Synthesis of sex steroids

Transcription

1 Synthesis of sex steroids CH 3 NAD(P)H NAD(P)+ Dehidroepiandroszteron Androszténdion 17- -hidroxiszteroid dehidrogenáz CH 3 dehydroepiandrosterone Dehidroepiandroszteron (DHEA) 3SDH Koleszterin CH 3 aromatase CH 3 Petefészek -Stratum Petefészek granulosum -Stratum granulosum 4 -Androsztén-3,17-dion Koleszterin androstenedione 17SDH Androszténdion Androszténdion Tesztoszteron Tesztoszteron androstenediol 5 -Androszténdiol Tesztoszteron Aromatáz Aromatáz 5 -reduktáz NADPH 5 reductase Tesztoszteron H Dihidrotesztoszteron (DHT) 5 dihydro Ösztron (E1) Ösztron (E1) estrone (C18) Ösztradiol (E2) Ösztradiol (E2) estradiol (C18)

2 Koleszterin Androszténdion 17-hydroxysteroid Koleszterin dehydrogenase enzymes 17SDH-I 17SDH-III Petefészek Petefészek -Stratum -Stratum granulosum granulosum Ösztron (E1) Ösztron (E1) Ösztriol estrone androstenedione 17SDH-II estradiol Ösztriol Androszténdion Tesztoszteron Tesztoszteron Aromatáz Aromatáz NADPH+H + NADPH+H + NADP + NADP + Ösztradiol (E2) Ösztradiol (E2) estrone estradiol reductase in cytosol placenta, ovaries, adipose tissue reductase in ER testis androstenedione oxidation=inactivation NAD + NADH+H + in ER liver, intestine, placenta

3 Testis, Leydig cell - P450c17 (17-hydroxylase/17,20 lyase) - 17-hydroxysteroid dehydrogenase : NAD(P)H, not a cytochrome P450! - N P cholesterol ester LH, hcg receptor cholesterol camp cholesterol P450 scc pregnenolone pregnenolone mitochondrium inner membrane progesterone 3SDH P pregnenolone 17 progesterone DHEA 17SDH androstenedione ER surface androstenediol

4 5 reductase NADPH + H + NADP + 5 reductase dihydro in target cells, on ER surface T,DHT induce its synthesis androgen effects testis spermatogenesis psychosexual identity protein synthesis in the muscle male voice male-type hair growth male external organs development and function of the prostate male-type hair growth male-type baldness - more efficient (binds to A receptor with higher affinity, DHT- A receptor complex is a better inducer) - no way back to estrogens

5 5 reductase deficiency (pseudohermaphroditismus masculinus) XY, testis normal plasma T, but DHT, T/DHT ratio female or mixed external sex organs the newborn is considered as a girl pubertal virilization diagnosis

6 Regulation of synthesis Long-acting GnRH analogues Pulsatile secretion Hypothalamus GnRH 10AAs, t 1/2 =2-5 min Adenohypophysis FSH LH Biol. effects inhibin A receptor antagonists Sertoli cell AR spermatogenesis Leydig cell dihydro P450c17 inhibitors 5 reductase inhibitors

7 Prostate cancer 1966 Nobel prize for castration therapy : practically androgen withdrawal If receptor-positive: hormone-therapy -Inhibit steroid biosynthesis -receptor antagonist BUT: androgen antagonist therapy favors androgenindependent tumor growth

8 Aromatase reaction localization: ser estradiol (C18) varies (granulosa cells), Placenta, adipose tissue, bones C19 ase X 2, H 2 leaves spontaneously

9 varies Two-cell theory theca interna interstitial cells - P450c17 (17-hydroxylase/17,20 lyase) - N P450c21, 17hydroxysteroid dehydrogenase, aromatase cholesterol cholesterol P P450 scc pregnenolone progesterone pregnenolone P450 scc cholesterol diffusion pregnenolone progesterone progesterone 3SDH pregnenolone 3SDH 17 pregnenolone 17 progesterone androstenedione aromatase estrone 17SDH DHEA androstenedione estradiol LDL-cholesterol, from plasma in luteal phase, after vascularization granulosa cell - 17hydroxysteroid dehydrogenase, aromatase - N P450c17, P450c21 Substrate dependent

10 varies: follicular phase Theca interna cells - 17-hydroxylase/17,20 liase - N 21-hydroxylase, 17- hydroxysteroid dehydrogenase, aromatase Cholesterol Androstenedione LH stimulates Granulosa cells - 17-hydroxysteroid dehydrogenase, aromatase - N 17-hydroxylase/17,20 liase, 21-hydroxylase: Substrate dependent! Androstenedione Estradiol FSH stimulates

11 Corpus luteum: LH surge differentiation in lutein cells Lutein cells 17 hydroxylase/17,20-liase Cholesterol progesterone, Less androgens aromatase vascularization cholesterol source Cholesterol progesterone, Less estrogens from less androgens

12 SERM: Selective Estrogen Receptor Modulator Interactions with ER conformational change Can be both agonists and antagonist Tissue-specific interactions with co-activators/co-repressors History: 1960s : clomifene ( E antagonist ) 1986: ERalpha cloned tamoxifen, raloxifen synthetic SERMs 2007: naturally occurring SERMs (27--chol)

13 Tamoxifen: agonist in bones (prevents osteoporosis) antagonist in breast tissue (breast cancer therapy) cancer pitfall: partial agonist in endometrium increases risk for endometrial

14 Placenta like the granulosa cell P450 scc 3SDH cholesterol pregnenolone progesterone fetal adrenal cortex + liver DHEAS sulfatase DHEA 17SDH androstenediol 16-DHEA 3SDH maternal/fetal adrenal cortex z.reticularis androstenedione aromatase estrone estradiol estriol In the absence of SF-1 (steroidogenic factor-1, a TF), placenta lacks several enzymes for de novo synthesis of steroid hormones (CYP45017) Placental steroid synthesis is dependent on fetal and maternal precursors

15 Inactivation of maternal steroids in the placenta 17SDH-II mother androstenedione oxidation=inactivation NAD + NADH+H + ER estradiol estrone vascular endothelial cells 11SDH2 mother cortisol cortisone NAD + NADH+H + oxidation=inactivation syncytiotrophoblast

16 Regulation of female sex steroid hormone synthesis diagnosis GnRH test Hypothalamus GnRH Adenohypophysis vulation induction clomifene GnRH gonadotropin test (FSH+LH) FSH ovaries LH FSH+LH E, P test E E/P oocyte uterus, endometrium proliferation secretion implantation menstruation