Cross‐Sex Hormone Therapy in Trans Persons Is Safe and Effective at Short‐Time Follow‐Up: Results from the European Network for the Investigation of Gender Incongruence



      Data on the effects of cross‐sex hormone therapy (CHT) are limited due to the low prevalence of gender dysphoria, small number of subjects treated at each center, lack of prospective studies, and wide variations in treatment modalities.


      The aim of this study is to report the short‐term effects of CHT on hormonal and clinical changes, side effects, and adverse events in trans men (female‐to‐male gender dysphoric persons) and trans women (male‐to‐female gender dysphoric persons).


      This was a multicenter 1‐year prospective study in 53 trans men and 53 trans women. Trans men received injections of testosterone undecanoate every 3 months. Trans women younger than 45 years received 50 mg cyproterone acetate (CA) and 4 mg estradiol valerate daily, whereas those older than 45 years received 50 mg CA daily together with 100 μg/24 hours transdermal 17‐β estradiol.

      Main Outcome Measures

      Sex steroids, prolactin, liver enzymes, lipids, hematocrit, blood pressure, anthropometrics, Ferriman and Gallwey score, and global acne grading scale were measured. Side effects, adverse events, and desired clinical changes were examined.


      No deaths or severe adverse events were observed. Two trans men developed erythrocytosis, and two had transient elevation of the liver enzymes. Trans men reported an increase in sexual desire, voice instability, and clitoral pain (all P ≤ 0.01). Testosterone therapy increased acne scores, facial and body hair, and prevalence of androgenetic alopecia. Waist–hip ratio, muscle mass, triglycerides, total cholesterol (C), and LDL‐C increased, whereas total body fat mass and HDL‐C decreased. Three trans women experienced transient elevation of liver enzymes. A significant increase in breast tenderness, hot flashes, emotionality, and low sex drive was observed (all P ≤ 0.02). Fasting insulin, total body fat mass, and prolactin levels increased, and waist–hip ratio, lean mass, total C, and LDL‐C decreased.


      Current treatment modalities were effective and carried a low risk for side effects and adverse events at short‐time follow‐up. Wierckx K, Van Caenegem E, Schreiner T, Haraldsen I, Fisher A, Toye K, Kaufman JM, and T'Sjoen G. Cross‐sex hormone therapy in trans persons is safe and effective at short‐time follow‐up: Results from the European Network for the Investigation of Gender Incongruence. J Sex Med 2014;11:1999–2011.


      To read this article in full you will need to make a payment
      ISSM Member Login
      Login with your ISSM username and password.
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Hembree W.C.
        • Cohen‐Kettenis P.
        • Delemarre‐van de Waal H.A.
        • Gooren L.J.
        • Meyer III, W.J.
        • Spack N.P.
        • Tangpricha V.
        • Montori V.M.
        Endocrine treatment of trans persons: An Endocrine Society clinical practice guideline.
        J Clin Endocrinol Metab. 2009; 94: 3132-3154
        • Gooren L.
        Care of transsexual persons.
        N Engl J Med. 2011; 364: 1251-1257
        • Moore E.
        • Wisniewski A.
        • Dobs A.
        Endocrine treatment of trans people. A review of treatment regimes, outcomes and adverse effects.
        J Clin Endocrinol Metab. 2003; 88: 3467-3473
        • Gooren L.J.
        • Giltay E.J.
        • Bunck M.C.
        Long‐term treatment of transsexuals with cross‐sex hormones: Extensive personal experience.
        J Clin Endocrinol Metab. 2008; 93: 19-25
        • Wierckx K.
        • Mueller S.
        • Weyers S.
        • Van Caenegem E.
        • Roef G.
        • Heylens G.
        • T'Sjoen G.
        A long‐term evaluation of cross‐sex hormone treatment in transsexual persons.
        J Sex Med. 2012; 9: 2641-2651
        • Schlatterer K.
        • Yassouridis A.
        • von Werder K.
        • Poland D.
        • Kemper J.
        • Stalla G.
        A follow‐up study for estimating the effectiveness of a cross‐gender hormone substitution therapy on transsexual patients.
        Arch Sex Behav. 1998; 27: 475-492
        • Prior J.
        • Vigna Y.
        • Watson D.
        Spironolactone with physiological female steroids for presurgical therapy of male‐to‐female transsexualism.
        Arch Sex Behav. 1989; 18: 49-57
        • Tangpricha V.
        • Ducharme S.H.
        • Barber T.W.
        • Chipkin S.R.
        Endocrinologic treatment of gender identity disorders.
        Endocr Pract. 2003; 9: 12-21
        • Seal L.J.
        • Franklin S.
        • Richards C.
        • Shishkareva A.
        • Sinclaire S.
        • Barret J.
        Predictive markers for mammoplasty and a comparison of side effect profiles in trans women taking various hormonal regimens.
        J Clin Endocrinol Metab. 2012; 97: 4422-4428
        • Dittrich R.
        • Binder H.
        • Cupisti S.
        • Hoffmann I.
        • Beckmann M.W.
        • Mueller A.
        Endocrine treatment of male‐to‐female transsexuals using gonadotropin‐releasing hormone agonist.
        Exp Clin Endocrinol Diabetes. 2005; 113: 586-592
        • Asscheman H.
        • Giltay E.J.
        • Megens J.A.
        • de Ronde W.P.
        • van Trotsenburg M.A.
        • Gooren L.J.
        A long‐term follow‐up study of mortality in transsexuals receiving treatment with cross‐sex hormones.
        Eur J Endocrinol. 2011; 164: 635-642
        • Kreukels B.P.
        • Haraldsen I.R.
        • Richter‐Appelt H.
        • Gijs L.
        • Cohen‐Kettenis P.
        A European network for the investigation of gender incongruence: The ENIGI initiative.
        Eur Psychiatry. 2012; 27: 445-450
        • Dreno B.
        • Khammari A.
        • Orain N.
        • Noray C.
        • Mérial‐Kieny C.
        • Méry S.
        • Nocera T.
        ECCA grading scale: An original validated acne scar grading scale for clinical practice in dermatology.
        Dermatology. 2007; 214: 46-51
        • Ferriman D.
        • Gallwey J.
        Clinical assessment of body hair growth in women.
        Clin Endocrinol Metab. 1966; 21: 1440-1447
        • Norwood O.T.
        Male pattern baldness: Classification and incidence.
        South Med J. 1975; 68: 1359-1365
        • Fiers T.
        • Casetta B.
        • Bernaert B.
        • Vandersypt E.
        • Debock M.
        • Kaufman J.M.
        Development of highly sensitive method for the quantification of estrone and estradiol in serum by liquid chromatography tandem mass spectrometry without derivatization.
        J Chromatogr B Analyt Technol Biomed Life Sci. 2012; 893: 57-62
        • Van Kesteren P.J.
        • Asscheman H.
        • Megens J.A.
        • Gooren L.J.
        Mortality and morbidity in trans subjects treated with cross‐sex hormones.
        Clin Endocrinol. 1997; 47: 337-342
        • Mueller A.
        • Kiesewetter F.
        • Binder H.
        • Beckmann M.W.
        • Dittrich R.
        Long‐term administration of testosterone undecanoate every 3 months for testosterone supplementation in female‐to‐male transsexuals.
        J Clin Endocrinol Metab. 2007; 92: 3470-3475
        • Asscheman H.
        • Gooren L.J.G.
        • Eklund P.L.
        Mortality and morbidity in trans patients with cross‐gender treatment.
        Metabolism. 1989; 38: 869-873
        • Toorians A.W.
        • Thomassen M.C.
        • Zweegman S.
        • Magdeleyns E.J.
        • Tans G.
        • Gooren L.J.
        • Rosing J.
        Venous thrombosis and changes of hemostatic variables during cross‐sex treatment in transsexual people.
        J Clin Endocrinol Metab. 2003; 88: 5723-5729
        • Elbers J.M.
        • Giltay E.J.
        • Teerlink T.
        • Scheffer P.G.
        • Asscheman H.
        • Seidell J.C.
        • Gooren L.J.
        Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects.
        Clin Endocrinol. 2003; 58: 562-571
        • Giltay E.J.
        • Lambert J.
        • Gooren L.J.
        • Elbers J.M.
        • Steyn M.
        • Stehouwer C.D.
        Sex steroids, insulin, and arterial stiffness in women and men.
        Hypertension. 1999; 34: 590-597
        • Gómez‐Gil E.
        • Zubiaurre‐Elorza L.
        • Esteva I.
        • Guillamon A.
        • Godás T.
        • Cruz Almaraz M.
        • Halperin I.
        • Salamero M.
        Hormone‐treated transsexuals report less social distress, anxiety and depression.
        Psychoneuroendocrinology. 2012; 37: 662-670
        • Mueller A.
        • Binder H.
        • Cupisti S.
        • Hoffmabb I.
        • Beckmann M.W.
        • Dittirch R.
        Effects on the male endocrine system of long‐term treatment with gonadotropin‐releasing hormone agonists and estrogens in male‐to‐female transsexuals.
        Horm Metab Res. 2006; 38: 183-187
        • Gooren L.J.
        • Harmsen‐louman W.
        • Van Kessel H.
        Follow‐up of prolactin levels in long‐term oestrogen‐treated male‐to‐female transsexuals with regard to prolactinoma induction.
        Clin Endocrinol. 1985; 22: 201-207
        • Asscheman H.
        • Gooren L.J.
        • Assies J.
        • Smits J.P.H.
        • De Slegte R.
        Prolactin levels and pituitary enlargement in hormone‐treated male‐to‐female transsexuals.
        Clin Endocrinol. 1988; 25: 583-588
        • Gooren L.
        • Van Der Veen E.A.
        • Kessel H.
        Modulation of prolactin secretion by gonadal steroids in men.
        in: McLeod R/M. Scampagmani U. Central and peripheral regulation of prolactin function. Raven Press, New York1980: 365-369
        • Schlatterer K.
        • Yassouridis A.
        • von Werder K.
        • Poland D.
        • Kemper J.
        • Stalla G.K.
        A follow‐up study for estimating the effectiveness of a cross‐gender hormone substitution therapy on transsexual patients.
        Arch Sex Behav. 1988; 27: 475-492
        • De Cuypere G.
        • T'Sjoen G.
        • Beerten R.
        • Selvaggi G.
        • De Sutter P.
        • Hoebeke P.
        • Monstrey S.
        • Vansteenwegen A.
        • Rubens R.
        Sexual and physical health after sex reassignment surgery.
        Arch Sex Behav. 2005; 34: 679-690
        • Wierckx K.
        • Elaut E.
        • Declerq E.
        • Heylens G.
        • Decuypere G.
        • Taes Y.
        • Kaufman J.M.
        • T'sjoen G.R.
        Prevalence of cardiovascular disease and cancer during CHT in a large cohort of trans persons: A case control study.
        Eur J Endocrinol. 2013; 169: 471-478
        • Dhejne C.
        • Lichtenstein P.
        • Boman M.
        • Johansson A.
        • Langström N.
        • Landén M.
        Long‐term follow‐up of transsexuals' persons undegoing sex reassignment surgery: Cohort study in Sweden.
        PLoS ONE. 2011; 6: e16885
        • Polderman K.H.
        • Gooren L.J.
        • Asscheman H.
        • Bakker A.
        • Heine R.J.
        Induction of insulin resistance by androgens and estrogens.
        J Clin Endocrinol Metab. 1994; 79: 265-271
        • Wang X.
        • Magkos F.
        • Mittendorfer B.
        Sex differences in lipid and lipoprotein metabolism: It's not just about sex hormones.
        J Clin Endocrinol Metab. 2011; 96: 885-893
        • Yialamas M.A.
        • Dwyer A.A.
        • Hanley E.
        • Lee H.
        • Pitteloud N.
        • Hayes F.J.
        Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism.
        J Clin Endocrinol Metab. 2007; 92: 4254-4259
        • Mauvais‐Jarvis F.
        • Clegg D.J.
        • Hevener A.L.
        The role of estrogens in control of energy balance and glucose homeostasis.
        Endocr Rev. 2013; 34: 309-338
        • Ågren U.M.
        • Anttila M.
        • Mäenpää‐Liukko K.
        • Rantala M.L.
        • Rautiainen H.
        • Sommer W.F.
        • Mommers E.
        Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β‐oestradiol compared with one containing levonorgestrel and ethinylestradiol on haemostasis, lipids and carbohydrate metabolism.
        Eur J Contracept Reprod Health Care. 2011; 16: 444-457
        • Mashchak C.A.
        • Lobo R.A.
        • Dozono‐Takano R.
        • Eggena P.
        • Nakamura R.M.
        • Brenner P.F.
        • Mishell Jr, D.R.
        Comparison of pharmacodynamic properties of various estrogen formulations.
        Am J Obstet Gynecol. 1982; 144: 511-518
        • Giltay E.J.
        • Gooren L.J.
        • Emeis J.J.
        • Kooistra T.
        • Stehouwer C.D.
        Oral ethinyl estradiol, but not transdermal 17beta‐estradiol, increases plasma C‐reactive protein levels in men.
        Thromb Haemost. 2000; 84: 359-360
        • Giltay E.J.
        • Gooren L.J.
        • Emeis J.J.
        • Kooistra T.
        • Stehouwer C.D.
        Oral, but not transdermal, administration of estrogens lowers tissue‐type plasminogen activator levels in humans without affecting endothelial synthesis.
        Arterioscler Thromb Vasc Biol. 2000; 20: 1396-1403
        • Scott Jr, R.T.
        • Ross B.
        • Anderson C.
        • Archer D.F.
        Pharmacokinetics of percutaneous estradiol: A crossover study using a gel and a transdermal system in comparison with oral micronized estradiol.
        Obstet Gynecol. 1991; 77: 758-764
        • Giltay E.J.
        • Elbers J.M.
        • Gooren L.J.
        • Emeis J.J.
        • Kooistra T.
        • Stehouwer C.D.
        Visceral fat accumulation is an important determinant of PAI‐levels in young, non‐obese men and women: Modulation by cross‐sex hormone administration.
        Arterioscler Thromb Vasc Biol. 1998; 18: 1719-1722
        • Van Caenegem E.
        • Wierckx K.
        • Taes Y.
        • Dedecker D.
        • Van de peer F.
        • Toye K.
        • Kaufman J.M.
        • T'sjoen G.
        Bone mass, bone geometry, and body composition in female‐to‐male transsexual persons after long‐term cross‐sex hormonal therapy.
        J Clin Endocrinol Metab. 2012; 97: 2503-2511
        • Wierckx K.
        • Elaut E.
        • Declercq E.
        • Heylens G.
        • De Cuypere G.
        • Taes Y.
        • Kaufman J.M.
        • T'Sjoen G.
        Prevalence of cardiovascular disease and cancer during cross‐sex hormone therapy in a large cohort of trans persons: A case‐control study.
        Eur J Endocrinol. 2013; 169: 471-478

      Linked Article

      • Erratum
        The Journal of Sexual MedicineVol. 13Issue 4
        • Preview
          In the article entitled “Cross-sex hormone therapy in trans persons is safe and effective at short-time follow-up: results from the European Network for the Investigation of Gender Incongruence” by Wierckx et al (J Sex Med 2014;11:1999–2011), there was an error in an author listing. The correct listing should be Alessandra D. Fisher.
        • Full-Text
        • PDF