This Article 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 WALDSTREICHER, J. Articles by CROWLEY, W. F. Search for Related Content PubMed PubMed Citation Articles by WALDSTREICHER, J. Articles by CROWLEY, W. F., JR.

Hyperfunction of the Hypothalamic-Pituitary Axis in Women with Polycystic Ovarian Disease: Indirect Evidence for Partial Gonadotroph Desensitization^*

JOANNE WALDSTREICHER, NANETTE F. SANTORO, JANET E. HALL, MARCO FILICORI and WILLIAM F. CROWLEY, JR.

Reproductive Endocrine Unit, Departments of Medicine and Gynecology, Vincent Research Laboratories, Massachusetts General Hospital Boston, Massachusetts 02114

Address requests for reprints to: Dr. William F. Crowley Jr., Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.

To examine gonadotropin secretory frequency as a component of the disordered neuroendocrine regulation of gonadotropin secretion in women with polycystic ovarian disease (PCOD), we measured serum gonadotropin concentrations in 12 women with PCOD at 10-min intervals for periods of 12-24 h. The patterns of LH and FSH release in these patients were compared to the findings of 24 studies in 21 age-matched normal women during the early, mid- and late follicular phases (EFP, MFP and LFP) of their cycles. Serum sex steroid levels during the 12-24 h of study in the women with PCOD were compared to those in normal women studied during the follicular phase.

The mean serum estradiol (E₂) level in the women with PCOD was similar to that in normal women studied in the EFP, but lower than those in normal women in the MFP (P < 0.05) and LFP (P < 0.01). Mean serum estrone, however, was significantly higher in women with PCOD than in women in the EFP and MFP (P < 0.05 and P < 0.02, respectively), but lower than that in women in the LFP (P < 0.02). Total and unbound testosterone (T) levels were significantly elevated in women with PCOD compared to those in normal women at all stages of the follicular phase (P < 0.001).

The mean serum LH concentration and LH pulse amplitude were markedly elevated in the women with PCOD compared to normal women at all three stages of the follicular phase (P < 0.05 or less). In addition, LH pulse frequency was faster in women with PCOD [24.8 ± 0.9 (±SE) pulses/24 h] than that in women in the EFP (15.6 ± 0.7; P < 0.01), MFP (22.2 ± 1.1; P < 0.05) and LFP (20.8 ± 1.2; P < 0.01). This increased LH pulse frequency in women with PCOD correlated with ambient serum E₂ levels on the day of study (r = 0.84; P < 0.001), but not with serum estrone, T, or unbound T. Repeat studies in four women with PCOD demonstrated a similarly abnormal gonadotropin secretory pattern in each.

We conclude that 1) women with PCOD have an increase in both the amplitude and frequency of LH secretion compared to those in normally cycling women throughout the follicular phase; 2) the defect in women with PCOD is reproducible; 3) this evidence of increased neuroendocrine secretion of LH as well as the relative suppression of FSH characteristic of this disorder suggest that partial pituitary desensitization secondary to increased frequency of GnRH secretion may exist in women with PCOD; and 4) the relationship between circulating E₂ levels and LH pulse frequency suggests an etiological role for this steroid in increasing the frequency of GnRH release.

^* This work supported by NICCHD Grants HD-15080 and RR-1066 and the Vincent Research Fund.

Recipient of a Research Fellowship from the Medical Research Council of Canada.

Current address: Department of Reproductive Medicine, University of Bologna, via Massarenti 13, Bologna, Italy.

Received April 13, 1987.

This article has been cited by other articles:

				M. Aubuchon, H. Lieman, D. Stein, H. W. Cohen, B. Isaac, G. Adel, V. Weitzman, M. Tetrokalashvili, A. J. Polotsky, and N. Santoro Metformin Does Not Improve the Reproductive or Metabolic Profile in Women With Polycystic Ovary Syndrome (PCOS) Reproductive Sciences, October 1, 2009; 16(10): 938 - 946. [Abstract] [PDF]

				M. G. Ropelato, M. C. Garcia Rudaz, M. E. Escobar, S. V. Bengolea, M. L. Calcagno, J. D. Veldhuis, and M. Barontini Acute Effects of Testosterone Infusion on the Serum Luteinizing Hormone Profile in Eumenorrheic and Polycystic Ovary Syndrome Adolescents J. Clin. Endocrinol. Metab., September 1, 2009; 94(9): 3602 - 3610. [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]

				R. L. Barbieri Clomiphene Versus Metformin for Ovulation Induction in Polycystic Ovary Syndrome: The Winner Is .... J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3399 - 3401. [Full Text] [PDF]

				A. Jain, A. J. Polotsky, D. Rochester, S. L. Berga, T. Loucks, G. Zeitlian, K. Gibbs, H. N. Polotsky, S. Feng, B. Isaac, et al. Pulsatile Luteinizing Hormone Amplitude and Progesterone Metabolite Excretion Are Reduced in Obese Women J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2468 - 2473. [Abstract] [Full Text] [PDF]

				S. S. Srouji, Y. L. Pagan, F. D'Amato, A. Dabela, Y. Jimenez, J. G. Supko, and J. E. Hall Pharmacokinetic Factors Contribute to the Inverse Relationship between Luteinizing Hormone and Body Mass Index in Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1347 - 1352. [Abstract] [Full Text] [PDF]

				I. E. Messinis Ovarian feedback, mechanism of action and possible clinical implications Hum. Reprod. Update, September 1, 2006; 12(5): 557 - 571. [Abstract] [Full Text] [PDF]

				V. De Leo, M.C. Musacchio, G. Morgante, P. Piomboni, and F. Petraglia Metformin treatment is effective in obese teenage girls with PCOS Hum. Reprod., September 1, 2006; 21(9): 2252 - 2256. [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]

				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]

				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]

				R. V. Mehta, K. S. Patel, M. S. Coffler, M. H. Dahan, R. Y. Yoo, J. S. Archer, P. J. Malcom, and R. J. Chang Luteinizing Hormone Secretion Is Not Influenced by Insulin Infusion in Women with Polycystic Ovary Syndrome Despite Improved Insulin Sensitivity during Pioglitazone Treatment J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2136 - 2141. [Abstract] [Full Text] [PDF]

				D. A. Ehrmann Polycystic Ovary Syndrome N. Engl. J. Med., March 24, 2005; 352(12): 1223 - 1236. [Full Text] [PDF]

				J. M. Adams, A. E. Taylor, W. F. Crowley Jr., and J. E. Hall Polycystic Ovarian Morphology with Regular Ovulatory Cycles: Insights into the Pathophysiology of Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4343 - 4350. [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]

				The Rotterdam ESHRE/ASRM-sponsored PCOS consensus Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS) Hum. Reprod., January 1, 2004; 19(1): 41 - 47. [Abstract] [Full Text] [PDF]

				C. K. Welt, A. E. Taylor, K. A. Martin, and J. E. Hall Serum Inhibin B in Polycystic Ovary Syndrome: Regulation by Insulin and Luteinizing Hormone J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5559 - 5565. [Abstract] [Full Text] [PDF]

				H. Kaneko, J. Todoroki, J. Noguchi, K. Kikuchi, K. Mizoshita, C. Kubota, and H. Yamakuchi Perturbation of Estradiol-Feedback Control of Luteinizing Hormone Secretion by Immunoneutralization Induces Development of Follicular Cysts in Cattle Biol Reprod, December 1, 2002; 67(6): 1840 - 1845. [Abstract] [Full Text] [PDF]

				R. B. Barnes, A. B. Namnoum, R. L. Rosenfield, and L. C. Layman The role of LH and FSH in ovarian androgen secretion and ovarian follicular development: Clinical studies in a patient with isolated FSH deficiency and multicystic ovaries: Case report Hum. Reprod., January 1, 2002; 17(1): 88 - 91. [Abstract] [Full Text] [PDF]

				S. Greisen, T. Ledet, and P. Ovesen Effects of androstenedione, insulin and luteinizing hormone on steroidogenesis in human granulosa luteal cells Hum. Reprod., October 1, 2001; 16(10): 2061 - 2065. [Abstract] [Full Text] [PDF]

				T. Sir-Petermann, L. Devoto, M. Maliqueo, P. Peirano, S.E. Recabarren, and L. Wildt Resumption of ovarian function during lactational amenorrhoea in breastfeeding women with polycystic ovarian syndrome: endocrine aspects Hum. Reprod., August 1, 2001; 16(8): 1603 - 1610. [Abstract] [Full Text] [PDF]

				S. Gill, A. E. Taylor, K. A. Martin, C. K. Welt, J. M. Adams, and J. E. Hall Specific Factors Predict the Response to Pulsatile Gonadotropin-Releasing Hormone Therapy in Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2428 - 2436. [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]

				C. Hadigan, C. Corcoran, S. Piecuch, W. Rodriguez, and S. Grinspoon Hyperandrogenemia in Human Immunodeficiency Virus-Infected Women with the Lipodystrophy Syndrome J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3544 - 3550. [Abstract] [Full Text]

				R.C. Chian, W.M. Buckett, T. Tulandi, and S.L. Tan Prospective randomized study of human chorionic gonadotrophin priming before immature oocyte retrieval from unstimulated women with polycystic ovarian syndrome Hum. Reprod., January 1, 2000; 15(1): 165 - 170. [Abstract] [Full Text] [PDF]

				A Preponderance of Basic Luteinizing Hormone (LH) Isoforms Accompanies Inappropriate Hypersecretion of Both Basal and Pulsatile LH in Adolescents with Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4629 - 4636. [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]

				S. B. Seminara, J. E. Hall, A. E. Taylor, W. F. Crowley Jr., and K. A. Martin The Reproductive Endocrine Associates of the Massachusetts General Hospital: Fifteen Years of Integrated Clinical Practice and Investigation J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 1912 - 1918. [Full Text]

				F. J. Hayes, D. J. McNicholl, D. Schoenfeld, E. E. Marsh, and J. E. Hall Free {alpha}-Subunit Is Superior to Luteinizing Hormone as a Marker of Gonadotropin-Releasing Hormone Despite Desensitization at Fast Pulse Frequencies J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 1028 - 1036. [Abstract] [Full Text]

				F. J. Hayes, A. E. Taylor, K. A. Martin, and J. E. Hall Use of a Gonadotropin-Releasing Hormone Antagonist as a Physiologic Probe in Polycystic Ovary Syndrome: Assessment of Neuroendocrine and Androgen Dynamics J. Clin. Endocrinol. Metab., July 1, 1998; 83(7): 2343 - 2349. [Abstract] [Full Text]

				G. M. Lockwood, S. Muttukrishna, N. P. Groome, D. R. Matthews, and W. L. Ledger Mid-Follicular Phase Pulses of Inhibin B Are Absent in Polycystic Ovarian Syndrome and Are Initiated by Successful Laparoscopic Ovarian Diathermy: A Possible Mechanism Regulating Emergence of the Dominant Follicle J. Clin. Endocrinol. Metab., May 1, 1998; 83(5): 1730 - 1735. [Abstract] [Full Text]

				C. L. Pastor, M. L. Griffin-Korf, J. A. Aloi, W. S. Evans, and J. C. Marshall Polycystic Ovary Syndrome: Evidence for Reduced Sensitivity of the Gonadotropin-Releasing Hormone Pulse Generator to Inhibition by Estradiol and Progesterone J. Clin. Endocrinol. Metab., February 1, 1998; 83(2): 582 - 590. [Abstract] [Full Text]

				V. De Leo, D. Lanzetta, D. D’Antona, A. la Marca, and G. Morgante Hormonal Effects of Flutamide in Young Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., January 1, 1998; 83(1): 99 - 102. [Abstract] [Full Text]

				A. Dunaif Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis Endocr. Rev., December 1, 1997; 18(6): 774 - 800. [Abstract] [Full Text]

				R. Hart and A. Magos The Ovary Surgical Innovation, December 1, 1997; 4(4): 210 - 218. [Abstract] [PDF]

				T. L. Daniels and S. L. Berga Resistance of Gonadotropin Releasing Hormone Drive to Sex Steroid-Induced Suppression in Hyperandrogenic Anovulation J. Clin. Endocrinol. Metab., December 1, 1997; 82(12): 4179 - 4183. [Abstract] [Full Text] [PDF]

				A. Arroyo, G. A. Laughlin, A. J. Morales, and S. S. C. Yen Inappropriate Gonadotropin Secretion in Polycystic Ovary Syndrome: Influence of Adiposity J. Clin. Endocrinol. Metab., November 1, 1997; 82(11): 3728 - 3733. [Abstract] [Full Text] [PDF]

				S. Franks Polycystic Ovary Syndrome N. Engl. J. Med., September 28, 1995; 333(13): 853 - 861. [Full Text] [PDF]

				R. Barnes and R. L. Rosenfield The Polycystic Ovary Syndrome: Pathogenesis and Treatment Ann Intern Med, March 1, 1989; 110(5): 386 - 399. [Abstract] [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]