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Biomedical subjects

R Sitruk-Ware

Publications and source records attributed to R Sitruk-Ware.

At least 19 recordsLinked to original sources
PubMed1995

[Pharmacology of oral contraceptives].

Oral contraceptives include two types of steroids; ethinyl-estradiol as the main estrogenic component which dose vary from 20 to 50 micrograms per tablet (mostly 30 to 35 micrograms) and progestins essentially derivatives of 19 nortestosterone. Derivatives of 19 norprogesterone such as nomegestrol acetate or ST 1435 are not used as oral contraceptives but are being evaluated through parenteral administration, e.g. implants or transdermal systems. The assessment of the pharmacological properties of these progestins indicate a high antigonadotropic and a high antiestrogenic properties for levonorgestrel and for the newer gestagens as well. Therefore very low doses are being used in the current oral contraceptives. However, there is a lower margin of security with the low dose contraceptives than with previous standard combinations and especially when concomitant medications are ingested such as enzyme-inducing agents. Selection of contraceptive methods should be discussed when specific co-medications are necessary.

Contraceptives, Oral, Synthetic↗
PubMed1995

Transdermal application of steroid hormones for contraception.

The concept of transdermal delivery (TD) for steroid application has nowadays been largely accepted for hormone replacement therapy in the menopause. It is only recently that the same concept has been envisaged for contraception. The skin can be penetrated by both estrogens and progestins, provided they are delivered in an appropriate solvent. About 10% of the total dose applied topically is actually absorbed. The transdermal delivery systems (TDS) presently available are either of the reservoir type (membrane-moderated system) or of the matrix dispersion type where the drug is dispersed into a polymer matrix. Estradiol (E2) is the most appropriate steroid for TD and can be combined with progestins to ensure a contraceptive effect. Only potent progestins should be used to achieve effective plasma levels with low doses in order to maintain an acceptable small surface of TDS. TDS changed weekly and delivering both E2 and levonorgestrel (L-NG) at daily dosages of 38.4 (+/- 7.5) and 28.8 (+/- 7.2) micrograms/10 cm2 per day respectively, showed ovulation suppression. Another progestin derived from norprogesterone (ST 1435) has been shown to penetrate the skin when suspended in acetylated lanolin or dissolved in a hydroalcoholic gel and to ensure ovulation suppression at a dose of 2 mg per day in a small number of cycles. These preliminary data demonstrate the feasibility of suppressing ovulation in women by transdermal absorption of steroids. Using TDS for contraception implies that such systems should be perfectly adhesive, well tolerated locally and achieve nearly 100% efficacy. These targets are very challenging, however, the potential advantages are so high that the concept deserves further development.

Absorption↗
PubMed1995

Cardiovascular risk at the menopause--role of sexual steroids.

From epidemiological and experimental evidence it has been concluded that ovarian steroids have a large variety of cardiovascular effects. Among these are a direct action on the vascular wall, alterations in hemodynamics, modification of protein metabolism involved in the arteriosclerosis process, and alterations in the risk of cardiovascular morbidity and mortality. Some of the earlier epidemiological studies indicated an increased risk of cardiovascular disease (CVD) in estrogen users, but later on the majority of the published studies reported consistently a striking decrease in CVD by about 50%. The consistency in the positive results observed in successive epidemiological reports from various countries strongly suggest a protective effect of hormone replacement therapy on CVD morbidity. However, the direct demonstration of a protective effect of estrogens on CVD morbidity and mortality can only be made by long-term prospective controlled studies.

Animals↗
PubMed1994

Progestogen use and decreased risk of breast cancer in a cohort study of premenopausal women with benign breast disease.

A cohort study of 1,150 premenopausal French women with benign breast disease diagnosed in two breast clinics between 1976 and 1979 was carried out to analyse the relationship between progestogen use and the risk of breast cancer. The follow-up accumulated 12,462 person-years. The risk of breast cancer was estimated using a Poisson regression analysis on person-time data and the proportional hazards model. In the latter analysis, cumulated progestogen use and age were considered as time-varying covariables and adjustment was performed on the main risk factors for breast cancer. Neither overall progestogen use nor the duration of use was found to be significantly associated with the risk of breast cancer. When progestogens were classified into two categories according to their hormonal potency (19-nortestosterone derivatives vs other progestogens), 19-nortestosterone derivative use was found to be significantly associated with a lower risk of breast cancer. In the adjusted model, the corresponding risk of breast cancer was 0.48 (95% confidence interval 0.25-0.90). In addition, there was a linear trend in the decrease of the relative risk of breast cancer with the duration of use (P = 0.02). These results do not support the hypothesis that progestogens might increase the breast cancer risk. They suggest, instead, that treatment with 19-nortestosterone derivatives might have a beneficial effect on the risk of breast cancer in women with benign breast disease.

Adult↗
PubMed1993

A risk-benefit appraisal of transdermal estradiol therapy.

Estrogen replacement therapy (ERT) is very effective in relieving many menopausal symptoms such as hot flushes, night sweats, urogenital atrophy and psychological disturbances. Moreover, it is effective in the prevention of postmenopausal osteoporosis and has a favourable effect on some risk factors for cardiovascular disease in the long term, via several mechanisms including mediating effects on the lipid profile. Most of these beneficial effects are maintained with transdermal estradiol therapy, involving the use of a cutaneous delivery system attached to the skin which delivers a controlled rate of estradiol over a period of up to 4 days. However, the clear demonstration of a favourable effect on some risk factors for cardiovascular disease remains to be established. Transdermal administration of estradiol appears to be at least as effective as oral conjugated estrogen therapy on most of the end-points which have been evaluated, but allows a lower dose to be used, avoiding some of the metabolic adverse effects experienced with oral treatment. Endocrinological adverse effects, such as breast tenderness, breakthrough bleeding and fluid retention, are similar in both treatments, and can be minimised by dose adjustments in most cases. The most common adverse effects related to transdermal therapy are local skin reactions at the site of application. These are usually mild and transient in nature, and can be overcome by changing the site of application. Serious risks of transdermal therapy appear to be the same as those for other forms of ERT, namely an increased risk of endometrial hyperplasia and cancer with estrogen therapy alone. However, combination therapy involving the sequential administration of a progestogen has been shown to substantially reduce the risk of endometrial proliferation. The potential increased risk of breast cancer has been controversial and appears to be minimal with ERT. The role of progestogens on breast cancer risk remains controversial, but the data to date do not indicate any significant change in risk when progestogens are added to ERT.

Administration, Cutaneous↗
PubMed1993

Percutaneous and transdermal oestrogen replacement therapy.

The benefits of oestrogen replacement therapy (ERT) have been widely recognized. However, among the drawbacks ascribed to ERT, metabolic disturbances have been observed, particularly after oral administration of oestrogens. Therefore, other routes of delivering oestrogens have been developed. The advantages of delivering drugs through the skin for systemic therapy have been widely recognized and represent a growing sector in drug development. Transdermal delivery of steroids is also a rapidly expanding field and in various clinical situations where hormonal replacement therapy is needed this route of administration is a real breakthrough, considering the relative toxicity of some steroids when given orally. Percutaneous application of steroids has been proven successful in various disorders. Various occlusive transdermal systems have also been designed, all of them aimed at achieving a constant release rate of the molecules contained in their reservoir through the intact skin. The skin itself, and especially the outermost layer, the stratum corneum, can play the role of a reservoir and a rate-controlling membrane. In the field of reproductive hormones, so far, oestradiol, progesterone and testosterone have been demonstrated to be good candidates for transdermal delivery. The effectiveness and the acceptability of transdermal delivery of oestradiol in postmenopausal women have been demonstrated. All the beneficial effects of oestrogen therapy can be achieved through skin delivery, e.g. symptoms relief as well as osteoporosis prevention.

Administration, Cutaneous↗
PubMed1993

[Side effects of third generation progestins].

A large number of publications on oral contraceptives (OC) can be found in the medical literature. These reports deal not only with mode of action or efficacy of OCs but also with side effects. Adverse drug reactions (ADR) are not accepted nor acceptable from a population of young women free of disease who expect from their mode of contraception to be fully efficient and devoid from side effects. In most instances, side effects observed with OCs as well as their efficacy are related to the total dose of steroïds contained in the combination, to the balance between the estrogen and the progestin content and to the specific characteristics of the molecules. Cardiovascular morbidity and mortality reported in OC users have been related firstly to the ethinylestradiol (EE) and as a first step, the estrogen dose has been reduced in the OCs synthesized in the 70s. Later on, cardiovascular risk has been correlated to lipid profile changes and progestins with androgenic properties have been made responsible for cardiovascular events reported in OC users. In order to minimize the incidence of ADRs and to induce beneficial changes in lipid patterns, new progestational molecules devoid of androgenic properties have been recently synthesized. Three compounds called "third generation" progestins, derived from levonorgestrel are presently available in Europe. These three gonane progestins demonstrate affinity for the androgenic receptor, but when administered together with EE do not oppose the estrogenic effect observed on protein markers such as the Sex Hormone Binding Globulin (SHBG) or the High Density Lipoprotein (HDL).(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Coagulation↗
PubMed1992

Estrogens, progestins and breast cancer risk in post-menopausal women: state of the ongoing controversy in 1992.

During the past 10 years an extensive literature has been generated concerning the risks and benefits of hormonal replacement therapy in post-menopausal women. Although some of the questions have been answered during this period, controversy about the risk of breast cancer continues. This paper attempts to evaluate the risk of breast cancer in the light of epidemiological, experimental and histological findings. An interpretation of the available data and practical therapeutic recommendations are given. It is concluded that no change in the currently recommended schedule of combined sequential estrogen progestin therapy is necessary at this stage.

Breast Neoplasms↗
PubMed1992

Cyclical mastalgia as a marker of breast cancer susceptibility: results of a case-control study among French women.

A matched case-control study in a population of urban, non-menopaused women living in Paris was performed between 1983 and 1985 to investigate the risk of breast cancer (BC) in relation to various factors with a particular interest in the effect of the use of oral contraceptive (OC) and the existence of cyclical mastalgia (CM). Two hundred and ten non-menopaused women, less than 45 years old, with newly diagnosed BC were compared to 210 controls from the same geographic area matched on year of birth, age, education level and age at first full term pregnancy (FFTP), when justified. The adjusted Relative Risk of BC (RRa) was significantly increased for a total duration of OC use longer than 72 months (RRa 2.80; 95% CI 1.56-5.01), as well as the RRa for OC use above 48 months before FFTP (3.26 95% CI 1.37-7.76) and, to a lesser extent, the RRa for OC use above 48 months after FFTP (2.02 95% CI 1.07-3.84) respectively. Adjustment was performed on familial history of BC, personal history of Benign Breast Disease (BBD), age at menarche. A previous history of cyclical mastalgia was found to be associated with an increased risk of BC. The significant increase remained after adjustment on the previously mentioned confounding factors and OC use: RRa 2.12; 95% CI (1.31-3.43). Under a precise definition related to the hormonal environment, mastalgia appear to be an interesting marker of breast cell susceptibility, the importance of which can only be validated by prospective studies.

Age Factors↗
PubMed1990

[Estrogen replacement therapy and cardiovascular disease in postmenopausal women. II. Mechanisms of action of estrogens].

Recent epidemiological studies indicate that replacement therapy with oestrogens reduces the cardiovascular risk in postmenopausal women. This protective effect has been ascribed to oestrogen-induced metabolic variations, and notably to the rise of HDL-cholesterol levels observed after oral administration of oestrogens. Recently, long term studies have shown that parenterally administered oestrogens (implants, percutaneous or transdermal administration) have the same effect on blood lipid profile as oral oestrogen over a period of 6 months or more. Factors other than blood lipid changes should be studied in an attempt to elucidate the exact mechanism through which postmenopausal oestrogen administration may reduce the risk of cardiovascular diseases.

Angiotensinogen↗
PubMed1990

[Estrogens and cardiovascular risk in postmenopausal women. I. Epidemiologic data].

The possible role of oestrogens in modifying the occurrence of ischaemic heart disease and cardiovascular disease (CVD) in general in postmenopausal women has long been controversial. Analysis of the literature indicates a difference between the epidemiological studies published before 1980 and those published recently. In the former, the risk in women using oestrogen replacement therapy (ERT) was either unchanged or increased when compared with those women who did not use ERT. In the latter the trend has changed and a clear protective effect of ERT has been shown. These contradictory results might be explained by a change in prescribing habits, using lower oestrogen doses and selecting women with no risk factor for CVD as candidates for long-term ERT.

Adult↗
PubMed1990

The use of the antiprogestin RU486 (mifepristone) as an abortifacient in early pregnancy--clinical and pathological findings; predictive factors for efficacy.

RU486, a potent antiprogesterone steroid was administered to 124 women requesting therapeutic abortion. All were less than 49 days from their last menstrual period. Ten of these subjects (Group I) received high doses of RU486 in a decremental dose regimen (400, 300, 200 and 100 mg/day) over 4 successive days and 14 received 50 mg/day for 7 days (Group II). A further 50 subjects (Group III) received 100 mg/day for seven days and the remaining 50 subjects (Group IV) received 450 mg in a single dose. In the first three groups, half the daily dose was given in the morning and the remainder in the evening. Blood was collected before, and on Days 4 and 7 and then once a week after commencing therapy until disappearance of circulating beta HCG. In addition to beta HCG, estradiol-17 beta (E2), progesterone (P), cortisol, and various metabolic and hematological parameters were measured. Plasma RU486 concentrations were also assayed in Group II, III and IV subjects on Day 7 of therapy and in some cases on Days 14 and 21. Ultrasonography was performed in all cases on Day 1 and on Day 14. All the patients bled within five days following RU486 administration, for 1 to 21 days. A complete abortion occurred in 60% in Group I, 50% in Group II, 86% in Group III, and 80% in Group IV. The difference between the last two groups and the first two was significant at p less than 0.01. The non-responders were submitted to a uterine vacuum aspiration. A stepwise discriminant analysis was performed and indicated that the best predictors of the outcome of therapy were beta HCG values and the gestational sac diameter. With these criteria, the prediction was accurate in 86.4% of the cases. The best results were obtained in the cases where the ultrasonic measurement of gestational sac was under 10 mm in diameter and the initial beta HCG values under 15,000 mIU/ml. Among the observed side effects were moderate pelvic cramps (20.9%), nausea (27%), fainting (4.8%); 61.3% of the women complained of fatigue. Heavy bleeding occurred in 15.3% of the women but only one of them required blood transfusion. In the patients with complete abortion, beta HCG values decreased to below 500 mIU/ml by Day 14 (but in 11 cases values fell below 2,000 mIU/ml only by Day 21). Plasma estradiol and progesterone also fell. Cortisol levels increased during therapy especially in subjects of Group I, but returned to basal values after termination of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Abortifacient Agents↗
PubMed1990

Estrogen therapy during menopause. Practical treatment recommendations.

The potential benefits of estrogen replacement therapy (ERT) for postmenopausal women are now generally recognised, and no scientist involved in this field of research will deny the gratifying results of hormone therapy. However, in the risk-benefit equation the adverse effects of ERT must be carefully considered. Most of the harmful adverse effects of ERT have been related firstly to the absence of progestational balance, and secondly to the fact that most of the estrogens previously available for clinical use were artificial and administered orally, resulting in intensive hepatic metabolism, leading to metabolic disturbances. The need for the addition of progestogen leads also to consideration of the adverse effects of these substances. During the past decade therapeutic improvements have been achieved. Knowledge about the different types of steroids now available, the right choice of dosage and duration of therapy according to the needs of the patient, and the new alternative delivery systems improves day by day. Various steroids are now available for clinical use. Among the estrogens, orally administered drugs, natural derivatives of estradiol, and nonoral drugs delivered by injection, implant, vaginal ring or cream, ointment or transdermal system are at the prescriber's disposal. Among the progestogens available to the prescriber and recommended to be added to ERT, the molecules derived from testosterone [norethisterone (norethindrone), norgestrel] are less prescribed than the molecules derived from progesterone (didrogesterone) or from 17-hydroxyprogesterone (medroxyprogesterone acetate). In menopausal therapy the latter derivatives from progesterone or 17-hydroxyprogesterone are preferable, but low doses of any type of progestogen could be both protective of the target organs and devoid of harmful effects. Careful consideration of contraindications of treatment and regular follow-up are prerequisites for safe therapy. Recent epidemiological data now demonstrate clearly that the use of ERT under these conditions affords protection against osteoporosis and cardiovascular disease. Clear benefits to women's health may therefore be obtained from the adequate choice and surveillance of therapy.

Estrogen Replacement Therapy↗
PubMed1989

Transdermal delivery of steroids.

The advantages of delivering drugs through the skin for systemic therapy have been widely recognized and represent a growing sector in drug development. Transdermal delivery of steroids is also a rapidly expanding field and in various clinical situations where hormonal replacement therapy is needed this route of administration is a real breakthrough, considering the relative toxicity of some steroids when given orally. Various transdermal systems have been designed, all of them aimed at achieving a constant release rate of the molecules contained in their reservoir through the intact skin. The skin itself, and especially the outermost layer, the stratum corneum, can play the roles of a reservoir and a rate-controlling membrane. So far, estradiol, progesterone and testosterone have been demonstrated to be good candidates for transdermal delivery. The effectiveness and the acceptability of transdermal delivery of estradiol in postmenopausal women have been demonstrated. The efficacy of topical administration of progesterone in patients with benign breast disease has also been proved. More recently, the high rate of acceptability and efficacy of transdermal testosterone in male hypogonadism has been demonstrated. The transdermal delivery of steroids is therefore expected to make a significant impact on the quality of patient care both in men and in women.

Administration, Cutaneous↗
PubMed1989

Risk factors for breast fibroadenoma in young women.

In a case-control study, 178 women diagnosed with fibroadenoma (FA) between 1976 and 1982 were compared with 178 age-matched controls in order to assess the risk factors for FA. Women who had a previous diagnosis of breast disease were excluded. The odds ratios (OR) of FA were calculated for different risk factors of breast disease from bivariate analysis as well as multivariate regression analysis. The highest ORs were found for a previous premenstrual mastalgia before first childbirth and a familial history (FH) of breast cancer (BC). Oral contraceptive (OC) use before a first full-term pregnancy (FFTP) does not modify this risk. Also current use of standard oral contraceptives (SOC) containing 50 micrograms of ethinyl estradiol per pill appeared to be protective and the correlation with FA was negative. These findings underline: (a) the predictive value of premenstrual mastalgia for the subsequent development of breast disease; (b) only current high-dose OC use is protective.

Adenofibroma↗