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Background: Obstetrical analgesia remains a matter of controversy because of the fear of neurotoxicity of local anesthetics on demyelinated fibers or their potential relationship with subsequent relapses. Objective: To assess the impact of neuraxial analgesia on the risk of relapse during the first 3 months post-partum, with a focus on women who experienced relapses during pregnancy. Methods: We analyzed data of women followed-up prospectively during their pregnancies and at least 3 months post-partum, collected in the Pregnancy in Multiple Sclerosis (PRIMS) and Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPARTMUS) studies between 1992–1995 and 2005–2012, respectively. The association of neuraxial analgesia with the occurrence of a post-partum relapse was estimated by logistic regression analysis. Results: A total of 389 women were included, 215 from PRIMS and 174 from POPARTMUS. In total, 156 women (40%) had neuraxial analgesia. Overall, 24% experienced a relapse during pregnancy and 25% in the 3 months post-partum. Women with a pregnancy relapse were more likely to have a post-partum relapse (odds ratio (OR) = 1.83, p = 0.02), independently of the use of neuraxial analgesia. There was no association between neuraxial analgesia and post-partum relapse (OR = 1.08, p = 0.78). Conclusion: Neuraxial analgesia was not associated with an increased risk of post-partum relapses, whatever multiple sclerosis (MS) activity during pregnancy.

Summary Background Hormonal methods for safe, reliable, and reversible contraception based on the suppression of spermatogenesis could soon become available. We have investigated the rate, extent, and predictors of reversibility of hormonal male contraception. Methods We undertook an integrated multivariate time-to-event analysis of data from individual participants in 30 studies published in 1990–2005, in which sperm output was monitored every month until recovery. The primary outcome was the time for the sperm concentration to recover to a threshold of 20 million per mL, an indicator of fertility. We undertook univariate and multivariate analyses, using Kaplan-Meier and Cox's methods. Findings 1549 healthy eugonadal men who were white (n=965), Asian (almost all Chinese men; n=535), or of other origins (n=49) and aged 18–51 years underwent 1283·5 man-years of treatment and 705 man-years of post-treatment recovery. These data represented about 90% of all published data from individuals using androgen or androgen-progestagen regimens. The median times for sperm to recover to thresholds of 20, 10, and 3 million per mL were 3·4 months (95% CI 3·2–3·5), 3·0 months (2·9–3·1), and 2·5 months (2·4–2·7), respectively. Multivariate Cox's analysis showed higher rates of recovery with older age, Asian origin, shorter treatment duration, shorter-acting testosterone preparations, higher sperm concentrations at baseline, faster suppression of spermatogenesis, and lower blood concentrations of luteinising hormone at baseline. The typical probability of recovery to 20 million per mL was 67% (61–72) within 6 months, 90% (85–93) within 12 months, 96% (92–98) within 16 months, and 100% within 24 months. Interpretation Hormonal male contraceptive regimens show full reversibility within a predictable time course. Various covariables affect the rate but not the extent of recovery, although their effect sizes are minor. These data are crucial for the further safe and practical development of such regimens.

In the last years there has been an extraordinary development in the synthesis of new progestins. These compounds are classified, in agreement with their structure, in various groups which include progesterone, retroprogesterones, 17 α -hydroxyprogesterones, 19-norprogesterones, 17 α -hydroxyprogesterone derivatives, androstane and estrane derivatives. The action of progestins is a function of many factors: its structure, affinity to the progesterone receptor or to other steroid receptors, the target tissue considered, the biological response, the experimental conditions, dose, and metabolic transformation. The information on the action of progestins in breast cancer patients is very limited. Positive response with the progestins: medroxyprogesterone acetate and megestrol acetate was obtained in post-menopausal patients with advanced breast cancer. However, extensive information on the effect of progestins was obtained in in vitro studies using hormone-dependent and hormone-independent human mammary cancer cell lines. It was demonstrated that in the hormone-dependent breast cancer cells, various progestins (nomegestrol acetate, tibolone, medrogestone, promegestone) are potent sulfatase inhibitory agents. The progestins can also involve the inhibition of mRNA of this enzyme. In another series of studies it was also demonstrated that various progestins are very active in inhibiting the 17 β -hydroxysteroid dehydrogenase for the conversion of estrone to estradiol. More recently it was observed that the progestins promegestone or medrogestone stimulate the sulfotransferase for the formation of estrogen sulfates. Consequently, the blockage in the formation of estradiol via sulfatase, or the stimulatory effect on sulfotransferase activity, by progestins can open interesting and new possibilities in clinical applications in breast cancer.

Although a steady increase in contraceptive use has been observed over the past decades, the contraceptive needs of a significant percent of couples have not yet been met. Emerging scientific opportunities may shape the future scientific agenda in reproductive research in the context of new and advanced technologies for the development of improved contraceptives. While long-acting methods, such as implants and IUDs seem preferable for women with compliance issues, mid-acting user-controlled methods such as 1-year vaginal rings proved effective and well accepted by women. Transdermal gels or sprays used daily have shown high acceptability as the methods can be used privately. Progesterone receptor modulators (PRMs) block ovulation and induce amenorrhea. In the future, contraceptives may be combined with other medicinal agents to provide dual protection against both pregnancy and another preventable condition, such as sexually transmitted infections. Also, the neuroprotective effects of progesterone and similar molecules are new areas of research supporting the development of novel contraceptives with added health benefits. Emerging areas of research, such as genomics and proteomics created a new scientific opportunity. New areas of basic research include studies on genes, proteins and enzymes involved in the reproductive system and permitted the discovery of new targets of the reproductive tract. Developing molecules to antagonize the function of one promising target may lead to a very specific contraceptive with possibly less side effects than hormonal contraceptives. Non-hormonal methods in women target meiosis as well as genes involved in follicular rupture and ovulation. These new approaches will ensure future development of non-hormonal contraceptives.

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.Data on 210 nonmenopaused women who had been diagnosed with breast cancer before age 45 at the Institut Curie in Paris, France were compared with 210 matched controls living in Paris to determine whether cyclical mastalgia could be a marker of estrogen susceptibility in relation to breast cancer. Women were more likely to develop breast cancer than controls if they had a family history of breast cancer (26% vs. 11%; adjusted relative risk [RRa] = 2.89, personal history of being breast diseases (24% vs. 6%; RRa = 5.55 [RRa for fibrocystic disease = 9.11]), oral contraceptive (OC) use )30% vs. 20% for 72 months; RRa = 2.8; p .01 for trend), and cyclical mastalgia (46% vs. 23%; RRa = 2.12). The risk of developing breast cancer increased steadily with duration of cyclical mastalgia (RRa = 1.12 for 6-48 months, 2.24 for 49-96 months, and 5.54 for 97 months; p .001 for trend). OC use for more than 48 months before the first full-term pregnancy posed a significantly higher risk than never use of OCs (RRa = 3.26; p .05 for trend). OCs' effect on breast cancer risk was still significant, but not as large, after the first full-term pregnancy (RRa = 2.02; p .05). Since cyclical mastalgia is sensitive to estrogen and a marker of breast susceptibility to estrogen, these results indicated that it could be used, along with other predictors, as a predictor of breast cancer. Prospective studies are needed to validate its significance.

To satisfy the needs of women with a wide variety of different medical histories and preferences, a wide choice of various forms of hormone replacement therapy (HRT) is desirable. The potential long-term benefits of HRT, in terms of osteoporosis, cardiovascular disease and dementia, require good compliance, which in turn requires an HRT formulation that is highly acceptable. An absence of weight gain and lack of androgenic effects are of great importance, as are predictable bleeding and positive effects on postmenopausal symptoms and quality of life. HRT should be tailored to each woman's needs by the choice of appropriate estrogens and particularly a progestogen with a suitable pharmacological profile. An ideal progestogen should be targeted at preventing endometrial hyperplasia without opposing the effects of estrogen on the vessels. Several new progestogens have been synthesized in recent years. Dienogest, the progestogenic component of a new hormone replacement therapy with estradiol valerate, has many desirable features, including antiandrogenic properties; in this respect, it is unique amongst progestogens derived from testosterone. Tailored HRT should treat symptoms, minimize risk factors, meet personal preferences and lifestyle needs, and not be contraindicated for concomitant diseases. During the next decade, optimal HRT must match a number of trends, including an aging population, and is likely to be influenced by the outcome of major trials such as the Women's Health Initiative trial whose negative results will impact the prescriptions, the advent of new compounds--particularly the selective estrogen receptor modulators and progestogen receptor modulators--and the introduction of new methods of delivery, including vaginal rings and medicated intrauterine systems.

The role of progestins in breast tissue is less well defined than in the endometrium. Although in vitro studies have shown that progestins induce a similar decrease in both estrogen and progesterone receptors and an increase in 17beta-estradiol dehydrogenase in the breast as in the endometrium, epidemiologic studies have suggested that progestins prevent endometrial cancer, but do not reverse the estrogen-related increase in breast cancer risk in long-term hormone-replacement therapy (HRT). Other studies have also suggested a protective effect for progestins on breast tissue. The dual effect of progesterone and progestins on the cell cycle has been demonstrated, suggesting that according to the duration of administration, the same steroid can induce cells to enter the multiplication phase or to enter a resting state. Progestins exert different effects according to the steroid from which they are derived, e.g. pregnanes derived from progesterone, estranes or gonanes derived from testosterone. Some estrane derivatives are able to stimulate breast cell multiplication in vitro through an estrogen receptor-mediated pathway. Most pregnanes do not exert such an effect. Also, some pregnane derivatives stimulate apoptosis, leading to cell death. However, it is well established that high doses of progestins have been successfully used in the treatment of advanced breast cancer as second-line endocrine therapy. Finally, striking differences have been observed in progestin use in Europe and in the USA. In France, where the rate of progestin use per head is higher than in the USA, the rate of breast cancer has not increased as sharply as observed in North America. Although cancer genesis is multifactorial, it may be concluded that progestins do protect endometrial tissue against the proliferative action of estrogen and if they do not protect breast tissue, at least they do not stimulate its proliferation. Also, they are useful agents as a second-line therapy for breast cancer, when used at high doses.

The discovery of mifepristone (ex-RU486) was the achievement of a large research programme on steroidal compounds with antihormone properties conducted at Roussel Uclaf in partnership with the INSERM unit of Pr. E. E. Baulieu. Mifepristone exhibited a strong affinity to the progesterone and the glucocorticoid receptors. Consequently, it exerted competitive antagonism to these hormones both in in vitro and animal experiments. The identification of the antiprogesterone activity led to propose mifepristone use for the termination of early human pregnancy. Mifepristone at the dose of 600 mg initially used alone, was then used with a subsequent low dose of prostaglandins that led to a success rate of 95% as a medical method for early termination of pregnancy. In parallel, other indications were extended to the cervical dilatation prior to surgical termination of pregnancy in the first trimester, in the therapeutic termination of pregnancy for medical reasons beyond the first trimester, and for labour induction in case of fetal death in utero. The efficacy and safety of that treatment have been confirmed on the basis of more than 10 years of use with close adherence to the approved recommendations. Besides the political and philosophical hurdles that delayed clinical research with this molecule, other potential indications either in gynecological or cancer areas should be further developed.

Antiprogestins are a promising class of therapeutic agents in the field of reproductive health. Mifepristone (exRU486) remains the leading compound of this class and is the only one presently used in clinical practice. Beyond the main action of antiprogestins on human pregnancy, these compounds may prove useful in the treatment of uterine leiomyomas and endometriosis, and for contraception. IN CANCEROLOGY: Rare tumors such as meningiomas or leiomyoarcomas expressing progesterone receptors may be successfully treated with these antihormones. MAIN INDICATIONS: The main characteristics of the different antiprogestins discovered so far are addressed and the key results from the large clinical studies conducted with mifepristone are described here for indications where the product is approved for clinical use: medical termination of pregnancy during the first trimester, cervical dilatation prior to surgical termination of pregnancy, preparation for prostaglandin action in the therapeutic termination of pregnancy beyond the first trimester, labor induction in case of foetal death in utero.

Percutaneous progesterone topically applied on the breast has been proposed and widely used in the relief of mastalgia and benign breast disease by numerous gynecologists and general practitioners. However, its chronic use has never been evaluated in relation to breast cancer risk. The association between percutaneous progesterone use and the risk of breast cancer was evaluated in a cohort study of 1150 premenopausal French women with benign breast disease diagnosed in two breast clinics between 1976 and 1979. The follow-up accumulated 12,462 person-years. Percutaneous progesterone had been prescribed to 58% of the women. There was no association between breast cancer risk and the use of percutaneous progesterone (RR = 0.8; 95% confidence interval 0.4-1.6). Although the combined treatment of oral progestogens with percutaneous progesterone significantly decreased the risk of breast cancer (RR = 0.5; 95% confidence interval 0.2-0.9) as compared with nonusers, there was no significant difference in the risk of breast cancer in percutaneous progesterone users versus nonusers among oral progestogen users. Taken together, these results suggest at least an absence of deleterious effects caused by percutaneous progesterone use in women with benign breast disease.

For a drug to produce its effect, it must be present in an appropriate concentration at the site of action. This concentration will be influenced by the dose, the rate and the amount of absorption, how the drug is distributed in the body, how it is metabolized and how rapidly it is excreted.

Hypoestrogenemia-derived urogenital symptoms after menopause manifest after some years of hormonal deficit and appear commonly in elderly, untreated women. In the urogenital tract low postmenopausal estrogen levels lead to vaginal irritation and dryness and to dyspareunia, often accompanied by other symptoms like uriesthesis, incontinence or recurrent infections. Every systemic estrogen treatment is accepted as efficient for the correction of urogenital symptoms, often even at doses lower than those necessary for the correction of vasomotor symptoms. Diverse local treatments have been proposed: estriol, promestriene and low-dose estrone or estradiol. Promestriene applied locally stimulates differentiation and maturation of vaginal mucosa and compensates local hypoestrogenic effects without marked hormonal effects outside the vagina. Vaginal application of estrone, on the other hand, has rather been proposed for systemic hormone substitution and elevated levels of estrone and estradiol observed in the plasma render this method in-appropriate in cases where strictly local effects are desired. Recently, very low doses of estradiol in a range of 7.5 micrograms/day have been proposed for the treatment of urogenital atrophy by means of a prolonged release regimen. Among the described preparations, those with strictly local (devoid of systemic) effects should be restricted to patients with contraindications for systemic substitution therapy. Local estrogen therapies are recommended for the treatment of complaints due to vulvar and vaginal atrophy. They have also been proposed by certain authors for the acceleration of the cervico-vaginal and vulvar cicatrisation after surgical interventions or postpartum. The presence of miction disorders in elderly postmenopausal women is also a point in favour of local treatment.

Hormonal replacement therapies of postmenopause have proven their beneficial effects on symptoms correction and on the decrease in bone loss. As far as cardiovascular disease risk is concerned, the epidemiologic trials that suggested a protective effect from estrogen therapy considered mainly the oral route. However, a positive effect of estradiol has been demonstrated on several surrogate markers for cardiovascular risk whether it is administered orally or parenterally. As regards the progestins, the type of molecules prescribed appears more relevant than the route of administration, the beneficial effects of estrogens being unaffected by the non-androgenic progestagens.

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.Oral contraceptives (OCs) contain two types of steroids: ethinyl estradiol (the estrogenic component [20-50 mcg/pill]) and progestins derived essentially from 19-nortestosterone. The progestins derived from 19-norprogesterone (e.g., nomegestrol acetate or ST 1435) are not yet used in OCs, but are being evaluated for parenteral administration. The study of pharmacologic properties of progestins suggests that levonorgestrel and its derivatives have a powerful antigonadotropic and antiestrogenic effect, which allow them to be effective at very low doses in new OCs. These derivatives are desogestrel, gestodene, and norgestimate. The margin of safety for levonorgestrel and its derivatives is limited, especially when taken with other medication, however. Drugs that reduce the efficacy of OCs include rifampicin, antiepileptic drugs (e.g., phenobarbital), antibiotics (neomycin, lincomycin, and ampicillin), griseofulvin (an enzyme-inducing drug), antimalarials, and antacids. Thus, selection of contraceptive methods must be discussed when certain concomitant medications are required.

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.

The risk/benefit ratio of hormone replacement therapy in the post-menopause period remains controversial due to the risk of breast cancer and the effects of progesterone on mammary tissues. We analyzed the epidemiological data available to evaluate the risk of breast cancer in subjects taking replacement hormones. Oestrogen prescribed alone has not been reported to increase the relative risk of breast cancer compared with subjects not taking hormone therapy. Only elevated levels of conjugated oestrogens have been found to increase the relative risk although sufficient data is not available for an analysis of long-term effects. Combination therapy was reported to have a protective effect in one study but the results have never been reproduced. Other studies have found no significant increase in the risk of breast cancer. Long-term results in subjects on progesterone replacement have not revealed any protector effect. Animal models have shown that progesterone opposes the proliferative effect of oestrogens on mammary tissue and would suggest that progesterone has a protective action. Most in vitro studies on human mammary tissue suggest that progesterone has an antioestrogenic effect on epithelial tissues. The epidemiological data available leads to the conclusion that the therapeutic regimen recommendations currently put forward remain valid. Further large long-term prospective randomized trials are needed to definitely answer the remaining questions.

New progestin molecules have been synthesized for the purpose of maintaining the antiovulatory and antiestrogenic effects of existing progestins while suppressing their undesirable androgenic effects. Desogestrel, gestodene, and norgestimate are 3 third generation progestins now available in Europe in combined oral contraceptives (OCs) containing ethinyl estradiol. The 3 gonane molecules all result from modifications in the structure of levonorgestrel which neutralize its androgenic activity. The 3 molecules maintain their affinity for the androgen receptors. A review of the literature suggests that the third generation OCs have no major disadvantages compared to other low dose preparations now being marketed. Among the fundamental differences between levonorgestrel and the 3 new gonanes, the absence of the androgenic effect reveals the predominant estrogenic effect on HDL cholesterol and sex hormone binding globulin (SHBG). It appears however that the absence of androgenic effect does not affect the antiestrogenic power of the molecule at the level of the target cells such as the endometrium, or at the level of the pituitary cells. As with all low-dose formulations, a nonnegligible percentage of patients conserves ovarian activity with follicular maturation and estrogen secretion. It remains to be demonstrated whether the 2-10% of users reporting undesirable effects such as breast tenderness, swelling, headaches, and irritability are those in whom ovarian activity is not completely suppressed. The percentage of women using the third generation gonanes who conserve ovarian activity seems to be lower than that of users of the older low-dose formulations. Carbohydrate tolerance differs little from that observed with levonorgestrel. Modifications of coagulation factors reflect the estrogen content and do not differ in the third generation gonanes and older low-dose formulations. It is difficult to identify major clinical advantages of any 1 of the new preparations because of the minor differences between them. Prospective, longterm epidemiologic studies will be needed to confirm possible cardiovascular benefits and the absence of increased mammary pathology.

Many publications have been dedicated to the mode of action, efficacy, and secondary effects of oral contraceptives (OCs). Healthy OC users neither accept side effects nor find them acceptable. In most, the level of effectiveness and the incidence of side effects are proportional to the total dose of steroids in the OC combination, the balance between the estrogen and progestin content, and the specific properties of the compounds. Cardiovascular events in OC users were first attributed to the ethinyl estradiol dose and, as a first step, the estrogen dose has been reduced in OCs produced since the 1970s. Next, the vascular risk has been correlated with changes in the lipid profile. Progestins with androgenic properties have been incriminated in unexpected vascular events because of their adverse effect on the lipid profile. In pursuit of minimizing these secondary effects and to favorably change lipid patterns, some new progestins without androgenic properties have been developed and are available in Europe. These new compounds, third generation progestins, are derived from levonorgestrel. These progestins belong to the gonane category and, because of their molecular structure, are capable of attaching themselves to the androgen receptor. They include gestodene, desogestrel, and norgestimate. The study of changes in the pattern of protein markers of the sex hormone binding globulin (SHBG) suggests very weak biological androgen activity when these progestins are administered with ethinyl estradiol. Likewise, the anti-estrogenic action of these progestins which have lost their partial androgenic effect is reduced. When these progestins are administered with the ethinyl estradiol, they do not obstruct the estrogenic effect on the level of protein markers, e.g., SHBG and high density lipoprotein. Although this effect is considered beneficial, the reduced estrogenic activity on antithrombin III, triglycerides, and perhaps target tissues may be considered a non-negligible disadvantage of the third generation progestins in the most recent OCs.

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.

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.

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)

In order to evaluate the importance of prolactin in the pathogenesis of benign breast diseases (BBD), serum prolactin (PRL) levels were determined before and during a TRH challenge test in 50 patients affected by various BBD studied during the luteal phase of their cycle. They were compared to 15 normal women also studied during the luteal phase. In all the subjects estradiol (E2) and progesterone (P) were also measured. The patients were studied as a total group and in different subgroups according to the type of their disease, before and after 3 months of treatment with a potent progestin, lynestrenol. No significant differences appeared between any group of patients and the control group either on the basal prolactin secretion or on its dynamic secretory pattern after TRH injection before and during treatment. The only significant difference observed between patients and controls was the progesterone values, respectively 6.86 +/- 0.9 ng/ml and 21.2 +/- 1.4 ng/ml. It can therefore be concluded that benign breast diseases are more likely to be related to an inadequate luteal phase than to any abnormality of prolactin secretion.

The corpus luteum function of 109 patients with benign breast disease was appreciated by way of plasma progesterone and estradiol determinations during the luteal phase. These patients had ovulatory cycles according to a biphasic basal body temperature curve; blood samples for plasma progesterone and estradiol estimation were collected between the first and the last day of the thermal plateau following the thermal nadir. Results obtained were compared to those observed in 50 normal ovulatory women. In the patients' group, the mean daily levels for progesterone ranged from 3.5 +/- 0.4 (SE) ng/ml to 8.1 +/- 3.8 (SE) ng/ml according to day of blood collection. These values are significantly different from the corresponding daily values observed in normal women. No significant difference was observed concerning plasma estradiol between patients and normal women. These findings indicate that women with benign breast disease have an inadequate corpus luteum function which may be secondary to an ovulation disorder. Pathophysiological implications resulting from this observation are discussed.

Estimations of estradiol, progesteron and other biochemical analyses support the hypothesis of a relative unopposed hyperestrogenism as cause of benign breast diseases. Additional factors are insufficient luteal phases combined with hyperprolactinemia or transient prolactin pulses. Progestagen treatment applied either topically or both orally and topically can correct the imbalance and perhaps prevent breast cancer.

One hundred eighty-four patients with benign breast disease (BBD) were studied and compared with 50 normal women. All of the women had ovulatory cycles according to a biphasic basal body temperature and a plasma prolactin in the normal range. Their corpus luteum function was evaluated by way of plasma progesterone (P) and estradiol (E2) determinations at days 5, 7, and 9 of the hyperthermic phase. In the 184 patients, plasma P over plasma E2 ratio during the luteal phase was found significantly lower than in normal women. When the patients were grouped according to type of breast lesions, it appeared that plasma P was constantly lower in all groups than in the normal women, while plasma E2 was either normal or elevated in the groups of patients with adenosis tumors and increased nodularity of both breasts. From these results it may be postulated that an imbalance in the secretion of E2 and P by the corpus luteum is a constant finding in women with benign breast disease.

The results of exploration of the corpus luteum in 125 patients with benign breast disease are analysed. In 109 patients, plasma oestradiol and progesterone were measured at various times during the hyperthermic phase of the menstrual cycle. The results obtained were compared with those obtained in normal women explored during the same phase of the cycle. The average daily values for plasma progesterone obtained in this group of 109 patients was significantly lower than that found in the normal women, whilst there was no change in oestradiol levels. In addition, 16 patients were studied daily throughout the period of hyperthermia. In 8 cases, there the hyperoestrogenism, with or without progesterone insifficiency of the corpus luteum. In all, secretory imbalance of the corpus luteum with a tendency to relative or absolute hyperoestrogenism was a constant finding in women with benign breast disease.

Since the luteinizing hormone-releasing hormone (LH-RH) has been identified and its mode of action understood, it has become possible to envisage a therapeutic use of long-acting, non toxic analogues. Biochemical modifications of the decapeptide have resulted in the synthesis of potent LH-RH antagonists and agonists. Paradoxically, however, the agonists, devised to induce ovulation, exert an antagonistic action due to a decrease in the number of pituitary LH-RH receptors and to desensitization of the pituitary gland to the decapeptide. These inhibitory effects are associated with the prolonged activity of the analogues, in contrast with the stimulant effects of physiological LH-RH which has a short half-life and is secreted by bursts. The direct action of LH-RH analogues on gonads suggested by animal experiments has not been found in man since human gonads are devoid of specific LH-RH receptors. Alterations in steroid production are consecutive to the rise in LH initially induced by LH-RH agonists. The complete gonadotropic inhibition which follows the administration of LH-RH antagonists or agonists suggests that these compounds could be used in man, notably for the treatment of hormone-dependent carcinomas and isosexual early puberty and in the field of contraception.

Since the luteinizing hormone-releasing hormone (LH-RH) has been identified and its mode of action understood, it has become possible to imagine a therapeutic use of long acting, nontoxic analogues. Biochemical modifications of the decapeptide have resulted in the synthesis of potent LH-RH antagonists and agonists. Paradoxically, however, the agonists, devised to induce ovulation, exert an antagonistic action due to a decrease in the number of pituitary LH-RH receptors and to desensitization of the pituitary gland to the decapeptide. These inhibitory effects are associated with the prolonged activity of the analogues, in contrast with the stimulant effects of physiological LH-RH which has a short 1/2-life and is secreted in bursts. These effects have been used in order to inhibit ovulation in female contraception. Preliminary studies clearly indicate a high efficiency of these molecules devoid of metabolic side effects. However, it appears necessary to add sequential progestin therapy on a monthly basis as estradiol levels are those of an early follicular phase. Such a peptide contraception aims at ovulation suppression and not at a complete blockage as in cases of endometriosis and estrogen-dependent cancers. (author's)

Progesterone (P), the natural hormone, binds to its specific receptors to induce specific progestational effects. In addition to this binding, P is able to interfere with the binding sites of other steroids. Therefore the natural hormone exhibits an anti-estrogenic activity, and anti-androgenic activity and also exerts anti-mineralocorticoid effects. For a long time progesterone could not be used in clinical applications because of a rapid liver inactivation after oral administration. An oral micronized preparation of progesterone is now available which produces adequate plasma and tissue levels of progesterone. The preparation reproduces the anti-estrogenic effect of the natural hormone on the endometrium at the dose of 200 mg daily. It also reproduces the anti-mineralocorticoid effect and has no androgenic action. No side effects have been reported as far as lipids profile, coagulation factors and blood pressure are concerned. Therefore oral micronized progesterone appears suitable for hormonal replacement therapy in various areas, essentially postmenopause therapy, premenstrual syndrome, correction of irregular cycles and pregnancy maintenance.

To assess a possible inhibitory effect of progestins on PRL secretion, serum PRL and estradiol levels were determined in 13 women with hyperprolactinemia due to a pituitary microadenoma before and after 3 months of treatment with a potent progestin, lynestrenol. PRL levels also were assessed during a TRH challenge test before and after treatment. Results were compared to those obtained in 10 normal women studied during the early follicular phase of their menstrual cycle and at the end of 3 months of treatment. The PRL response to TRH was blunted in patients before lynestrenol therapy. After therapy, basal serum PRL levels were significantly decreased, and the response to TRH was almost abolished. No change occurred in the normal women. The estradiol level was 80.5 +/- 7.5 (+/- SEM) pg/ml in patients before treatment and decreased to 29.2 +/- 5.0 pg/ml after therapy. Therefore, lynestrenol, a potent 19-nortestosterone derivative, exhibits in vivo an anti-PRL effect that could be related to its antiestrogenic and/or androgenic activities.

Progesterone exerts most of its actions through its specific receptors. However, synthetic progestins and progesterone itself may bind with other steroid receptors, thus producing a variety of effects. For instance, some nonsteroid derivatives produce virilizing effects by acting on testosterone receptors. In contrast, other derivatives may inhibit or potentiate the actions of androgens. Similar interactions of progestins with gluco- or mineralocorticoid receptors have been reported. The therapeutic applications of progestins are therefore extremely numerous. An improved knowledge of the mode of action of individual available progestins results in better management of a wide variety of clinical disorders including, amongst others, endometrial pathology, benign breast diseases, hirsutism and acne.