Effects of progestogens on the postmenopausal breast.

The potential for an increased risk of breast cancer linked to the use of synthetic progestins combined with oral estrogens is one of the main putative reasons for discouraging postmenopausal women from using any type of hormone replacement therapy (HRT) for more than a few years. Because no definitive proof exists, the available epidemiological results can be interpreted according to what seems biologically plausible to each investigator, including potential differences between various schedules of various steroids in various species and in vitro models. More than 60 years after the discovery of progesterone, the main effects of this endogenous steroid on the physiopathology of the breast during a normal luteal phase are still controversial. The lack of consensus on such basic knowledge concerning one of the most important targets of a natural ovarian hormone discovered in 1934 is amazing. In the most cited studies, nothing has been done to measure progesterone in plasma and to correlate the extremely disparate cytological results with extremely erratic steroid levels at the time of surgical stress. In a recent study, with a better design, the physiological rise of endogenous progesterone during the luteal phase coincided with a drop in proliferation of breast epithelial cells, which appears to be only slightly delayed in comparison with what is described in the endometrium. Differences in doses and schedules of treatments with various synthetic progestins have largely contributed to the inconsistency in clinical recommendations. Based on the analysis of proliferation markers in surgical biopsies from normal human postmenopausal breast tissue, it is plausible that mitogenic activity is not identical during therapy with unopposed estrogens versus estrogens combined with progestogens, and is higher during HRT that combines oral conjugated equine estrogens with medroxyprogesterone acetate than during HRT that combines transdermal estradiol and progesterone. It is misleading to put all progestogens in the same bag irrespective of their chemical structure, and, more important, their effect may vary according to whether it is estrone or estradiol that is mainly accumulated in the breast tissue. The hypothesis of progesterone decreasing the proliferative effect of estradiol in the postmenopausal breast remains highly plausible.

[Compliance with hormone replacement therapy in menopause: effect of an original education program. The COMET study]. / Observance du traitement hormonal substitutif de la ménopause: effet d'un programme d'éducation original. L'étude COMET.

OBJECTIVE: To study the impact of an original education program on compliance to hormone replacement therapy (HRT) in post-menopausal women. METHODS: Data were obtained from 1,192 post-menopausal women (age: 53 +/- 5 years) included in the study with an onset less than six months: E2 gel (n = 791) or patch (n = 401) + progestins, and randomized in either educational program (Ep = 600) or regular verbal counselling (VC = 592). A patient is considered bad compliant with HRT when she prematurely stopped the study, whatever the reason of the cessation. The groups EP and VC are homogeneous for the age distribution, the HRT regimen, the date of onset and the climateric symptoms scores. RESULTS: There is a significant difference between EP and VC groups in compliance, respectively 86 and 81% (p < 0.027). This difference is partially explained by the significant improvement in the patch subgroups (EP: 86% versus VC: 77%, p = 0.028). The trend observed in the gel group is not significant (EP: 85% and VC: 82%) due to the high level of compliance usually noticed in women treated with the gel and the verbal counselling. The significative difference in the compliance observed during the verbal counselling between the continuous (76%) and the sequential (86%, p = 0.001) HRT regimen disappears with the educational program (continuous: 84% and sequential: 87%, NS). CONCLUSION: This first large study on the HRT compliance in France, using a patient educational material, validates its efficacy to reach a better compliance than with regular verbal counselling. Even though in the daily practice, about 40% of the patients discontinue the treatment during the first year, 81% of the women followed in this study continue to receive the HRT after nine months of use. The original educational program of the COMET study improves significatively this high compliance (+ 5% from the verbal counselling). Thus, the combination of the doctor verbal counselling and an educational material is desirable to obtain a good compliance with HRT.

Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women.

The largest-to-date randomized trial (Women's Health Initiative) comparing the effects of hormone replacement therapy (HRT) and a placebo concluded that the continuous use of an oral combination of conjugated equine estrogens (CEE) and medroxy-progesterone acetate (MPA) increases the risk of breast cancer. This conclusion may not apply to women taking other estrogen and progestin formulations, as suggested by discrepancies in the findings of in vitro studies, epidemiological surveys and, mostly, in vivo studies of human breast epithelial cell proliferation showing opposite effects of HRT combining CEE plus MPA or estradiol plus progesterone. To evaluate the risk of breast cancer associated with the use of the latter combination, commonly prescribed in France, a cohort including 3175 postmenopausal women was followed for a mean of 8.9 years (28 367 woman-years). In total, 1739 (55%) of these women were users of one type of estrogen replacement with systemic effect during at least 12 months, any time after the menopause, and were classified as HRT users. Among them, 83% were receiving exclusively or mostly a combination of a transdermal estradiol gel and a progestin other than MPA. Some 105 cases of breast cancer occurred during the follow-up period, corresponding to a mean of 37 new cases per 10 000 women/year. Using multivariate analysis adjusted for the calendar period of treatment, date of birth and age at menopause, we were unable to detect an increase in the relative risk (RR) of breast cancer (RR 0.98, 95% confidence interval (CI): 0.65-1.5) in the HRT users. The RR of breast cancer per year of use of HRT was 1.005 (95% CI 0.97-1.05). These results do not justify early interruption of such a type of HRT, which is beneficial for quality of life, prevention of bone loss and cardiovascular risk profile, without the activation of coagulation and inflammatory protein synthesis measured in users of oral estrogens.

Risks and benefits of hormone replacement therapy.

Menopause, the permanent cessation of menstruation, is due to ovarian failure, which may lead to oestrogen deficiency diseases, particularly osteoporosis, cardiovascular disease and cerebrovascular disease. Mortality and morbidity caused by these conditions can be modified by using hormone replacement therapy, but the benefits of this therapy must be weighed against the increased risk of breast cancer and the symptomatic side-effects the treatment may cause. The combination of transdermal oestrogen and natural progesterone offers the most favourable risk-to-benefit profile.

Pharmacodynamics of oestrogens and progestogens.

The ovaries cyclically secrete estradiol and progesterone. Cyclic ovarian estradiol secretion is associated with a bone-saving and vascular protection effect. Endogenous progesterone does not modify the vasodilator effect of oestrogens. At physiological concentrations, the natural sex steroids have low antigonadotropic effects. More potent synthetic derivatives with more antigonadotropic effects were synthesized in the 1950s. After the menopause, there is no longer any need to use hormonal steroids as antigonadotropics. In addition, vascular contraindications are more common in an older population. Contraceptive steroids (particularly ethinyl estradiol) are therefore rarely used. The oestrogen that is most widely prescribed for post-menopausal replacement is a complex formulation of conjugated oestrogens of equine origin that is administered orally in a single daily dose. Improvements in hormone replacement therapy may result from the use of parenteral estradiol (providing sufficient doses are reached) and of a progestogen chemically more similar to progesterone.

Oral micronized progesterone.

This review sought to examine the rationale for selecting an oral micronized progesterone formulation rather than a synthetic progestin for some of the main indications for progestogens. Unopposed estrogen use is associated with a high risk (relative risk, 2.1 to 5.7) of endometrial hyperplasia and adenocarcinoma, and it has been understood for some time that a progestogen must be added for at least 10 to 14 days per month to prevent these effects. However, the most commonly used synthetic progestins, norethisterone and medroxyprogesterone acetate, have been associated with metabolic and vascular side effects (eg, suppression of the vasodilating effect of estrogens) in both experimental and human controlled studies. All comparative studies to date conclude that the side effects of synthetic progestins can be minimized or eliminated through the use of natural progesterone, which is identical to the steroid produced by the corpus luteum. The inconvenience associated with the use of injectable, rectal, or vaginal formulations of natural progesterone can be circumvented by using orally administered micronized progesterone. The bioavailability of micronized progesterone is similar to that of other natural steroids, and interindividual and intraindividual variability of area under the curve is similar to that seen with synthetic progestins. A clear dose-ranging effect has been demonstrated, and long-term protection of the endometrium has been established. Micronized progesterone has been used widely in Europe since 1980 at dosages ranging from 300 mg/d (taken at bedtime) 10 days a month for women wishing regular monthly bleeding to 200 mg 14 days a month or 100 mg 25 days a month for women willing to remain amenorrheic. This therapy is well tolerated, with the only specific side effect being mild and transient drowsiness, an effect minimized by taking the drug at bedtime. The prospective, comparative Postmenopausal Estrogens/Progestin Intervention trial has recommended oral micronized progesterone as the first choice for opposing estrogen therapy in nonhysterectomized postmenopausal women.

Endometrial hyperplasia. Risks, recognition and the search for a safe hormone replacement regimen.

Endometrial hyperplasia is an acknowledged risk of unopposed estrogen replacement therapy (ERT). Several categories of hyperplasia are now recognized, among which atypical complex hyperplasia is the most likely to progress to carcinoma. Adding a synthetic progestin or natural progesterone to estrogen therapy has been shown to decrease or eliminate the endometrial risk associated with ERT. However, the addition of synthetic progestins has been associated with uncomfortable side effects, reversal of some of the cardiovascular and metabolic benefits of estrogen, and unwanted bleeding. The use of natural micronized progesterone in lieu of synthetic progestins alleviates the former two drawbacks, while careful scheduling of estrogen and progesterone dosing can eliminate the latter. In Europe, where natural progesterone has been in use for some time, a cyclic combined regimen comprising estrogen and 100 mg micronized progesterone administered on days 1-25 has been shown to provide endometrial safety, absence of bleeding and a high rate of tolerability.

Estradiol and progesterone regulate the proliferation of human breast epithelial cells.

OBJECTIVE: To study the effects of estradiol and progesterone on the proliferation of normal human breast epithelial cells in vivo. DESIGN: Double-blind randomized study. SETTING: Departments of gynecology and of cell biology at a university hospital. PATIENT(S): Forty postmenopausal women with untreated menopause and documented plasma FSH levels of >30 mIU/mL and estradiol levels of <20 pg/mL. INTERVENTION(S): Daily topical application to both breasts of a gel containing a placebo, estradiol, progesterone, or a combination of estradiol and progesterone during the 14 days preceding esthetic breast surgery or excision of a benign lesion. MAIN OUTCOME MEASURE(S): Plasma and breast tissue concentrations of estradiol and progesterone. Epithelial cell cycles were evaluated in normal breast tissue by counting mitoses and performing quantitative proliferating cell nuclear antigen immunolabeling analyses. RESULT(S): Increasing the estradiol concentration enhanced the number of cycling epithelial cells, whereas increasing the progesterone concentration significantly limited the number of cycling epithelial cells. CONCLUSION(S): Exposure to progesterone for 14 days reduced the estradiol-induced proliferation of normal breast epithelial cells in vivo.

Hormone replacement therapy: clinical benefits and side-effects.

Beside well-established clinical benefits, the current doses of oestrogens may induce clinical side-effects leading to non-compliance and loss of efficacy. During a normal menstrual cycle the incidence of any cyclic discomfort is consistently reported to be lowest during the mild-follicular phase when plasma E2 remains between 60 and 150 pg/ml. The incidence of pregnancy-like symptoms such as bloating, breast tenderness and mood swings tends to increase in mid-luteal phase when E2 increases upto 150 pg/ml. On the other hand incidence of asthenia, sleep disturbances, depressive mood, headaches and migraines increase during perimenstrual days when E2 drops to 40 pg/ml or below. Accordingly experimental and human studies in castrated animals and postmenopausal women suggest that plasma E2 around 100 pg/ml is optimal for treatment of hot flushes, prevention of bone loss and cardiovascular protection. Due to large interindividual variation in estrogen clearance rate, it is unlikely that any standardized unique dose of oral or non-oral formulations will reproduce the optimal levels in all postmenopausal users. Efforts for individual titration are mandatory to improve compliance and actual efficacy on a long term. Because older postmenopausal women tend to have a better clinical tolerance to low E2 levels, objective markers of efficacy should also be identified when the aim of HRT is the prevention of osteoporosis or vascular diseases. In addition clinical and metabolic side-effects related to added progestins can be substantially reduced by the use of lower dose inducing amenorrhea and by progesterone instead of synthetic steroids.

Effect of progesterone and its 5 alpha and 5 beta metabolites on symptoms of premenstrual syndrome according to route of administration.

Orally administered progesterone may have advantages over other routes of administration in the treatment of premenstrual syndrome (PMS) because of substantially higher levels of the anxiolytic metabolites 5 alpha and 5 beta pregnanolone. The only previous placebo-controlled trial which used oral progesterone reported beneficial effects in the treatment of PMS. The present study, a double-blind crossover trial, compared the administration of 300 mg daily oral progesterone with 200 mg daily vaginal progesterone and matched placebos for 10 days premenstrually. Although there was a significant treatment effect on symptoms, no difference between active treatments and placebo was found. The trial was terminated with 25 women completing treatment as it was evident that no clinically significant effect of either form of progesterone was likely to be detected even with twice the sample size. Serum levels of progesterone and metabolites showed that oral administration resulted in supraphysiological levels of 5 alpha and 5 beta metabolites and there was a negative correlation between 5 alpha pregnanolone levels and anxiety. However, this did not translate to overall reduction in premenstrual distress or anxiety beyond that achieved by placebo, as measured by validated questionnaires.

[Metabolic and vascular risks with oral contraceptives]. / Risques métaboliques et vasculaires de la contraception orale.

Despite selectivity in prescriptions and changes in formulations, combined oral contraceptives still increase the relative risk of thrombo-embolic accidents. The main mechanism implies ethinyloestradiol accumulation in the liver and related consequences, not for circulating lipoproteins, but for coagulation/fibrinolysis balance. Most serious concerns should be directed to subjects having preexisting arterial or venous wall alterations or hemostatic disorders. Restriction of oral contraceptive use extended to all subjects suspected of carrying these risks has been highly effective for prevention of coronary accidents but less for prevention of stroke or venous thrombosis. The crude number of vascular accidents remains very low in women below 35 years old, non smokers, without hypertension, diabetes, dyslipidemia nor cardiac valve disease, without personal or familial history of thrombosis, and without any significant increase in weight, blood pressure and triglycerides while using pills.

Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo.

OBJECTIVE: To study the effect of E2 and P on the epithelial cell cycle of normal human breast in vivo. DESIGN: Double-blind, randomized study. Topical application to the breast of a gel containing either a placebo, E2, P, or a combination of E2 and P, daily, during the 10 to 13 days preceding breast surgery. PATIENTS: Forty premenopausal women undergoing breast surgery for the removal of a lump. MAIN OUTCOME MEASURES. Plasma and breast tissue concentrations of E2 and P. Epithelial cell cycle evaluated in normal breast tissue areas by counting mitoses and proliferating cell nuclear antigen immunostaining quantitative analyses. RESULTS: Increased E2 concentration increases the number of cycling epithelial cells. Increased P concentration significantly decreases the number of cycling epithelial cells. CONCLUSION: Exposure to P for 10 to 13 days reduces E2-induced proliferation of normal breast epithelial cells in vivo.

Influence of route of administration on progesterone metabolism.

While inducing similar progesterone levels, the ratio of 5 alpha- and 5 beta-pregnanolone/progesterone plasma concentrations has been dramatically increased after oral as opposed to vaginal administration, in a cross-over study. The known psychotropic effects of 5 alpha- and 5 beta-pregnanolone lead to different indications and precautions for oral and vaginal administration of progesterone.

[A "no-bleeding" substitute hormone treatment with an oral microdose progesterone. A prospective multicenter study]. / Recherche d'un traitement hormonal substitutif "sans règles" avec la progestérone micronisée orale. Etude multicentrique prospective.

AIMS: Study of influence of different sequences of oral micronized progesterone (Pg) on endometrial morphology and the incidence of bleeding. DESIGN: Prospective comparative multicentric study conducted in 101 post-menopausal patients. PATIENTS AND METHODS: 98 patients who did not wish any regular withdrawal bleeding were given percutaneous oestradiol 17-beta (E2) (1.5 mg/d) associated with micronized Pg (100 mg/d) at bedtime during either 21 out of 28 days (group I), or 25 days per calendar month (group III), during a minimum of 6 months. For those wishing withdrawal bleeding (n = 3), E2 (3 mg/d) during 25 days was associated with Pg (300 mg/d) from the 16th to the 25th day of the month (group III). Endometrial biopsies were performed after 6 months of the same treatment and blindly analysed; transvaginal ultrasonography (measurement of endometrial mucosa thickness) was done in case of insufficient amount of tissue. RESULTS: Groups I and II: 61% of the endometrium were quiescent without mitosis, 23% were slightly active with rare mitoses, 8% partly secretory and 4% subatrophic. Sampling was inadequate in the remaining 4%. Mitotic activity of glands was low on the overall samplings (average < 0.53/1,000 cells). The average mucosa thickness was at 3.9 mm. No bleeding (spotting or withdrawal bleeding) occurred in 73.3% and 82.1% of cycles at the 3rd and 6th months of administration, respectively. Group III: endometrium were quiescent or slightly active and combined with frequent withdrawal bleeding. CONCLUSIONS: A relatively low dose of oral progesterone (100 mg/d) combined with E2 during 21d/28d or 25 d/month efficiently controls proliferation, induces a very low endometrial cyclic activity--while reducing spottings--and maintains an amenorrhea in the majority of women. This simple treatment is likely to improve compliance.

[Estrogens, progestins and vascular risks]. / Oestrogènes, progestatifs et risques vasculaires.

Animal and human studies have indicated that the progression of atherosclerosis, notably in the coronary vessels, is accelerated by hypo-estrogenism and slowed down by estrogens. The principal favourable effect of endogenous or exogenous estrogens is not that they modify, quantitatively or qualitatively, blood cholesterol: it is that they prevent cholesterol from accumulating in the arterial wall. This favourable effect of estrogens is completed by other mechanisms which modify platelet aggregation, prostacyclin/thromboxane equilibrium, endothelin, etc., and which improve arterial wall morphology and vasoactive reactions. Some synthetic progestogens, given with oestrogens for endometrium control, may compromise these spectacular vascular benefits, but this is not the case with natural progesterone. Until now, the possible risk of thrombo-embolism has limited the prophylactic use of hormonotherapy and imposed contraindications. This risk is due to imbalance in hepatic (procoagulant effect) and peripheral (fibrinolytic effect) stimulations and therefore is to be feared specifically with oral oestrogens and their hepatic first-pass effect. In the absence of randomized trials, it is difficult to evaluate the true importance of this risk in the general population or in specific high-risk groups, but several surveys suggest that it persists even with the minimal doses currently administered orally. On the other hand, there is no known theoretical risk when oestradiol is given parenterally, which in France is the favoured method. This type of replacement therapy with oestradiol should be more often prescribed to subjects with atherogenic hyperlipidaemia, arterial hypertension or ischaemic coronary disease: not only it is not contraindicated, but it should soon become an indication.