Norpregnane Derivatives Research Articles

Menopausal hormone therapy and risk of incident hypertension: role of the route of estrogen administration and progestogens in the E3N cohort.

Although menopausal hormone therapy (MHT) remains the most effective treatment for vasomotor symptoms of menopause, its association with the development of arterial hypertension remains unclear. We sought to explore associations between different formulations of MHT and incident hypertension among menopausal women in a prospective cohort study. We used the Etude Epidémiologique de femmes de la Mutuelle Générale de l'Education (E3N) cohort, a French prospective population-based study initiated in 1990 on 98,995 women. Out of these, 49,905 menopausal women with complete information on the use of MHT, and without prevalent hypertension at inclusion were included. The mean age of the population at baseline was 54.2 ± 4.3 years, and 32,183 (64.5%) reported ever using MHT. Among these women, 10,173 cases of incident hypertension were identified over an average follow-up time of 10.6 years. Compared with women who never used MHT, those who ever used it had an increased risk of incident hypertension (adjusted HR 1.07, 95% CI 1.02-1.12) after adjustment for body mass index and other potential confounders. Oral but not transdermal estrogen use was associated with an increased risk of hypertension (adjusted HR = 1.09; 95% CI: 1.04-1.14 and HR = 1.03; 95% CI: 0.99-1.07, respectively). However, the HRs associated with oral and transdermal estrogens did not differ significantly (P-homogeneity = 0.09). Regarding the role of concomitant progestogens, pregnane and norpregnane derivatives were significantly associated with hypertension risk (HR = 1.12; 95% CI: 1.06-1.19 and HR = 1.06; 95% CI: 1.01-1.13, respectively). MHT was associated with a modest but significant increased risk of incident hypertension, especially when using oral estrogen in combination with a progestogen such as pregnane and norpregnane derivatives. Surveillance of blood pressure should be added to the medical surveillance of MHT users.

MENOPAUSAL HORMONE THERAPY AND RISK OF INCIDENT HYPERTENSION: IMPACT OF THE ROUTE OF ESTROGEN ADMINISTRATION AND PROGESTOGENS IN THE E3N COHORT

Objective: Although menopausal hormone therapy (MHT) remains the most efficacious treatment for vasomotor symptoms of menopause, its effects on the development of arterial hypertension remain unclear. We sought to determine the effect of different formulations of MHT on incident hypertension among menopausal women in a large prospective cohort study. Design and method: We used data from the E3N cohort study, a French prospective population-based study initiated in 1990 of 98,995 women. Out of these, 49,905 menopausal women with complete information on the use of MHT, and without prevalent hypertension at inclusion were included. Hypertension cases were self-reported and validated using the national drug reimbursement database. Results: Among these women with a mean age was 54.2 ± 4.3 years, 10 173 cases of hypertension were identified in an average follow-up time of 10.6 years and 32 183 (64.5%) of the women reported ever using MHT. Compared with women who never used MHT, those who ever used it had an increased risk of incident hypertension (adjusted HR 1.07, 95% CI 1.02–1.12) after adjustment for body mass index and other potential confounders (Table 1). When formulation was taken into account, oral but not transdermal estrogen use was associated with an increased risk of hypertension (adjusted HR = 1.09; 95% CI: 1.04–1.14 and HR = 1.03; 95% CI: 0.99–1.07, respectively). Regarding the impact of concomitant progestogens, pregnane and norpregnane derivatives were significantly associated with hypertension risk (HR = 1.12; 95% CI: 1.06–1.19 and HR = 1.06; 95% CI: 1.01–1.13, respectively). Conclusions: Use of MHT was associated with an increased risk of incident hypertension, especially when using oral estrogen and pregnane and norpregnane derivative in case of combined treatment. Surveillance of blood pressure should be added to the medical surveillance of MHT users.

Postmenopausal hormone use and cutaneous melanoma risk: A French prospective cohort study

Cutaneous melanoma has been suspected to be influenced by female hormones. Several studies reported a positive association between menopausal hormone therapy (MHT) use and melanoma risk; however, previous findings were conflicting. We sought to explore the associations between MHT use and melanoma risk in a prospective cohort of women in France, where a particularly wide variety of MHT formulations are available. E3N is a prospective cohort of 98,995 French women aged 40-65 years in 1990. MHT use was assessed through biennial self-administered questionnaires. We used Cox proportional hazards regression models adjusted for age and skin cancer risk factors. Over 1990-2008, 444 melanoma cases were ascertained among 75,523 postmenopausal women. Ever use of MHT was associated with a higher melanoma risk (hazard ratio (HR) = 1.35, 95% confidence intervals (CI) = 1.07-1.71). The association was strongest among past users (HR = 1.55, CI = 1.17-2.07, homogeneity for past vs. recent use: p = 0.11), and users of MHT containing norpregnane derivatives (HR = 1.59, CI = 1.11-2.27), although with no heterogeneity across types of MHT (p = 0.13). Among MHT users, the association was similar across durations of use. However, a higher risk was observed when treatment onset occurred shortly after menopause (<6 months: HR = 1.55, CI = 1.16-2.07 vs. ≥2 years). Associations between MHT use and melanoma risk were similar after adjustment for UV exposure, although MHT users were more likely to report sunscreen use than nonusers. Our data do not support a strong association between MHT use and melanoma risk. Further investigation is needed to explore potential effect modification by UV exposure on this relationship.

Hormone therapy during the transition and the early postmenopausal period: choosing the progestogen

The type of progestogen used in menopausal HT affects the properties of the regimen concerning the breast and the cardiovascular system. RCTs and observational studies indicate that the addition of a progestogen to the estrogen increases the risk of breast cancer. According to large prospective observational studies, natural progesterone and dydrogesterone may be associated with a smaller risk of breast cancer compared to other progestins. Concerning the risk of thromboembolism, nor-pregnane derivatives are associated with a higher risk compared to other progestogens.

Effects of micronized progesterone added to non-oral estradiol on lipids and cardiovascular risk factors in early postmenopause: a clinical trial

BackgroundMuch attention has been drawn to the deleterious effects of adding progestins to estrogen as hormone therapy (HT) in postmenopausal women. Some widely prescribed progestins have been shown to partially oppose the beneficial effects of estrogens on surrogate markers of cardiovascular disease (CVD) risk. Progestins with higher androgenic activity may interfere with lipid profile and glucose tolerance, and could affect mechanisms of estrogen-induced C-reactive protein (CRP) stimulation. Recent data have shown that norpregnane derivatives, but not micronized progesterone, increase the risk of venous thromboembolism among transdermal estrogens users. The aim of the present study was to assess the effects of combining micronized progesterone with non-oral estrogen therapy on lipid profile and cardiovascular risk factors in a sample of early postmenopausal women.MethodsClinical trial including 40 women receiving intranasal 17β estradiol 3 mg/day for two months and 46 women receiving percutaneous 17β estradiol gel 1.5 mg/day for three months (E2). Both groups received an additional 200 mg/day of micronized progesterone by vaginal route 14 days/month (E2+P). Outcome measures included body weight, waist circumference, body mass index (BMI), lipid profile and ultra-sensitive C-reactive protein (usCRP) at baseline and during the E2 or E2+P portions of treatment.ResultsMean age was 51±3 years. Mean time since menopause was 22.2±10 months. Most participants were overweight; HT did not change BMI. E2 and E2+P did not affect waist circumference and weight. Menopausal symptoms improved after HT. The effects of intranasal and percutaneous estradiol were similar, regardless of the addition of progesterone. Similarly, for the overall group of 86 women, micronized progesterone did not alter the response to E2. Blood pressure, glucose, insulin, HDL-c, triglycerides, and usCRP remained constant with or without micronized progesterone. Total cholesterol decreased after E2, and progesterone maintained this reduction. LDL-c levels were similar at baseline and with E2, and lower during E2+P in relation to baseline.ConclusionsCyclic, short term exposure to vaginal micronized progesterone did not alter the metabolic and cardiovascular effects of non-oral E2 in early, apparently healthy, postmenopausal women.Trial registrationClinicalTrials.gov NCT01432028

Activated protein C resistance among postmenopausal women using transdermal estrogens

Although the route of estrogen administration is known to be an important determinant of the thrombotic risk among postmenopausal women using hormone therapy, recent data have shown that norpregnane derivatives but not micronized progesterone increase venous thromboembolism risk among transdermal estrogens users. However, the differential effects of progesterone and norpregnanes on hemostasis have not yet been investigated. We set up a cross-sectional study among healthy postmenopausal women aged 45 to 70 years. The impact of activated protein C (APC) on endogenous thrombin potential was investigated in the plasma samples of 108 women who did not use any hormone therapy (n = 40) or who were treated with transdermal estrogens combined with micronized progesterone (n = 30) or norpregnane derivatives (n = 38). After exclusion of women with factor V Leiden and/or G20210A prothrombin gene mutations, there was no significant change in APC sensitivity among women who used transdermal estrogens combined with micronized progesterone compared with nonusers. Women using transdermal estrogens combined with norpregnanes were less sensitive to APC than were nonusers (P = 0.003) or users of transdermal estrogens combined with micronized progesterone (P = 0.004). In addition, prothrombin fragment 1 + 2 concentration was higher in users of transdermal estrogens plus norpregnanes than in nonusers (P = 0.004). Other hemostatic parameters did not vary significantly across the different subgroups. Transdermal estrogens combined with norpregnanes may induce APC resistance and activate blood coagulation. These results provide a biological support to epidemiological data regarding the potential thrombogenic effects of norpregnanes. However, these findings need to be confirmed in a randomized trial.

Hormone therapy and risk of venous thromboembolism among postmenopausal women

Venous thromboembolism, either deep vein thrombosis or pulmonary embolism, is a serious side-effect of postmenopausal hormone therapy. Current use of oral estrogens increases the risk of venous thromboembolism, especially during the first year of treatment, but past users of hormone therapy have a similar risk as never-users. Among women at high risk for venous thromboembolism (for example, thrombogenic mutations, obesity), oral estrogens use further enhances the thrombotic risk. Recent studies have shown that transdermal estrogens might be safe with respect to thrombotic risk. The difference in thrombotic risk between oral and transdermal estrogens may be partially explained by changes in hemostasis. Few data are currently available regarding the impact of progestogens on venous thromboembolism risk, but norpregnane derivatives might be thrombogenic. Individual assessment of the benefit–risk ratio is needed before initiating treatment and oral estrogens should be avoided among women at high risk for venous thromboembolism.

Response to Letter Regarding Article, “Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women: Impact of the Route of Estrogen Administration and Progestogens: The ESTHER Study”

We thank Drs Micheletti and Chevallier for their interest in our report.1 First, we believe that odds ratios (ORs) and 95% confidence intervals (CIs) estimated from logistic regressions provide adequate information about significance and the size and direction of the effect of norpregnane derivatives. Because elevation in venous thromboembolism (VTE) risk is substantial (OR: 4) and significantly different from 1 (with the 95% CI not crossing 1), our results suggest a thrombogenic effect of norpregnanes, and the probability value ( P <0.006) indicates that the probability of the result being due to chance is very small. Second, only the main effects …

Letter by Micheletti and Chevallier Regarding Article, “Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women: Impact of the Route of Estrogen Administration and Progestogens: The ESTHER Study”

To the Editor: We read with interest the report by Canonico and colleagues1 that shows a differential association of oral and transdermal estrogen with venous thromboembolism (VTE) risk among postmenopausal women. In addition, their data suggest that norpregnane derivatives may be thrombogenic (with a 4-fold-increased VTE risk), whereas micronized progesterone and pregnane derivatives appear safe with respect to …

Are Some Types of Hormone Therapy Safer Than Others?

Despite great strides in hormone therapy (HT) research, clinical trial data on the benefit-to-risk profile of different formulations, doses, and routes administration of HT remain lacking. Most of the large-scale clinical trials1–3 have tested oral conjugated equine estrogens with or without medroxyprogesterone acetate, and data on nonoral routes and different types and doses of estrogens and progestogens have been limited. The evidence is mounting that route of delivery and possibly type and dose of HT are important factors, particularly for venous thromboembolism (VTE). Results of clinical trials4,5 and observational studies6 have been concordant in demonstrating an increased risk of VTE with oral exogenous HT. Recent studies suggest that VTE risk may be lower with transdermal than oral estrogen7 and with estrogen alone than with combined therapy.4 However, in the absence of rigorous evidence from large-scale clinical trials on differential effects by hormone formulation or route of delivery, should these findings influence clinical practice? Article p 840 The Estrogen and Thromboembolism Risk (ESTHER) study,7 published in the current issue of Circulation , adds important, relevant data to bolster the case that HT type and route of delivery do indeed make a difference. This well-designed, French, multicenter case-control study of VTE enrolled 271 consecutive cases of VTE in women (age, 45 to 70 years) and matched them to hospital and community controls. Current HT use was present in 46% of the VTE cases compared with 37% of controls. Oral HT users had 4-fold-increased odds of VTE; however, there was no increased risk among transdermal hormone users (odds ratio, 0.9). Previous randomized trials have suggested that the risk of VTE may …

Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women

Oral estrogen therapy increases the risk of venous thromboembolism (VTE) in postmenopausal women. Transdermal estrogen may be safer. However, currently available data have limited the ability to investigate the wide variety of types of progestogen. We performed a multicenter case-control study of VTE among postmenopausal women 45 to 70 years of age between 1999 and 2005 in France. We recruited 271 consecutive cases with a first documented episode of idiopathic VTE (208 hospital cases, 63 outpatient cases) and 610 controls (426 hospital controls, 184 community controls) matched for center, age, and admission date. After adjustment for potential confounding factors, odds ratios (ORs) for VTE in current users of oral and transdermal estrogen compared with nonusers were 4.2 (95% CI, 1.5 to 11.6) and 0.9 (95% CI, 0.4 to 2.1), respectively. There was no significant association of VTE with micronized progesterone and pregnane derivatives (OR, 0.7; 95% CI, 0.3 to 1.9 and OR, 0.9; 95% CI, 0.4 to 2.3, respectively). In contrast, norpregnane derivatives were associated with a 4-fold-increased VTE risk (OR, 3.9; 95% CI, 1.5 to 10.0). Oral but not transdermal estrogen is associated with an increased VTE risk. In addition, our data suggest that norpregnane derivatives may be thrombogenic, whereas micronized progesterone and pregnane derivatives appear safe with respect to thrombotic risk. If confirmed, these findings could benefit women in the management of their menopausal symptoms with respect to the VTE risk associated with oral estrogen and use of progestogens.

Effects of progestins of human proliferative endometrium: An in vitro model of potential clinical relevance

Endometrium biopsy is a useful indicator of endometrium proliferation and is clinically relevant to diagnose cell proliferation and to evaluate response to progestin treatment and to monitor hormone replacement therapy. The aim of our study was to investigate the in vitro effects of progesterone and synthetic progestins on endometrium explants with a particular focus on estradiol receptor (ER) and progesterone receptor (PR) expression which reflects through cell secretion the hormone treatment efficiency. Most widely used progestagens belonging to three distinctive groups were investigated, i.e, medroxyprogesterone acetate (MPA), norethindrone acetate (NOR) and nomegestrol acetate (TX) which are respectively pregnane, 19-nortestosterone and norpregnane derivatives. We used organ culture from human proliferative endometrium, in which tissue integrity, particularly gland/stroma relationships are preserved. Progestins induce epithelial cell secretion and most effects were observed at the highest concentration tested (10(-7) M) and by TX and MPA on homogeneous and on heterogeneous (including also secretory glands) proliferative endometrium respectively. In these conditions, ER as well as PR expression were decreased on both glandular and stromal cells. In contrast, progesterone at 10(-7) M significantly decreased only PR, in glands and in stroma of homogeneous proliferative endometrium, and just in stroma of heterogeneous endometrium. NOR exhibited less effects. At lower concentrations (10(-8) M, 10(-9) M), significantly less effects were observed by synthetic progestins on proliferative endometrium. The experiments show that the different types of progestins do not exhibit in vitro similar effects. Since progestins variably act on proliferative endometrium, the exposure of endometrium explants to progestins may be a useful tool to predict clinical response to hormone therapy (individual "hormonogram") and to monitor endometrium proliferation.