Endocrine Treatment of Male-to-Female Transsexuals Using Gonadotropin-Releasing Hormone Agonist

 

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Abstract

In transsexual people, cross-sex hormone therapy is an important component of medical treatment. In male-to-female transsexuals, feminizing effects should be achieved before irreversible sex reassignment surgery (SRS) is considered. The most common treatment regimen in male-to-female transsexuals is a combination of ethinyl oestradiol and cyproterone acetate, with the exception of transdermal oestradiol-17β in individuals over the age of 40. The mortality and morbidity rates with this treatment regimen have been reported in more than 800 patients. Typical side effects include venous thrombosis, elevated liver enzymes, symptomatic gallstones, hyperprolactinaemia and depression. Sixty male-to-female transsexuals were treated with monthly injections of gonadotropin-releasing hormone agonist (GnRHa) and oral oestradiol-17β valerate for 2 years to achieve feminisation until SRS. There was a significant decline in gonadotropins, total testosterone and calculated free testosterone. In general, the treatment regimen was well accepted. An equal increase in breast size was achieved compared to common hormone therapy. Two side effects were documented. One, venous thrombosis, occurred in a patient with a homozygous MTHFR mutation. One patient was found to be suffering from symptomatic preexisting gallstones. No other complications were documented. Liver enzymes, lipids, and prolactin levels were unchanged. Significantly increased oestradiol and SHBG serum levels were detectable. In addition, an increase in bone mass density, in the femoral neck and lumbar spine, was recorded. We conclude that cross-sex hormone treatment of male-to-female transsexuals using GnRHa and oestradiol-17β valerate is effective, and side effects and complication rates can be reduced using the treatment regimen presented here.

References

• 1 Adlercreutz H, Tenhunen R. Some aspects of the interaction between natural and synthetic female sex hormones and the liver.  Am J Med. 1970;  49 630-648
  PubMedGoogle Scholar
• 2 Aedo A R, Landgren B M, Diczfalusy E. Pharmacokinetics and biotransformation of orally administered oestrone sulphate and oestradiol valerate in postmenopausal women.  Maturitas. 1990;  12 333-343
  CrossrefPubMedGoogle Scholar
• 3 Aldinger K, Ben Menachem Y, Whalen G. Focal nodular hyperplasia of the liver associated with high-dosage estrogens.  Arch Intern Med. 1977;  137 357-359
  CrossrefPubMedGoogle Scholar
• 4 Anderson G L, Limacher M, Assaf A R, Bassford T, Beresford S A, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard B V, Hsia J, Hubbell A, Jackson R, Johnson K C, Judd H, Kotchen J M, Kuller L, LaCroix A Z, Lane D, Langer R D, Lasser N, Lewis C E, Manson J, Margolis K, Ockene J, O'Sullivan M J, Phillips L, Prentice R L, Ritenbaugh C, Robbins J, Rossouw J E, Sarto G, Stefanick M L, Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S. Women's Health Initiative Steering Committee . Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.  J Am Med Assoc. 2004;  291 1701-1712
  CrossrefPubMedGoogle Scholar
• 5 Asscheman H, Gooren L, Assies J, Smith J, De Slegte R. Prolactin levels and pituitary enlargement in hormone-treated male to female transsexual people.  Clin Endocrinol (Oxford). 1988;  28 583-588
  PubMedGoogle Scholar
• 6 Asscheman H, Gooren L, Eklund P. Mortality and morbidity in transsexual patients with cross-gender hormone treatment.  Metabolism. 1989;  38 869-873
  CrossrefPubMedGoogle Scholar
• 7 Berrut G, Ghali A, Quere I, Ternisien C, Gallois I, Roy P M, Marre M, Fressinaud P. A common mutation C677 T in the 5,10-methyltetrahydrofolate reductase gene is associated to idiopathic deep venous thrombosis.  Revue de Médecine Interne. 2003;  24 569-576
  PubMedGoogle Scholar
• 8 Cushman M, Kuller L H, Prentice R, Rodabough R J, Psaty B M, Stafford R S, Sidney S, Rosendaal F R. Women's Health Initiative Investigators . Estrogen plus progestin and risk of venous thrombosis.  J Am Med Assoc. 2004;  292 1573-1580
  CrossrefPubMedGoogle Scholar
• 9 den Heijer M. Hyperhomocysteinaemia as a risk factor for venous thrombosis: an update of the current evidence.  Clinical Chemistry and Laboratory Medicine CCLM/FESCC. 2003;  41 1404-1407
  PubMedGoogle Scholar
• 10 Futterweit W. Endocrine management of transsexual: hormonal profiles of serum prolactin, testosterone, and estradiol.  New York State J Medicine. 1980;  80 1260-1264
  PubMedGoogle Scholar
• 11 Gooren L, Assies J, Asscheman H, de Slegte R, van Kessel H. Estrogen-induced prolactinoma in a man.  J Clin Endocrinol Metab. 1988;  66 444-446
  CrossrefPubMedGoogle Scholar
• 12 Hamburger C. Endocrine treatment of male and female transsexualism. Green R, Money J Transsexualism and Sex Reassignment. Baltimore; Johns Hopkins Press 1969: 291-307
  Google Scholar
• 13 Hannaford P, Croft P, Kay C. Oral contraception and stroke.  Stroke. 1994;  25 935-942
  PubMedGoogle Scholar
• 14 Harry Benjamin International Gender Dysphoria Association .The Harry Benjamin International Gender Dysphoria Association standards of care for gender identity disorders. 6th version (November 17th, 2001). http://www.hbigda.org/soc.html. Retrieved 2002. 
  Google Scholar
• 15 Kacar S, Akdogan M, Kosar Y, Parlak E, Sasmaz N, Oguz P, Aydog G. Estrogen and cyproterone acetate combination-induced autoimmune hepatitis.  J Clin Gastroenterol. 2002;  35 98-100
  PubMedGoogle Scholar
• 16 Khosla S, Melton 3rd L J. Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen.  J Clin Endocrinol Metab. 1998;  83 2266-2274
  CrossrefPubMedGoogle Scholar
• 17 Kuhl H. Pharmacology of estradiol and estriol.  Menopause Rev. 2000;  5 23-44
  PubMedGoogle Scholar
• 18 Levy A, Crown A, Reid R. Endocrine intervention for transsexuals.  Clin Endocrinol. 2003;  59 409-418
  CrossrefPubMedGoogle Scholar
• 19 Lin A D, Chen K K, Lin A T, Chang Y H, Wu H H, Kuo J Y, Huang W J, Hsu Y S, Chung H J, Chang L S. Antiandrogen-associated hepatotoxicity in the management of advanced prostate cancer.  J Chinese Med Assoc. 2003;  66 735-740
  PubMedGoogle Scholar
• 20 Meyer W JR, Webb A, Stuart C A, Finkelstein J W, Lawrence B, Walker P A. Physical and hormonal evaluation of transsexual patients: a longitudinal study.  Arch Sexual Behavior. 1986;  15 121-138
  PubMedGoogle Scholar
• 21 Michel A, Mormont C, Legros J. A psycho-endocrinological overview of transsexualism.  Eur J Endocrinol. 2001;  145 365-376
  CrossrefPubMedGoogle Scholar
• 22 Miyaji Y, Saika T, Yamamoto Y, Kusaka N, Arata R, Ebara S, Nasu Y, Tsushima T, Kumon H. Effects of gonadotropin-releasing hormone agonists on bone metabolism markers and bone mineral density in patients with prostate cancer.  Urology. 2004;  64 128-131
  CrossrefPubMedGoogle Scholar
• 23 Moore E, Wisniewski A, Dobs A. Endocrine treatment of transsexual people: a review of treatment regimens, outcomes, and adverse effects.  J Clin Endocrinol Metab. 2003;  88 3467-3473
  CrossrefPubMedGoogle Scholar
• 24 Ongphiphadhanakul B, Rajatanavin R, Chanprasertyothin S, Piaseu N, Chailurkit L. Serum oestradiol and oestrogen-receptor gene polymorphism are associated with bone mineral density independently of serum testosterone in normal males.  Clin Endocrinol. 1998;  49 803-809
  CrossrefPubMedGoogle Scholar
• 25 Rosing J, Curvers J, Tans G. Oral contraceptives, thrombosis and haemostasis.  Eur J Obstet Gynecol Reprod Biol. 2001;  95 193-197
  CrossrefPubMedGoogle Scholar
• 26 Rossouw J E, Anderson G L, Prentice R L, LaCroix A Z, Kooperberg C, Stefanick M L, Jackson R D, Beresford S A, Howard B V, Johnson K C, Kotchen J M, Ockene J. Writing Group for the Women's Health Initiative Investigators . Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative Randomized Controlled Trial.  J Am Med Assoc. 2002;  288 321-333
  CrossrefPubMedGoogle Scholar
• 27 Schlatterer K, Auer D P, Yassouridis A, von Werder K, Stalla G K. Transsexualism and osteoporosis.  Exp Clin Endocrinol Diabetes. 1998;  106 365-368
  Article in Thieme ConnectPubMedGoogle Scholar
• 28 Slemenda C W, Longcope C, Zhou L, Hui S L, Peacock M, Johnston C C. Sex steroids and bone mass in older man: positive associations with serum estrogens and negative associations with androgens.  J Clin Invest. 1997;  100 1755-1759
  CrossrefPubMedGoogle Scholar
• 29 Smith M R. Management of treatment-related osteoporosis in men with prostate cancer.  Cancer Treatment Reviews. 2003;  29 211-218
  CrossrefPubMedGoogle Scholar
• 30 Smith M R, Fallon M A, Lee H, Finkelstein J S. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial.  J Clin Endocrinol Metab. 2004;  89 3841-3846
  CrossrefPubMedGoogle Scholar
• 31 Stadel B V. Oral contraceptives and cardiovascular disease.  New Engl J Med. 1981;  305 612-618 672-677
  PubMedGoogle Scholar
• 32 Tans G, Bouma B N, Buller H R, Rosing J. Changes of hemostatic variables during oral contraceptive use.  Sem Vascular Med. 2003;  3 61-68
  PubMedGoogle Scholar
• 33 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 hormone treatment in transsexual people.  J Clin Endocrinol Metab. 2003;  88 5723-5729
  CrossrefPubMedGoogle Scholar
• 34 Townsend M F, Sanders W H, Northway R O, Graham Jr S D. Bone fractures associated with luteinizing hormone-releasing hormone agonists used in the treatment of prostate carcinoma.  Cancer. 1997;  79 545-550
  CrossrefPubMedGoogle Scholar
• 35 Van Kesteren P. Recent advances in gender dysphoria. Paper presented at a conference of the Royal Society of Medicine Sexual Health and Reproductive Medicine Section 2002; London: 16 April 2002. 
  Google Scholar
• 36 Van Kesteren P, Lips P, Deville W, Popp-Snijders C, Asscheman H, Megens J, Gooren L. The effect of one-year cross-sex hormonal treatment on bone metabolism and serum insulin-like growth factor-1 in transsexuals.  J Clin Endocrinol Metab. 1996;  81 2227-2232
  CrossrefPubMedGoogle Scholar
• 37 Van Kesteren P, Asscheman H, Megens J, Gooren L. Mortality and morbidity in transsexual subjects treated with cross-sex hormones.  Clin Endocrinol (Oxford). 1997;  47 337-342
  CrossrefPubMedGoogle Scholar
• 38 Van Kesteren P, Lips P, Gooren L J, Asscheman H, Megens J. Long-term follow-up of bone mineral density and bone metabolism in transsexuals treated with cross-sex hormones.  Clin Endocrinol (Oxford). 1998;  48 347-354
  CrossrefPubMedGoogle Scholar
• 39 Vermeulen A, Verdonck L, Kaufmann J M. A critical evaluation of simple methods for the estimation of free testosterone in serum.  J Clin Endocrinol Metab. 1999;  84 3666-3672
  CrossrefPubMedGoogle Scholar
• 40 Vermeulen A, Kaufman J M, Goemaere S, van Pottelberg I. Estradiol in elderly men.  Aging Male. 2002;  5 98-102
  PubMedGoogle Scholar
• 41 Ylostalo P, Laakso L, Viinikka L, Ylikorkala O, Vihko R. Cyproterone acetate in the treatment of hirsutism.  Acta Obstetricia Gynecologica Scandinavica. 1981;  60 399-401
  PubMedGoogle Scholar

1 Ralf Dittrich and Helge Binder contributed equally to the authorship.

Dr. Andreas Mueller

Department of Obstetrics and Gynaecology
Erlangen University Hospital

Universitätsstraße 21 - 23

91054 Erlangen

Germany

Phone: + 4991318533553

Fax: + 49 9 13 18 53 35 52

Email: andreas.mueller@gyn.imed.uni-erlangen.de