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), , dehydroepiandrosterone sulphate (DHEA-S), 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 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,

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Table 1 Clinical data and predicted height (means Ϯ 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 Ϯ 1:513:2 Ϯ 1:1 Height (cm) 175:5 Ϯ 2:9 177:7 Ϯ 2:8 175:4 Ϯ 2:7 177:9 Ϯ 2:6 Weight (kg) 54:8 Ϯ 10:063:1 Ϯ 9:355:0 Ϯ 7:564:3 Ϯ 7:0 Skeletal age (years) 12:8 Ϯ 0:814:4 Ϯ 0:812:7 Ϯ 0:814:5 Ϯ 0:8 Predicted height (cm) 184:0 Ϯ 2:7 180:8 Ϯ 3:0 184:6 Ϯ 4:0 180:8 Ϯ 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 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 Ϯ 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 Ϯ 129 ¹86 Ϯ 123 ¹98 Ϯ 108 ¹111 Ϯ 130a 0.2 mg daily 17 478 Ϯ 110 ¹130 Ϯ 114 ¹164 Ϯ 110 ¹225 Ϯ 100a

FT4 (pmol/l) 0.1 mg daily 9 13:53 Ϯ 1:50 ¹0:03 Ϯ 2:74 ¹0:10 Ϯ 2:17 ¹0:47 Ϯ 2:19 0.2 mg daily 21 14:12 Ϯ 1:87 ¹0:32 Ϯ 2:03 ¹0:70 Ϯ 2:45 ¹1:28 Ϯ 2:29 TSH (mU/ml) 0.1 mg daily 8 1:60 Ϯ 0:60 ¹0:16 Ϯ 0:45 0:35 Ϯ 1:00 ¹0:02 Ϯ 0:70 0.2 mg daily 17 1:50 Ϯ 0:50 0:26 Ϯ 0:52 0:44 Ϯ 0:99 0:11 Ϯ 0:45 Prolactin (mU/ml) 0.1 mg daily 15 183 Ϯ 50 229 Ϯ 213a 136 Ϯ 112a 81 Ϯ 84 0.2 mg daily 20 198 Ϯ 86 375 Ϯ 252a 226 Ϯ 132a 182 Ϯ 176 Testosterone (nmol/l) 0.1 mg daily 7 0:55 Ϯ 0:26 ¹0:07 Ϯ 0:35 ¹0:18 Ϯ 0:23 ¹0:16 Ϯ 0:39 0.2 mg daily 14 0:55 Ϯ 0:38 ¹0:21 Ϯ 0:35 ¹0:23 Ϯ 0:36 ¹0:23 Ϯ 0:38 DHEA-S (ng/ml) 0.1 mg daily 14 752 Ϯ 296 ¹334 Ϯ 198 ¹369 Ϯ 227 ¹279 Ϯ 246 0.2 mg daily 20 765 Ϯ 434 ¹305 Ϯ 267 ¹348 Ϯ 258 ¹286 Ϯ 236 Cortisol (ng/ml) 0.1 mg daily 14 93 Ϯ 50 216 Ϯ 87 270 Ϯ 66 197 Ϯ 81 0.2 mg daily 19 99 Ϯ 45 229 Ϯ 133 274 Ϯ 132 263 Ϯ 144

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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 Ϯ S.D.; asterisks indicate a significant difference versus the value at the start (P < 0.05 Bonferroni test). ‘a’ indicates a statistically significant difference between the values of group A and group B at a given time point (Mann–Whitney U test, P < 0.05). absolute values of some selected parameters are represented in Figs 1–3. Figure 1 shows the levels of total IGF-I before and after 3, 6 and 12 months of therapy. In both groups, IGF-I concentrations were significantly suppressed after 3 months of treatment. In group A, IGF-I levels remained at that level up to 12 months, whereas in the girls receiving 0.2 mg total IGF-I further decreased at 6 and 12 months of therapy. At all time points, the suppression of IGF-I was more accentuated in group B Figure 3 DHEA-S and testosterone concentrations before than in group A and reached statistical significance and during therapy of constitutionally tall girls with 0.1 mg after a treatment period of 12 months. 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 Ϯ S.D.; asterisks indicate a significant difference versus the value at the start (P < 0.05 Bonferroni test).

FT4 and TSH values were barely influenced by oestrogen therapy (Table 2) and remained within the normal range in the two groups. In group B, FT4 con- tinued to decline during the first year. In both groups, the changes in TSH concentration inversely correlated with the FT4 levels, increasing temporarily at 6 months of therapy. A marked increase in prolactin concentration occurred in both groups with maximal levels after 3 months of therapy (Fig. 2). The stimulation of prolactin secretion by oestrogens was more pronounced in group B at each time point. The levels of DHEA-S decreased significantly Figure 2 Prolactin concentrations before and during therapy of (P < 0.05) by about 40% after 3 months of treatment constitutionally tall girls with 0.1 mg ethinyloestradiol daily (group A, and remained suppressed for at least 12 months, irre- white bars) or 0.2 mg daily (group B, dark bars) at 0, 3, 6 and 12 spective of the dose used. Testosterone concentrations months of therapy. Values represent mean Ϯ S.D.; asterisks were also clearly influenced by oestrogen therapy and indicate a significant difference versus the value at the start (P < 0.05 Bonferroni test). ‘a’ (P < 0:05) and ‘b’ (P < 0:01) indicate a decreased about 40% (P < 0.05) after 6 months (Fig. 3). statistically significant difference between the values of group A and Serum cortisol levels increased 3-fold in both groups group B at a given time point (Mann–Whitney U test). during the whole study period (Table 2).

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During oestrogen therapy, serum cholesterol levels A decrease in serum IGF-I may also be the result of rose 25% in both groups. After 12 months of therapy, a reduction in serum IGF binding (IGFBPs). the antithrombin III activity was unaffected in group However, IGFBP-3, which is the main IGFBP present A but significantly decreased by 12% in group B in serum, was not altered by oestrogen replacement (P < 0.05). therapy in postmenopausal women (20, 21) and was even increased by similar doses in primates at all ages (23). Discussion The alterations in the pituitary–thyroid axis that we In this study we have measured the influence of two observed were small and therefore may not be of any pharmacological doses of oestrogens on the plasma physiological significance. Indeed, FT4 concentrations levels of various hormones in constitutionally tall girls. did not change during ethinyloestradiol treatment Treatment with ethinyloestradiol at doses of 0.1 and with 0.1 mg and barely decreased in the girls receiving 0.2 mg daily resulted in an effective growth inhibition, 0.2 mg. These results are in agreement with those of thus confirming earlier reports (5–7). Whether even other studies (26). lower doses are equally effective on the growth process In our study population, the treatment with high remains to be assessed. doses of ethinyloestradiol reduced circulating DHEA-S Our results show that the administration of 0.1 or levels by about 40%. Accordingly, ethinyloestradiol 0.2 mg ethinyloestradiol is accompanied by important in contraceptive doses also reduced DHEA-S levels by changes in the serum levels of various hormones: a 20–40% (27, 28). However, oestrogen replacement suppression of total IGF-I, DHEA-S and testosterone failed to change DHEA-S levels in subjects with impaired and an increase of prolactin and cortisol. FT4 and TSH ovarian function such as Turner patients (9) or post- levels did not change significantly. menopausal women (20, 29). These findings strongly In children and adolescents the effect of ethinyl- suggest that the ovaries contribute substantially to oestradiol on growth appears to depend on the dose the serum DHEA-S levels and contradict the generally (14). Physiological doses up to 0.03 mg daily stimulated accepted view that only about 5–10% of circulating growth rate and increased serum IGF-I levels during DHEA-S is of ovarian origin. Moreover, there is no con- spontaneous (15) and induced (16) puberty. Pharma- vincing evidence indicating that oestrogens can inhibit cological doses of 0.25 mg and higher, however, resulted adrenal androgen synthesis (9). The decline in serum in growth inhibition and a decrease in serum IGF-I testosterone that we observed during oestrogen therapy levels both in constitutionally tall girls (2, 8, 17) and may also be the result of inhibition of ovarian function, in acromegalic patients (18). Our data indicate that this since both ovaries and adrenals equally contribute to is also the case when doses of 0.1 and 0.2 mg are used. testosterone production in females. The effect of oestrogens on serum IGF-I, however, The rise in cortisol concentration most probably not only depends on the dose but also on the age of resulted from an increase in transcortin levels. This the patient. Whereas physiological doses of oestrogens effect on cortisol has been well documented with high increase IGF-I levels in young girls, similar doses sup- and low oestrogen doses and has been shown to be press IGF-I when given as contraceptives in young reversible once the treatment is arrested (9, 27). adult females (19) or as oral replacement therapy Our observation that oestrogens increase prolactin in postmenopausal women (20–22). A similar age- levels has been previously reported (30, 31). Oestrogens dependent effect of oestrogens on IGF-I was recently transiently enhanced prolactin release both in vitro reported in primates in whom low doses facilitated (32, 33) and in vivo (34, 35). Trygstad (36) observed IGF-I secretion during adolescence, but decreased IGF-I galactorrhoea and high prolactin levels in 16 out of levels once the animal reached adulthood (23). 680 girls treated with high doses of oestrogens. In our The increase of total IGF-I in adolescent girls by population, no hyperprolactinaemia nor galactorrhoea physiological doses of oestrogens is caused by an was found. Since the oestrogen-induced prolactin increase in growth hormone (GH) secretion (24). Sur- release was shown to be antagonized by medroxypro- prisingly, the suppression of IGF-I observed in adults gesterone acetate (37), it is indicated to add sufficient with similar doses is also accompanied by an enhanced amounts of progesterone derivatives to the therapy. GH secretion (20, 21). Weissberger et al. therefore It is unclear to what extent these hormonal changes speculated that oral oestrogen administration inhibits contribute to the growth-inhibiting effect of pharmaco- IGF-I production (20). These authors demon- logical doses of oestrogens. One of the striking effects strated that IGF-I levels were not suppressed in of oestrogen treatment in our patients was the accel- postmenopausal women with transdermal oestrogen eration of skeletal maturation, which was also observed replacement therapy, in whom the liver was not exposed by other authors (9). Bone age advanced by 20 months to high concentrations of oestrogens as opposed to in group A and by 22 months in group B after 12 oral replacement. In addition, studies in animals con- months of therapy. Bone age maturation is known to firmed the inhibitory effect of oestrogens on hepatic be accelerated by IGF-I, thyroxine and androgens, but mRNA synthesis for IGF-I (25). all these hormones were suppressed by oestrogen

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