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Improving current contraceptives and discover novel methods easy to use with added health benefits would meet the needs of couples who seek alternatives to current methods. New delivery systems target user-controlled, longer-acting options to provide choice, user's autonomy and improve compliance. Self-injections, microarray patches, pod rings able to deliver several molecules aim to prevent both pregnancies and sexually transmitted infections. Improved intrauterine systems and non-surgical permanent methods are also on the research agenda. The search for novel methods must continue, to curb maternal mortality led by multiple pregnancies and unsafe abortion, still a burden in many countries., (© 2021 médecine/sciences – Inserm.)

Recent data suggests that a "window of opportunity" to decrease the risk of mortality and coronary heart disease (CHD) exists, when initiation hormone replacement therapy (HRT) in menopausal women aged of 50 to 59 years, or within the 10 years following the onset of menopause. The risks of HRT are rare, especially in young postmenopausal women with symptoms who use HRT for long periods of time, and have lower rates of mortality and CHD than comparable postmenopausal women who do not use HRT Newer evidence suggests that there are distinct differences between synthetic molecules and estradiol ; the physiological hormone may be preferable especially from a non-oral delivery system as thrombosis risk is the lowest with such therapy. In addition, natural progesterone does not reverse the benefits of estrogen, particularly in the nervous system and the vessels, and seems to be neutral on breast cancer risk. HRT must be individualized and tailored according to symptoms and each woman's individual risk profile, her preferences and expectations.

Therapeutic Applications: 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.

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.

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.

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)

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.

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.

The amount of progesterone and estradiol secreted by human corpus luteum depends upon an adequate release of FSH and LH by pituitary gland during follicular phase and ovulation. In this paper, plasma determination of progesterone and estradiol were carried out in 109 women with benign breast disease during the luteal phase of their menstrual cycle. Results obtained were compared with those observed in 25 normal women studied in the same conditions. In women with benign breast disease, the curve of daily progesterone concentrations during luteal phase was lower than that of normal women. The progesterone peak at 5th day of luteal phase was only 8,1 +/- 3.8 ng/ml instead of 17.2 +/- 3.5 ng/ml in normal women. No significative difference was observed concerning plasma estradiol between patients and normal women. These results indicate that women with benign breast disease have an inadequate corpus luteum function which may be the result of disorder of ovulation. Pathophysiological implications resulting from this observation are discussed.

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.