Pharmacokinetics of sex steroids in patients with thalassaemia major

Aims-To assess the pharmacokinetics of oral, intramuscular, or transdermal hormone replacement in patients with p thalassaemia major. Methods-Oral (testosterone undecanoate 40 mg) and intramuscular (testosterone propionate 15 mg, phenylpropionate 30 mg, isocaproate 30 mg and decanoate 50 mg) testosterone and transdermal (1711 oestradiol 25 jug and 50 ,ug) oestradiol were evaluated in 21 male (16-29 years) and 11 female (19-26 years) patients with a6 thalassaemia major and various forms ofhypogonadism. Results-In male patients given oral testosterone, peak testosterone concentrations were observed either two to four hours or seven hours after administration; intramuscular testosterone produced peak values seven days after injection. Transdermal 17al oestradiol given to female patients produced a biphasic pattern with an initial peak concentration occurring at 36 hours and a secondary rise at 84 hours. Conclusions-The results indicate that oral androgens should be given twice daily in cases of hypogonadism, and where growth is incomplete, lower than recommended doses. If intramuscular testosterone is used, smaller doses of 10-25 mg should be given every one to two weeks. Transdermal administration of 25-50 ,g 17,8 oestradiol generally produces a plasma E2 value in the early to mid-follicular phase range (100-300 pmol/l). This is appropriate in adults but excessive for prepubertal girls. Diffuse iron infiltration of tissues does not seem to interfere with the absorption of androgens and oestrogens from the gut, muscle, or skin. (7 Clin Pathol 1993;46:660-664) Modem treatment has increased the life expectancy of patients with ,B thalassaemia major so that more of them reach sexual maturity. In fact, De Sanctis et al found that 45% of patients completed puberty spontaneously (personal observations). Many thalassaemic patients, however, still have primary or secondary hypogonadism which manifests as infantilism, pubertal arrest, primary or secondary amenorrhoea in females, or impotence in males.IA For all these conditions, some form of hormone replacement therapy (HRT) is required. Because hypogonadism, once established, is almost certainly irreversible, many thalassaemics will require HRT long term. Such patients are susceptible to chronic active hepatitis,5 6 impaired glucose tolerance or frank diabetes mellitus,7 thromboembolism,9 cholelithiasis'° and cardiomyopathy associated with cardiac failure." Because all these conditions can be adversely affected by hormonal treatment, HRT may have deleterious effects in some patients with thalassaemia major. To minimise the potential risks of such treatment, excessively high sex hormonal concentrations should be avoided during treatment. Moreover, as linear growth depends on several interacting factors, including sex hormones, a disproportionally high concentration of androgens or oestrogens could adversely affect the final height of thalassaemics receiving HRT. Little is known about the pharmacokinetics of oral, intramuscular, or transdermal hormone replacement in thalassaemics, or for that matter in healthy adolescents. Hence a study was performed to assess these kinetics in a group of patients with fi thalassaemia major. Methods Twenty one male patients with ,B thalassaemia major, aged 16 to 29 years, with varying clinical and hormonal degrees of hypogonadism, were given, at random, either 40 mg testosterone undecanoate (Restandol, Organon Laboratories, Italy) by mouth (n = 13) or 125 mg depot testosterone (Sustanon, Organon Laboratories) intramuscularly (n = 8). The latter contains 15 mg testosterone propionate, 30 mg testosterone phenylpropionate, 30 mg testosterone isocaproate and 50 mg testosterone decanoate. Two patients had primary hypothyroidism and were receiving L-thyroxine, two had insulin dependent diabetes mellitus, and one had impaired glucose tolerance. Nineteen patients had liver disease: they either had raised serum glutamyl transpeptide (r GT), raised serum aspartate transaminase (AST) activities, or both, or evidence of chronic hepatitis on liver biopsy. Eleven female patients with /1 thalassaemia, aged 19 to 26 years, with arrested puberty (n = 2), primary amenorrhoea (n = 8), or secondary amenorrhoea (n = 1) had their serum oestrone (El), 17,B oestradiol (17f,E2) Department of Obstetrics and Gynaecology, University College and Middlesex Medical School, London M Katz H H G McGarrigle Department of Haematology Whittington Hospital, London B Wonke Department of Pediatrics, Arcispedale, S Anna, Ferrara, Italy V De Sanctis C Vullo Department of Nuclear Medicine, Arcispedale, S Anna Ferrara, Italy B Bagni Correspondence to: DrM Katz, Departnent of Obstetrics and Gynaecology, University College and Middlesex School of Medicine, 86-96 Chenies Mews, London WC1E 6HX Accepted for publication 20 January 1993 660 group.bmj.com on July 11, 2017 Published by http://jcp.bmj.com/ Downloaded from