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Transdermal estradiol substitution therapy for the induction of puberty in female hypogonadism

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Abstract

Fifteen patients aged 14.5–27.3 years (mean ± SE 18.8 ± 0.9) with pubertal development failure underwent replacement therapy with estradiol (E2) using a transdermal therapeutic system (TTS). Fourteen of them were affected by hypogonadotropic hypogonadism (11 with thalassemia major, 3 with multiple pituitary hormone deficiency), the 15th patient had an asymmetric gonadal dysgenesis (karyotype 45, X 0/46, XY). Two sizes (5 and 10 cm2) of E2 TTS, delivering respectively 25 and 50 µg of E2 a day for 3 1/2 days, were used in this study. All patients were initially given the lower dose of 25 µg, twice weekly for 3 weeks each month; 6 months after starting therapy, 5–10 mg oral medroxyprogesterone acetate (MPA) daily was added during the third week. Later, the following sequence was used: 25 µg E2 TTS (wice weekly), on days 1 through 14, and 50 µg E2 TTS (twice weekly), on days 15 through 25 of each month. On days 15 through 25, 5 mg daily of MPA were administered orally. The period of treatment ranged from 0.5 to 3 years. Breast development was obtained in all cases. The vaginal maturation index rose. Ultrasonography showed an increase of uterine size and uterine shape became of pubertal type. Withdrawal bleeding occurred in all patients. Plasma E2 levels rose to normal levels, estrone (E1) levels increased slightly. No change in plasma SHBG levels was observed. Urinary E2, E1 and estriol rose to maximum levels the 3rd day after the application of each system. Neither systemic side effects nor adverse metabolic effects were observed except for an increased sensitivity to the platelet aggregating agents. Patches were well tolerated and none of them was lost. In conclusion transdermal E2 therapy has been effective in inducing puberty in hypogonadal adolescents, providing physiological plasma estrogen concentrations. Moreover the harmful effects which are caused by oral E2 administration were not observed.

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References

  1. Olive D.L., Hammond C.B. Secondary amenorrhea: hypogonadotropinism. In: Krieger D.T., Bardin C.W. (Eds), Current therapy in Endocrinology and Metabolism. BC Decker Inc., Toronto, Philadelphia, 1985, p. 196.

    Google Scholar 

  2. Leyendecker G., Wildt L., Hausman M. Pregnancies following chronic intermittent (pulsatile) administration of GnRH by means of a portable pump. J. Clin. Endocrinol. Metab. 51: 1214, 1980.

    Article  PubMed  CAS  Google Scholar 

  3. Gompel A., de Plunkett T., Mandelbaun J., Mauvais-Jarvis P. Induction de l’ovulation par la pompe à la gonadoreline. Principes. Indications. Resultats. Presse Méd. 17: 963, 1985.

    Google Scholar 

  4. Mandel F.P., Geola F.L., Meldrum D.R., LU J.H.K., Eggena P., Sambhi M.P., Hershman J.M., Judd H.L. Biological effects of various doses of vaginally administered conjugated equine estrogens in postmenopausal women. J. Clin. Endocrinol. Metab. 57: 133, 1983.

    Article  PubMed  CAS  Google Scholar 

  5. De Lignieres B., Basdevant A., Thomas G., Thalabard J.C., Mercier-Bodard C., Conard J., Guyene T., Mairon N., Corvol P., Guy-Grand B., Mauvais-Jarvis P., Sitruk-Ware R. Biological effects of estradiol-17β in postmenopausal women: oral versus percutaneous administration. J. Clin. Endocrinol. Metab. 62: 536, 1986.

    Article  PubMed  Google Scholar 

  6. Holst J., Cajander S., Carlström K., Damber M.G., von Shoultz B. A comparison of liver protein induction in postmenopausal women during oral and percutaneous oestrogen replacement therapy. Br. J. Obstet. Gynecol. 90: 355, 1983.

    Article  CAS  Google Scholar 

  7. Nilsson B., Holst J., Von Schoultz B. Serum levels of unbound 17 β-oestradiol during oral and percutaneous postmenopausal replacement therapy. Br. J. Obstet. Gynecol. 91: 1031, 1984.

    Article  CAS  Google Scholar 

  8. Schenkel L., Barlier D., Gay C., Gschwind T. Substitution estrogénique par système transdermique. Rev. Fr. Gynécol. Obstét. 83: 453, 1988.

    PubMed  CAS  Google Scholar 

  9. Gurpide E. Metabolic influences on the action of estrogens: therapeutic implications. Pediatrics 62: 1114, 1978.

    PubMed  CAS  Google Scholar 

  10. Geola F.L., Frumar A.M., Tataryn I.V., LU K.H., Hershman J.M., Eggena P., Sambhi M.P., Judd H.L. Biological effects of various doses of conjugated equine estrogens in postmenopausal women. J. Clin. Endocrinol. Metab. 51: 620, 1980.

    Article  PubMed  CAS  Google Scholar 

  11. Mandel F.P., Geola F.L., LU J., Eggena P., Sambhi M.P., Hershman J.M., Judd H.L. Biological effects of various doses of ethinylestradiol in postmenopausal women. Obstet. Gynecol. 59: 673, 1982.

    PubMed  CAS  Google Scholar 

  12. Place V.A., Powers M., Darley P.E., Schenkel L., Good W.R. A double-blind comparative study of Estraderm and Premarin in the amelioration of postmenopausal symptoms. Am. J. Obstet. Gynecol. 15: 1092, 1985.

    Article  Google Scholar 

  13. Powers M.S., Schenkel L., Darley P.E., Good W.R., Balestra J.C., Place V.A. Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17 β-estradiol: Comparison with conventional oral estrogens used for hormone replacement. Am. J. Obstet. Gynecol. 152: 1099, 1985.

    Article  PubMed  CAS  Google Scholar 

  14. Steingold K.A., Laufer L., Chetkowski R.J., De Fazio J.D., Matt D.W., Meldrum D.R., Judd H.L. Treatment of hot flushes with transdermal estradiol administration. J. Clin. Endocrinol. Metab. 61: 627, 1985.

    Article  PubMed  CAS  Google Scholar 

  15. Tanner J.M. Growth at adolescence. Blackwell, Oxford, 1962.

    Google Scholar 

  16. Salardi S., Orsini L.F., Cacciari E., Bovicelli L., Tassoni P., Reggiani A. Pelvic ultrasonography in premenarcheal girls: relation to puberty and sex hormone concentrations. Arch. Dis. Child. 60: 120, 1985.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Nahoul K., Adeline J., Paysaut F., Scholler R. Radioimmunoassay of plasma and urine 6 β-hydroxycortisol: Levels in healthy adults and in hypercortisolemic states. J. Steroid Biochem. 17: 343, 1982.

    Article  PubMed  CAS  Google Scholar 

  18. Warnick G.R., Albers J.J. A comprehensive evaluation of the heparin-manganese procedure for estimating high density lipoprotein cholesterol. J. Lipid Res. 19: 65, 1978.

    PubMed  CAS  Google Scholar 

  19. Gidez L.I., Miller G.J., Burnstein M., Slagle S., Eder H.A. Separation and quantitation of subclasses of human plasma high density lipoproteins by a simple precipitation procedure. J. Lipid Res. 23: 1206, 1982.

    PubMed  CAS  Google Scholar 

  20. Assmann G., Jabs H.U., Kohnert U., Nolte W., Schriewer H. LDL-cholesterol determination in blood serum following precipitation of LDL with polyvinylsulphate. Clin. Chim. Acta 140: 77, 1984.

    Article  PubMed  CAS  Google Scholar 

  21. Bick L.R., Kovacs I., Fekete L.F.A. A new two-stage functional assay for antithrombin III (heparin cofactor): clinical and laboratory evaluation. Thromb. Res. 8: 745, 1976.

    Article  PubMed  CAS  Google Scholar 

  22. Breddin V.K., Bauke J. Thrombozytenagglutination und Gefaßrankheiten. Blut 11: 144, 1965.

    Article  Google Scholar 

  23. Born G.V.R. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 194: 921, 1962.

    Article  Google Scholar 

  24. Pacchiarini L., Storti C., Zucchella M., Salerno J.A., Grignani G., Fratino P. Fibrinopeptide A levels in patients with acute ischaemic heart disease. Hemostasis 19: 147, 1989.

    CAS  Google Scholar 

  25. Cisternino M., Bozzola M., Chiara A., Biscaldi I., Squillacioti F., Grignani G., Perani G., Roger M., Severi F. Transdermal estradiol substitution therapy for female hypogonadism in thalassemia major. Adolesc. Pediatr. Gynecol. 3: 25, 1990.

    Article  Google Scholar 

  26. Padwick M.L., Endacott J., Whitehead M.I. Efficacy, acceptability, and metabolic effects of transdermal estradiol in the management of postmenopausal women. Am. J. Obstet. Gynecol. 152: 1085, 1985.

    Article  PubMed  CAS  Google Scholar 

  27. Whitehead M.I., Padwick M.L., Endacott J., Pryse-Davies J. Endometrial response to transdermal estradiol in postmenopausal women. Am. J. Obstet. Gynecol. 152: 1079, 1985.

    Article  PubMed  CAS  Google Scholar 

  28. Toy J.L., Davies J.A., McNicol G.P. The comparative effects of a synthetic and a “natural” oestrogen on the haemostatic mechanism in patients with primary amenorrhoea. Br. J. Obstet. Gynecol. 35: 359, 1978.

    Article  Google Scholar 

  29. Poller L., Thomson J.M., Coope J. Conjugate equine oestrogens and blood clotting: a follow-up report. Br. Med. J. 1: 935, 1977.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  30. Conard J., Cazenave B., Samama M., Horellou M.H., Zorn J.R., Neau C. AT III content and antithrombin activity in oestrogenprogestogen and progestogen-only treated women Thromb. Res. 18: 675, 1980.

    Article  PubMed  CAS  Google Scholar 

  31. Wijburg F.A., van den Berg W., van Teunenbroeck A., Weening R.S. Thrombo-embolic complications after splenectomy in HbE-β-Thalassaemia. Lancet 2: 444, 1988.

    Google Scholar 

  32. Hirsh J., Dacie J.V. Persistent post-splenectomy thrombocytosis and thromboembolism: a consequence of continuing anemia. Br. J. Haematol. 12: 44, 1966.

    Article  PubMed  CAS  Google Scholar 

  33. Di Palma A., Morateli S., Cavallini A., Gamberini M.R., Guerra S., Vullo C., Ballerini G., Bagni B. Evaluation of β-Thromboglobulin and fibrinopeptide A plasma levels and bleeding time in splenectomized thalassaemic patients with insulin dependent diabetes mellitus. Eur. J. Pediatr. 146: 326, 1987 (Abstract).

    Google Scholar 

  34. Schaefer E.J., Foster D.M., Zech L.A., Lindgren F.T., Brewer H.B., Levy R.I. The effect of estrogens administration on plasma lipoprotein metabolism in premenopausal females. J. Clin. Endocrinol. Metab. 57: 262, 1983.

    Article  PubMed  CAS  Google Scholar 

  35. Godsland I.F., Wynn V., Path F.R.C., Crook D., Miller N.E. Sex, plasma lipoproteins, and atherosclerosis: prevailing assumptions and outstanding questions. Am. Heart J. 114: 1467, 1987.

    Article  PubMed  CAS  Google Scholar 

  36. Pike M.C., Henderson B.E., Mack T.M., Lobo R.A., Ross R.K. Stroke prevention and oestrogen replacement. Lancet 2: 1034, 1989.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Clinica Pediatrica, Università di Pavia, Pavia, Italia

    Mariangela Cisternino, M. Bozzola & F. Severi

  2. Dipartimento di Medicina Interna e Terapia Medica, Sezione di Patologia Medica e di Clinica Medica I, Università di Pavia, Pavia, Italia

    G. Grignani & G. Perani

  3. Clinica Ostetrica e Ginecologica, I.R.C.C.S. Policlinico San Matteo, Università di Pavia, Pavia, Italia

    P. Sampaolo

  4. Fondation de Recherche en Hormonologie, Fresnes, France

    K. Nahoul & M. Roger

Authors
  1. Mariangela Cisternino
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  2. K. Nahoul
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  3. M. Bozzola
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  4. G. Grignani
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  5. G. Perani
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  6. P. Sampaolo
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  7. M. Roger
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  8. F. Severi
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Cisternino, M., Nahoul, K., Bozzola, M. et al. Transdermal estradiol substitution therapy for the induction of puberty in female hypogonadism. J Endocrinol Invest 14, 481–488 (1991). https://doi.org/10.1007/BF03346847

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  • DOI: https://doi.org/10.1007/BF03346847

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