An analysis of the relationship between insulin resistance and the activity of steroid C17,20-lyase and 3β-hydroxysteroid dehydrogenase in ovaries and adrenals in women with polycystic ovary syndrome

Summary:

Polycystic ovary syndrome (PCOS) is connected with insulin resistance (IR), and often with the hypersecretion of adrenal androgens. Mutual relationships between IR and adrenal and ovarian steroidogenesis were investigated in the group of 19 oligo/amenorhoeic women with PCOS. The age and body mass index (BMI) of the patients were 21 ± 4.7 years and 26.4 ± 5 kg/m2 (average ± SD), respectively. All underwent a 60-minute adrenocorticotrophic hormone (ACTH) stimulation test, a gonadoliberin analogue (GnRHa) test with buserelin and an oral glucose tolerance test (oGTT) in the early follicular phase of the menstrual cycle. When absolute stimulated steroid levels after GnRHa were studied, a significant positive correlation between DHEA and area under curve during oGTT for C peptide (AUC-CP) (r = 0.477, p = 0.039) and a borderline negative correlation (r = -0.404, p = 0.087) between AUC-CP and 17-OH progesterone, were found. Considering steroid values after ACTH, a significant positive correlation of IR index was found only with 17-OH-progesterone (r = 0.499, p = 0.03). When stimulated enzymatic activities (expressed as product/precursor ratios) were analyzed using factor analysis, a positive relationship between IR and ovarian C17,20-lyase in both Δ4 and Δ5 pathway was revealed. On the other hand, no relationship was confirmed between IR and enzymatic activities in the adrenals. The authors conclude that insulin resistance and/or hyperinsulinemia is probably not the primary factor responsible for the exaggerated adrenal androgen secretion found in a great number of patients with PCOS.

Insulin resistance - C17,20-hydroxylase/lyase - adrenal-polycystic ovary

References

• 1 Adams J, Franks S, Polson D W. Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropine releasing hormone.  Lancet. 2 1375-1379 1985; 
• 2 Azziz R, Bradley E L, Potter H D, Boots L R. Adrenal androgen excess in women: lack of a role for 17-hydroxylase and 17,20- lyase dysregulation.  J Clin Endocrinol Metab. 80 400-405 1995; 
• 3 Azziz R, Bradley E L, Potter H D, Parker C R, Boots L R. Chronic hyperinsulinemia and the adrenal androgen response to acute corticotropin-(1-24) stimulation in hyperandrogenic women.  Am J Obstet Gynecol. 172 1251-1256 1995; 
• 4 Carmina E, Gonzalez F, Chang L, Lobo R A. Reassessment of adrenal androgen secretion in women with polycystic ovary syndrome.  Obstet Gynecol. 85 971-976 1995; 
• 5 Carmina E, Gonzalez F, Vidali A, Stanczyk F Z, Ferin M, Lobo R A. The contributions of oestrogen and growth factors to increased adrenal androgen secretion in polycystic ovary syndrome.  Hum Reprod. 14 307-311 1999; 
• 6 Carmina E, Lobo R A. Adrenal hyperandrogenism in the pathophysiology of polycystic ovary syndrome.  J Endocrinol Invest. 21 580-588 1998; 
• 7 Ditkoff E C, Fruzzetti F, Chang L, Stanzyk F Z, Lobo R A. The impact of estrogen on adrenal androgen sensitivity and secretion in polycystic ovary syndrome.  J Clin Endocrinol Metab. 80 603-607 1995; 
• 8 Dunaif A. Insulin resistance and the polycystic ovary syndrome: Mechanism and implication for pathogenesis.  Endocrine Rev. 18 774-800 1997; 
• 9 Duncan M H, Singh B M, Wise P H, Carter G, Alaghband-Zadeh J. A simple measure of insulin resistance.  Lancet. 346 120-121 1995; 
• 10 Ehrmann D A, Barnes R, Rosenfield R L. Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion.  Endocrine Rev. 16 322-399 1995; 
• 11 Franks S, Gharani N, Gilling-Smith C. Polycystic ovary syndrome: evidence for a primary disorder of ovarian steroidogenesis.  J Steroid Biochem Mol Biol. 69 269-272 1999; 
• 12 Gilling-Smith C, Willis D S, Beard R W, Franks S. Hypersecretion of androstenedione by isolated theca cells from polycystic ovaries.  J Clin Endocrinol Metab. 79 1158-1165 1994; 
• 13 Gonzales F, Chang L, Horab T, Stanczyk F Z, Criskard K , Lobo A R. Adrenal dynamic responses to physiologic and pharmacologic ACTH stimulation before and after ovarian steroid modulation in women with polycystic ovary syndrome.  Fertil Steril. 71 439-444 1999; 
• 14 Hill M, Lukác D, Lapcík O, Sulcová J, Hampl R, Pouzar V, Stárka L. Age relationships and sex differences in serum levels of pregnenolone and 17-hydroxypregnenolone in healthy subjects.  Clinical Chemistry and Laboratory Medicine. 37 439-447 1999; 
• 15 Lanzone A, Fulghesu A M, Guido M, Fortini A, Caruso A, Mancuso A. Differential androgen response to ACTH stimulation in polycystic ovarian syndrome: relationship with insulin secretion.  Fertil Steril. 58 296-301 1992; 
• 16 Larsson H, Ahren B. Insulin resistant subjects lack islet adaptation to short- term dexamethasone-induced reduction in insulin sensitivity.  Diabetologia. 42 936-943 1999; 
• 17 Martikainen H, Salmela P, Nuojua-Huttunen S, Perala J, Leinonen S, Knip M, Ruokonen A. Adrenal steroidogenesis is related to insulin in hyperandrogenic women.  Fertil Steril. 66 564-570 1996; 
• 18 Miller W L. Early steps in androgen biosynthesis: from cholesterol to DHEA.  Bailliére's Clin Endocrinol Metab. 12 67-81 1998; 
• 19 Moghetti P, Castello R, Negri C, Tosi F, Spiazzi G G, Brun E, Balducci R, Toscano V, Munggeo M. Insulin infusion amplifies 17 α hydroxycorticosteroid intermediate response to ACTH in hyperandrogenic women: apparent relative impairment of 17, 20 lyase activity.  J Clin Endocrinol Metab. 81 881-886 1996; 
• 20 Rittmaster R S, Deshwal N, Lehman L. The role of adrenal hyperandrogenism, insulin resistance and obesity in the pathogenesis of polycystic ovarian syndrome.  J Clin Endocrinol Metab. 76 1295-1300 1993; 
• 21 Rosenfield R L. Editorial: Evidence that idiopathic functional adrenal hyparandrogenism is caused by dysregulation of adrenal steroidogenesis and that hyperinsulinemia may be involved.  J Clin Endocrinol Metab. 81 878-879 1995; 
• 22 Sahin Y, Kelestimur F. 17hydroxyprogesterone response to buserelin testing in the polycystic ovary syndrome.  Clin Endocrinol. 39 151-155 1993; 
• 23 Stanczyk F Z, Chang L, Carmina E, Putz Z, Lobo R A. Is 11βhydroxyandrostenedione a better marker of adrenal androgen excess than dehydroepiandrosterone sulfate?.  Am J Obstet Gynecol. 165 1837-1842 1991; 
• 24 Stárka L, Matys Z, Janata J . Der Nachweis von Dehydroepiadrosterone in menschlichen sklerocystischen ovarien.  Clin Chim Acta. 7 776-779 1962; 
• 25 Unluhzarci K, Kelestimur F, Sahin Y, Bayram F. The treatment of insulin resistance does not improve adrenal cytochrome P 450c17α enzyme dysregulation in PCOS.  Eur J Endocrinol. 140 56-61 1999; 
• 26 Vuguin P, Linder B, Rosenfeld R G, Saenger P , DiMartino-Nardi J. The roles of insulin sensitivity, insulin-like growth factor I (IGF-I) and IGF-binding protein-1 and-3 in the hyperandrogenism of African-American and Caribbean Hispanic girls with premature adrenarche.  J Clin Endocrinol Metab. 84 2037-2042 1999;