Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: second report of the Hormones and Urogenital Therapy Committee.

OBJECTIVE: To evaluate the efficacy of estrogen therapy in the treatment of postmenopausal women with symptoms and signs associated with urogenital atrophy, by meta-analysis of available data. METHODS: We searched the literature (Excerpta Medica, Biosis, MEDLINE, and hand search) for studies published between January 1969 and April 1995. Criteria for inclusion were English-language articles, peer-reviewed original publications, and urogenital atrophy assessed by at least one of the following outcomes: patient symptoms, physician report, pH, or cytologic change. Data had to allow comparison between treated and control groups in controlled trials or an estimated change from baseline in uncontrolled series. Meta-analytic methods were applied separately to controlled clinical trials and uncontrolled studies. RESULTS: Of the 77 relevant articles reviewed, nine contained ten randomized controlled trials. Meta-analysis of these using the Stouffer method revealed a statistically significant benefit of estrogen therapy for all outcomes studied. In 54 uncontrolled case series, the patient symptoms were treated by 24 different treatment modalities. All routes of administration appeared to be effective and maximum benefit was obtained between 1 and 3 months after the start of treatment. As expected, the least systemic absorption of estrogen was seen with estriol (administered orally or vaginally), then vaginal estradiol as measured by pretherapy and posttherapy serum estradiol and estrone. CONCLUSION: Estrogen is efficacious in the treatment of urogenital atrophy and low-dose vaginal estradiol preparations are as effective as systemic estrogen therapy in the treatment of urogenital atrophy in postmenopausal women.

Pharmacokinetic data on estradiol in light of the estring concept. Estradiol and estring pharmacokinetics.

The pharmacokinetics and pharmacodynamics of estradiol in humans are briefly reviewed in this paper. The estradiol vaginal ring was designed and developed to obtain controlled local delivery of very low doses of estradiol resulting in a marginal effect on plasma concentrations of estradiol, associated with a margin of safety over a prolonged period of time. Three clinical studies in postmenopausal women with signs and symptoms while plasma levels remain virtually unchanged in the lower part of the normal postmenopausal range. No pharmacodynamic effects of estrogen could be detected, reflecting a very low systemic exposure. The estradiol exposure and the plasma concentration time course during treatment with first and second ring during first month of the intended three month treatment period are compared. The very low systemic exposure is discussed in relation to existing therapies. Ongoing pharmacokinetic work with estradiol vaginal ring is briefly described. It is concluded that the estradiol vaginal ring is a very stable alternative to existing vaginal therapies, resulting in a very low systemic exposure to estradiol, and is associated with a minimal risk of drug interaction and has a high margin of safety.

New kinetic data on estradiol in light of the vaginal ring concept.

The principal estrogen produced by the functioning premenopausal ovary is 17 beta-estradiol. At the point of irreversible ovarian failure, at menopause, the production of estradiol decreases dramatically, which results in circulating serum levels less than 120 pmol/l. It is important to recognise the pharmacokinetic and metabolic outcomes associated with dosage and route of delivery of estrogen. One of the most promising methods of administering estrogen replacement therapy (ERT) for local effects is the estradiol vaginal ring designed for a controlled continuous low release (7.5 micrograms estradiol/24 h) over a period of 90 days. The present study was undertaken to characterise the basal endogenous turnover of estradiol in postmenopausal women. Information on the disposition of estradiol after an intravenous dose formed the base of the kinetic model. The rate of extent of absorption of estradiol was assessed after ring application. Individual serum concentrations of estradiol were analysed without subtraction of the basal estradiol levels. The results indicate a rapidly eliminated compound (plasma clearance 2 l/min) with a distribution of approximately 50 l, resulting in an efficient half-life of about 20 min. The endogenous production was highly variable (< 1-44 micrograms/24 h). The steady-state estradiol levels following ring application did not increase and were well within the normal basal estradiol range seen in untreated women. In light of the present findings, the low daily dose, the low availability of estradiol across the vaginal wall and the controlled local delivery, favour the use of the estradiol vaginal ring.

Adrenergic innervation of the human endolymphatic sac.

Adrenergic innervation of the human endolymphatic sac (ES) has not been verified previously. To investigate this question a sensitive histofluorescence method for visualization of catecholamines and serotonin, using a solution composed of sucrose-potassium phosphate-glyoxylic acid (SPG) in cryostat sections, was employed. Three human ES specimens were obtained during surgery for acoustic neuroma. Distinct fluorescence in the subepithelial tissue, indicating the presence of monoaminergic neurones and their axonal varicosities, was observed. SPG-positive terminal nerve fibres around small ES capillaries and subendothelially were also seen. Like the effects of sympathetic stimulation elsewhere in the human body, the ES might respond to such stimulation with, for example, vasoconstriction and increased transepithelial water transport. Since the ES is thought to be responsible for maintaining inner ear fluid homeostasis, adrenergic influence could be important for it to function properly.

The antiprogestational agent RU 486 as an abortifacient in early human pregnancy: a comparison of three dose regimens.

Three different regimens of RU 486, a progesterone receptor blocking agent, were compared for their ability to terminate early human pregnancy. One-hundred-fifty-three healthy women with a gestational length less than 49 days from the last menstrual period were recruited to the study and randomly allocated to one of three treatment regimens: 1) RU 486 10 mg x 2 for seven days; 2) RU 486 25 mg x 2 for seven days; or 3) RU 486 50 mg x 2 for seven days. No significant difference in efficacy was seen between the three dose regimens. Treatment with 10 mg x 2 x VII resulted in 73 per cent complete abortions, 25 mg x 2 x VII in 66 per cent and 50 mg x 2 x VII in 64 per cent complete abortions. Response to treatment, measured as reported onset of bleeding and passage of products of conception, however, occurred significantly later on the 10 mg x 2 regimen than on the other two dose regimens. In each treatment group, women who subsequently aborted completely had significantly lower pretreatment levels of hCG than women with incomplete abortion or continuing pregnancy. The treatment was well tolerated by the women and except for one woman who experienced a profound bleeding necessitating a blood transfusion, no serious side effects were seen.

Effects of the antiprogesterone RU 486 in normal women. I. Single-dose administration in the midluteal phase.

The response to a single oral dose of the antiprogesterone RU 486 was studied in the midluteal phase in 26 normal women. Each subject received a dose between 50 and 800 mg RU 486 on days 6 to 8 after the luteinizing hormone surge and blood samples were taken over the following 48 hours. Another group of five patients received a single oral dose of 200 mg RU 486 and blood sampling was extended for 14 days. Menses were induced in all women but one within 3 days after RU 486 administration. Two distinct patient populations emerged. In nine of the subjects, there was a single bleeding episode and the treatment cycle was significantly shorter (p less than 0.05) than the following cycle. In 16 of these 25 patients a second bleeding episode occurred 19.0 +/- 0.8 days after the luteinizing hormone surge. The total treatment cycle was significantly prolonged (p less than 0.05) when compared with the following cycle. In the group with a single bleeding episode, there was a significant decline in follicle-stimulating hormone, estradiol, and progesterone over the 48-hour sampling period, but there was no change in these values in the group with two bleeding episodes. These two groups could not be separated on the basis of RU 486 dose or serum levels. After the four higher doses, there was a dose-dependent rise in serum prolactin. There were no alterations in mean cortisol values with the three lower doses, but there was a significant increase at 24 and 48 hours after the higher doses. Serum levels of RU 486 were maximal between 1 and 4 hours and the half-life of serum RU 486 was determined to be 24 hours.

Early pregnancy termination with antiprogestins: a comparative clinical study of RU 486 given in two dose regimens and Epostane.

Mifepristone, (RU 486, Roussel Uclaf, Romainville, France), a progesterone (P) receptor blocking agent, and Epostane, (WIN 32,729, Sterling-Winthrop, Guildford, United Kingdom), a P synthesis inhibitor, were compared for their ability to terminate early human pregnancy. Seventy-eight healthy women, with a gestational length of less than 49 days from the last menstrual period and who requested termination of pregnancy, were recruited to the study. The patients were randomly allocated to three treatment regimens: (1) Mifepristone 25 mg bid for 7 days; (2) Mifepristone 50 mg bid for 7 days; and (3) Epostane 200 mg qid for 7 days. The results of the study confirmed that both compounds are potent abortifacients in early human pregnancy. No difference in efficacy was seen between the two dose regimens of Mifepristone, which both resulted in 61% complete abortions. Seventy-three percent aborted completely in the Epostane group. Subjective side effects, especially nausea, were more common in the women treated with Epostane, but no serious side effects were seen.

PIP: Two contragestational agents, Mifepristone and Epostane, were compared in 78 pregnancy terminations at 49 days or less gestation. Mifepristone (RU 486, Roussel Uclaf, Romainville, France) is a steroid that antagonizes progesterone receptor binding in the decidua. It was taken twice daily at 25 or 50 mg for 7 days. Epostane (WIN 32,729, Sterling-Winthrop, Guildford, United Kingdom) is a progesterone synthesis inhibitor at 3B-hydroxy steroid dehydrogenase level acting on the endometrium. Women took 200 mg 4 times daily for 7 days. The criteria for complete abortion were bleeding and cervical dilatation with passage of products of gestation by Day 7, return to normal uterine size by Day 14 with hCG less than 10% of initial level. 61% of both Mifepristone groups aborted completely, and 83% of the women who completed the Epostane schedule did so. 3 women abandoned the Epostane regimen because of nausea. Only 2 incomplete abortions occurred in the Mifepristone group; the rest failed to abort and had vacuum aspiration on Day 7. Variations in blood chemistries and analysis of progesterone, hCG, estradiol and cortisol are discussed. The week-long treatment with Epostane is probably necessary, but dose and length of treatment with Mifepristone could be manipulated to get a more rapid response. Although the patients were satisfied with these regimens, they were not as efficient as vacuum aspiration or prostaglandin suppositories. Possibly both antiprogestins and even prostaglandins could be combined for better results.

Familial Menière's disease: a genetic investigation.

Familial forms of Meniere's disease in which the main etiologic factor is probably genetic are described. Among ninety-one patients with Meniere's disease from the county of Uppsala, the disease could be classified as being of familial origin in 14%. Different modes of inheritance were revealed. Aberrations in chromosome 7 were found in one mother and her daughter.

Termination of early human pregnancy with epostane.

Fifty-six healthy women, with a gestational length of less than 49 days from the last menstrual period, who requested termination of pregnancy were treated with Epostane, a progesterone synthesis inhibitor. Epostane, which competitively inhibits the 3 beta-hydroxy steroid dehydrogenase enzyme system, was given in the dose 200 mg X 4 for seven days. Physical examination, routine laboratory screening and determination of hCG, progesterone, estradiol and cortisol was performed on days 0, 7 and 14. The treatment resulted in 84% complete abortions (90% among women completing therapy). Two women experienced vaginal bleeding only, while 7 were non-responders. Among subjective side effects nausea dominated totally and was also the reason for discontinuation in 4 cases. The average length of bleeding among women with complete abortions was 10.7 days and the decrease in hemoglobin and hematocrit was very slight. Routine laboratory values remained within the normal range. Cortisol levels were elevated on day 7 compared to days 0 and 14, but all single values were within the normal limits.

PIP: 56 healthy women, with a gestational length of 49 days from the last menstrual period, who requested termination of pregnancy were treated with Epostane, a progesterone synthesis inhibitor. Epostane, which competitively inhibits the 3 beta-hydroxy steroid dehydrogenase enzyme system, was given in the dose 200 mg x 4 for 7 days. Physical examination, routine laboratory screening, and determination of hCG, progesterone, estriadol, and cortisol were performed on days 0, 7, and 14. The treatment resulted in 84% complete abortions (90% among women completing therapy). 2 women experienced vaginal bleeding only, while 7 were non-responders. Among subjective side effects nausea dominated totally and was also the reason for discontinuation in 4 cases. The average length of bleeding among women with complete abortions was 10.7 days and the decrease in hemoglobin and hematocrit was very slight. Routine laboratory values remained within the normal range. Cortisol levels were elevated on day 7 compared to days 0 and 14, but all single values were within the normal limits.

Pharmacokinetics and metabolism of RU 486.

The effects of dose on the initial pharmacokinetics and metabolism of an antiprogesterone steroid RU 486 (mifepristone) were studied in healthy female volunteers after administration of RU 486 as a single dose of 50-800 mg. The concentrations of RU 486 and its monodemethylated, dimethylated and hydroxylated non-demethylated metabolites were measured specifically after Chromosorb-column chromatography by HPLC. Their relative binding affinities to the human uterine progesterone receptor were also determined. Micromolar concentrations of the parent compound in blood were reached within the first hour after oral administration. The pharmacokinetics of RU 486 followed two distinct patterns in a dose-dependent fashion. With a low dose of 50 mg the pharmacokinetics followed an open two-compartment model with a half-life of over 27 h. With the doses of 100-800 mg the initial redistribution phase of 6-10 h was followed by zero-order kinetics up to 24 h or more. Importantly, after ingestion of doses higher than 100 mg of RU 486 there were no significant differences in plasma concentrations of RU 486 within the first 48 h, with the exception of plasma RU 486 concentrations at 2 h. After single oral administration of 200 mg unchanged RU 486 was found 10 days later in two subjects. The elimination phase half-life with this dose, calculated between day 5 and 6, was 24 h. Micromolar concentrations of monodemethylated, didemethylated and non-demethylated hydroxylated metabolites were measured within 1 h after oral administration of RU 486. In contrast to plasma RU 486 concentrations, circulating plasma concentrations of metabolites increased in a dose-dependent fashion. With higher doses the metabolite concentrations were close to, or even in excess to the parent compound. The relative binding affinities of RU 486, monodemethylated, didemethylated and hydroxylated metabolites (progesterone = 100%) to the human progesterone receptor were 232, 50, 21, and 36, respectively. The existence of a high affinity-limited capacity serum binding protein would explain the long half-life and the observed diverging dose-dependent pharmacokinetics. The extravasation of RU 486 after the saturation of serum binding sites would explain the blunted serum peak concentrations of RU 486 with higher doses. The return of the drug back to circulation thereafter explains the zero-order kinetics. High concentrations of circulating metabolites capable of binding to the progesterone receptor suggest a significant contribution of these steroids in the overall antiprogestational action.

Effects of Epostane on progesterone synthesis in early human pregnancy.

Healthy women requiring abortion in early normal pregnancy were recruited to study the abortifacient effects of different doses of Epostane, an inhibitor of 3 beta-hydroxy steroid dehydrogenase, that previously has been shown to interfere with progesterone production in the luteal phase of humans and to have abortifacient effects in animals. A single dose of 100 mg resulted in decreasing progesterone and estradiol, which rapidly recovered, and none of the women started to bleed. Repeated doses of 50 or 100 mg during one day resulted in a more pronounced decrease in both progesterone and estradiol, but no bleeding. When treatment was prolonged over several days with 100 mg X 4 for five days and 400 mg X 2 for four days, respectively, a suppression of progesterone and estradiol was found and two out of four and eight out of ten women started to bleed and subsequently aborted. The treatment was well tolerated by most of the women. Routine laboratory parameters remained unaltered throughout treatment. Cortisol levels remained within the normal range.