European Journal of Endocrinology (1999) 141 579–584 ISSN 0804-4643 CLINICAL STUDY Hormonal changes during the first year of oestrogen treatment in constitutionally tall girls Ewa Wajs-Kuto, Lieve Op De Beeck, Raoul P A Rooman and Marc V L Du Caju Department of Pediatrics, University Hospital Antwerp, Wilrijkstraat 10–2650 Antwerp, Belgium (Correspondence should be addressed to E Wajs-Kuto; Email: [email protected]) Abstract Objective: Oestrogens are used to inhibit growth in girls with constitutionally tall stature. We studied the changes in different hormones that accompany such therapy. Subjects and methods: In this longitudinal study we examined the levels of total insulin-like growth factor-I (IGF-I), free thyroxine (FT4), thyrotrophin (TSH), testosterone, dehydroepiandrosterone sulphate (DHEA-S), cortisol and prolactin in two groups of girls receiving ethinyloestradiol at a dose of either 0.1 mg daily (group A, n = 22) or 0.2 mg daily (group B, n = 36). Hormonal measurements were performed at start of therapy and after 3, 6 and 12 months. Results: In both groups the levels of IGF-I, testosterone and DHEA-S were reduced while the concentrations of cortisol and prolactin were increased. The pituitary–thyroid axis was not signifi- cantly affected by this therapy. The girls receiving 0.2 mg ethinyloestradiol daily had lower IGF-I levels after 12 months of therapy and had higher serum prolactin concentrations than the girls treated with 0.1 mg daily. The reduction in predicted height and the advancement in bone age were similar in both groups. Conclusions: Therapy with pharmacological doses of ethinyloestradiol changes the levels of several hormones including IGF-I, testosterone, DHEA-S, prolactin and cortisol but the role of the respective changes in the inhibition of growth is not clear. The suppression of DHEA-S levels by 40% suggests that the ovaries contribute significantly to the production of this hormone in pubertal girls. European Journal of Endocrinology 141 579–584 Introduction parents >2 S.D. above the mean), (b) height >2 S.D. for age, according to the standards of Tanner et al. (10), (c) For more than 50 years, high doses of oestrogens, predicted height of more than 180 cm and (d) exclusion ranging from 0.3 to 1.0 mg daily, have been used to of endocrine and other disorders that may explain reduce final height in constitutionally tall girls (1–4). their tall stature. Skeletal age was evaluated by X-ray Recently, comparative trials have shown that a dose of of the left hand according to the method of Greulich ethinyloestradiol as low as 0.1 mg/day was equally and Pyle (11). Final height was predicted by the method effective in reducing final height (5–7). Limited data of Bayley and Pinneau (12). have been published on the hormonal changes that Before the start of therapy, each patient had reached accompany the treatment with the high doses (8, 9), at least a breast development stage III according to but no such data are available on treatment with lower Marshall and Tanner (13). Ethinyloestradiol was given doses. We therefore measured serum levels of total every day: the girls who started treatment after 1995 insulin-like growth factor-I (IGF-I), free thyroxine (FT4), (group A; n = 22) received 0.1 mg and those who started thyrotrophin (TSH), prolactin, testosterone, dehydro- before 1995 (group B; n = 36) 0.2 mg ethinyloestradiol epiandrosterone sulphate (DHEA-S) and cortisol in daily. This treatment was supplemented with medroxy- constitutionally tall girls receiving 0.1 or 0.2 mg/day progesterone acetate at a dose of 10 mg for the first 12 ethinyloestradiol. days of each month. Informed consent was obtained from patients and parents. Blood samples were collected at the start of therapy and Subjects and methods at 3, 6 and 12 months of treatment, between 0800 and Fifty-eight constitutionally tall girls were included in 1200 h. IGF-I (Biosource Europe, Fleurus, Belgium), FT4 this longitudinal study. The diagnosis was based on (a) (Amerlex M, Amersham, Cardiff, UK), testosterone (Orion familial occurrence of tall stature (height of one or both Diagnostica, Espoo, Finland), DHEA-S (Immunotech, q 1999 Society of the European Journal of Endocrinology Online version via http://www.eje.org Downloaded from Bioscientifica.com at 09/25/2021 12:34:16AM via free access 580 E Wajs and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (1999) 141 Table 1 Clinical data and predicted height (means 6 S.D.) at the start and after 12 months of therapy in constitutionally tall girls receiving 0.1 mg (group A, n ¼ 22) and 0.2 mg (group B, n ¼ 36) of ethinyloestradiol daily. Group A Group B Months of therapy: 012012 Chronological age (years) 13:6 6 1:513:2 6 1:1 Height (cm) 175:5 6 2:9 177:7 6 2:8 175:4 6 2:7 177:9 6 2:6 Weight (kg) 54:8 6 10:063:1 6 9:355:0 6 7:564:3 6 7:0 Skeletal age (years) 12:8 6 0:814:4 6 0:812:7 6 0:814:5 6 0:8 Predicted height (cm) 184:0 6 2:7 180:8 6 3:0 184:6 6 4:0 180:8 6 3:2 Marseilles, France), cortisol (DiaSorin, Stillwater, MN, the groups at different time points were compared using USA) were assayed by radioimmunoassay. Prolactin and Bonferroni test. The results between both groups at TSH (Wallac Delfia, Turku, Finland) were measured by a a particular time point were compared by the Mann– fluorometric immunoassay. For all the determinations Whitney U test. A P value <0.05 was considered the inter-assay and intra-assay variation was less than significant. 5%, except for IGF-I where it was less than 10%. The levels of luteinizing hormone (LH) and follicle-stimulat- ing hormone (FSH) were measured to assess compliance Results and remained below the detection level. In addition, The clinical data including chronological age, height, changes in total cholesterol were measured and weight, skeletal age and height prediction at the start antithrombin III activity was determined to assess the and after 12 months of therapy were comparable in risk for thromboembolic complications. For each para- both groups (Table 1). After 12 months of treatment, meter, patients were only included in the analysis if data the predicted height was significantly diminished were available for all four time points. (P < 0.001) in both groups. The results were analysed using the Statistical The differences between the concentrations of the Package for Social Sciences (SPSS). The auxological hormones at the start and after 3, 6 and 12 months of data were analysed by t-test. Hormonal data within therapy are summarized in Table 2. In addition, the Table 2 Hormonal changes (means 6 S.D.) in constitutionally tall girls treated with ethinyloestradiol. The table shows the absolute values at the start and the difference (positive or negative) after 3, 6 and 12 months of therapy. For each parameter, patients were only included when data were available for all four time points (a: P < 0.05 for differences between the groups at a given time point; Mann–Whitney U test). Number D values D values D values of cases Values at start after 3 months after 6 months after 12 months IGF-I (ng/ml) 0.1 mg daily 14 413 6 129 ¹86 6 123 ¹98 6 108 ¹111 6 130a 0.2 mg daily 17 478 6 110 ¹130 6 114 ¹164 6 110 ¹225 6 100a FT4 (pmol/l) 0.1 mg daily 9 13:53 6 1:50 ¹0:03 6 2:74 ¹0:10 6 2:17 ¹0:47 6 2:19 0.2 mg daily 21 14:12 6 1:87 ¹0:32 6 2:03 ¹0:70 6 2:45 ¹1:28 6 2:29 TSH (mU/ml) 0.1 mg daily 8 1:60 6 0:60 ¹0:16 6 0:45 0:35 6 1:00 ¹0:02 6 0:70 0.2 mg daily 17 1:50 6 0:50 0:26 6 0:52 0:44 6 0:99 0:11 6 0:45 Prolactin (mU/ml) 0.1 mg daily 15 183 6 50 229 6 213a 136 6 112a 81 6 84 0.2 mg daily 20 198 6 86 375 6 252a 226 6 132a 182 6 176 Testosterone (nmol/l) 0.1 mg daily 7 0:55 6 0:26 ¹0:07 6 0:35 ¹0:18 6 0:23 ¹0:16 6 0:39 0.2 mg daily 14 0:55 6 0:38 ¹0:21 6 0:35 ¹0:23 6 0:36 ¹0:23 6 0:38 DHEA-S (ng/ml) 0.1 mg daily 14 752 6 296 ¹334 6 198 ¹369 6 227 ¹279 6 246 0.2 mg daily 20 765 6 434 ¹305 6 267 ¹348 6 258 ¹286 6 236 Cortisol (ng/ml) 0.1 mg daily 14 93 6 50 216 6 87 270 6 66 197 6 81 0.2 mg daily 19 99 6 45 229 6 133 274 6 132 263 6 144 Downloaded from Bioscientifica.com at 09/25/2021 12:34:16AM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (1999) 141 Hormonal changes in oestrogen-treated tall girls 581 Figure 1 Total serum IGF-I concentrations before and during therapy of constitutionally tall girls with 0.1 mg ethinyloestradiol daily (group A, white bars) or 0.2 mg daily (group B, dark bars) at 0, 3, 6 and 12 months of therapy. Values represent mean 6 S.D.; asterisks indicate a significant difference versus the value at the start (P < 0.05 Bonferroni test).