How do You initiate Oestrogen Therapy in a Girl Who has Not Undergone Puberty?

Peter C. Hindmarsh

Disclosures

Clin Endocrinol. 2009;71(1):7-10. 

In This Article

Process of Pubertal Induction

Induction of puberty needs to use low doses of oestrogen and to take place over a similar time frame to normal puberty (approximately 3 years). The choice of oestrogen matters little at this point it is more the low dosage that is important. Oral oestrogen therapy has been associated with lower IGF-1 concentrations[7] but this does not seem to be a major clinical problem. Transdermal preparations may overcome this and also have the advantage of avoiding first-pass metabolism by the liver and high exposure of the liver to oestrogen. The matrix-like transdermal patches or a gel can be used to minimize oestrogen dose.[8,9] The author tends to use ethinyloestradiol in the first instance but an equivalent low dose of 17β-oestradiol would be appropriate. Patches (25 μg) can be cut into smaller sizes to allow low-dose oestrogen exposure and can certainly allow development through to Breast Stage 3 development. Data on a schedule for the completion of pubertal induction are required.[8] Oestragel data are available for the whole of pubertal induction using doses chosen on the experiences of oestrogen replacement therapy in adults and the bioequivalence of oral oestrogens, transdermal patches or oestradiol gel.[9] The induction programme for ethinyloestradiol and oestragel are depicted in Table 1. It is important to realize that these doses are only a guide to what might be expected 'on average' and individual tailoring of dose and timing will be required.

The effect of oestradiol on height velocity is dose-dependent reaching a maximum between 6 and 8 μg of ethinyl oestradiol.[10,11] Thereafter, and certainly by the time the 10 μg dose has been reached, height velocity declines because of a maturational effect of oestrogen on the epiphyseal growth plate. The time increments in Table 1 can be extended around the time of peak height velocity. Decisions can be modified depending on the change in bone age that should be assessed at the start of treatment and yearly thereafter.

Inevitably there are a series of 'trade-offs' that will need to be negotiated. Low pubertal induction may be the right approach for optimizing growth, but may not be advantageous for uterine development and/or bone mineralization. In the absence of evidence, a pragmatic view negotiated with the young person is probably the only way forward until such information becomes available.

Once a dose of 10 μg per day of ethinyloestradiol has been reached and certainly by 15 μg breakthrough bleeding can be expected and a regular 3-week cycle of progesterone such as Norethisterone (5 mg twice daily for 5 days) should be introduced to promote endometrial shedding. If this is not performed, then endometrial hyperplasia can result from the unopposed oestrogen leading to frequent, unpredictable and heavy menstrual loss. The final step in pubertal induction is to establish the person on adult hormone replacement therapy. The dose chosen will depend upon adequate oestrogenization as reflected in patients reporting menstrual blood loss, the assessment of uterine size by a pelvic ultrasound examination and the attainment of an adequate bone mineral density. The choice of oestrogen preparation, patch, gel or oral contraceptive pill will depend largely on patient choice and the preference of the Clinician. In general, natural oestrogen delivered by the transdermal route is to be preferred due to its effect on lipid profiles, inflammatory markers and blood pressure,[12] although larger studies are warranted to determine the overall effect size.

Higher doses of oestrogen for hormone replacement therapy (HRT) maintenance have been advocated.[13] The argument for this approach is to improve the attainment of peak bone mass and to gain purported effects on cardiovascular health. Further, unlike the oral contraceptive pill approach, HRT allows for more continuous oestrogen exposure. Alternatively, longer uninterrupted use of the oral contraceptive for, say, 3 months might be an option. Against this are the risks of thrombotic complications, uncertain effects on cardiovascular risk and breast cancer risk. There are data, however, to suggest that oral contraceptive pills containing 20 μg ethinyloestradiol do not have beneficial effects on bone mass[14,15] and there is a need to establish the safest and most effective oestrogen preparation to use. A suggested monitoring plan is shown in Table 1.

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