Pioglitazone improves insulin action and normalizes menstrual cycles in a majority of prenatally androgenized female rhesus monkeys.
Journal: 2007/September - Reproductive Toxicology
ISSN: 0890-6238
Abstract:
OBJECTIVE
To determine whether pioglitazone will improve menstrual cyclicity in a fetal programming model for polycystic ovary syndrome.
METHODS
Eight prenatally androgenized (PA) and 5 control female rhesus monkeys of similar age, body weight and body mass index received an oral placebo daily for 6-7 months followed, after at least 90 days, by daily oral dosing with pioglitazone (3mg/kg) for an additional 6-7 months. Blood was sampled thrice weekly to monitor ovulatory function, and a variety of endocrine challenges were performed to quantify changes in ovarian, gonadotropin and glucoregulatory function.
UNASSIGNED
Pioglitazone normalized menstrual cycles in 5 out of 8 (62%) PA females (pioglitazone responsive; Pio(RESP)). Pioglitazone increased serum 17alpha-hydroxyprogesterone responses to an hCG injection in Pio(RESP) PA females, while diminishing serum progesterone, and increasing DHEA and estradiol responses to hCG in Pio(RESP) PA and all normal females.
CONCLUSIONS
Insulin resistance plays a mechanistic role in maintaining anovulation in a majority of PA female monkeys.
Relations:
Content
Citations
(21)
References
(68)
Grants
(110)
Diseases
(2)
Conditions
(1)
Drugs
(7)
Chemicals
(8)
Organisms
(2)
Processes
(2)
Affiliates
(1)
Similar articles
Articles by the same authors
Discussion board
Reprod Toxicol 23(3): 438-448

Pioglitazone improves insulin action and normalizes menstrual cycles in a majority of prenatally androgenized female rhesus monkeys

National Primate Research Center, University of Wisconsin, Madison, WI 53715
Endocrinology-Reproductive Physiology Program, University of Wisconsin, Madison, WI 53715
Dean Clinic and Center for Women’s Health Research University of Wisconsin, Madison, WI 53715
Department of Obstetrics and Gynecology, University of Wisconsin, Madison, WI 53715
Department of Physiology, University of Wisconsin, Madison, WI 53715
Department of Medicine, University of Wisconsin, Madison, WI 53715
Reproductive Medicine and Infertility Associates, Woodbury, MN 55125
Author to whom reprint requests should be addressed: David H Abbott, Ph.D., National Primate Research Center, University of Wisconsin, 1223 Capitol Court, Madison, Wisconsin 53715, USA. Telephone: 608-263-3583. Fax: 608-263-3524. e-mail: ude.csiw.etamirp@ttobba
Publisher's Disclaimer

Abstract

PURPOSE OF THE STUDY

To determine whether pioglitazone will improve menstrual cyclicity in a fetal programming model for polycystic ovary syndrome.

BASIC PROCEDURES

Eight prenatally androgenized (PA) and 5 control female rhesus monkeys of similar age, body weight and body mass index received an oral placebo daily for 6–7 months followed, after at least 90 days, by daily oral dosing with pioglitazone (3mg/kg) for an additional 6–7 months. Blood was sampled thrice weekly to monitor ovulatory function, and a variety of endocrine challenges were performed to quantify changes in ovarian, gonadotropin and glucoregulatory function.

MOST IMPORTANT FINDINGS

Pioglitazone normalized menstrual cycles in 5 out of 8 (62%) PA females (pioglitazone responsive; PioRESP). Pioglitazone increased serum 17α-hydroxyprogesterone responses to an hCG injection in PioRESP PA females, while diminishing serum progesterone, and increasing DHEA and estradiol responses to hCG in PioRESP PA and all normal females.

PRINCIPAL CONCLUSIONS

Insulin resistance plays a mechanistic role in maintaining anovulation in a majority of PA female monkeys.

Keywords: androgen excess, anovulation, insulin resistance, hyperglycemia, hyperlipidemia
Abstract

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Footnotes

References

  • 1. Barnes RB, Rosenfield RL, Ehrmann DA, Cara JF, Cuttler L, Levitsky LL, Rosenthal IMOvarian hyperandrogynism as a result of congenital adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women. J Clin Endocrinol Metab. 1994;79:1328–1333.[PubMed][Google Scholar]
  • 2. Abbott DH, Dumesic DA, Franks SDevelopmental origin of polycystic ovary syndrome - a hypothesis. J Endocrinol. 2002;174:1–5.[PubMed][Google Scholar]
  • 3. Xita N, Tsatsoulis AReview: fetal programming of polycystic ovary syndrome by androgen excess: evidence from experimental, clinical, and genetic association studies. J Clin Endocrinol Metab. 2006;91:1660–1666.[PubMed][Google Scholar]
  • 4. Abbott DH, Dumesic DA, Eisner JR, Kemnitz JW, Goy RW. The prenatally androgenized female rhesus monkey as a model for polycystic ovarian syndrome. In: Dewailly D, editor. Androgen Excess Disorder in Women. Philadelphia, PA: Lippincot-Raven Press; 1997. pp. 369–382. [PubMed]
  • 5. Abbott DH, Dumesic DA, Eisner JR, Colman RJ, Kemnitz JWInsights into the development of PCOS from studies of prenatally androgenized female rhesus monkeys. Trends Endocrinol Metab. 1998;9:62–67.[PubMed][Google Scholar]
  • 6. Eisner JR, Barnett MA, Dumesic DA, Abbott DHOvarian hyperandrogenism in adult female rhesus monkeys exposed to prenatal androgen excess. Fertil Steril. 2002;77:167–172.[PubMed][Google Scholar]
  • 7. Zhou R, Bird IM, Dumesic DA, Abbott DHAdrenal hyperandrogenism is induced by fetal androgen excess in a rhesus monkey model of polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:6630–6637.[Google Scholar]
  • 8. Abbott DH, Eisner JR, Colman RJ, Kemnitz JW, Dumesic DA. Prenatal androgen excess programs for PCOS in female rhesus monkeys. In: Chang RJ, Dunaif A, Hiendel J, editors. Polycystic Ovary Syndrome. New York: Marcel Dekker, Inc.; 2002. pp. 119–133. [PubMed]
  • 9. Abbott DH, Barnett DK, Bruns CM, Dumesic DAAndrogen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome? Hum Reprod Update. 2005;11:357–374.[PubMed][Google Scholar]
  • 10. Padmanabhan V, Manikkam M, Recabarren S, Foster DPrenatal testosterone excess programs reproductive and metabolic dysfunction in the female. Mol Cell Endocrinol. 2006;246:165–174.[PubMed][Google Scholar]
  • 11. Sullivan SD, Moenter SMPrenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder. Proc Natl Acad Sci U S A. 2004;101:7129–7134.[Google Scholar]
  • 12. Foecking EM, Szabo M, Schwartz NB, Levine JENeuroendocrine 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. 2005;72:1475–1483.[PubMed][Google Scholar]
  • 13. Dunaif A, Segal KR, Futterweit W, Dobrjansky AProfound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38:1165–1174.[PubMed][Google Scholar]
  • 14. Ehrmann DA, Barnes RB, Rosenfield RLPolycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr Rev. 1995;16:322–353.[PubMed][Google Scholar]
  • 15. Franks SPolycystic ovary syndrome. N Engl J Med. 1995;333:853–861.[PubMed][Google Scholar]
  • 16. Dunaif AInsulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997;18:774–800.[PubMed][Google Scholar]
  • 17. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith LPregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod. 2002;17:2858–2864.[PubMed][Google Scholar]
  • 18. Norman RJ, Wang JX, Hague WShould we continue or stop insulin sensitizing drugs during pregnancy? Curr Opin Obstet Gynecol. 2004;16:245–250.[PubMed][Google Scholar]
  • 19. Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed MJ, Franks SImprovement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol. 1992;36:105–111.[PubMed][Google Scholar]
  • 20. Huber-Buchholz MM, Carey DG, Norman RJRestoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab. 1999;84:1470–1474.[PubMed][Google Scholar]
  • 21. Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb RThe insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1996;81:3299–3306.[PubMed][Google Scholar]
  • 22. Ehrmann DA, Schneider DJ, Sobel BE, Cavaghan MK, Imperial J, Rosenfield RL, Polonsky KSTroglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1997;82:2108–2116.[PubMed][Google Scholar]
  • 23. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali REffects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med. 1998;338:1876–1880.[PubMed][Google Scholar]
  • 24. Lord JM, Flight IH, Norman RJMetformin in polycystic ovary syndrome: systemic review and meta-analysis. BMJ. 2003;327:951–953.[Google Scholar]
  • 25. Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Fereshetian AG, O’Keefe M, Ghazzi MN PCOS/Troglitazone Study GroupTroglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab. 2001;86:1626–1632.[PubMed][Google Scholar]
  • 26. Hanefeld M, Belcher GSafety profile of pioglitazone. Int J Clin Pract Suppl. 2001;121:27–31.[PubMed][Google Scholar]
  • 27. Brettenthaler N, De Geyter C, Huber PR, Keller UEffect of the insulin sensitizer pioglitazone on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2004;89:3835–3840.[PubMed][Google Scholar]
  • 28. Romualdi D, Guido M, Ciampelli M, Giuliani M, Leoni F, Perri C, Lanzone ASelective effects of pioglitazone on insulin and androgen abnormalities in normo-and hyperinsulinaemic obese patients with polycystic ovary syndrome. Hum Reprod. 2003;18:1210–1218.[PubMed][Google Scholar]
  • 29. Mitwally MF, Kuscu NK, Yalcinkaya TMHigh ovulatory rates with use of troglitazone in clomiphene-resistant women with polycystic ovary syndrome. Hum Reprod. 1999;14:2700–2703.[PubMed][Google Scholar]
  • 30. Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, Zanolin E, Muggeo MMetformin 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. 2000;85:139–146.[PubMed][Google Scholar]
  • 31. Fleming R, Hopkinson Z, Wallace ROvarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind, placebo-controlled trial. J. Clin. Endocrinol. Metab. 2002;87:569–574.[PubMed][Google Scholar]
  • 32. Glueck CJ, Moreira A, Goldenberg N, Sieve L, Wang PPioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin. Hum Reprod. 2003;18:1618–1625.[PubMed][Google Scholar]
  • 33. Goy RW, Robinson JAPrenatal exposure of rhesus monkeys to patent androgens: morphological, behavioral, and physiological consequences. Banbury Report. 1982;11:355–378.[PubMed][Google Scholar]
  • 34. Robinson JR, Goy RW Comparative Primate Biology, Volume 3: Reproduction and Development. New York, NY: Alan R. Liss, Inc.; 1986. Steroid hormones and the ovarian cycle; pp. 63–91. [PubMed][Google Scholar]
  • 35. Resko JA, Goy RW, Robinson JA, Norman RLThe pubescent rhesus monkey: some characteristics of the menstrual cycle. Biol Reprod. 1982;27:354–361.[PubMed][Google Scholar]
  • 36. Hutz RJ, Dierschke DJ, Wolf RCSeasonal effects on ovarian folliculogenesis in rhesus monkeys. Biol Reprod. 1985;33:653–659.[PubMed][Google Scholar]
  • 37. Kemnitz JW, Elson DF, Roecker EB, Baum ST, Bergman RN, Meglasson MDPioglitazone increases insulin sensitivity, reduces blood glucose, insulin, and lipid levels, and lowers blood pressure, in obese, insulin-resistant rhesus monkeys. Diabetes. 1994;43:204–211.[PubMed][Google Scholar]
  • 38. Berria R, Gastaldelli A, Lucidi S, Belfort R, De Filippis E, Easton C, Brytzki R, Cusi K, Jovanovic L, DeFronzo RReduction in hematocrit level after pioglitazone treatment is correlated with decreased plasma free testosterone level, not hemodilution, in women with polycystic ovary syndrome. Clin Pharmacol Ther. 2006;80:105–114.[PubMed][Google Scholar]
  • 39. Glintborg D, Hermann AP, Andersen M, Hagen C, Beck-Nielsen H, Veldhuis JD, Henriksen JEEffect of pioglitazone on glucose metabolism and luteinizing hormone secretion in women with polycystic ovary syndrome. Fertil Steril. 2006;86:385–397.[PubMed][Google Scholar]
  • 40. Dumesic DA, Abbott DH, Eisner JR, Goy RWPrenatal exposure of female rhesus monkeys to testosterone propionate increases serum luteinizing hormone levels in adulthood. Fertil Steril. 1997;67:155–163.[PubMed][Google Scholar]
  • 41. Cheung BW, Cartier LL, Russlie HQ, Sawchuk RJThe application of sample pooling methods for determining AUC, AUMC and mean residence times in pharmacokinetic studies. Fundam Clin Pharmacol. 2005;19:347–354.[PubMed][Google Scholar]
  • 42. Robinson JA, Goy RW. Steroid hormones and the ovarian cycle. In: Dukelow WR, Erwin J, editors. Comparative Primate Biology, VOL. 3: Reproductive and Development. New York: Alan R. Liss. Pgs; 1986. pp. 63–91. [PubMed]
  • 43. Bergman RN. Lilly lecture. Toward physiological understanding of glucose tolerance. Minimal-model approach. Diabetes. 1989;38:1512–1527.[PubMed]
  • 44. Wickenheisser JK, Nelson-DeGrave VL, Hendricks KL, Legro RS, Strauss JF, 3rd, McAllister JMRetinoids and retinol differentially regulate steroid biosynthesis in ovarian theca cells isolated from normal cycling women and women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:4858–4865.[PubMed][Google Scholar]
  • 45. Ibanez L, Hall JE, Potau N, Carrascosa A, Prat N, Taylor AEOvarian 17-Hydroxyprogesterone hyperresponsiveness to gonadotropin-releasing hormone (GnRH) agonist challenge in women with polycystic ovary syndrome is not mediated by luteinizing hormone hypesecretion - evidence from GnRH agonist and human chorionic gonadotropin stimulation testing. J Clin Endocrinol Metab. 1996;81:4103–4107.[PubMed][Google Scholar]
  • 46. Gilling-Smith C, Story H, Rogers V, Franks SEvidence for a primary abnormality of thecal cell steroidogenesis in the polycystic ovary syndrome. Clin Endocrinol (Oxf) 1997;47:93–99.[PubMed][Google Scholar]
  • 47. Barnes RB, Rosenfield RL, Burstein S, Ehrmann DAPituitary-ovarian responses to nafarelin testing in the polycystic ovary syndrome. N Engl J Med. 1989 Mar 2;320(9):559–565.[PubMed][Google Scholar]
  • 48. Ferin M, Warren M, Dyrenfurth I, Vande Wiele RL, White WFResponse of rhesus monkeys to LHRH throughout the ovarian cycle. J Clin Endocrinol Metab. 1974;38:231–237.[PubMed][Google Scholar]
  • 49. Dumesic DA, Schramm RD, Peterson E, Paprocki AM, Zhou R, Abbott DHImpaired developmental competence of oocytes in adult prenatally androgenized female rhesus monkeys undergoing gonadotropin stimulation for in vitro fertilization. J Clin Endocrinol Metab. 2002;87:1111–1119.[PubMed][Google Scholar]
  • 50. Saltzman W, Schultz-Darken NJ, Scheffler G, Wegner FH, Abbott DHSocial and reproductive influences on plasma cortisol in female marmoset monkeys. Physiol Behav. 1994;56:801–810.[PubMed][Google Scholar]
  • 51. Barash H, Akov SImproved 63 Ni radiochemical assay of free fatty acids in plasma. Clin. Chem. 1987;33:176–179.[PubMed][Google Scholar]
  • 52. Gresl TA, Colman RJ, Roecker EB, Havighurst TC, Huang Z, Allison DB, Bergman RN, Kemnitz JWDietary restriction and glucose regulation in aging rhesus monkeys: a follow-up report at 8.5 yr. Am J Physiol Endocrinol Metab. 2001;281:757–765.[PubMed][Google Scholar]
  • 53. Sokal RR, Rohlf FJ Biometry. 3 ed. New York: W. H. Freeman and Co.; 1995. the principles and practice of statistics in biological research; pp. 413–422. [PubMed][Google Scholar]
  • 54. Bercovitch FBEstradiol concentrations, fat deposits, and reproductive strategies in male rhesus macaques. Horm Behav. 1992;26:272–282.[PubMed][Google Scholar]
  • 55. Giannini S, Serio M, Galli APleiotropic effects of thiazolidinediones: taking a look beyond antidiabetic activity. J Endocrinol Invest. 2004;27:982–991.[PubMed][Google Scholar]
  • 56. Froment P, Gizard F, Defever D, Staels B, Dupont J, Monget PPeroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition. J Endocrinol. 2006;189:199–209.[PubMed][Google Scholar]
  • 57. Ferruzzi P, Ceni E, Tarocchi M, Grappone C, Milani S, Galli A, Fiorelli G, Serio M, Mannelli MThiazolidinediones inhibit growth and invasiveness of the human adrenocortical cancer cell line H295R. J Clin Endocrinol Metab. 2005;90:1332–1339.[PubMed][Google Scholar]
  • 58. Komar CMPeroxisome proliferator-activated receptors (PPARs) and ovarian function--implications for regulating steroidogenesis, differentiation, and tissue remodeling. Reprod Biol Endocrinol. 2005;30:3–41.[Google Scholar]
  • 59. Game BA, He L, Jarido V, Nareika A, Jaffa AA, Lopes-Virella MF, Huang YPioglitazone inhibits connective tissue growth factor expression in advanced atherosclerotic plaques in low-density lipoprotein receptor-deficient mice. Atherosclerosis. 2006 Aug 8; [Epub ahead of print] [[PubMed][Google Scholar]
  • 60. Seto-Young D, Paliou M, Schlosser J, Avtanski D, Park A, Patel P, Holcomb K, Chang P, Poretsky LDirect thiazolidinedione action in the human ovary: insulin-independent and insulin-sensitizing effects on steroidogenesis and insulin-like growth factor binding protein-1 production. J Clin Endocrinol Metab. 2005;90:6099–6105.[PubMed][Google Scholar]
  • 61. Dumesic DA, et al Unpublished results. [PubMed]
  • 62. Coffler MS, Patel K, Dahan MH, Yoo RY, Malcom PJ, Change RJEnhanced granulosa cell responsiveness to follicle-stimulating hormone during insulin infusion in women with polycystic ovary syndrome treated with pioglitazone. J Clin Endocrinol Metab. 2003;88:5624–5631.[PubMed][Google Scholar]
  • 63. Velazquez E, Acosta A, Mendoza SGMenstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol. 1997;90:392–395.[PubMed][Google Scholar]
  • 64. Zhou R, Turk JM, Hable KW, Padmanabhan V, Dumesic DA, Abbott DH. Luteal phase defects in prenatally androgenized female rhesus monkeys. Philadelphia, PA. Abstract P3-16 presented at the 85th Annual Meeting of the Endocrine Society.2003. [PubMed]
  • 65. Lunn SF, Fraser HM, Mason HDStructure of the corpus luteum in the ovulatory polycystic ovary. Hum Reprod. 2002;17:111–117.[PubMed][Google Scholar]
  • 66. Joseph-Horne R, Mason H, Batty S, White D, Hillier S, Urquhart M, Franks SLuteal phase progesterone excretion in ovulatory women with polycystic ovaries. Hum Reprod. 2002;17:1459–1463.[PubMed][Google Scholar]
  • 67. Ayabe T, Tsutsumi O, Momoeda M, Yano T, Mitsuhashi N, Taketani YImpaired follicular growth and abnormal luteinizing hormone surge in luteal phase defect. Fertil Steril. 1994;61:652–656.[PubMed][Google Scholar]
  • 68. Soules MR, McLachlan RI, Ek M, Dahl KD, Cohen NL, Bremner WJLuteal phase deficiency: characterization of reproductive hormones over the menstrual cycle. J Clin Endocrinol Metab. 1989;69:804–812.[PubMed][Google Scholar]
  • 69. Soules MR, Clifton DK, Cohen NL, Bremner WJ, Steiner RALuteal phase deficiency: abnormal gonadotropin and progesterone secretion patterns. J Clin Endocrinol Metab. 1989;69:813–820.[PubMed][Google Scholar]
  • 70. Vasudevan AR, Balasubramanyam AThiazolidinediones: a review of their mechanisms of insulin sensitization, therapeutic potential, clinical efficacy, and tolerability. Diabetes Technol Ther. 2004;6:850–863.[PubMed][Google Scholar]
  • 71. Lohrke B, Viergutz T, Shahi SK, Pohland R, Wollenhaupt K, Goldammer T, Walzel H, Kanitz WDetection and functional characterisation of the transcription factor peroxisome proliferator-activated receptor gamma in lutein cells. J Endocrinol. 1998;159:429–439.[PubMed][Google Scholar]
  • 72. Willis DS, White J, Brosens, Franks S. Effect of 15-deoxy-delta (12,14)-prostaglandin J2 (PGJ2) a peroxisome proliferators activating receptor g (PPARg) ligand on human ovarian steroidogenesis. San Diego. Abstract P3-247 presented at the 81st Meeting of the Endocrine Society.1999. [PubMed]
  • 73. Arlt W, Auchus RJ, Miller WLThiazolidinediones but not metformin directly inhibit the steroidogenic enzymes P450c17 and 3 beta-hydroxysteroid dehydrogenase. J Biol Chem. 2001;276:16767–16771.[PubMed][Google Scholar]
  • 74. Gonzalez-Robayna IJ, Alliston TN, Buse P, Firestone GL, Richards JSFunctional and subcellular changes in the A-kinase-signaling pathway: relation to aromatase and Sgk expression during the transition of granulosa cells to luteal cells. Mol Endocrinol. 1999;13:1318–1337.[PubMed][Google Scholar]
  • 75. Murphy BDModels of luteinization. Biol Reprod. 2000;63:2–11.[PubMed][Google Scholar]
  • 76. Somers JP, Benyo DF, Little-Ihrig L, Zeleznik AJLuteinization in primates is accompanied by loss of a 43-kilodalton adenosine 3′,5′-monophosphate response element-binding protein isoform. Endocrinology. 1995;136:4762–4768.[PubMed][Google Scholar]
  • 77. Levrant SG, Barnes RB, Rosenfield RLA pilot study of the human chorionic gonadotrophin test for ovarian hyperandrogenism. Hum Reprod. 1997;12:1416–1420.[PubMed][Google Scholar]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.