A randomized trial of transdermal and oral estrogen therapy in adolescent girls with hypogonadism

Sejal Shah, Nikta Forghani, Eileen Durham, E Kirk Neely, Sejal Shah, Nikta Forghani, Eileen Durham, E Kirk Neely

Abstract

Background: Adolescent females with ovarian failure require estrogen therapy for induction of puberty and other important physiologic effects. Currently, health care providers have varying practices without evidence-based standards, thus investigating potential differences between oral and transdermal preparations is essential. The purpose of this study was to compare the differential effects of treatment with oral conjugated equine estrogen (OCEE), oral 17β estradiol (OBE), or transdermal 17β estradiol (TBE) on biochemical profiles and feminization in girls with ovarian failure.

Study design: 20 prepubertal adolescent females with ovarian failure, ages 12-18 years, were randomized to OCEE (n = 8), OBE (n = 7), or TBE (n = 5) for 24 months. Estrogen replacement was initiated at a low dose (0.15 mg OCEE, 0.25 mg OBE, or 0.0125 mg TBE) and doubled every 6 months to a maximum dose of 0.625 mg/d OCEE, 1 mg/d OBE, or 0.05 mg/d TBE. At 18 months, micronized progesterone was added to induce menstrual cycles. Biochemical markers including sex hormones, inflammatory markers, liver enzymes, coagulation factors, and lipids were obtained at baseline and 6 month intervals. Differences in levels of treatment parameters between the groups were evaluated with one-way analysis of variance (ANOVA). The effect of progesterone on biochemical markers was evaluated with the paired t-test.

Results: Mean (±SE) estradiol levels at maximum estrogen dose (18 months) were higher in the TBE group (53 ± 19 pg/mL) compared to OCEE (14 ± 5 pg/mL) and OBE (12 ± 5 pg/mL) (p ≤ 0.01). The TBE and OBE groups had more effective feminization (100% Tanner 3 breast stage at 18 months). There were no statistical differences in other biochemical markers between treatment groups at 18 months or after the introduction of progesterone.

Conclusions: Treatment with transdermal 17β estradiol resulted in higher estradiol levels and more effective feminization compared to oral conjugated equine estrogen but did not result in an otherwise different biochemical profile in this limited number of heterogeneous patients. OBE and TBE provide safe and effective alternatives to OCEE to induce puberty in girls, but larger prospective randomized trials are required.

Clinical trials identifier: NCT01023178.

Keywords: Clinical trial; Estrogen; Female; Feminization; Hormone replacement therapy; Puberty.

Figures

Figure 1
Figure 1
Enrollment, randomization, and follow-up of the study participants.
Figure 2
Figure 2
Estradiol (panel a) and estrone sulfate (panel b) from baseline through 24 months of estrogen-alone therapy in patients treated with oral conjugated estrogen (OCEE), oral 17β estradiol (OBE) or transdermal 17β estradiol (TBE). (*) TBE, OBE subject with reported non-adherence.
Figure 3
Figure 3
Proportion of subjects in each treatment group to reach Tanner breast stage 3 assessed at each study interval.

References

    1. Torres-Santiago L, Mericq V, Taboada M, Unanue N, Klein KO, Singh R, Hossain J, Santen RJ, Ross JL, Mauras N. Metabolic effects of oral versus transdermal 17beta-estradiol (E(2)): a randomized clinical trial in girls with Turner syndrome. J Clin Endocrinol Metab. 2013;98:2716–2724.
    1. Keiss W, Conway G, Ritzen M. Induction of puberty in the hypogonadal girl – practices and attitudes of pediatric endocrinologists in Europe. Horm Res. 2002;57:66–71.
    1. Ostberg JE, Storry C, Donald AE, Attar MJ, Halcox JP, Conway GS. A dose–response study of hormone replacement in young hypogonadal women: effects on intima media thickness and metabolism. Clin Endocrinol (Oxf) 2007;66:557–564.
    1. Anderson G. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized control trial. JAMA. 2004;294:1701–1712.
    1. Brynhildsen J, Hammar M. Lipids and clotting factors during low dose transdermal estradiol/norethisterone use. Maturitas. 2005;50:344–352.
    1. Modena M, Sismondi P, Mueck A. Transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits. Maturitas. 2005;52:1–10.
    1. Scarabin P, Oger E, Plu-Bureau G. Differential association of oral and transdermal estrogen replacement therapy with venous thromboembolism risk. Lancet. 2003;362:428–432.
    1. Ichikawa J, Sumino H, Ichikawa S. Different effects of transdermal and oral estrogen therapy on the renin angiotensin system, plasma bradykinin levels, and blood pressure on normotensive postmenopausal women. Am J Hypertens. 2006;19:744–749.
    1. Cesari M, Penninx BW, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, Rubin SM, Ding J, Simonsick EM, Harris TB, Pahor M. Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation. 2003;108:2317–2322.
    1. Ridker PM, Rifai N, Cook NR, Bradwin G, Buring JE. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA. 2005;294:326–333.
    1. Yilmazer M, Fenkci V, Fenkci S. Hormone replacement therapy, CRP and fibrinogen in healthy postmenopausal women. Maturitas. 2003;46:245–253.
    1. de Kraker AT, Kenemans P, Smolders RG, Kroeks MV, van der Mooren MJ. The effects of 17 beta-oestradiol plus dydrogesterone compared with conjugated equine oestrogens plus medroxyprogesterone acetate on lipids, apolipoproteins and lipoprotein(a) Maturitas. 2004;49:253–263.
    1. Lantiga G, Simmons A, Kamps W. Imminent ovarian failure in childhood cancer survivors. Eur J Cancer. 2006;42:1415–1420.
    1. Jadoul P, Anckaert E, Dewandeleer A, Steffens M, Dolmans MM, Vermylen C, Smitz J, Donnez J, Maiter D. Clinical and biologic evaluation of ovarian function in women treated by bone marrow transplantation for various indications during childhood or adolescence. Fertil Steril. 2011;96:126–133. e123.
    1. Grady D, Wenger N, Herrington D. Postmenopausal hormone therapy increases risk of venous thromboembolic disease: the heart estrogen/progesterone replacement study. Ann Intern Med. 2000;132:689–696.
    1. Lacriox A. Estrogen with and without progestin: benefits and risks of short term use. Am J Med. 2005;118:79–87.
    1. Scarabin P, Alhenc-Gelas M, Plu-Bureau G. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. Atherosclerosis, Thrombosis, Vascular Biol. 1997;17:3071–3078.
    1. Davenport ML. Approach to the patient with Turner syndrome. J Clin Endocrinol Metab. 2010;95:1487–1495.
    1. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499–511.
    1. Mauras N, Shulman D, Hsiang HY, Balagopal P, Welch S. Metabolic effects of oral versus transdermal estrogen in growth hormone-treated girls with turner syndrome. J Clin Endocrinol Metab. 2007;92:4154–4160.
    1. Nabhan ZM, Dimeglio LA, Qi R, Perkins SM, Eugster EA. Conjugated oral versus transdermal estrogen replacement in girls with Turner syndrome: a pilot comparative study. J Clin Endocrinol Metab. 2009;94:2009–2014.
    1. Bondy C. Care of girls and women with Turner syndrome: a guideline of the Turner syndrome study group. J Clin Endocrinol Metabolism. 2007;1:10–25.
    1. Pedreira C, Hameed R, Kanumakala S. Health care problems of Turner syndrome in the adult woman: a cross sectional study of the Victorian cohort and a case for transition. Internal Med J. 2006;36:54–57.
    1. Warren M, Chua A. Appropriate use of estrogen replacement therapy in adolescents and young adults with Turner syndrome and hypopituitarism in light of the Women’s Health Initiative. Growth Hormone IGF Res. 2006;16(suppl):S98–S102.
    1. Taboada M, Santen R, Lima J, Hossain J, Singh R, Klein KO, Mauras N. Pharmacokinetics and pharmacodynamics of oral and transdermal 17beta estradiol in girls with Turner syndrome. J Clin Endocrinol Metab. 2011;96:3502–3510.
    1. Ankarberg-Lindgren C, Elfving M, Wikland KA, Norjavaara E. Nocturnal application of transdermal estradiol patches produces levels of estradiol that mimic those seen at the onset of spontaneous puberty in girls. J Clin Endocrinol Metab. 2001;86:3039–3044.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться