This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted 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 Pastor, C. L. Articles by Marshall, J. C. Search for Related Content PubMed PubMed Citation Articles by Pastor, C. L. Articles by Marshall, J. C.

Polycystic Ovary Syndrome: Evidence for Reduced Sensitivity of the Gonadotropin-Releasing Hormone Pulse Generator to Inhibition by Estradiol and Progesterone¹

Division of Endocrinology and the Center for Research in Reproduction (J.C.M.), University of Virginia, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: C. L. Pastor, M.D., Box 511, Division of Endocrinology, Department of Internal Medicine, University of Virginia, Health Sciences Center, Charlottesville, Virginia 22908.

Plasma LH is commonly elevated in women with the polycystic ovary syndrome (PCOS), but the underlying mechanisms are uncertain. We tested the hypothesis that the elevated LH in part reflects a reduced sensitivity of the hypothalamic GnRH pulse generator to suppression by estradiol (E₂) and progesterone (P). In an initial protocol, normal controls (beginning on cycle days 8–10) and women with PCOS were given E₂ transdermally and P by vaginal suppository (three times daily), to achieve plasma concentrations similar to those in the midluteal phase of an ovulatory cycle, for 21 days. Blood was obtained at 10-min intervals for 12 h before and on days 5, 10, 20, and 28 (7 days after E₂ and P were discontinued). LH pulse amplitude and LH pulse frequency were suppressed in both PCOS and normal controls, but LH pulse frequency fell more rapidly in controls and was lower by day 10 (P < 0.05). Based on this time course a dose-response study was performed, in which E₂ in constant dosage and varying concentrations of P were administered for 7 days. Pulsatile LH release was appraised on days 1 and 7. The frequency of LH pulse secretion was reduced in controls and was lower than that in patients with PCOS on day 7 (P < 0.0001). Plasma P concentrations of 13–15 ng/mL suppressed LH pulse frequency to a similar degree in PCOS and controls. In contrast, lower concentrations (P < 10 ng/mL) were more effective in suppressing GnRH/LH pulse frequency in controls (by >45% of basal) than in PCOS (<40%; P < 0.01).

The data indicate that E₂ and P can inhibit the activity of the hypothalamic GnRH pulse generator in women with PCOS. However, higher plasma concentrations of P were required to reduce GnRH/LH pulse frequency in PCOS compared to controls, suggesting an insensitivity of the GnRH pulse generator to suppression by E₂ and P. These results suggest that an abnormality in the regulation of hypothalamic GnRH secretion is present in PCOS and may be a factor in the etiology of the disorder in adolescence.

This article has been cited by other articles:

				S. K. Blank, C. R. McCartney, S. Chhabra, K. D. Helm, C. A. Eagleson, R. J. Chang, and J. C. Marshall Modulation of Gonadotropin-Releasing Hormone Pulse Generator Sensitivity to Progesterone Inhibition in Hyperandrogenic Adolescent Girls--Implications for Regulation of Pubertal Maturation J. Clin. Endocrinol. Metab., July 1, 2009; 94(7): 2360 - 2366. [Abstract] [Full Text] [PDF]

				B. Bordini, E. Littlejohn, and R. L. Rosenfield Blunted Sleep-Related Luteinizing Hormone Rise in Healthy Premenarcheal Pubertal Girls with Elevated Body Mass Index J. Clin. Endocrinol. Metab., April 1, 2009; 94(4): 1168 - 1175. [Abstract] [Full Text] [PDF]

				T. L. Steckler, C. Herkimer, D. A. Dumesic, and V. Padmanabhan Developmental Programming: Excess Weight Gain Amplifies the Effects of Prenatal Testosterone Excess On Reproductive Cyclicity--Implication for Polycystic Ovary Syndrome Endocrinology, March 1, 2009; 150(3): 1456 - 1465. [Abstract] [Full Text] [PDF]

				C. R. McCartney, K. A. Prendergast, S. K. Blank, K. D. Helm, S. Chhabra, and J. C. Marshall Maturation of Luteinizing Hormone (Gonadotropin-Releasing Hormone) Secretion across Puberty: Evidence for Altered Regulation in Obese Peripubertal Girls J. Clin. Endocrinol. Metab., January 1, 2009; 94(1): 56 - 66. [Abstract] [Full Text] [PDF]

				M. A. Lawson, S. Jain, S. Sun, K. Patel, P. J. Malcolm, and R. J. Chang Evidence for Insulin Suppression of Baseline Luteinizing Hormone in Women with Polycystic Ovarian Syndrome and Normal Women J. Clin. Endocrinol. Metab., June 1, 2008; 93(6): 2089 - 2096. [Abstract] [Full Text] [PDF]

				M. P. Bernuci, R. E. Szawka, C. V. V. Helena, C. M. Leite, H. E. Lara, and J. A. Anselmo-Franci Locus Coeruleus Mediates Cold Stress-Induced Polycystic Ovary in Rats Endocrinology, June 1, 2008; 149(6): 2907 - 2916. [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]

				C. R. McCartney, S. K. Blank, and J. C. Marshall Progesterone acutely increases LH pulse amplitude but does not acutely influence nocturnal LH pulse frequency slowing during the late follicular phase in women Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E900 - E906. [Abstract] [Full Text] [PDF]

				C. R. McCartney, S. K. Blank, K. A. Prendergast, S. Chhabra, C. A. Eagleson, K. D. Helm, R. Yoo, R. J. Chang, C. M. Foster, S. Caprio, et al. Obesity and Sex Steroid Changes across Puberty: Evidence for Marked Hyperandrogenemia in Pre- and Early Pubertal Obese Girls J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 430 - 436. [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]

				C. R. McCartney, K. A. Prendergast, S. Chhabra, C. A. Eagleson, R. Yoo, R. J. Chang, C. M. Foster, and J. C. Marshall The Association of Obesity and Hyperandrogenemia during the Pubertal Transition in Girls: Obesity as a Potential Factor in the Genesis of Postpubertal Hyperandrogenism J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1714 - 1722. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, and C. Y. Bowers Somatotropic and Gonadotropic Axes Linkages in Infancy, Childhood, and the Puberty-Adult Transition Endocr. Rev., April 1, 2006; 27(2): 101 - 140. [Abstract] [Full Text] [PDF]

				Y. L. Pagan, S. S. Srouji, Y. Jimenez, A. Emerson, S. Gill, and J. E. Hall Inverse Relationship between Luteinizing Hormone and Body Mass Index in Polycystic Ovarian Syndrome: Investigation of Hypothalamic and Pituitary Contributions J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1309 - 1316. [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]

				J. C. Marshall Obesity in Adolescent Girls: Is Excess Androgen the Real Bad Actor? J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 393 - 395. [Full Text] [PDF]

				S. A.R. Doi, M. Al-Zaid, P. A. Towers, C. J. Scott, and K. A.S. Al-Shoumer Irregular cycles and steroid hormones in polycystic ovary syndrome Hum. Reprod., September 1, 2005; 20(9): 2402 - 2408. [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]

				S. Chhabra, C. R. McCartney, R. Y. Yoo, C. A. Eagleson, R. J. Chang, and J. C. Marshall Progesterone Inhibition of the Hypothalamic Gonadotropin-Releasing Hormone Pulse Generator: Evidence for Varied Effects in Hyperandrogenemic Adolescent Girls J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2810 - 2815. [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]

				C. R. McCartney, A. B. Bellows, M. B. Gingrich, Y. Hu, W. S. Evans, J. C. Marshall, and J. D. Veldhuis Exaggerated 17-hydroxyprogesterone response to intravenous infusions of recombinant human LH in women with polycystic ovary syndrome Am J Physiol Endocrinol Metab, June 1, 2004; 286(6): E902 - E908. [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]

				E. W. C. M. van Dam, F. Roelfsema, J. D. Veldhuis, S. Hogendoorn, J. Westenberg, F. M. Helmerhorst, M. Frolich, H. M. J. Krans, A. E. Meinders, and H. Pijl Retention of estradiol negative feedback relationship to LH predicts ovulation in response to caloric restriction and weight loss in obese patients with polycystic ovary syndrome Am J Physiol Endocrinol Metab, April 1, 2004; 286(4): E615 - E620. [Abstract] [Full Text] [PDF]

				C. A. Eagleson, A. B. Bellows, K. Hu, M. B. Gingrich, and J. C. Marshall Obese Patients with Polycystic Ovary Syndrome: Evidence that Metformin Does Not Restore Sensitivity of the Gonadotropin-Releasing Hormone Pulse Generator to Inhibition by Ovarian Steroids J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5158 - 5162. [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]

				J. D. Veldhuis, S. M. Pincus, M. C. Garcia-Rudaz, M. G. Ropelato, M. E. Escobar, and M. Barontini Disruption of the Synchronous Secretion of Leptin, LH, and Ovarian Androgens in Nonobese Adolescents with the Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3772 - 3778. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, S. M. Pincus, M. C. Garcia-Rudaz, M. G. Ropelato, M. E. Escobar, and M. Barontini Disruption of the Joint Synchrony of Luteinizing Hormone, Testosterone, and Androstenedione Secretion in Adolescents with Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 72 - 79. [Abstract] [Full Text]

				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]

				J. E. Robinson, R. A. Forsdike, and J. A. Taylor In Utero Exposure of Female Lambs to Testosterone Reduces the Sensitivity of the GnRH Neuronal Network to Inhibition by Progesterone Endocrinology, December 1, 1999; 140(12): 5797 - 5805. [Abstract] [Full Text]

				R. A. Abbud, R. K. Ameduri, J. S. Rao, T. M. Nett, and J. H. Nilson Chronic Hypersecretion of Luteinizing Hormone in Transgenic Mice Selectively Alters Responsiveness of the {alpha}-Subunit Gene to Gonadotropin-Releasing Hormone and Estrogens Mol. Endocrinol., September 1, 1999; 13(9): 1449 - 1459. [Abstract] [Full Text]

				L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice The Insulin-Related Ovarian Regulatory System in Health and Disease Endocr. Rev., August 1, 1999; 20(4): 535 - 582. [Abstract] [Full Text] [PDF]

				E. W. C. M. Van Dam, F. Roelfsema, J. D. Veldhuis, F. M. Helmerhorst, M. Frolich, A. E. Meinders, H. M. J. Krans, and H. Pijl Increase in daily LH secretion in response to short-term calorie restriction in obese women with PCOS Am J Physiol Endocrinol Metab, April 1, 2002; 282(4): E865 - E872. [Abstract] [Full Text] [PDF]