The Role of Progesterone Metabolism and Androgen Synthesis in Renal Blood Pressure Regulation

 

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Abstract

11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) plays a crucial role in converting hormonally active cortisol into inactive cortisone, conferring specificity onto the human mineralocorticoid receptor (MR). Progesterone binds with even higher affinity to the MR, but acts as an MR antagonist. How aldosterone is able to keep its function as predominant MR ligand in clinical situations with high progesterone concentrations, such as pregnancy, is not clear. We have shown in vitro that the human kidney possesses an effective enzyme system that metabolizes progesterone to inactive metabolites in a process similar to the inactivation of cortisol by 11β-HSD2. In studies on patients with adrenal insufficiency, we have shown that the in vivo anti-mineralocorticoid activity of progesterone is diminished by inactivating metabolism of progesterone, local formation of the deoxycorticosterone mineralocorticoid from progesterone, and inhibition of 11β-HSD2 by progesterone and its metabolites resulting in decreased inactivation of cortisol and hence increased MR binding by cortisol. The enzymes involved in progesterone metabolism are also responsible for the capability of the human kidney to convert pregnenolone to DHEA and androstenedione leading to the formation of active androgens, testosterone and 5α-DH-testosterone. Locally produced androgens might be responsible for the observed difference in blood pressure between men and women and higher susceptibility to hypertension in men.

References

• 1 Stockand J D. New ideas about aldosterone signaling in epithelia.  Am J Physiol Renal Physiol. 2002;  282 F559-F576
  PubMedGoogle Scholar
• 2 Arriza J L, Weinberger C, Cerelli G, Glaser T M, Handelin B L, Housman D E, Evans R M. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor.  Science. 1987;  237 268-275
  CrossrefPubMedGoogle Scholar
• 3 Funder J W, Pearce P T, Smith R, Smith A I. Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated.  Science. 1988;  242 583-585
  CrossrefPubMedGoogle Scholar
• 4 Edwards C R, Stewart P M, Burt D, Brett L, McIntyre M A, Sutanto W S, de Kloet E R, Monder C. Localisation of 11 beta-hydroxysteroid dehydrogenase-tissue specific protector of the mineralocorticoid receptor.  Lancet. 1988;  2 986-989
  PubMedGoogle Scholar
• 5 Quinkler M, Oelkers W, Diederich S. Clinical implications of glucocorticoid metabolism by 11beta-hydroxysteroid dehydrogenases in target tissues.  Eur J Endocrinol. 2001;  144 87-97
  CrossrefPubMedGoogle Scholar
• 6 Walker E A, Stewart P M. 11beta-hydroxysteroid dehydrogenase: unexpected connections.  Trends Endocrinol Metab. 2003;  14 334-339
  PubMedGoogle Scholar
• 7 New M I, Levine L S, Biglieri E G, Pareira J, Ulick S. Evidence for an unidentified steroid in a child with apparent mineralocorticoid hypertension.  J Clin Endocrinol Metab. 1977;  44 924-933
  CrossrefPubMedGoogle Scholar
• 8 Werder E, Zachmann M, Vollmin J A, Veyrat R, Prader A. Unusual steroid excretion in a child with low renin hypertension.  Research in steroids. 1974;  6 385-389
  PubMedGoogle Scholar
• 9 Stewart P M, Corrie J E, Shackleton C H, Edwards C R. Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle.  J Clin Invest. 1988;  82 340-349
  CrossrefPubMedGoogle Scholar
• 10 Stewart P M, Krozowski Z. 11beta-hydroxysteroid dehydrogenase.  Vitamins and Hormones. 1999;  57 249-324
  PubMedGoogle Scholar
• 11 Quinkler M, Stewart P M. Hypertension and the cortisol-cortisone shuttle.  J Clin Endocrinol Metab. 2003;  88 2384-2392
  CrossrefPubMedGoogle Scholar
• 12 Oelkers W K. Effects of estrogens and progestogens on the renin-aldosterone system and blood pressure.  Steroids. 1996;  61 166-171
  CrossrefPubMedGoogle Scholar
• 13 Murakami T, Watanabe Ogura E, Tanaka Y, Yamamoto M. High blood pressure lowered by pregnancy.  Lancet. 2000;  356 1980
  CrossrefPubMedGoogle Scholar
• 14 Rupprecht R, Reul J M, van Steensel B, Spengler D, Soder M, Berning B, Holsboer F, Damm K. Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands.  Eur J Pharmacol. 1993;  247 145-154
  PubMedGoogle Scholar
• 15 Souque A, Fagart J, Couette B, Davioud E, Sobrio F, Marquet A, Rafestin Oblin ME. The mineralocorticoid activity of progesterone derivatives depends on the nature of the C18 substituent.  Endocrinology. 1995;  136 5651-5658
  CrossrefPubMedGoogle Scholar
• 16 Johansson E D, Jonasson L E. Progesterone levels in amniotic fluid and plasma from women. I. Levels during normal pregnancy.  Acta Obstet Gynecol Scand. 1971;  50 339-343
  PubMedGoogle Scholar
• 17 Rosenthal H E, Slaunwhite W R , Sandberg A A. Transcortin: a corticosteroid-binding protein of plasma. X. Cortisol and progesterone interplay and unbound levels of these steroids in pregnancy.  J Clin Endocrinol Metab. 1969;  29 352-367
  PubMedGoogle Scholar
• 18 Nolten W E, Lindheimer M D, Oparil S, Ehrlich E N. Desoxycorticosterone in normal pregnancy. I. Sequential studies of the secretory patterns of desoxycorticosterone, aldosterone, and cortisol.  Am J Obstet Gynecol. 1978;  132 414-420
  PubMedGoogle Scholar
• 19 Quinkler M, Johanssen S, Grossmann C, Bähr V, Müller M, Oelkers W, Diederich S. Progesterone metabolism in the human kidney and inhibition of 11beta-hydroxysteroid dehydrogenase type 2 by progesterone and its metabolites.  J Clin Endocr Metabol. 1999;  84 4165-4171
  CrossrefPubMedGoogle Scholar
• 20 Quinkler M, Johanssen S, Bumke-Vogt C, Oelkers W, Bahr V, Diederich S. Enzyme-mediated protection of the mineralocorticoid receptor against progesterone in the human kidney.  Mol Cell Endocrinol. 2001;  171 21-24
  CrossrefPubMedGoogle Scholar
• 21 Quinkler M, Meyer B, Bumke-Vogt C, Grossmann C, Gruber U, Oelkers W, Diederich S, Bahr V. Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor.  Eur J Endocrinol. 2002;  146 789-799
  CrossrefPubMedGoogle Scholar
• 22 Laidlaw J C, Ruse J L, Gornall A G. The influence of estrogen and progesterone on aldosterone excretion.  J Clin Endocr Metabol. 1962;  22 161-171
  PubMedGoogle Scholar
• 23 Landau R L, Bergenstal D M, Lugibihl K, Kascht M E. The metabolic effects of progesterone in man.  J Clin Endocrinol Metab. 1955;  15 1194-1215
  PubMedGoogle Scholar
• 24 Landau R L, Lugibihl K, Bergenstal D M, Dimick D F. The metabolic effects of progesterone in man: Dose response relationships.  J Lab Clin Med. 1957;  50 613-620
  PubMedGoogle Scholar
• 25 Landau R L, Lugibihl K. Inhibition of the sodium-retaining influence of aldosterone by progesterone.  J Clin Endocrinol Metab. 1958;  18 1237-1245
  PubMedGoogle Scholar
• 26 Oparil S, Ehrlich E N, Lindheimer M D. Effect of progesterone on renal sodium handling in man: relation to aldosterone excretion and plasma renin activity.  Clin Sci Mol Med. 1975;  49 139-147
  PubMedGoogle Scholar
• 27 Oelkers W, Schöneshöfer M, Blümel A. Effects of progesterone and four synthetic progestagens on sodium balance and the renin-aldosterone system in man.  J Clin Endocrinol Metab. 1974;  39 882-890
  PubMedGoogle Scholar
• 28 Quinkler M, Meyer B, Oelkers W, Diederich S. Renal inactivation, mineralocorticoid generation, and 11beta-hydroxysteroid dehydrogenase inhibition ameliorate the antimineralocorticoid effect of progesterone in vivo.  J Clin Endocrinol Metab. 2003;  88 3767-3772
  CrossrefPubMedGoogle Scholar
• 29 Burt V L, Whelton P, Roccella E J, Brown C, Cutler J A, Higgins M, Horan M J, Labarthe D. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988 - 1991.  Hypertension. 1995;  25 305-313
  Google Scholar
• 30 Stamler R, Stamler J, Riedlinger W F, Algera G, Roberts R H. Weight and blood pressure. Findings in hypertension screening of 1 million Americans.  JAMA. 1978;  240 1607-1610
  CrossrefPubMedGoogle Scholar
• 31 Bachmann J, Feldmer M, Ganten U, Stock G, Ganten D. Sexual dimorphism of blood pressure: possible role of the renin-angiotensin system.  J Steroid Biochem Mol Biol. 1991;  40 511-515
  CrossrefPubMedGoogle Scholar
• 32 Harshfield G A, Alpert B S, Pulliam D A, Somes G W, Wilson D K. Ambulatory blood pressure recordings in children and adolescents.  Pediatrics. 1994;  94 180-184
  PubMedGoogle Scholar
• 33 August P. Hypertension in men.  J Clin Endocrinol Metab. 1999;  84 3451-3454
  CrossrefPubMedGoogle Scholar
• 34 Reckelhoff J F, Zhang H, Srivastava K, Granger J P. Gender differences in hypertension in spontaneously hypertensive rats: role of androgens and androgen receptor.  Hypertension. 1999;  34 920-923
  PubMedGoogle Scholar
• 35 Reckelhoff J F, Granger J P. Role of androgens in mediating hypertension and renal injury.  Clin Exp Pharmacol Physiol. 1999;  26 127-131
  CrossrefPubMedGoogle Scholar
• 36 Ding Y, Sigmund C D. Androgen-dependent regulation of human angiotensinogen expression in KAP-hAGT transgenic mice.  Am J Physiol Renal Physiol. 2001;  280 F54-60
  PubMedGoogle Scholar
• 37 Wilson C M, McPhaul M J. A and B forms of the androgen receptor are expressed in a variety of human tissues.  Mol Cell Endocrinol. 1996;  120 51-57
  CrossrefPubMedGoogle Scholar
• 38 Pelletier G. Localization of androgen and estrogen receptors in rat and primate tissues.  Histol Histopathol. 2000;  15 1261-1270
  PubMedGoogle Scholar
• 39 Reckelhoff J F, Zhang H, Granger J P. Testosterone exacerbates hypertension and reduces pressure- natriuresis in male spontaneously hypertensive rats.  Hypertension. 1998;  31 435-439
  PubMedGoogle Scholar
• 40 Brignardello E, Gallo M, Aragno M, Manti R, Tamagno E, Danni O, Boccuzzi G. Dehydroepiandrosterone prevents lipid peroxidation and cell growth inhibition induced by high glucose concentration in cultured rat mesangial cells.  J Endocrinol. 2000;  166 401-406
  CrossrefPubMedGoogle Scholar
• 41 Quinkler M, Bumke-Vogt C, Meyer B, Bahr V, Oelkers W, Diederich S. The human kidney is a progesterone-metabolizing and androgen-producing organ.  J Clin Endocrinol Metab. 2003;  88 2803-2809
  CrossrefPubMedGoogle Scholar
• 42 Bumke-Vogt C, Bahr V, Diederich S, Herrmann S M, Anagnostopoulos I, Oelkers W, Quinkler M. Expression of the progesterone receptor and progesterone-metabolising enzymes in the female and male human kidney.  J Endocrinol. 2002;  175 349-364
  CrossrefPubMedGoogle Scholar
• 43 Dunn J F, Nisula B C, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma.  J Clin Endocrinol Metab. 1981;  53 58-68
  CrossrefPubMedGoogle Scholar
• 44 Winkel C A, Simpson E R, Milewich L, MacDonald P C. Deoxycorticosterone biosynthesis in human kidney: potential for formation of a potent mineralocorticosteroid in its site of action.  Proc Natl Acad Sci U S A. 1980;  77 7069-7073
  PubMedGoogle Scholar

Dr. M. Quinkler, M. D.

Division of Medical Sciences · University of Birmingham · Queen Elizabeth Hospital

Edgbaston · Birmingham B15 2TH · UK

Phone: + 44 (121) 414 2764

Fax: + 44 (121) 415 8712

Email: M.O.Quinkler@bham.ac.uk