Therapeutic Aspects

Treatment of delayed puberty and/or primary amenorrhea requires precise etiological diagnosis, determination of bone age and evaluation of the psychological consequences to the patient and her family in order to evaluate the most appropriate way to give explanations, reassurance and information on the prognosis.

Specific treatment must be undertaken when possible to improve pubertal development. This includes surgical treatment of tumors or abnormalities of the genitalia, medical treatment of general diseases, and correction of negative energetic balance by improving quantitative and qualitative food intake, body weight and body fat mass and by reducing intensive sports activity. It also includes treatment of endocrine diseases; pituitary-associated deficiencies must be corrected, in particular GH deficiency, because this will accelerate pubertal maturation.

Correction of associated hypothyroidism or inhibition of the corticotrophic axis by dexamethasone in case of adrenal hyperplasia may also be needed.

In cases of PCO, menstruation can easily be obtained by sequential treatment with progesterone: natural micronized progesterone (Utrogestan® 200 mg/day orally, 10 or 15 days/month), an isomer of progesterone, dydroprogesterone (Duphaston® 10 mg/day) or a pregnane compound such as chlormadinone acetate (Luteran® 5 mg/day). Weight reduction will also be necessary. If hyperandrogenia is significant and not well accepted, cyproterone acetate, another pregnane compound with high antiandrogenic and antigonadotropic effects, can be used (Androcur® 50 mg daily for 15 days associated with estradiol 1 mg daily for 25 days) in pubertal girls with PCO.

Constitutional delay of growth and puberty is classically a situation of waiting and observing until pubertal development occurs spontaneously; meanwhile, parents and patients must be reassured. Some girls will have serious psychological difficulties because of comparisons with their peers and very low self-esteem regarding their short stature and their physical infantile appearance.

This can affect success at school, work or socially. In such cases, estrogen administration may have psychobehavioral benefits for such patients. A short, low-dose estrogen treatment (estradiol 0.5 mg/day orally for 3 months) can be proposed at a chronological age of 14/15 years and repeated to induce the beginning of pubertal development, in particular breast development, without advancing bone age too much. This can be continued up to 13 years of bone age. This treatment may help to distinguish between isolated gonadotropin deficiency and constitutional delay of puberty and may induce the beginning of spontaneous pubertal development.

Definitive lack of pubertal development due to an organic congenital or acquired disease requires a protocol of estrogenization with several goals: (1) to allow the development and maintenance of secondary sex characteristics; (2) to induce the maturation of internal genital organs for future menstruation and adequate uterine development to allow successful pregnancy (nidation); (3) to induce a correct peripubertal growth spurt without reducing the final height; (4) to improve the constitution of bone mass and prevent accelerated loss, and (5) to prevent cardiovascular disease.

Age of treatment has been widely discussed in the past. It depends in fact on the achieved height, bone age and, in case of Turner syndrome, the associated GH treatment. Estrogen therapy is usually started at a bone age between 12and 13 years. In Turner syndrome, GH treatment is systematically proposed.

If GH therapy is started early (between 2 and 10 years), estrogen treatment can be initiated at an age-appropriate time (12/13 years) without compromising adult height. If GH is started later, estrogen therapy will be delayed; however, the statural gain will be lower.

Estrogen therapy will begin with low, continuous and progressively increasing doses, without progesterone during the first year of treatment. Ethinyl estradiol, a synthetic estrogen, has been widely used (2μg/day in the beginning to 20μg at the final adult sequential treatment). Natural estrogens (17β-estradiol) with fewer metabolic side effects are now frequently used (0.2mg to 2mg/day) either orally (micronized estradiol) or by transdermic administration (17β-estradiol). Estrogens are first given alone for 1 year with progressive doses up to 0.5 mg estradiol daily and then associated with progesterone. Natural progesterone, 17-hydroxyprogesterone or pregnanes is given in a sequential mode from day 15 to day 24 of the cycle. After 2 or 3 years, adult doses will be adapted.

Follow-up will include clinical signs, bone age, ultrasonographic size of the uterus, bone mineral content evaluated by dual-energy X-ray absorpsiometry and psychological evolution and tolerance.

Explanations and information about this chronic hormonal replacement therapy will be given to the patient and her family; the future chances of fertility by ovarian stimulation by menotropins or LHRH pulsatile administration in case of IHH will be discussed. Information concerning oocyte donation should also be suggested in cases of hypergonadotropic hypogonadism.

References

Provided by ArmMed Media
Revision date: June 14, 2011
Last revised: by Sebastian Scheller, MD, ScD