Pubertal induction and maintenance therapy for individuals with Turner syndrome, using transdermal estrogens: Approach for the first 18 to 24 months

Typical age range	Time from start of treatment	E2 (dose delivered/24 hours)	Progestin dose	Notes
11 to 12 years	0 to 12 months	3 mcg, increasing to 6.25 mcg	–	Start estrogen to initiate puberty at age 11 to 12 years if there is no breast development. Fractionated patch dosing: Start by cutting one-quarter of a 25-mcg matrix estrogen patch*^¶ At first, apply this patch in the evening and remove in the morning After 4 to 6 months, start wearing the same portion of the patch continuously Change the patch as directed on the manufacturer's insert (once or twice weekly)^Δ
12 to 12.5 years	12 to 18 months	12.5 mcg	–	Increase to one-half patch, worn continuously, and replace as directed on the manufacturer's insert (once or twice weekly). Some patients who have already achieved an acceptable adult height may benefit from a more rapid advancement to 25 and 37.5 mcg/day dosing.
12.5 to 13.5 years	18 to 30 months	25 mcg	Give progestins 12 days/month: 200 mg micronized oral progesterone^◊ OR 10 mg oral medroxyprogesterone	Increase to 1 full estrogen patch (25 mcg dose). Progestin therapy should begin after approximately 2 years of estrogen monotherapy (typically around 13 to 14 years of age) or when vaginal breakthrough bleeding first occurs. Spontaneous vaginal breakthrough bleeding usually coincides with an E2 dose of 37.5 to 50 mcg/day, which is usually reached after 30 to 36 months of escalating E2 therapy.
13.5 to 14 years	30 to 36 months	37.5 mcg	Continue as above	Increase to 37.5 mcg/day estrogen patch.
14 to 14.5 years	36 to 42 months	50 mcg	Continue as above	Increase to 50 mcg/day estrogen patch.
14.5 to 15 years	42 to 48 months	75 mcg	Continue as above	Increase to 75 mcg/day estrogen patch.
15 years and thereafter	48 months and thereafter	100 mcg	Continue as above	Increase to 100 mcg/day estrogen patch. This is the typical dose for treatment of primary ovarian insufficiency in adults. Further details are available in the UpToDate topic on management of spontaneous primary ovarian insufficiency (premature ovarian failure).

This protocol is but one of many that can be used. This specific protocol is used in the author's clinic and is individualized depending on patient circumstances and desires. For example, older girls may prefer to start at 25 mcg of estrogen. The estrogen-progestin replacement should be continued until approximately age 50 years, the average age of menopause, to mimic the hormonal patterns of women with functioning ovaries.
Alternatives to the transdermal estrogen patch include:

Oral micronized E2, starting at 0.25 mg daily and gradually advancing to the usual adult dose of 2 mg daily.
Oral ethinyl estradiol, starting at 2 mcg daily and gradually advancing to the adult dose of 10 mcg daily.
Transdermal estradiol gel (eg, Divigel), starting at 0.25 mg daily and gradually advancing to 1 mg daily^[1]. The appropriate dose for a gel preparation is substantially higher than for a transdermal patch due to differences in absorption.

Neither ethinyl estradiol nor topical estradiol gels are optimal choices for pubertal induction. Ethinyl estradiol is a potent synthetic estrogen used in most combined oral contraceptives. It has a greater effect on hepatic protein synthesis than other estrogens and is the most thrombogenic^[2]. Estradiol gels are not preferred, because of the potential for transfer of estrogens to other children.

E2: 17-beta estradiol.
* Transdermal estradiol is the preferred form; other forms may be used if this is not available or not tolerated by the patient, as outlined in the legend.
¶ Vivelle Dot, a matrix transdermal patch, is small and tends to adhere well. The 25-mcg patch is designed to deliver 25 mcg in each 24-hour period, when applied twice weekly. The cutting technique cannot be used for a reservoir-type patch, as this would make the entire dose available at once.
Δ An alternative approach is to use twice this portion of the patch but replace it less frequently than recommended. For example, start pubertal initiation using one-half patch and replace once weekly (rather than one-quarter patch, replaced twice weekly)^[1].
◊ Give micronized oral progesterone before bedtime because it may cause mild drowsiness.

References:

Klein KO, Rosenfield R, Santen RJ, et al. Estrogen Replacement in Turner Syndrome: Literature Review and Practical Considerations. J Clin Endocrinol Metab 2018.
Lucaccioni L, Wong SC, Smyth A, et al. Turner syndrome--issues to consider for transition to adulthood. Br Med Bull 2015; 113:45.

Modified from: Davenport ML. Approach to the patient with Turner syndrome. J Clin Endocrinol Metab 2010; 95:1487.

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Pubertal induction and maintenance therapy for individuals with Turner syndrome, using transdermal estrogens: Approach for the first 18 to 24 months