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Estrogen Replacement Therapy Overview

Estrogen Replacement Therapy Overview

Estrogen Replacement Therapy (ERT) is an important treatment for adolescents and women with Turner Syndrome (TS). The below overview is provided by Lournaris Torres-Santiago, MD and Nelly Mauras, MD, from Nemours Children’s Health System in Jacksonville, FL.

Note: The information in this post is educational and is not meant to replace medical advice from your doctor(s). Always consult with a medical professional regarding any specific health concerns.

Why ERT for TS Patients Is Important

Primary ovarian failure affects the vast majority of females with TS. Estrogen plays an important role in many body functions, including supporting bone health, cardiovascular protection, breast and uterus growth and development, and influencing mood and fat distribution, among others. If estrogen replacement therapy (ERT) is not initiated and maintained during the reproductive years, it can have a negative impact in these areas. Hence, adequate estrogen replacement is an essential component in the care of girls and women with TS. 

The optimal ERT regimen continues to be an area of study. The proper timing, form, dose, and route of estrogen replacement in females with TS are all important considerations. 

The latest research supports the use a type of estrogen called estradiol as the first choice, for three reasons: First, it is identical to what the ovaries naturally make. Second, it is the most physiological. Third, levels can be measured through bloodwork to help determine the best dose for the patient. Conjugated equine estrogen (e.g., Premarin®) is no longer recommended as a form of ERT, since it contains hundreds of estrogen metabolites of different potency, which can increase thromboembolic (blood clot) risk. 

Route of ERT Administration

Estradiol, the purer form of estrogen, can be prescribed in injectable, transvaginal, oral, or transdermal (TD, or patch) forms (Table 1). Research studying the metabolic effects of estradiol compared both oral TD routes of administration in a group of girls with TS.

Research Results

After 12 months of treatment, despite similar estradiol concentrations in both groups, there were no differences in body composition, lean body mass, adiposity, bone mass accrual, or energy expenditure, LH/FSH (pituitary hormones that increase with the onset of puberty) suppression, and lipid concentrations between the groups. IGF-I concentrations (an indirect measure of growth hormone action) trended lower in the transdermal group, but still remained within normal range. Although the blood estradiol levels were comparable in both groups, estrone and estrone sulfate concentrations were considerably higher than normal after oral than after TD estrogen.

Furthermore, using the transdermal route achieved concentrations closer to those of normally menstruating, age-matched adolescents. Bio estrogen is estrogen shown to have a biologic effect by activating the estrogen receptor. The levels of bio estrogen were substantially higher after oral administration.  

Additional Research

Multiple large epidemiologic studies have carefully examined the thromboembolic risk of estrogen. They have concluded that oral estrogen (all types included) has a higher risk for clotting problems than estrogen via the TD route. This is believed to be due to the first passage of estrogen via the portal (liver) circulation when given orally, affecting the clotting system. The latest consensus guidelines in the management of estrogen replacement in girls and women with TS suggest that TD estradiol is more physiologic and recommend the use of TD estradiol whenever possible, with monthly cycling with oral progesterone. 

Latest Findings

More recently, we had the opportunity to examine stored sera in the girls in the study described above. We measured a panel of 12 estrogen metabolites after 12 months of oral vs. transdermal estradiol. When estradiol was taken orally, we detected considerably higher levels of metabolites that impair DNA repair (“genotoxic estrogens”) compared to levels measured after estradiol was given TD. Although not studied in older women with TS, these metabolites have been implicated in increasing breast cancer risk in post-menopausal women, giving another reason for caution in their use. We recommend at least informed discussion of therapeutic choices before starting estrogen therapy in girls. We also recommend reassessment of current programs in adult women. 

From Klein, et.al J Clin Endocrinol Metab. 2018;103(5):1790‐1803.(with permission)

Timing and Dosing of Estrogen Replacement

It is widely accepted that the goal of ERT is to mimic the normal progression of puberty in girls, while maximizing growth potential and minimizing risks. Early treatment with growth hormone (GH) has a better chance of improving growth, especially if started prior to initiating feminization. In instances where GH therapy has been delayed, a delicate balancing of growth promotion and timely feminization are essential. This needs to be individualized with each patient. GH can be used simultaneously with estradiol.

In general, estradiol should be initiated between 11 and 12 years of age, assuming levels of LH/FSH are high. Maximizing height is a priority in some cases. In this case, estrogen replacement can be delayed, but no later than 14 years of age. Initiation with low doses of estradiol (14 µg daily estradiol, or ½ of the 25µg patch (12.5µg), using patches changed twice per week, is recommended. The dose can then be slowly increased every six months over two to three years, to achieve a typical maximum of 100 µg a day (Table 1).

The levels of estradiol can now be measured in the laboratory to assure that one achieves levels comparable to menstruating adolescents. This allows for breast development in a physiologic way. If there is no breakthrough bleeding, we can add progesterone, the second hormone produced by the ovaries. These are oral pills given for 7 to 10 days per month, to allow for menstruation. Oral medroxyprogesterone has traditionally been used. However, now micronized progesterone – identical to the natural product and without added pro-clotting risk – is also available. 

Adolescent girls with TS should be feminized at the normal physiologic time. It is preferable to use transdermal estradiol, which produces a more physiologic milieu, in order to achieve normal levels in plasma.

Length of Therapy

Once adult replacement doses are reached, treatment should continue until the usual age of menopause (~50 years of age). After this time, risks vs. benefits of continuing therapy will need to be individually evaluated. 

Edited by Susan Herman, TSF volunteer blog editor.


To learn more about ERT, read our FAQ.

References: 

Torres‐Santiago L, Mericq V, Taboada M, Unanue N, Kelin KO, singh R, Hossain J, Santen R, 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(7):2716‐2724.

Gravholt CH, Andersen NH, Conway GS,   Dekkers OM ,  Geffner ME ,  Klein KO,   Lin  AE, Mauras  N ,  Quigley  CA , Rubin  K ,  Sandberg  DE ,  Sas TCJ , Silberbach  M, Söderström-Anttila V ,  Stochholm  K,  Alfen-van derVeldenJA, Woelfle  J ,  Backeljauw  PF for International Turner Syndrome Consensus Group.  Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol. 2017;177(3):G1‐G70.

Sweetland S, Beral V, Balkwill A, Liu B, Benson VS, Canonico M, Green J, Reeves GK, The Million Women Study C.Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study. Journal of thrombosis and haemostasis: JTH. 2012;10:2277–2286.

Mauras N, Torres-Santiago L, Santen R, Mericq V, Ross JL, Colon-Otero, G, et al.  Impact of route of administration on genotoxic oestrogens concentrations using oral vs transdermal oestradiol in girls with Turner syndrome

2019 Jan;90(1):155-161. 

Klein KO, Rosenfield R, Santen RJ, Gawlik AM, Backeljauw PF, Gravholt CH, Sas TCJ, Mauras N. Estrogen replacement in Turner syndrome: literature review and practical considerations. J Clin Endocrinol Metab. 2018;103(5):1790‐1803.

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