Background: Pubertal tempo of breast development on natural sex-steroid replacement therapy in girls with multiple pituitary hormone deficiencies (MPHD) and pubertal growth spurts on adequate GH-treatment regimens were unknown in 1989 and are still not known.
Objective and Hypotheses: A hypothesis driven prototype trial1,2 was initiated in the late 80ies aiming to mimic normal puberty regarding both pubertal maturation (degree and tempo of breast development) and growth (pubertal height gain and adult height). For the first time, a more physiological substitution with transdermal 17ß-estradiol was used together with rhGH-doses of ≥33ug/kg/day.
Study Design: Approved by Swedish Ethical Committees, MPHD girls received transdermal 17ß-estradiol treatment, within a randomised national trial on rhGH-doses during puberty (TRN number 88-177).
Six girls with at least one prepubertal year on rhGH treatment dose 33µg/kg/day were randomized to rhGH 33 or 67µg/kg/day during puberty (Genotropin®, Kabi/Pharmacia/Pfizer). Sex-steroid replacement was 17ß-estradiol patches in slowly increasing doses (5,10,12.5,25,50µg/day) mimicking the spontaneous pubertal tempo3. For this purpose, pharmaceutical estradiol patches (Estraderm®, Ciba-Geigy) were produced and donated.
Methods: Breast development was assessed according to Tanner3 (stage 1-5).
Height outcome: Adult heightSDS (AHSDS) vs total height references. Pubertal height gain was estimated as change from heightSDS at start of 17ß-estradiol-replacement (calculated vs prepubertal height reference) to AH. Results are given as median (range).
Results: The MPHD girls had a history of oncology treatment (n =3) and craniopharyngeomas (n=3). Age at start of 17ß-estradiol replacement was median 13.1yrs (range 12.6-14.1).
Breast Development: Time from start of 17ß-estradiol patch treatment (B1) until B2 was 0.3yrs (0.2 to 0.4); B2-B3 1.2yrs (0.8-1.7); B3-B4 1.7yrs (0.5-2.4); B4-B5 1.5yrs (1.0-3.1). Time for B2-B4 was 3.0yrs (1.7-4.2). The start of estradiol treatment was 2yrs late, and the tempo of median breast maturation became 1yr prolonged, compared to published3 normal ranges.
Pubertal Height Gain: Total pubertal gain in heightSDS was +0.8 (0-1.15); expressed in cm 21.1 (11.8-21.6). AHSDS was 0.075 (-1.33 to 0.31); expressed in cm 168.0 (159.5-169.5).
Conclusion: This hypothesis driven prototype trial initiated in 1989, show for the first time that it is possible to normalize puberty in MPHD girls, both regarding the tempo of maturation of breast development, and to achieve a normal pubertal growth spurt and AH by using a more physiological substitution therapy with transdermal 17ß-estradiol and adequate rhGH-doses. This allows earlier age for pubertal induction.
1,2Albertsson-Wikland et al, Acta.Pead.1999;88(suppl):80-84;Horm.Res.Ped.2014;82:158-170.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology