Estrogen Hormone Replacement Therapy Research Articles

The D&T Report

The D&T Report

Rationale for low-dose systemic hormone replacement therapy and review of estradiol 0.5 mg/NETA 0.1 mg

The menopausal transition is associated with several symptoms, for which both non-pharmacological and pharmacological measures are available to provide relief. However, present knowledge indicates that the former is not highly effective, and that the latter, in terms of systemic oestrogen and progestogen-based hormone replacement therapy (HRT), although being effective (e.g. on vasomotor symptoms, bleeding control, bone mineral density, vaginal atrophy and quality of life), can be associated with some caveats. Amongst these are an increased risk for coronary heart disease, breast cancer, venous thromboembolism and stroke. In recent years, literature has indicated a dose dependency for HRT on some of the caveats, hence authorities (Food and Drug Administration, and the European Medicines Agency) and menopause societies (International Menopause Society and North American Menopause Society) now recommend that women deemed in need of HRT should receive the lowest possible dose without compromising the effect of symptom relief. Estradiol 0.5 mg/norethisterone acetate (NETA) 0.1 mg, despite being a lower dose than conventional hormones, is a compound, among a few other low-dose options, that can be used in such therapy. As a first-line oral option, it has demonstrated its effectiveness (which seems comparable to other compounds), with high tolerability and, apparently, no safety concerns, in a 6-month study. Further long-term clinical trials and observational studies are mandatory in order to capture any potential harm as well as to elucidate this compound's full potential. Following a thorough literature search using PubMed and MEDLINE from the earliest publication dates through to January 2008, including results from various types of clinical trials and statements on HRT, we review the rationale for these recommendations. We also review the effects and safety of a novel 'ultra-low-dose' oral continuous combined HRT tablet, estradiol 0.5 mg/NETA 0.1 mg.

Characteristics of contractile activity in the renal artery of ovariectomized rats

The incidence of cardiovascular disease is markedly lower in cycling, pre-menopausal women and post-menopausal women receiving estrogen than in men or untreated post-menopausal women. Clinical studies demonstrate a protective role of estrogen in hormone replacement therapy in terms of reducing cardiovascular risk. However, the benefits of hormone replacement therapy in cardiovascular disease remain unclear. We investigated the effects of estrogen on the contractile responses of the renal artery of ovariectomized Wistar rats (OVX) compared to both ovariectomized 17 beta-estradiol-treated rats (OVXE) and sham-operated (control) rats. Isometric contraction of renal artery was recorded with a strain gauge transducer. The maximum contractile response of the renal artery smooth muscle to KCl (80 mM) in the OVXE group was significantly higher than that in both the control and OVX groups. The phenylephrine (PE) concentration-response curves in all three groups indicated a greater sensitivity at lower concentrations of PE following treatment with 100 microM L-arginine methyl ester (L-NAME). The EC50 values for PE in the three groups were 2 times lower in the presence of L-NAME than those lacking exposure to L-NAME. The EC50 value for PE in the OVX group was approximately 3 times lower in the presence of L-NAME than in those lacking exposure to L-NAME and 100 nM BMY 7378, an alpha 1D-adrenoceptor antagonist. The rate of relaxation of the PE-induced contraction (T1/2) was significantly reduced in the OVX group relative to both the control and OVXE groups. T1/2 values after treatment with 100 microM L-NAME were slower than those lacking exposure to L-NAME in all groups. Further, the T1/2 value of the OVX group was 2 times greater than that of the control; this change was reversed in the OVXE group. In conclusion, our results suggest that estrogen regulates contraction and relaxation in the renal artery via NO synthase activity and alteration of the Ca2+ transport systems.

Black Cohosh: Insights into its Mechanism(s) of Action

The Women's Health Initiative found that combination estrogen and progesterone hormone replacement therapy increases breast cancer and cardiovascular disease risk, which compelled many women to seek herbal alternatives such as black cohosh extract (BCE) to relieve their menopausal symptoms. While several clinical trials document the efficacy of BCE in alleviating menopausal symptoms, preclinical studies to determine how BCE works have yielded conflicting results. Part of this is because there is not a universally accepted method to standardize the dose of black cohosh triterpenes, the presumed active ingredients in the extract. Although the mechanism by which BCE relieves symptoms is unknown, several hypotheses have been proposed: it acts 1) as a selective estrogen receptor modulator, 2) through serotonergic pathways, 3) as an antioxidant, or 4) on inflammatory pathways. We found that while the most prominent triterpene in BCE, 23-epi-26-deoxyactein, suppresses cytokine-induced nitric oxide production in brain microglial cells, the whole BCE extract actually enhanced this pathway. A variety of activities have been reported for black cohosh and its compounds, but the absorption and tissue distribution of these compounds is unknown.

The protective side of progesterone

According to Jerry's commentary [1], exogenous oestrogen and progesterone potently inhibit tumorigenesis, representing an interesting strategy to prevent breast cancer, but we feel that the concerns noted by Jerry deserve further comment. According to the Million Women Study [2], when progesterone was included in the hormone replacement therapy (HRT) formulation, the odds ratio fell from 1.3 to 1.1, indicating a protective effect exerted by progesterone, though no significant difference in the relative risk of ovarian cancer was registered in the subgroups of women who used oestrogen only compared with those who used the combination. Long durations of use of unopposed oestrogen and of oestrogen plus progestin, especially sequential regimens, have been reported to be associated with increased ovarian cancer risk. In preclinical models, combined progestins circumvent the anti-apoptotic action of the long isoform of Fas-associating protein with death domain-like interleukin-1 beta-converting enzyme (FLICE)-like inhibitory protein, an anti-apoptosis mediator, representing an effective therapy for ovarian cancer cells [3]. In premenopausal women, combined oral contraceptives (OC) have been described to be effective at decreasing the risk of epithelial ovarian carcinoma, even though the strongest risk reduction has been associated either with low- or high-potency progestin formulations. Some synthetic progestins, when added to oestrogen in HRT for menopausal symptoms, have been reported to increase the risk of breast cancer more than oestrogen alone. Progestin use in breast cancer survivors is associated with an increased breast cancer risk compared with its non-use [4]. However, outside pregnancy, progesterone endogenously produced or exogenously administered does not have a cancer-promoting effect on breast tissue. The greater breast cancer risk related to the use of HRT containing oestrogen and synthetic androgenic progestin (19-nortestosterone derivatives) could be due to the non-progesterone-like effects enhancing the oestrogen proliferative effect on oestrogen-sensitive cancer cells. In postmenopausal women, progesterone is added to prevent the carcinogenic effect of oestrogen on the uterus [5]. In premenopausal women, the potency of the progestin in most OC appears adequate to provide a protective effect against endometrial cancer. Higher progestin-potency OC may be more protective than lower progestin potency OC among women with a larger body habitus. Progestagens counteract the adverse effect of oestrogens on the endometrium, the effect being greater the more days every month that they are added to oestrogen and the more obese that women are. Finally, because hormones may play a crucial role in the development of breast, endometrial and ovarian cancer, the impact on cancer risk of progestins included in HRT or OC formulations remains a major interest.

Immunomodulatory Effects of Cimicifugae Rhizoma Extracts in Macrophages

Cimicifugae Rhizoma (CR) belongs to the Ranunculaceae family, which has been traditionally used to treat climacteric complaints, antipyretics and diaphoresis as an alternative medicine for estrogen hormone replacement therapy with estrogens. Recently, it has been reported that different extract fractions of CR have various effects such as anti-allergic, anti-inflammatory and anti-proliferative activities. The current study investigated the immunomodulatory effects of Cimicifugae Rhizoma water extracts (CRE) in the macrophage-like cell line, Raw 264.7. Our results showed that CRE (1～50 ㎍/mL) stimulated tumoricidal activity and NO production, whereas phagocytic activity was inhibited at the same concentrations. Additionally, iNOS mRNA expression was significantly increased in Raw 264.7 exposed to CRE as demonstrated by RT-PCR. These results indicate that the tumoricidal activity induced by CRE may be mediated by the production of NO and these activities may be useful for the treatment of diseases such as cancer.

Type and Duration of Exogenous Hormone Use Affects Breast Cancer Histology

It is unclear whether hormone replacement therapy (HRT), in addition to increasing risk for breast cancer, affects the type of breast cancer diagnosed. We conducted this investigation to assess whether the type of hormone used (none, estrogen, progesterone, or combined) and duration of use influences subsequent breast cancer histology. We performed a retrospective cohort analysis among women listed as incident cases of breast malignancy in the Kaiser Permanente Northern California Cancer Registry during 2003 (n = 2830). Type and duration of hormone used (none, estrogen, progesterone, or combined) before breast cancer diagnosis was obtained from electronic pharmacy records. The association between type and duration of hormone use with characteristics of subsequent breast cancers was examined. Among women aged >50 years (n = 1701), any use of estrogen, progesterone, or combination therapy was not associated with an increased risk of estrogen receptor (ER)-positive disease. However, >6 months' use of combined HRT increased the odds of ER-positive tumors (odds ratio, 1.65; 95% confidence interval, 1.07-2.5; P = .02). Estrogen HRT patients were more likely than nonusers to present with low-grade (P = .05), and early-stage tumors (P = .03). This trend was not seen in combined HRT users. Short-duration HRT did not increase the likelihood of ER-positive breast cancer. However, prolonged duration of combined HRT, but not estrogen or progesterone alone, resulted in a marked increase in ER-positive disease. Our findings suggest that the effect of combined HRT on breast cancer incidence or progression is not immediate and that long-term use is more likely to affect breast cancer histology.

The benefits of oestrogens on postprandial lipid metabolism are lost in post‐menopausal women with Type 2 diabetes

Women with Type 2 diabetes appear to lose the protection against cardiovascular disease (CVD) afforded by oestrogens. We examined the effects of oestrogen hormone replacement therapy (HRT) on postprandial clearance of dietary fat in non-diabetic and diabetic post-menopausal women. In a cross-sectional study, fasting subjects [HRT+ and HRT- control and diabetic women; Type 2 diabetes (DM) HRT+n = 8, DM HRT-n = 14, control HRT+n = 7, control HRT-n = 11] consumed a meal containing the stable isotope 1,1,1-[13]C-tripalmitin, with blood and breath sampled for 6 and 24 h, respectively, in the postprandial period. In diabetic women, there were no differences between the HRT+ and HRT- groups for any of these parameters. In contrast, in HRT+ compared with HRT- control women, the triglyceride (TG) area under the curve was lower [AUC; HRT+ median (range) 7.7 (4.1, 12.8) mmol/l per 6 h, HRT- 9.7 (3.9, 18.5) mmol/l per 6 h, P < 0.05] and [13]C-palmitic acid in the TG fraction was also lower [HRT+ 23.2 (10.3, 41.3) ng/ml per 6 h, HRT- 47.7 (12.6, 77.2) ng/ml per 6 h, P < 0.05], suggesting the lower postprandial triglyceridaemia associated with HRT in non-diabetic women is because of better chylomicron clearance. The oestrogen-associated advantage in clearance of dietary lipid we observed in non-diabetic post-menopausal women is not seen in post-menopausal diabetic women. This is likely to promote an atherogenic lipoprotein profile and may contribute to the loss of CVD protection seen in diabetic women.

Levonorgestrel intrauterine system for endometrial protection

Progestogen is added to estrogen in hormone replacement therapy solely to provide endometrial protection, so it is logical to deliver it to its site of action. The levonorgestrel intrauterine system, which delivers 20 mug levonorgestrel per day, is now licensed for use as the progestogen component of continuous combined hormone replacement therapy. No cases of endometrial hyperplasia or carcinoma, and no significant increase in endometrial thickness, have been reported in clinical trials. The bleeding profile is similar to that obtained with other types of continuous combined hormone replacement therapy. The levonorgestrel intrauterine system thus provides a potentially bleed-free alternative to sequential therapy for perimenopausal women.

The Effect of Combined Estrogen and Progesterone Hormone Replacement Therapy on Disease Activity in Systemic Lupus Erythematosus: A Randomized Trial

The Effect of Combined Estrogen and Progesterone Hormone Replacement Therapy on Disease Activity in Systemic Lupus Erythematosus: A Randomized Trial

The Effect of Combined Estrogen and Progesterone Hormone Replacement Therapy on Disease Activity in Systemic Lupus Erythematosus: A Randomized Trial

The Effect of Combined Estrogen and Progesterone Hormone Replacement Therapy on Disease Activity in Systemic Lupus Erythematosus: A Randomized Trial

Pregnancy, progesterone and progestins in relation to breast cancer risk

In the last two decades the prevailing opinion, supported by the “estrogen augmented by progesterone” hypothesis, has been that progesterone contributes to the development of breast cancer (BC). Support for this opinion was provided by the finding that some synthetic progestins, when added to estrogen in hormone replacement therapy (HRT) for menopausal complaints, increase the BC risk more than estrogen alone. However, recent findings suggest that both the production of progesterone during pregnancy and the progesterone endogenously produced or exogenously administered outside pregnancy, does not increase BC risk, and could even be protective. The increased BC risk found with the addition of synthetic progestins to estrogen in HRT seems in all likehood due to the fact that these progestins (medroxyprogesterone acetate and 19-nortestosterone-derivatives) are endowed with some non-progesterone-like effects which can potentiate the proliferative action of estrogens. The use of progestational agents in pregnancy, for example to prevent preterm birth, does not cause concern in relation to BC risk.

Oestrogens and insulin secretion

There is a persistent perception that oestrogens have an adverse effect on carbohydrate metabolism. It might therefore be expected that their use would result in a corresponding increase in the incidence of diabetes. Recent evidence from clinical trials suggesting that women on postmenopausal oestrogen hormone replacement therapy (HRT) have a reduced incidence of type 2 diabetes therefore appears paradoxical. Short-term supraphysiological oestrogen administration has an adverse effect on glucose tolerance, resulting from suppression of first-phase insulin secretion and increased insulin resistance. Oestrogen-induced increases in glucocorticoid activity could account for these effects. Oestrogen-induced deterioration in glucose tolerance is, however, accompanied by a reduction in fasting glucose, an effect that could be accounted for by glucagon antagonism. These short-term effects contrast with long-term preservation of insulin secretion and glucose homeostasis by oestrogens. In animal studies, ovariectomy is associated with decreased insulin secretion and increased risk of diabetes, whereas oestrogen administration protects against diabetes and increases the insulin response to glucose. The mechanism is uncertain, but direct effects on the pancreas via steroid receptors or indirect effects via oestrogen-induced glucagon antagonism and subclinical increases in glucocorticoids and growth hormone could all contribute. Recent evidence that HRT increases the risk of cardiovascular disease suggests that it should not be used for the prevention of diabetes, but the mechanism responsible for this benefit merits further investigation and might lead to new therapies.

The Effect of Combined Estrogen and Progesterone Hormone Replacement Therapy on Disease Activity in Systemic Lupus Erythematosus: A Randomized Trial

Obstetrics & Gynecology: September 2005 - Volume 106 - Issue 3 - p 636-637 doi: 10.1097/01.AOG.0000177943.46507.3d

Oral implications of osteoporosis

The association between osteoporosis and oral health remains a matter of controversy. It is important to confirm whether there is a role of osteoporosis in bone loss in the jaws, periodontal diseases, tooth loss, and other oral tissue changes. The objective of this article is to review and summarize the published literature on the associations between osteoporosis and various oral conditions such as bone loss in the jaws, periodontal diseases, and tooth loss. A search of the computerized database MEDLINE was conducted. Clinical information concerning systemic osteoporosis and animal studies reporting possible associations between osteoporosis and changes in the dental and oral tissues were included. The review focus was on studies involving (1) methods for assessing bone mineral density (BMD); (2) methods for assessing osteoporosis-related changes in intraoral sites; (3) associations between mandibular BMD and skeletal BMD; (4) changes in the jaws, periodontal tissues, and temporomandibular joint concurrent with osteoporosis; (5) changes in the oral tissues following estrogen deficiency; and (6) effects of estrogen-hormone replacement therapy and/or calcium and vitamin D on oral health. Ninety-seven studies conducted in various parts of the world were identified. Evidence from prospective studies supports the contention that individuals with osteoporosis may be at increased risk for the manifestations of oral osteoporosis; however, such risk is not definitively proven. Studies suggest that findings on dental panoramic radiographs may be used to detect individuals with low BMD. Further well-controlled studies are needed to better elucidate the inter-relationship between systemic and oral bone loss and to clarify whether dentists could usefully provide early warning for osteoporosis risk.

Benefit and safety of 28-day transdermal estrogen regiment during vaginal hysterectomy (a controlled trial)

Objectives assessment of benefit and safety of 28-day transdermal 17-βestradiol regiment during vaginal hysterectomy. Methods Two-hundred and sixty-nine postmenopausal women, undergoing vaginal hysterectomy were divided into: transdermal estrogen hormone replacement therapy (TEHRT) group ( n = 119) with 28-day transdermal 17-βestradiol 50 mg/day, 14 days before and after operation; and vaginal estrogen hormone replacement therapy (VEHRT) group ( n = 150) with 14-day preoperative vaginal conjugated estrogen 0.625 mg/day. The effect on: endometrium, wound healing, infection, recurrent organ prolapse were evaluated. Results Pain symptoms, vaginal fetid discharge, swelling, crusting ( p < 0.001); visible wound opening on the 4 week control ( p < 0.01); patient assessment of outcome ( p < 0.001) were in favor of TEHRT. On the fifth postoperative day, VEHRT group showed: higher leukocytes increase ( p < 0.01); more patients with leukocytes ‘count higher than 15 × 10 9 L −1 ( p < 0.001) and afternoon body temperature higher than 38 °C ( p < 0.01). On the last follow-up control (VEHRT-28.3 months and TEHRT-24.5 months) TEHRT group had more patients with stage 0 of the apical segment ( p < 0.05). Point C was higher and total vaginal length longer in TEHRT group ( p < 0.01; p < 0.05). Frequency, constipation, painful coitus, incontinence during intercourse were more frequent in VEHRT ( p < 0.001; p < 0.05; p < 0.05; p < 0.05). Endometrium with a thickness between 2 and 4 mm, was more frequent in the TEHRT group ( p < 0.05). There were no significant differences in occurrence of more thickened endometrium and more significant morphological changes (endometrial polyp, simplex hyperplasia) between the groups. In none of the patients from the both study groups complex hyperplasia, atypical hyperplasia or endometrial carcinoma were observed. Conclusions The 28-day transdermal 17-βestradiol regiment seems to be safe and effective procedure.

Estrogen receptor-α variants are associated with lipoprotein size distribution and particle levels in women: The Framingham Heart Study

Plasma lipid profile is affected by endogenous estrogen levels and hormone replacement therapy (HRT). As plasma lipid concentrations have a significant heritable basis and the effects of both endogenous estrogen and use of HRT are mediated by estrogen receptors, we sought to investigate the relationships between polymorphisms in estrogen receptor-α ( ESR1) and plasma lipid and lipoprotein concentrations. We analyzed data from 854 women (mean age 52 ± 10 years) from the Framingham Heart Study. A TA repeat in the promoter region, c.30T > C in exon 1, c.454-397T > C, and c.454-351A > G in intron 1, all in linkage disequilibrium (LD), were significantly associated with low-density lipoprotein (LDL) particle size and concentration of small LDL particles. Women with the c.454-397C allele had larger LDL particle size (21.09 ± 0.02 nm versus 21.01 ± 0.03 nm, p = 0.021) concurrent with lower small LDL particle concentration (0.47 ± 0.02 mmol/L versus 0.58 ± 0.03 mmol/L, p = 0.008). Moreover, the TA[L]– c.30C– c.454-397C– c.454-351G haplotype (frequency, 32%) was associated with lower small LDL particle concentrations (−0.06 ± 0.03 mmol/L change associated with each copy of this haplotype, p = 0.011) when compared to the TA[S]– c.30T– c.454-397T– c.454-351A haplotype (frequency, 46%), where L and S are long and short TA repeats. Our results suggest that common ESR1 polymorphisms have a significant effect on lipoprotein metabolism in women.

The Effect of Combined Estrogen and Progesterone Hormone Replacement Therapy on Disease Activity in Systemic Lupus Erythematosus: A Randomized Trial

There is concern that exogenous female hormones may worsen disease activity in women with systemic lupus erythematosus (SLE). To evaluate the effect of hormone replacement therapy (HRT) on disease activity in postmenopausal women with SLE. Randomized, double-blind, placebo-controlled noninferiority trial conducted from March 1996 to June 2002. 16 university-affiliated rheumatology clinics or practices in 11 U.S. states. 351 menopausal patients (mean age, 50 years) with inactive (81.5%) or stable-active (18.5%) SLE. 12 months of treatment with active drug (0.625 mg of conjugated estrogen daily, plus 5 mg of medroxyprogesterone for 12 days per month) or placebo. The 12-month follow-up rate was 82% for the HRT group and 87% for the placebo group. The primary end point was occurrence of a severe flare as defined by Safety of Estrogens in Lupus Erythematosus, National Assessment-Systemic Lupus Erythematosus Disease Activity Index composite. Severe flare was rare in both treatment groups: The 12-month severe flare rate was 0.081 for the HRT group and 0.049 for the placebo group, yielding an estimated difference of 0.033 (P = 0.23). The upper limit of the 1-sided 95% CI for the treatment difference was 0.078, within the prespecified margin of 9% for noninferiority. Mild to moderate flares were significantly increased in the HRT group: 1.14 flares/person-year for HRT and 0.86 flare/person-year for placebo (relative risk, 1.34; P = 0.01). The probability of any type of flare by 12 months was 0.64 for the HRT group and 0.51 for the placebo group (P = 0.01). In the HRT group, there were 1 death, 1 stroke, 2 cases of deep venous thrombosis, and 1 case of thrombosis in an arteriovenous graft; in the placebo group, 1 patient developed deep venous thrombosis. Findings are not generalizable to women with high-titer anticardiolipin antibodies, lupus anticoagulant, or previous thrombosis. Adding a short course of HRT is associated with a small risk for increasing the natural flare rate of lupus. Most of these flares are mild to moderate. The benefits of HRT can be balanced against the risk for flare because HRT did not significantly increase the risk for severe flare compared with placebo.

Oestrogen plus progestin hormone replacement therapy increases venous thrombosis in postmenopausal women

QuestionDoes oestrogen plus progestin hormone replacement therapy increase the risk of venous thrombosis in postmenopausal women?Study designDouble-blind, randomised controlled trial.Main resultsIn postmenopausal women, oestrogen plus progestin hormone replacement therapy increased the risk of venous thrombosis, deep vein thrombosis and pulmonary embolism compared with placebo (see results table). Older, obese or overweight women taking hormone replacement therapy had an increased risk of venous thrombosis (see results table). The homozygous variant of Factor V Leiden was associated with an increased risk of venous thrombosis (OR 7.5, 95% CI 0.6 to 87.8).Authors’ conclusionsOestrogen plus progestin hormone replacement therapy significantly increased the risk of venous thrombosis in postmenopausal women. Increasing age, excess weight and obesity, and the Factor V Leiden genetic variant significantly increased the risk of venous thrombosis associated with this hormone replacement therapy.

Postmenopausal hormone therapy and cancer risk

Postmenopausal Hormone Replacement Therapy has been implicated in the development of four frequent female tumors: endometrial cancer, breast cancer, ovarian cancer and colorectal cancer. Estrogens are only weak genotoxic, mutagenic carcinogens, but could induce tumors by way of accumulation of incessant DNA replication damage. While estrogen (only) hormone replacement therapy (ERT) increases the risk of endometrial carcinoma and probably of ovarian carcinoma, ERT seems to be neutral for the breast and colorectal cancer. With combined estrogen progestagen replacement therapy (HRT), there is no increased risk of endometrial cancer nor of ovarian cancer. The risk of breast cancer, however, is slightly increased with long-term use. Colorectal cancer risk is probably reduced with combined HRT use. Data are only available for oral use; for transdermal, intranasal and other use no data are available.