback loops. Three studies were performed on gonadectomized postpubertal sheep to determine whether the inhibitory actions of progesterone on episodic LH release are also sex-specific and engendered by early in utero exposure to testosterone. In each study, the pulsatile pattern of LH release was determined both before and after the sc implantation of a progesterone releasing CIDR device. The studies involved 7 female, 7 male, and 12 androgenized female sheep (T60 (n = 7) and T30 (n = 5) groups; 200 mg testosterone propionate/week im to the mother for 60 or 30 days, respectively, from day 30–90 or 60–90 of pregnancy). The first two studies were performed in the anestrous season in the presence (Exp 1) or absence (Exp 2) of a low circulating concentration of estradiol. Exp 3 was carried out in the breeding season in the absence of exogenous estrogen. In all three studies progesterone inhibited LH pulse frequency only in the females. Progesterone had no action on mean LH concentrations or the frequency or amplitude of LH pulses in the males or either group of androgenized ewes. We conclude that the inhibition of episodic LH release by progesterone is sexually differentiated in the sheep, males being less responsive than females to steroid negative feedback. Further, these sex differences are a consequence of in utero exposure to androgens for a period as short as 30 days between days 60 and 90 of a 147-day pregnancy.

This article has been cited by other articles:

				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]

				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]

				R. L. Goodman, M. N. Lehman, J. T. Smith, L. M. Coolen, C. V. R. de Oliveira, M. R. Jafarzadehshirazi, A. Pereira, J. Iqbal, A. Caraty, P. Ciofi, et al. Kisspeptin Neurons in the Arcuate Nucleus of the Ewe Express Both Dynorphin A and Neurokinin B Endocrinology, December 1, 2007; 148(12): 5752 - 5760. [Abstract] [Full Text] [PDF]

				C. E. Roselli, H. Stadelman, R. Reeve, C. V. Bishop, and F. Stormshak The Ovine Sexually Dimorphic Nucleus of the Medial Preoptic Area Is Organized Prenatally by Testosterone Endocrinology, September 1, 2007; 148(9): 4450 - 4457. [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]

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

				S.K. Blank, C.R. McCartney, and J.C. Marshall The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome Hum. Reprod. Update, July 1, 2006; 12(4): 351 - 361. [Abstract] [Full Text] [PDF]

				N. Xita and A. Tsatsoulis Fetal Programming of Polycystic Ovary Syndrome by Androgen Excess: Evidence from Experimental, Clinical, and Genetic Association Studies J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1660 - 1666. [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]

				H. N. Sarma, M. Manikkam, C. Herkimer, J. Dell'Orco, K. B. Welch, D. L. Foster, and V. Padmanabhan Fetal Programming: Excess Prenatal Testosterone Reduces Postnatal Luteinizing Hormone, But Not Follicle-Stimulating Hormone Responsiveness, to Estradiol Negative Feedback in the Female Endocrinology, October 1, 2005; 146(10): 4281 - 4291. [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]

				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]

				S. D. Sullivan and S. M. Moenter GABAergic Integration of Progesterone and Androgen Feedback to Gonadotropin-Releasing Hormone Neurons Biol Reprod, January 1, 2005; 72(1): 33 - 41. [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]

				S. D. Sullivan and S. M. Moenter Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: Implications for a common fertility disorder PNAS, May 4, 2004; 101(18): 7129 - 7134. [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]

				S. D. Sullivan and S. M. Moenter Neurosteroids Alter {gamma}-Aminobutyric Acid Postsynaptic Currents in Gonadotropin-Releasing Hormone Neurons: A Possible Mechanism for Direct Steroidal Control Endocrinology, October 1, 2003; 144(10): 4366 - 4375. [Abstract] [Full Text] [PDF]

				M. Gahr Male Japanese quails with female brains do not show male sexual behaviors PNAS, June 24, 2003; 100(13): 7959 - 7964. [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]

				T. P. Sharma, C. Herkimer, C. West, W. Ye, R. Birch, J. E. Robinson, D. L. Foster, and V. Padmanabhan Fetal Programming: Prenatal Androgen Disrupts Positive Feedback Actions of Estradiol but Does Not Affect Timing of Puberty in Female Sheep Biol Reprod, April 1, 2002; 66(4): 924 - 933. [Abstract] [Full Text] [PDF]

				C. A. Eagleson, M. B. Gingrich, C. L. Pastor, T. K. Arora, C. M. Burt, W. S. Evans, and J. C. Marshall Polycystic Ovarian Syndrome: Evidence that Flutamide Restores Sensitivity of the Gonadotropin-Releasing Hormone Pulse Generator to Inhibition by Estradiol and Progesterone J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4047 - 4052. [Abstract] [Full Text]

				M.-L. Goubillon, R. A. Forsdike, J. E. Robinson, P. Ciofi, A. Caraty, and A. E. Herbison Identification of Neurokinin B-Expressing Neurons as an Highly Estrogen-Receptive, Sexually Dimorphic Cell Group in the Ovine Arcuate Nucleus Endocrinology, November 1, 2000; 141(11): 4218 - 4225. [Abstract] [Full Text] [PDF]