Effects of vaginally-administered oestriol on post-menopausal urogenital disorders: a cytohormonal study.

Forty post-menopausal women with urogenital disorders who were inpatients in the same geriatric hospital were treated with oestriol (E3) for 6 weeks. For the first 2 weeks 0.5 mg E3 (Leo AB, Sweden) was administered intravaginally every day. Over the following 4 weeks the patients received the same quantity either once or twice weekly as a maintenance dose. Oestrogen influence on the vaginal and urethral epithelium was assessed by means of the karyopyknotic index (KPI), while the degree of maturation of the vaginal epithelium was estimated visually. Urinary bacteria were cultivated. A pronounced and progressive rise in KPI was seen in both the vaginal and the urethral epithelium following daily E3 treatment. However, neither of the two maintenance dosages was sufficient to sustain the initial maturation of the vaginal and urethral epithelium induced by E3, since the KPI returned to pretreatment values within 4 weeks. The effect of E3 administration on the vaginal epithelium was overestimated by the visual assessment method. No changes were seen in urinary bacteria. Medroxyprogesterone acetate was given before and after E3 treatment. None of the women suffered from withdrawal bleeding.

Estriol in the postmenopause.

Estriol is regarded as a mild and brief-acting hormone and, as such, has been prescribed for over four decades as a therapeutic agent for postmenopausal women with urogenital disorders. The dosages administered and the results obtained have varied considerably in earlier studies. Pharmacokinetic studies of estriol and the effects induced on the target tissues have been contradictory. The pharmacokinetics of unconjugated estriol after vaginal and oral medication was studied. One mg estriol applied vaginally resulted in plasma estriol concentrations similar to those obtained when 10 mg estriol was given orally. The clinical importance of the enterohepatic recirculation on plasma estriol concentrations after orally administered estriol was demonstrated. Factors that influence the pharmacokinetics of estriol are the time of estriol administration, fat-rich food, as well as the spacing of meals. Thus, the enterohepatic recirculation of estriol affects the plasma estriol elevation time and thereby the potency of estriol. The enterohepatic recirculation seemed to be less important in vaginal administration of estriol as the first liver passage is circumvented. Instantaneous and substantial conjugation of estriol in the liver is thereby avoided. By cytological assessment of the vaginal and the urethral epithelium in 40 patients treated in a geriatric hospital, the commonly recommended maintenance dosages of estriol (0.5 mg vaginally 1-2 times per week) were found to be too low to cure vaginal and urethral atrophy in very old women. This study suggests that estriol is a biologically potent estrogen by both oral and vaginal administration. The route and the time of administration, the food habits as well as the dosages given are factors which contribute to the estrogenicity of estriol. In clinical use, vaginal treatment seems preferable because the first liver passage is avoided. Vaginal administration allows a more standardized estriol regimen, while the oral treatment is more difficult to tailor for suit most women's needs.

Plasma oestriol following vaginal administration: morning versus evening insertion and influence of food.

The aim of this trial was to study the vaginal absorption of oestriol and to investigate whether morning rather than evening oestriol administration would produce different plasma oestriol patterns. The influence of food intake on plasma oestriol levels was also investigated. Nine post-menopausal women were given 0.5 mg oestriol (ovula supplied by Leo AB, Sweden) intravaginally every evening for 16 days. Thereafter, 1 mg oestriol was given every evening for another 5 days, except on treatment days 18 and 19 when 1 mg oestriol was given in the morning instead. Venous blood samples were collected at frequent intervals on day 19 (morning administration) and a meal was allowed 4 h later. On the day 21 (evening administration), venous blood samples were taken at frequent intervals during the night and no meal was given until the next morning. Plasma concentrations of unconjugated oestriol were measured by means of a specific radioimmunoassay (RIA). A difference was seen in the plasma oestriol patterns when the results following morning and evening administration were compared. However, no significant difference as regards the total 24-h systemic availability of oestriol was observed. A minimal increase in plasma oestriol levels was seen after a meal in the case of both morning and evening intravaginal oestriol administration, possibly as a result of enterohepatic recirculation.

Enterohepatic recirculation of oestriol: inhibition by activated charcoal.

We have earlier reported on a prolonged effect of orally administered oestriol caused by its enterohepatic recycling after reabsorption from the intestine. The aim of the present study was to test if oral administration of activated charcoal could inhibit the enterohepatic recirculation of orally given oestriol. Plasma concentrations of unconjugated oestriol were measured using a specific radioimmunoassay (RIA). Twelve mg oestriol administered orally to postmenopausal women resulted in elevated plasma oestriol levels for more than 24 h. Plasma oestriol fluctuations in relation to meals were seen. When activated charcoal was given 3 h after oestriol administration, the plasma oestriol concentration declined without further fluctuations and returned to the pretreatment value within 6 h. Our data indicate that oestriol given orally undergoes enterohepatic recirculation after reabsorption from the intestine since administration of charcoal, which binds steroids, resulted in a rapidly declining oestriol level. It is concluded that the prolonged oestriol elevation, which is normally seen, is caused by enterohepatic recycling.

Enterohepatic recirculation of oestriol studied in cholecystectomized and non-cholecystectomized menopausal women.

This study was done to evaluate the absorption of a single oral dose of 12 mg oestriol (Triovex, Leo AB, Sweden) and to confirm the hypothesis that the enterohepatic recirculation can prolong the plasma oestriol elevation obtained. Twelve menopausal women, six of whom had been cholecystectomized earlier, were given 12 mg oestriol orally. Fatty meals were given immediately after drug administration and then at four hourly intervals. Fat was given to induce the bileflow and provide oestriol to the intestine for deconjugation and enterohepatic recycling. One of the non-cholecystectomized women also remained fasting for 24 hours after oestriol administration. Plasma concentrations of unconjugated oestriol were measured by a specific RIA-method. In all women the plasma oestriol levels were considerably elevated for 24 hours. In the non-cholecystectomized women the plasma oestriol levels fluctuated in relation to meals whereas in the cholecystectomized women the fluctuations were not as pronounced, indicating that the release of biliary oestriol metabolites is the source of intestinal degradation and reabsorption to the systemic circulation. Fasting also gave increased and stable plasma oestriol levels. After a high oral dosage of oestriol, the enterohepatic recycling renders oestriol an enhanced potency since the plasma oestriol elevation time is prolonged.