P. Stubbe

Turner syndrome: Spontaneous growth in 150 cases and review of the literature

The spontaneous growth of 150 patients with Turner syndrome from three German centers-90 with 45,X0 constitution, 60 with other chromosomal abnormalities-has been analyzed. The mean adult height was found to be (n=14) 146.8 cm. It was observed that growth in these patients can be divided into four phases: (1) Intrauterine growth, which is retarded; (2) Height development, which is normal up to abone-age of about 2 years; (3) Between a bone-age of 2 and 11 years when stunting of growth is most marked; (4) After a bone-age of 11 years—the time at which puberty should normally start—the growth phase is prolonged, but total height gain is only little below normal levels. No difference in height could be observed between cases with X0 karyotype and other chromosomal variants. The data are compared with those in the literature.

Spontaneous growth in Turner's syndrome.

Growth in Turners syndrome can be divided into four phases: intrauterine growth is slightly retarded, normal growth occurs up to a hone age of about 3 years, with a tendency to compensate for the loss in growth during intrauterine life, stunting of growth is severe during childhood, after a hone age of about 10 years — the time when puberty normally starts ‐ the growth phase is prolonged, hut total height gain is not essentially reduced. Based on a study of 150 patients with Turners syndrome whose spontaneous growth was observed, standards of height and height velocity (means and SDs) were calculated to allow mathematical analysis of the spontaneous growth and growth during treatment in these patients. The auxological characteristics in Turners syndrome do not support the assumption that GH deficiency playsa primary role in the pathogenesis of the growth disorder.

Effect of different oestrogen doses on final height reduction in girls with constitutional tall stature

The effects of different doses of oestrogens in constitutionally tall girls were evaluated in two centres for paediatric endocrinology. In one centre, 38 girls were treated with a high oestrogen dose of 0.3 to 0.5 mg ethinyloestradiol (EE) daily. In the other, 44 girls received a comparably low dose of 0.1 mg EE per day. Height prediction (HP), chronological age (CA), and height at the onset of treatment were comparable in both groups. Although the duration of treatment was significantly longer in those receiving the low dose, the cumulative oestrogen dose was still significantly lower. The dose of EE had no effect on final height reduction (high dose group: 4.9±2.6 cm, low dose group: 5.1±2.4 cm). Final height was more reduced in both groups when treatment was started at an early bone age (BA) (≤13 years). No serious side effects were observed in either group, however weight gain was more pronounced in girls receiving the higher dose. We conclude that treatment of constitutionally tall girls with low doses of oestrogens is equally effective in reducing the final height as the usually administered high doses. The lowest effective dose has to be determined in a randomized, prospective clinical trial.

Hypergonadotropic hypogonadism, SHBG deficiency and hyperprolactinaemia: a transient phenomenon during induction chemotherapy in leukemic children.

Five pubertal boys (puberty stage Iv–V) and four prepubertal girls with acute lymphoblastic leukemia were treated with a combination of prednisone, vincristine, daunorubicin and l-asparaginase for remission induction. The hypothalamopituitary-gonadal axis was investigated by measuring basal plasma levels of LH, FSH, and PRL in both groups as well as the response to LHRH/TRH stimulation in pubertal boys before, on day 10, 21, and 28 during induction therapy and 23 days after the induction phase (day 51). Furthermore, the binding capacity of sex-hormone-binding globulin (SHBG), plasma levels of testosterone (T) and estradiol (E2) were monitored as well as the testicular volumes of the boys.Within three weeks of induction chemotherapy, plasma T, E2 and the binding capacity of SHBG decreased in both groups, together with a reduction of testicular volumes in the boys. Concommitantly, basal LH, FSH, and PRL values doubled with a normal gonadotrophin response to LHRH. The PRL response to TRH increased at the end of the induction phase, when chemotherapy with vincristine, daunorubicin and l-asparaginase was terminated, but prednisone treatment was continued for 7 another days.During the subsequent prophylactic irradiation of the central nervous system combined with other antileukemic drugs, all hormonal values including testicular volumes in pubertal boys became normal within a period of 3 weeks. Our data clearly demonstrate that an induction chemotherapy regimen such as that employed by the Berlin protocol leads to a transient castrating effect at the gonadal level and to a transient failure of synthesis of SHBG at the hepatic level. Increased prolactin values as well as an increased response to TRH may be related to a decrease in T indicating the existence of a negative feed-back-loop mechanism between T and PRL.

Transient secondary hypothyroidism and thyroxine binding globulin deficiency in leukemic children during polychemotherapy: An effect of L-asparaginase

Recently it has been observed that L-asparaginase causes transient thyroxine binding globulin (TBG) deficiency in adults. In the present study we investigated the influence of L-asparaginase on the pituitary-thyroid axis and on the synthesis of TBG. 14 children with acute lymphoblastic leukemia were treated with a combination of L-asparaginase, vincristine, prednisone and daunomycin for remission induction. Thyroid function was monitored by measuring total T4, free T4, total T3, TSH and TBG with specific radioimmunoassays before, during and after treatment. Within 3 weeks of L-asparaginase therapy total T4 fell significantly from 10.7±1.6 to 2.9±1.8 μg/100 ml, free T4 from 1.77±0.4 to 0.94±0.35 ng/100 ml, total T3 from 0.99±0.23 to 0.35±0.2 ng/ml and TBG from 29.4±3.6 to 8.0±3.8 μg/ml. Basal TSH values tinuation of L-asparaginase, but following further treatment with other antileukemic agents, all values became normal within 2–4 weeks. In 6 patients with hypothyroid free T4 values TRH induced TSH release was totally blocked during L-asparaginase therapy. Our data clearly demonstrated that L-asparaginase caused a transient TBG deficiency. Total T4 and T3 were in the hypothyroid range because of low TBG concentrations. In addition to TBG deficiency transient, secondary hypothyroidism occurred in approximately 40–50% of all patients treated with L-asparaginase. These alterations were most likely caused by drug induced inhibition of protein synthesis. Under certain circumstances thyroid hormone replacement might be life-saving in severely ill patients suffering from transient, drug induced hypothyroidism.

Pulsatile secretion of luteinizing hormone and sleep-related gonadotropin rhythms in girls with premature thelarche

The concentrations of LH, FSH and PRL were determined in serum samples obtained at night in 1–2 h intervals as well as at 15 min intervals during a 3 h period between 9 and 12 p.m. and 9 and 12 a.m. in three girls with premature thelarche, who had not developed further signs of precocious puberty for more than 18 months.A sleep-dependent LH and FSH increase was documented in all of them with a predominance of FSH secretion during sleep and after LHRH stimulation. In all three girls an episodic pattern of LH was found during sleep. In daytime minor fluctuations of LH secretion were found in two patients whereas in one patient an episodic LH pattern was demonstrable with minor peak values as during sleep.Normal PRL secretion during sleep as well as after TRH stimulation excludes a permissive role of this hormone in premature thelarche.We conclude that in girls with isolated premature thelarche a matured hypothalamo-pituitary gonadotropin axis is active comparable to normal pubertal children.

Iodine-induced hypothyroidism and goiter following lipiodolTM lymphography

Hypothyroid goiter is a rare but well recognized complication following long term administration of iodine containing expectorants and disinfectants in children. Only few reports exist on iodine-induced hypothyroidism after a single injection of the iodized radiopaque dye Lipiodol. A 15-year-old boy with previously normal thyroid function is described who developed hypothyroid goiter within six weeks following bipedal lymphography. Urinary iodine excretion was extremely elevated up to 18 mg/day while serum concentrations of total thyroxine were below the euthyroid range and thyrotropin levels were elevated. After oral L-thyroxine treatment the goiter disappeared. Thyroid function remained normal when treatment was discontinued after five months although iodine excretion was still 50 times higher (2.5 mg/day) than in normal age matched children. The observed alterations of the thyroid gland were caused by a long lasting Wolff-Chaikoff effect with a delayed adaptation to high iodide concentrations.

Sleep-related gonadotropin rhythms in children following treatment of acute leukemia: recovery of the hypothalamo-pituitary-gonadal axis after chemotherapy and CNS-irradiation.

ABSTRACT. Twelve children (5 girls and 7 boys, between the ages of 6 and 20 years) in complete remission from previous ALL who had completed their entire anti‐leukemic treatment program and who had been off all chemotherapy for at least one year, were included in a study of sleep‐related prolactin and gonadotropin rhythms. All the patients had received prophylactic CNS‐irradiation. The patients in early puberty showed a sleep‐dependent FSH rhythm. Patients in middle‐to‐late puberty had sleep‐related FSH and LH rhythms, and estradiol and testosterone plasma concentrations were normal for their pubertal stage, suggesting recovery of the hypothalamo‐pituitary‐gonadal feedback system. We conclude that the neuro‐endocrine axis is not permanently injured by CNS‐irradiation and anti‐leukemic therapy.

Oxandrolone treatment for growth promotion in Turner's syndrome

Progressive growth failure in patients with the pure form or mosaicism of Turners syndrome causes short stature. Oxandrolone (Ox) has been reported as being effective in producing acceleration in height in these patients. 25 patients 10 to 17 years old were treated orally with Ox in a dosage of 0.1 mg/kg/day for 1 to 3.5 years. Growth velocity per year (mean ± SD) for all patients was 2.8 ± 1.0 cm before treatment and 5.3 ± 2.1, 3.9 ± 1.9 and 2.8 ± 1.8 cm after 1,2 and 3 years of therapy, respectively. Patients younger than 14 years exhibited the best response. Bone age remained retarded during treatment. Using the method of Bayley and Pinneau for height prediction we found that the estimated height increased from 143.2 ± 5.4 to 145.8 ± 5.9 cm for all patients after 1 year of treatment. A 3 year follow-up of 8 patients showed an increase of predicted height from 140.6 ± 5.1 cm to 146.1 ± 4.6 cm. Our data indicate that Ox has a beneficial effect (p < 0.001) on growth velocity for the first year of therapy and may cause a moderate gain in final adult height.

REDUCTION OF FINAL HEIGHT IN TALL GIRLS FOLLOWING ESTROGEN ADMINISTRATION IS NOT DOSE DEPENDANT

Effects of Ethinylestradiol (EE) in girls with tall stature were assessed in a collaborative study of two centers comparing 38 girls (I), receiving 0.3 - 0.5 mg EE daily, with 44 girls on 0.1 mg EE daily (II). To minimize errors of height prediction (HP) bone ages (BA) were determined according to GREULICH and PYLE by using the mean of four determinations of both centers. Final height (FH) was predict according to the tables of BAYLEY and PINNEAU and was measured at a chronological age (CA) of 19.8 ± 1.2 years (y). Prior to EE administration the following findings did not differ (I vs II): CA (12.5 vs 12.4 y), BA (12.4 vs 12.4 y), length (+3,2 vs + 3.2 SDS) and HP (+3.8 vs +3.8 SDS). Evaluation of the differences between SDS of HP and SDS of FH showed no difference with respect to dose, however, an increased BA at the onset was correlated with a smaller reduction (Table I).Cumulative dose (218±86 vs 64±20 mg), BA at the end (15±0.5 vs 15.9±0.5y) and growth after discontinuation of EE (2.7±1.8 vs 1.8±1.2 cm) did differ.Conclusion: 0.1 mg EE is as effective as 0.3 mg EE daily.