Lotte Schenkel

Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17β-estradiol: Comparison with conventional oral estrogens used for hormone replacement

This open-label, multiple-crossover study compared the pharmacokinetics and pharmacodynamics of transdermal 17 beta-estradiol and two oral forms of estrogen replacement therapy in postmenopausal women. The transdermal systems delivered either 0.025, 0.05, or 0.1 mg/day; oral dosages were 2 mg of micronized 17 beta-estradiol or 1.25 mg of conjugated equine estrogens. Transdermal estradiol provided serum and urinary levels of estradiol conjugates typical of the early follicular phase of the premenopausal woman and an estradiol/estrone ratio that approximated 1. The increments of both serum and urinary estradiol showed dose proportionality. Serum levels of estradiol obtained 24 hours after oral administration of estrogens were in a range similar to the steady-state levels obtained with transdermal estradiol delivery. Oral estrogens, however, induced an excessive rise in estrone to levels far beyond those observed in premenopausal women. Continuous application of transdermal estradiol over 3 weeks did not result in any accumulation of estradiol or estradiol conjugates. After only three doses of oral estrogens, there were signs of retention of estrogens. Suppression of gonadotropins by oral and transdermal administration of estrogens was in a similar range. This observation supports the conclusions that levels of circulating estradiol are relevant to efficacy, and that excessively high levels of estrone after oral administration of estrogens merely represents a nonphysiologic precursor or metabolite pattern.

A new transdermal delivery system for estradiol

Abstract The successful introduction of nitroglycerin transdermal delivery systems for the prophylactic treatment of angina pectoris has spawned an explosion of interest in this route of drug delivery in the field of pharmaceutics. Since that time, we have gained a great deal more knowledge concerning the design of membrane controlled delivery systems. This route of administration has been proposed and investigated in a number of disease states using several drugs. We would like to report our experience in investigating the transdermal route for long term treatment of postmenopausal symptoms using estradiol replacement therapy. The rationale for the development of a transdermal estradiol system is associated with the metabolic and pharmacological effects of orally administered estrogen replacement in post-menopausal women. Because estradiol is metabolized almost completely on first pass through the liver, orally administered estrogens result in nonphysiologic levels of the estrogenic metabolites of the natural ovarian hormone. Transdermal delivery of estradiol successfully by-passes the first pass effect and results in a more normal estrogen blood profile. The results of several biopharmaceutics studies demonstrate the characteristics of the membrane controlled delivery system which was designed around pharmacologic principles. In addition, a number of clinical trials have shown that total required doses of estradiol provided transdermally are only a fraction of those required by the oral route. We will also discuss problems associated with adequately defining total drug input from transdermal devices when working in these very small dosing ranges.

A double-blind comparative study of Estraderm and Premarin in the amelioration of postmenopausal symptoms

Patients whose postmenopausal symptoms were being satisfactorily controlled with conjugated equine estrogens, either 0.625 mg/day (n = 57) or 1.25 mg/day (n = 67), participated in a study that compared the efficacy of these oral regimens with that of 17 beta-estradiol, 0.1 mg/day, administered through intact skin. The study was a multicenter, double-blind, randomized, parallel-group trial during which two thirds of the patients who received each dosage of conjugated equine estrogens were changed to an estradiol transdermal system while the remainder continued with conjugated equine estrogens. A total of 124 patients was included in the analysis of efficacy. The analysis revealed no significant differences between the estradiol transdermal system and conjugated equine estrogens in control of hot flushes or other postmenopausal symptoms and no statistically significant differences between treatment groups in regard to estrogen-related side effects. Minor topical reactions to the transdermal systems were reported during only about 20% of study weeks. Thus, transdermal estradiol, 0.1 mg/day, appears to be equally effective as conjugated equine estrogens, 0.625 or 1.25 mg/day, for controlling postmenopausal symptoms and is well tolerated.

Transdermal administration of oestrogen/progestagen hormone replacement therapy

The effects of an oestrogen/progestagen transdermal therapeutic system (TTS) were evaluated in sixteen oestrogen-deficient women. The patients applied conventional oestradiol-TTS for 14 days, then two combined norethisterone acetate/oestradiol patches for a further 14 days. The treatment was repeated for five cycles. Ten patients then underwent metabolic studies. One patient had amenorrhoea, but the rest experienced regular withdrawal bleeding which was seldom heavy. Fourteen endometrial biopsy samples were taken during the fifth treatment cycle; none showed proliferative or hyperplastic features. The effects of transdermal norethisterone acetate on symptoms, lipid metabolism, and psychological status were determined by comparing features in the oestrogen-only phase and in the combined phase; the effects were very mild. These preliminary findings show that transdermal progestagen can be successfully administered in hormone replacement therapy to prevent endometrial proliferation while minimising the adverse effects that may be seen with oral administration.

Transdermal absorption of estradiol 101 from different body sites is comparable

Abstract A study was conducted with Estraderm TTS m 10 postmenopausal women to assess potential differences of estradiol uptake from different skin sites. Estradiol conjugates in morning urine samples were determined to monitor estradiol uptake. Estraderm TTS 50 or 25 was administered in a randomized sequence to 6 different sites (abdomen, buttocks, upper thigh, lower back, lateral thorax, upper arm); each system was left in situ for 3 days. The urinary estradiol values were subjected to analysis of variance; there was no significant difference between sites of application, but a highly significant difference between subjects. No significant difference was found between urinary estradiol values obtained during application to the abdomen, the buttocks, the lower back, the lateral thorax or the upper arm. If subjected to paired t-test analysis, the difference between abdomen (100%) and upper thigh (85%) was significant. In conclusion: Estraderm TTS applied at any site on the trunk or the upper arm will result in comparable absorption.

Does low-dose, transdermal, norethisterone acetate reliably cause endometrial transformation in postmenopausal oestrogen-users?

In a prospective study, the symptomatic, psychological and endometrial effects of a combined oestradiol/progestogen transdermal therapeutic system which delivers a low daily dose of norethisterone acetate have been investigated in 18 postmenopausal women. Treatment was given in 28 day cycles. Patients received transdermal oestradiol 50 micrograms/day continuously and transdermal norethisterone acetate, 0.1-0.15 mg/day, was added for 14 days. Treatment was given for between 5 and 7 cycles. One patient discontinued therapy because of a skin reaction. Low dose, transdermal norethisterone acetate caused few adverse symptomatic or psychological side-effects and appeared well tolerated. Fourteen endometrial samples were obtained during the combined (norethisterone acetate/oestradiol) phase of the 5th, 6th or 7th treatment cycle. None showed hyperplastic or malignant change but proliferative endometrium, indicative of an inadequate progestational stimulus, was observed in 4 biopsy samples. Three of these patients had reported breakthrough bleeding during therapy. For these reasons, we regard this dose of transdermal norethisterone acetate as inadequate in combination with transdermal oestradiol 50 micrograms/day for routine use in postmenopausal oestrogen users.