Endocrinology, Vol 108, 1441-1449, Copyright © 1981 by Endocrine Society

ARTICLES

Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells

EY Adashi, AJ Hsueh and SS Yen

The role of insulin in the regulation of basal and gonadotropin- releasing hormone (GnRH)-stimulated release of LH and FSH was investigated in vitro using primary cultures of rat anterior pituitary cells from adult ovariectomized rats. Anterior pituitary cells were incubated for 2 days in the presence or absence of insulin in a serum- free medium. At the end of the insulin treatment, the cells were washed and reincubated in the presence or absence of GnRH, and the LH and FSH released into the medium were measured by RIA. Treatment with insulin (1.0 microgram/ml) for 2 days resulted in significant increases in both the basal and the maximal release of LH and FSH, as well as a 3.2- and 6.3-fold decrease in the ED50 values for GnRH in terms of LH and FSH release, respectively. Treatment with increasing concentrations (0.1- 10,000 ng/ml) of insulin, led to a dose-dependent increase in the GnRH (3 X 10(-10) M)-stimulated release of both LH and FSH. This effect of insulin was significant (P less than 0.05) at a physiological concentration of 1 ng/ml (24 microU/ml) with an ED50 value of 40 ng/ml. Increasing duration of exposure to insulin resulted in time-dependent increases in the GnRH (3 X 10(-10) M)-stimulated release of LH, becoming significant at 24 h with maximal enhancement observed by 48 h. The effect of insulin was specific; epidermal or fibroblast growth factor did not enhance LH release. The augmenting effect of insulin was not associated with cellular proliferation or an overall change in protein or LH synthesis. Furthermore, the effect of insulin was independent of the ambient glucose concentration. Insulin was, however, without effect on gonadotrophs cultured in a serum-supplemented medium. Our findings suggest that the gonadotroph constitutes a target cell of insulin and that insulin may act directly on the anterior pituitary in the regulation of gonadotropin release.

This article has been cited by other articles:

				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]

				J. Ballester, M.C. Munoz, J. Dominguez, M.J. Palomo, M. Rivera, T. Rigau, J.J. Guinovart, and J.E. Rodriguez-Gil Tungstate administration improves the sexual and reproductive function in female rats with streptozotocin-induced diabetes Hum. Reprod., August 1, 2007; 22(8): 2128 - 2135. [Abstract] [Full Text] [PDF]

				M.L. Hendriks, J.C.F. Ket, P.G.A. Hompes, R. Homburg, and C.B. Lambalk Why does ovarian surgery in PCOS help? Insight into the endocrine implications of ovarian surgery for ovulation induction in polycystic ovary syndrome Hum. Reprod. Update, May 1, 2007; 13(3): 249 - 264. [Abstract] [Full Text] [PDF]

				R. S. Legro A 27-Year-Old Woman With a Diagnosis of Polycystic Ovary Syndrome JAMA, February 7, 2007; 297(5): 509 - 519. [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]

				M.A. Checa, A. Requena, C. Salvador, R. Tur, J. Callejo, J.J. Espinos, F. Fabregues, J. Herrero, and (Reproductive Endocrinology Interest Group of the Insulin-sensitizing agents: use in pregnancy and as therapy in polycystic ovary syndrome Hum. Reprod. Update, July 1, 2005; 11(4): 375 - 390. [Abstract] [Full Text] [PDF]

				N. Pitteloud, M. Hardin, A. A. Dwyer, E. Valassi, M. Yialamas, D. Elahi, and F. J. Hayes Increasing Insulin Resistance Is Associated with a Decrease in Leydig Cell Testosterone Secretion in Men J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2636 - 2641. [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]

				J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, A. D. Rogol, J. C. Lovejoy, M. Sheffield-Moore, N. Mauras, and C. Y. Bowers Endocrine Control of Body Composition in Infancy, Childhood, and Puberty Endocr. Rev., February 1, 2005; 26(1): 114 - 146. [Abstract] [Full Text] [PDF]

				K. Patel, M. S. Coffler, M. H. Dahan, R. Y. Yoo, M. A. Lawson, P. J. Malcom, and R. J. Chang Increased Luteinizing Hormone Secretion in Women with Polycystic Ovary Syndrome Is Unaltered by Prolonged Insulin Infusion J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5456 - 5461. [Abstract] [Full Text] [PDF]

				V. De Leo, A. la Marca, and F. Petraglia Insulin-Lowering Agents in the Management of Polycystic Ovary Syndrome Endocr. Rev., October 1, 2003; 24(5): 633 - 667. [Abstract] [Full Text] [PDF]

				D. Romualdi, M. Guido, M. Ciampelli, M. Giuliani, F. Leoni, C. Perri, and A. Lanzone Selective effects of pioglitazone on insulin and androgen abnormalities in normo- and hyperinsulinaemic obese patients with polycystic ovary syndrome Hum. Reprod., June 1, 2003; 18(6): 1210 - 1218. [Abstract] [Full Text] [PDF]

				J. C. Lopez-Alvarenga, T. Zarinan, A. Olivares, J. Gonzalez-Barranco, J. D. Veldhuis, and A. Ulloa-Aguirre Poorly Controlled Type I Diabetes Mellitus in Young Men Selectively Suppresses Luteinizing Hormone Secretory Burst Mass J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5507 - 5515. [Abstract] [Full Text] [PDF]

				B. Baccetti, A. la Marca, P. Piomboni, S. Capitani, E. Bruni, F. Petraglia, and V. De Leo Insulin-dependent diabetes in men is associated with hypothalamo-pituitary derangement and with impairment in semen quality Hum. Reprod., October 1, 2002; 17(10): 2673 - 2677. [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]

				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]

				S. E. Oberfield Metabolic Lessons from the Study of Young Adolescents with Polycystic Ovary Syndrome--Is Insulin, Indeed, the Culprit? J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3520 - 3525. [Full Text]

				L. Ibáñez, C. Valls, N. Potau, M. V. Marcos, and F. de Zegher Sensitization to Insulin in Adolescent Girls to Normalize Hirsutism, Hyperandrogenism, Oligomenorrhea, Dyslipidemia, and Hyperinsulinism after Precocious Pubarche J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3526 - 3530. [Abstract] [Full Text]

				P. Moghetti, R. Castello, C. Negri, F. Tosi, F. Perrone, M. Caputo, E. Zanolin, and M. Muggeo Metformin Effects on Clinical Features, Endocrine and Metabolic Profiles, and Insulin Sensitivity in Polycystic Ovary Syndrome: A Randomized, Double-Blind, Placebo-Controlled 6-Month Trial, followed by Open, Long-Term Clinical Evaluation J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 139 - 146. [Abstract] [Full Text]

				R.D. Murray, R.M. Davison, R.C. Russell, and G.S. Conway Clinical presentation of PCOS following development of an insulinoma: Case Report Hum. Reprod., January 1, 2000; 15(1): 86 - 88. [Abstract] [Full Text] [PDF]

				L. Ciotta, V. De Leo, F. Galvani, A. La Marca, and A. Cianci Endocrine and metabolic effects of octreotide, a somatostatin analogue, in lean PCOS patients with either hyperinsulinaemia or lean normoinsulinaemia Hum. Reprod., December 1, 1999; 14(12): 2951 - 2958. [Abstract] [Full Text] [PDF]

				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]

				M. Nagamani, C. Osuampke, and M. E. Kelver Increased Bioactive Luteinizing Hormone Levels and Bio/Immuno Ratio in Women with Hyperthecosis of the Ovaries: Possible Role of Hyperinsulinemia J. Clin. Endocrinol. Metab., May 1, 1999; 84(5): 1685 - 1689. [Abstract] [Full Text]

				C. Weil, F. Carré, O. Blaise, B. Breton, and P.-Y. Le Bail Differential Effect of Insulin-Like Growth Factor I on in Vitro Gonadotropin (I and II) and Growth Hormone Secretions in Rainbow Trout (Oncorhynchus mykiss) at Different Stages of the Reproductive Cycle Endocrinology, May 1, 1999; 140(5): 2054 - 2062. [Abstract] [Full Text]

				A. E. Taylor, J. Hubbard, and E. J. Anderson Impact of Binge Eating on Metabolic and Leptin Dynamics in Normal Young Women J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 428 - 434. [Abstract] [Full Text]

				J. E. Nestler, D. J. Jakubowicz, W. S. Evans, and R. Pasquali Effects of Metformin on Spontaneous and Clomiphene-Induced Ovulation in the Polycystic Ovary Syndrome N. Engl. J. Med., June 25, 1998; 338(26): 1876 - 1880. [Abstract] [Full Text] [PDF]

				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]

				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]

				J. E. Nestler and D. J. Jakubowicz Lean Women with Polycystic Ovary Syndrome Respond to Insulin Reduction with Decreases in Ovarian P450c17{alpha} Activity and Serum Androgens J. Clin. Endocrinol. Metab., December 1, 1997; 82(12): 4075 - 4079. [Abstract] [Full Text] [PDF]

				A. E. Taylor, B. McCourt, K. A. Martin, E. J. Anderson, J. M. Adams, D. Schoenfeld, and J. E. Hall Determinants of Abnormal Gonadotropin Secretion in Clinically Defined Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., July 1, 1997; 82(7): 2248 - 2256. [Abstract] [Full Text] [PDF]

				J. E. Nestler and D. J. Jakubowicz Decreases in Ovarian Cytochrome P450c17{alpha} Activity and Serum Free Testosterone after Reduction of Insulin Secretion in Polycystic Ovary Syndrome N. Engl. J. Med., August 29, 1996; 335(9): 617 - 623. [Abstract] [Full Text] [PDF]