Mediterranean Society for Reproductive Medicine

Tam metin

(1)XIV Meeting of the. Mediterranean Society for Reproductive Medicine.. Endocrine status of PCOS P.Inaudi, MD, PhD Department of Molecular Medicine and of Development. . Obstetrics, Gynecology and Reproductive Medicine, . University of Siena, Italy.

(2) PCOS prevalence is between 4 to 12% of women in reproductive age. PCOS account for 50-90% of . normogonadotropic anovulation. Oligomenorrhea or anovulation are . present in 75% of women with PCOS.

(3) White, smooth, sclerotic ovaries with thickened capsules, multiple. .. follicles in various stages of development and atresia. Clinical features of 1557 patients with PCOS. Hirsutism. 63.9%. Acne. 31.6%. Infertility. 24.8%. Acanthosis nigricans Menstrual cycle status . 3.6%. Regular 25.0%. Oligo.. 51.5%. Amen.. 23.0%. Balen et al. Hum Repord 1995.

(4) Polycystic Ovary Syndrome. Defined by two of the following three features. • Oligo or anovulation. • Clinical or biochemical sign of hyperandrogenism. • Polycystic ovaries. Rotterdam consensus 2003.

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(6) Hypothalamo-pituitary.

(7) Secrezione pulsatile del GnRH.

(8) Inaudi P et al., Fertil Steril 58: 51, 1992.

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(12) LH-Androgens. • The increase of LH pulse frequency and amplitude lead to a persistent high LH circulating levels that contribute to enhance the theca androgen production.. • The hyperandrogenism may contribute to the increased LH secretion through an impairement of the negative estrogen feedback on the activity of the hypothalamopituitary axis.

(13) LH/FSH-Androgens. The unbalanced LH/FSH ratio results in the reduction of the FSHinduced aromatase activity aggravating the androgen excess. LH receptor. ATP. CHOLESTEROL C AMP. +. THECA CELL. ANDROSTENEDIONE blood circulation basament membrane ANDROSTENEDIONE. + ATP. C AMP. ESTROGENS. FSH receptor. follicular fluid. GRANULOSA CELL.

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(15) Mineralocorticoides. Glucocorticoids. PCOS. Side chain clivage enzyme. 17α-hydroxylase. 17-20 lyase. 3β-hydroxysteroiddehydrogenase.

(16) Theca cells steroidogenesis in PCOS. Ovarian hyperandrogenism in PCOS . is attributed to an intrinsic defect . Cholesterol. of steroidogenesis, . 5 steroids. …amplified by . the elevated level of LH and insulin. 4 steroids. and by the reduction of SHBG with . consequent increase of the free steroids . concentrations.

(17) In PCOS accellerated early follicle growth, mainly linked to hyperandrogenism,. leads to small follicle excess with a consequent . increase of AMH which interfere with follicle FSH . responsiveness.. The reduced FSH responsiveness and premature . luteinisation of granulosa cells interfere with the . selection of the dominant follicle and induce a . follicular growth arrest. Follicle growth. +. androgens. Follicle excess. +. FSH. -. AMH. Overexpression of LH receptors. In granulosa cells of < 5 mm follicles. premature . luteinisation of granulosa . Follicular arrest.

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(19) Mean (± standard error) insulin sensitivity (Si) as determined by the modified rapid intravenous glucose tolerance test and 24-hour mean insulin levels in lean and obese women with polycystic ovary syndrome (LPCO, OPCO) and their respective controls Yen & Jaffe's Reproductive Endocrinology (Sixth Edition), 2009, 489–516.

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(21) Insulin. • Insulin seems to have a synergistic action with LH in stimulating the androgen production by PCOS theca cells . Poretsky L Endocrine Rev 1999. • Insulin stimulate in vitro the 17αhydroxylase/17-20 lyase activity.

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(23) Anti-Mullerian Hormone. protein produced by the granulosa cells and growing follicles. AMH (ng/ml) 4. In women AMH serum levels can be almost undetectable at birth, with a little increase noted after puberty. A continuous reduction in AMH levels is seen till the menopause. 3. 2. AMH (ng/ml) 4. 1. 3 0 5. 10 15 20 25 30 35 40 45 50 55 60. 2. Age (years). Serum AMH levels have been measured at different times during the menstrual cycle, suggesting minimal fluctuation. This be consistent with continuous noncyclic growth of small follicles. 1. 0 EFP Ov LP Menstrual cycle.

(24) Anti-Mullerian Hormone actions in the ovary Ø Inhibition of follicular activation and growth. Ø Inhibition of FSH stimulated growth. Ø Inhibition of granulosa cells growth. FSH. FSH. Ø Inhibition of aromatase . Ø Inhibition of LH receptor expression. -. -. Primordial Antral. AMH. Primary. Preantral.

(25) AMH as a marker of ovarian reserve in ageing women. Recent studies indicate AMH as a novel measure of ovarian reserve AMH (ng/ml) 2. AMH (ng/ml) 4. 3. 2. 1. r : - 0.578. 1. p<0.05. 0. 0. 35 before. after surgery. Ovariectomy in regularly cycling women is associated to disappearance of AMH in 3-5 days, demonstrating that circulating AMH is exclusively of ovarian origin. 40. 45 Age (years). 50. 55. Serum AMH levels show a progressive decrease with age, which correlates with antral follicle counts. La Marca A, J Soc Gynecol Investig. 2005.

(26) AMH as a marker of ovarian reserve in patients undergoing ART. 16. Inhibin B. 150. 14. 130 110. AFC. *. 12. 90. 10. 70. 8. 50. 6. 30. 4. 10. *. 2. -10 Normal. 0. Poor. Normal. FSH. 12. *. 10 8 6 4 2 0 Normal. Poor. 2 1,8 1,6 1,4 1,2 1 0,8 0,6 0,4 0,2 0. Poor. AMH Normal Poor. * Normal. Poor. AMH serum levels were lower in the poor responders than in normal responding women. Logistic regression analysis in predictive models of poor or normal response showed that both antral follicle count and AMH serum levels were equally important for prediction. van Rooij IA, Hum Reprod. 2002.

(27) Serum AMH as markers of ovarian function. ü marker of ovarian reserve in aging women. ü marker of ovarian reserve in women undergoing ART ü possible marker of ovarian dysfunction.

(28) AMH and PCOS. • AMH may favorize the hyperandrogenic status by. inhibiting the FSH activity on granulosa cells or . by suppression of aromatase activity . Pigny P JCEM 2003. • Paracrine and autocrine actions of AMH on androgens . production could be mediated by the AMH receptors . detected on the theca cells of maturing follicle. Ingraham HA 2000.

(29) Inhibins and the hypothalamus-pituitary-ovarian axis 124 aa. 116 aa. α subunit. βA subunit. 115 aa βB subunit. α -SS-SS-. GnRH. hypothalamus. + inhibin A. βA. pituitary. LH/ FSH ovary. -SS-SS-. α βB. + inhibin B. Inhibin A Inhibin B.

(30) Serum inhibin A and inhibin B throughout the menstrual cycle. ü inhibin A is secreted mainly by the corpus luteum. ü inhibin B is secreted by antral follicles in response to FSH. ü involved in the negative feedback on FSH secretion during luteal-follicular transition. ü inhibin B is the major marker of follicular growth Groome et al., JCE&M 1996.

(31) Serum inhibin A and inhibin B as markers of ovarian function. Inhibin A ü marker of luteal activity. Inhibin B ü marker of follicular development.

(32) Serum inhibin B correlates with successful ovulation in infertile women. Inhibin B and estradiol levels are significantly increase in serum and follicular fluid of women who responder and are correlate to the follicle size. Inhibin B is a marker of follicular development and may proposed as an effective additive marker for ovarian follicular capacity Luisi et al., J Ass Reprod Genet 2003.

(33) Serum inhibin B and PCOS. healthy controls. PCOS women. laparoscopic ovarian diathermy. a large cohort of small follicles may secrete high levels of inhibin B and perpetuate the ‘vicious cycle’ of inadequate follicular development and dysovulation. Lockwood et al. JCE&M 1998.

(34) Serum inhibin A, inhibin B and PCOS healthy controls from day 3, daily FSH (75-127.5 IU i.m.). anovulatory PCOS treated PCOS. when single follicle >16 mm, hCG i.m. (5000 IU. Anderson et al.. Clin Endocrinol 1998. normal. induced. during ovulation induction. without. with secondary follicle from 10-16 mm.

(35) Serum inhibin A, inhibin B and PCOS Absent biologically relevant associations between serum inhibin B concentrations and characteristics of polycystic ovary syndrome in normogonadotrophic anovulatory infertility Inhibin B serum concentrations are normal in most normogonadotrophic anovulatory women with PCOS; serum inhibin B assay cannot be recommended in for routine screening in normogonadotrophic anovulatory infertility Laven et al. Hum Reprod, 2001. Do basal inhibin A and inhibin B levels have value in the diagnosis of polycystic ovary syndrome? There was no significant difference in mean basal inhibin A or inhibin B levels between the two groups (control VS PCOS). Basal inhibin A or B levels cannot be used in the diagnosis of PCOS Torgac et al. Gynecol Endocrinol. 2005.

(36) Serum total inhibin and PCOS A. B *. *. 1000. Inhibin A (pg/ml). Total Inhibin (pg/ml). 1000 300. 200. 100. 100. *. Overweight. Lean. 10. 0. 1. Control. Overweight. Lean. Control. PCOS. PCOS. C. D. 200. 120. 150. # 100. 50. Inhibin B (pg/ml). Inhibin B (pg/ml). *. Control PCOS-Overweight PCOS-Lean. 100 80 60 40 20 0. 0. Control. Overweight. PCOS. Lean. 0. 50. 100 150 200 250 300 350 400. Total Inhibin (pg/ml). PCOS women have high serum concentration of total inhibin but not of inhibin A or B PCOS women may have an impaired processing of Fert Steril. 2007 α-inhibin precursor proteins.

(37) conclusions. Endocrine. • Increased androgens. • High LH. • Low FSH . • High AMH. • High Insulin. • High total inhibin. • Low SHBG. Methabolic. • Lipids and glucose dismethabolism. • Hypertension. • High PCR. • High homocysteine. • Obesity. • High cardiovascular risk. • High risk for diabetes.

(38) LH. FSH. estradiol. AMH. androgens. hyperinsulinemia. insulin resistance. obesity. dyslipidemia.

(39) Thanks.

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