[en] OBJECTIVES: Combined oral contraceptives (COCs) decrease testosterone (T) levels. This study investigated restoration of T and other androgen concentrations during COC use by 'co-administration' of dehydroepiandrosterone (DHEA). STUDY DESIGN: In this randomized, double-blind, placebo-controlled study in 99 new COC starters (18-35 years old with body mass index range 18-34kg/m(2)), a COC containing 30mcg ethinylestradiol (EE) and 3mg drospirenone (DRSP) was used for 3cycles, followed by 6cycles of the same COC combined with either 50mg/day DHEA or placebo. Total T, albumin, sex hormone-binding globulin (SHBG), DHEA-sulfate (DHEA-S), Delta4-androstenedione (AD), 3alpha-androstanediol glucuronide (ADG) and estradiol (E2) were measured, whereas free T and the free T index (FTI) were calculated. Assessments took place at baseline (no COC use), after the run-in period (COC use alone) and during the treatment period (DHEA or placebo). RESULTS: During COC use alone, androgen levels decreased, especially total T by 62% and free T by 86%, and SHBG increased by 243%. Total T increased with DHEA compared to placebo (change from end of run-in period to end of treatment period - 1.3+/-1.2nmol/L vs. 0.0+/-0.4nmol/L; p<.0001) - and was restored to baseline levels. Free T and the FTI increased significantly (p<.0001), but the free T level was still 53% below baseline levels. DHEA-S, AD and ADG increased significantly to levels above baseline (p<.0001 for each). DHEA had no effect on SHBG, albumin and E2. CONCLUSIONS: An EE/DRSP containing COC strongly suppressed endogenous androgen concentrations in all users. The addition of 50mg DHEA to a COC regimen containing EE/DRSP restored total T to baseline levels, but free T levels were restored by only 47% as most of the T remains bound to SHBG. IMPLICATIONS: When using a COC that increases SHBG considerably, a daily dose of 50mg DHEA is insufficient to normalize free T levels completely.
Disciplines :
Reproductive medicine (gynecology, andrology, obstetrics)
Author, co-author :
Zimmerman, Yvette
Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique
Pintiaux, Axelle ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique
Minon, Jean-Marc
Fauser, B. C. J. M.
Cobey, K.
Coelingh Bennink, H. J. T.
Language :
English
Title :
Restoring testosterone levels by adding dehydroepiandrosterone to a drospirenone containing combined oral contraceptive: I. Endocrine effects.
Publication date :
2015
Journal title :
Contraception
ISSN :
0010-7824
Publisher :
Elsevier, New York, United States - New York
Volume :
91
Issue :
2
Pages :
127-33
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright (c) 2015 Elsevier Inc. All rights reserved.
Y. Zimmerman, M.J. Eijkemans, H.J. Coelingh Bennink, M.A. Blankenstein, and B.C. Fauser The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis Hum Reprod Update 20 2014 76 105
C.M. Coenen, C.M. Thomas, G.F. Borm, J.M. Hollanders, and R. Rolland Changes in androgens during treatment with four low-dose contraceptives Contraception 53 1996 171 176
G. Bachmann, J. Bancroft, G. Braunstein, H. Burger, S. Davis, and L. Dennerstein Female androgen insufficiency: the Princeton consensus statement on definition, classification, and assessment Fertil Steril 77 2002 660 665
A. Traish, A.T. Guay, and R.F. Spark Are the Endocrine Society's Clinical Practice Guidelines on Androgen Therapy in Women misguided? A commentary J Sex Med 4 2007 1223 1234 [discussion 34-5]
M. Gingnell, J. Engman, A. Frick, L. Moby, J. Wikström, and M. Fredrikson Oral contraceptive use changes brain activity and mood in women with previous negative affect on the pill-a double-blinded, placebo-controlled randomized trial of a levonorgestrel-containing combined oral contraceptive Psychoneuroendocrinology 38 2013 1133 1144
B.J. Oddens Women's satisfaction with birth control: a population survey of physical and psychological effects of oral contraceptives, intrauterine devices, condoms, natural family planning, and sterilization among 1466 women Contraception 59 1999 277 286
S.A. Sanders, C.A. Graham, J.L. Bass, and J. Bancroft A prospective study of the effects of oral contraceptives on sexuality and well-being and their relationship to discontinuation Contraception 64 2001 51 58
M. Wallwiener, L.-M. Wallwiener, H. Seeger, A.O. Mueck, S. Zipfel, and J. Bitzer Effects of sex hormones in oral contraceptives on the female sexual function score: a study in German female medical students Contraception 82 2010 155 159
W. Arlt, H.-G. Justl, F. Callies, M. Reincke, D. Hübler, and M. Oettel Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression J Clin Endocrinol Metab 83 1998 1928 1934
S. Legrain, C. Massien, N. Lahlou, M. Roger, B. Debuire, and B. Diquet Dehydroepiandrosterone replacement administration: pharmacokinetic and pharmacodynamic studies in healthy elderly subjects J Clin Endocrinol Metab 85 2000 3208 3217
G.M. Meno-Tetang, R.A. Blum, K.E. Schwartz, and W.J. Jusko Effects of oral prasterone (dehydroepiandrosterone) on single-dose pharmacokinetics of oral prednisone and cortisol suppression in normal women J Clin Pharmacol 41 2001 1195 1205
A.J. Morales, J.J. Nolan, J.C. Nelson, and S.S. Yen Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age J Clin Endocrinol Metab 78 1994 1360 1367
Y. Zimmerman, J.-M. Foidart, A. Pintiaux, J.-M. Minon, B.C.J.M. Fauser, and K. Cobey Restoring testosterone levels by adding dehydroepiandrosterone to a drospirenone containing combined oral contraceptive: II Clinical effects Contraception 91 2015 134 142
D. Mansour Welcome developments in contraception Trends Urol Gynaecol Sex Health 14 2009 4 6
R. Sodergard, T. Backstrom, V. Shanbhag, and H. Carstensen Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature J Steroid Biochem 16 1982 801 810
A. Vermeulen, L. Verdonck, and J.M. Kaufman A critical evaluation of simple methods for the estimation of free testosterone in serum J Clin Endocrinol Metab 84 1999 3666 3672
U.M. Ågren, M. Anttila, K. Mäenpää-Liukko, M.-L. Rantala, H. Rautiainen, and W.F. Sommer Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17beta-oestradiol in comparison to one containing levonorgestrel and ethinylestradiol on markers of endocrine function Eur J Contracept Reprod Health Care 16 2011 458 467
I.J. Duijkers, C. Klipping, P. Grob, and T. Korver Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17 beta-oestradiol on ovarian function in comparison to a monophasic combined oral contraceptive containing drospirenone and ethinylestradiol Eur J Contracept Reprod Health Care 15 2010 314 325
R. Haring, A. Hannemann, U. John, D. Radke, M. Nauck, and H. Wallaschofski Age-specific reference ranges for serum testosterone and androstenedione concentrations in women measured by liquid chromatography-tandem mass spectrometry J Clin Endocrinol Metab 97 2012 408 415
I. Wiegratz, C. Jung-Hoffmann, and H. Kuhl Effect of two oral contraceptives containing ethinylestradiol and gestodene or norgestimate upon androgen parameters and serum binding proteins Contraception 51 1995 341 346
I. Wiegratz, E. Kutschera, J.H. Lee, C. Moore, U. Mellinger, and U.H. Winkler Effect of four different oral contraceptives on various sex hormones and serum-binding globulins Contraception 67 2003 25 32
A.C. Heijboer, Y. Zimmerman, T. de Boer, H. Coelingh Bennink, and M.A. Blankenstein Peculiar observations in measuring testosterone in women treated with oral contraceptives supplemented with dehydroepiandrosterone (DHEA) Clin Chim Acta 430 2014 92 95
L.R. Granger, S. Roy, and D.R. Mishell Jr. Changes in unbound sex steroids and sex hormone binding globulin-binding capacity during oral and vaginal progestogen administration Am J Obstet Gynecol 144 1982 578 584
L. Speroff, and M. Fritz Clinical gynecologic endocrinology and infertility 7th ed. 2005 Lippincott Williams & Wilkins Philadelphia
H.G. Burger Androgen production in women Fertil Steril 77 Suppl. 4 2002 S3 S5
W.M. Groenestege, H.N. Bui, J. ten Kate, P.P.C.A. Menheere, W.P. Oosterhuis, and H.L. Vader Accuracy of first and second generation testosterone assays and improvement through sample extraction Clin Chem 58 2012 1154 1156
J. Taieb, B. Mathian, F. Millot, M.-C. Patricot, E. Mathieu, and N. Queyrel Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women, and children Clin Chem 49 2003 1381 1395
K.K. Miller, W. Rosner, H. Lee, J. Hier, G. Sesmilo, and D. Schoenfeld Measurement of free testosterone in normal women and women with androgen deficiency: comparison of methods J Clin Endocrinol Metab 89 2004 525 533
C.A. Burtis, E.R. Ashwood, and D.E. Bruns Tietz textbook of clinical chemistry and molecular diagnostics 5th ed. 2012 Elsevier St Louis Saunders
S. Rinaldi, A. Geay, H. Déchaud, C. Biessy, A. Zeleniuch-Jacquotte, and A. Akhmedkhanov Validity of free testosterone and free estradiol determinations in serum samples from postmenopausal women by theoretical calculations Cancer Epidemiol Biomarkers Prev 11 2002 1065 1071
K. Carlstrom, R. Karlsson, and B. Von Schoultz Diurnal rhythm and effects of oral contraceptives on serum dehydroepiandrosterone sulfate (DHEAS) are related to alterations in serum albumin rather than to changes in adrenocortical steroid secretion Scand J Clin Lab Invest 62 2002 361 368
G.L. Hammond, M.S. Langley, P.A. Robinson, S. Nummi, and L. Lund Serum steroid binding protein concentrations, distribution of progestogens, and bioavailability of testosterone during treatment with contraceptives containing desogestrel or levonorgestrel Fertil Steril 42 1984 44 51
S. Legrain, and L. Girard Pharmacology and therapeutic effects of dehydroepiandrosterone in older subjects Drugs Aging 20 2003 949 967