Pre-pubertal Low Dose Transdermal Estradiol in Turner Syndrome

The investigators hypothesize that ultra-low dose TDE will improve neurocognitive measures without a negative impact on growth and pubertal maturation in the peripubertal period. To test this hypothesis, investigators will conduct a prospective single center pilot trial and recruit up to 15 girls with TS and POI (FSH>10 in the past year), ages 8 to <11.5 years who will receive ultra-low dose TDE \[defined as 1/8th patch of 0.025mg/24h applied weekly (delivering 3.125mcg/24h)\] for 6 months to address the following objectives.

Primary: Study the effect of ultra-low dose TDE therapy on processing speed and working memory. The investigators will administer the Pattern Comparison Processing Speed Test as well as the List Sorting Working Memory test NIH toolbox EnglishV3 at baseline, and 6-months of TDE treatment.

Secondary: Assess change in pubertal status, FSH, LH and estradiol levels with ultra-low dose TDE therapy. Height, weight measurements, assessment of Tanner staging for breast development, laboratory measurements of ultrasensitive estradiol, FSH, LH, lipid profile at baseline and 6-months of TDE treatment will be completed

• Estradiol transdermal patch 0.025mg/24 hours- 1/8th fractionated patch (Drug): Estradiol transdermal patch 0.025mg/24 hours- 1/8th fractionated patch will be applied and changed weekly for 6 months

Primary outcomes

• Pattern Comparison processing speed test [6 months]: Changes in the Pattern Comparison processing speed test (PC) at 6 months on the NIH toolbox EnglishV3 compared to baseline. Pattern Comparison processing speed test (PC) is a measure of the speed of information processing. Participants see a pair of simple pictures on the iPad screen and must quickly discern whether the pictures are the same or different. The total raw score is the number of items answered correctly during the 80 seconds of presentation time (Max 133 items). The raw score is converted to a age-adjusted normative scores. The Median Response Time Per Item is also available.
• List Sorting Working Memory (LSWM) test [6 months]: Changes in the List sorting working memory test on the NIH toolbox EnglishV3 at 6 months compared to baseline. The List Sorting Working Memory test measures a participant's working memory, the ability to hold information in a short-term buffer and then manipulate the information. Pictures and written names of different foods and animals are displayed with accompanying audio-recorded and visual prompts, and the participant is asked to say the items back in size order from smallest to largest, first within a single dimension and then on two dimensions. The raw score (up to 24 Max) is then converted to age-adjusted normative scores.

Secondary outcomes

• Breast Tanner stage [6 months]: Changes in breast sexual maturity rating (Tanner staging) on examination over 6 months with ultra-low dose estradiol treatment
• Pubertal hormone changes [6 months]: Changes in serum estradiol (measured in pg/mL), after 6 months of ultra-low dose estradiol treatment compared to baseline.
• LH [6 months]: Luteinizing hormone (LH) (measured in U/L) over 6 months of estradiol therapy
• FSH [6 months]: Change in Follicle stimulating hormone (FSH) measured in U/L over 6 months of estradiol therapy

Other outcomes

• Height velocity [6 months]: Change in annualized height velocity (in cm/year) over 6 months of treatment with ultra-low dose estradiol. This will be calculated based on height measurements (in cm) at baseline and 6 months.
• Lipid profile [6 months]: Changes in lipid profile (total cholesterol, triglycerides, high density lipoproteins, low density lipoproteins) over 6 months of treatment with ultra-low dose estradiol will be assessed.

Sex: Female, ages: 8 Years to 12 Years

Inclusion Criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Female, aged 8 years up to 11 y and 180 days with karyotype confirmed Turner syndrome
4. FSH result> 10miu/mL in the past 12 months. Since variability in FSH is not uncommon, a single measure of FSH >10mIU/mL in the past calendar year will be deemed sufficient for inclusion into the study even if repeat measures may be under 10mIU/mL.
5. Ability to take the transdermal estradiol medication and be willing to adhere to the treatment regimen
6. Ability to complete the primary endpoint testing in English. Non-English speakers may be recruited if the participant is capable of performing the English version of the tests.

Exclusion Criteria:

1. Spontaneous thelarche with breast Tanner stage 3 or more, spontaneous menarche or history of abnormal uterine bleeding.
2. Previous estrogen exposure
3. Cognitive impairment is severe enough to prevent assessment of the primary outcome measures.
4. Untreated hypothyroidism or celiac disease: Individuals may be recruited if on treatment and stable medication dose in past 3 months.
5. Subjects known to have Y-chromosome material unless they have undergone gonadectomy and have fully external female genitalia
6. History of any type of malignancy
7. History of a known clotting disorder/deep venous thrombosis
8. Any clinically significant abnormality as determined by the principal investigator.