Endometrial safety of continuous combined hormone replacement therapy with 17beta-oestradiol (1 or 2 mg) and dydrogesterone

Objectives: To determine the endometrial safety of oral 17β-oestradiol combined continuously with dydrogesterone in preventing endometrial proliferation. Methods: The low dose group comprised three 52-week (13 cycles of 28 days) studies (two of which were double blind) using a 17β-oestradiol dose of 1 mg daily combined with dydrogesterone 2.5, 5, 10 or 20 mg daily. The high dose group comprised two 24-week double-blind studies using a 17β-oestradiol dose of 2 mg daily combined with dydrogesterone 2.5, 5, 10 or 15 mg daily. Endometrial safety was verified by aspiration endometrial biopsies. Inadequate progestational response was defined as proliferative endometrium, endometrial polyp, hyperplasia and carcinoma. Results: Data was evaluable from 650 healthy postmenopausal women in the low dose group and 310 in the high dose group. Endometrial protection was achieved with dydrogesterone at doses of 5 mg or higher combined with 1 or 2 mg 17β-oestradiol. The success rate was 97%, 97% and 98% in women receiving 1/5, 1/10 and 1/20 mg, respectively, and 95%, 98% and 91% in women receiving 2/5, 2/10 and 2/15 mg, respectively. A lower success rate was achieved with the 2.5 mg dydrogesterone dosage (93% in the 1/2.5 mg group and 85% in the 2/2.5 mg group) due to more cases of proliferative endometrium. None of the women in the low dose group developed hyperplasia or carcinoma; five (0.7%) had endometrial polyps. In the high dose group, one woman given 2.5 mg dydrogesterone developed hyperplasia; there were no cases of carcinoma. Conclusion: 5 mg daily dydrogesterone appears to be the lowest effective dose to ensure endometrial safety in a continuous combined regimen with 1 or 2 mg 17β-oestradiol.     

Cell cycle analysis and detection of proliferative cell nuclear antigen of the endometrium after hormone replacement therapy

Background: To understand the effect of sequential combined hormone replacement therapy (HRT) on the postmenopausal endometrium. Methods: Sonographic endometrial thickness, endometrial histopathology, flow cytometric cell cycle analysis and the level of proliferative cell nuclear antigen (PCNA) were studied. Results: One hundred and thirty-eight postmenopausal women were enrolled in this study. Among which, 97 women had their endometrium being adequately obtained; the most frequent type of histopathology was normal endometrium (91.8%). Endometrial hyperplasia was found in seven patients (7.2%), including typical simple hyperplasia (n=1, 1%), focal simple hyperplasia (n=5, 5.2%) and complex hyperplasia without atypia (n=1, 1%). The proliferative fractions (PF; S plus G₂–M phase) of cells from normal and hyperplastic endometrium of menopausal women after HRT were 8.18 and 8.95%, respectively, which were lower than those from 29 premenopausal women without HRT. The level of PCNA of normal and hyperplastic endometrium in postmenopausal women after HRT was about 80 and 84%, respectively, of that from premenopausal endometrium. Conclusions: Our study showed the PF of the cell cycle and the level of PCNA were not increased in the menopausal endometrium under HRT as compared to the premenopausal controls.     

Unscheduled bleeding in continuous combined hormone therapy users

Continuous combined hormone therapy (HT) is effective for menopausal vasomotor symptoms and vaginal dryness but commonly leads to unscheduled vaginal bleeding and spotting. Unscheduled bleeding is disliked by women and may lead to invasive investigations to exclude underlying pelvic pathology. In most cases investigations do not reveal any underlying cause for the bleeding.     

Endometrial safety of continuous combined hormone replacement therapy with 17β-oestradiol (1 or 2 mg) and dydrogesterone

Objectives: To determine the endometrial safety of oral 17β-oestradiol combined continuously with dydrogesterone in preventing endometrial proliferation. Methods: The low dose group comprised three 52-week (13 cycles of 28 days) studies (two of which were double blind) using a 17β-oestradiol dose of 1 mg daily combined with dydrogesterone 2.5, 5, 10 or 20 mg daily. The high dose group comprised two 24-week double-blind studies using a 17β-oestradiol dose of 2 mg daily combined with dydrogesterone 2.5, 5, 10 or 15 mg daily. Endometrial safety was verified by aspiration endometrial biopsies. Inadequate progestational response was defined as proliferative endometrium, endometrial polyp, hyperplasia and carcinoma. Results: Data was evaluable from 650 healthy postmenopausal women in the low dose group and 310 in the high dose group. Endometrial protection was achieved with dydrogesterone at doses of 5 mg or higher combined with 1 or 2 mg 17β-oestradiol. The success rate was 97%, 97% and 98% in women receiving 1/5, 1/10 and 1/20 mg, respectively, and 95%, 98% and 91% in women receiving 2/5, 2/10 and 2/15 mg, respectively. A lower success rate was achieved with the 2.5 mg dydrogesterone dosage (93% in the 1/2.5 mg group and 85% in the 2/2.5 mg group) due to more cases of proliferative endometrium. None of the women in the low dose group developed hyperplasia or carcinoma; five (0.7%) had endometrial polyps. In the high dose group, one woman given 2.5 mg dydrogesterone developed hyperplasia; there were no cases of carcinoma. Conclusion: 5 mg daily dydrogesterone appears to be the lowest effective dose to ensure endometrial safety in a continuous combined regimen with 1 or 2 mg 17β-oestradiol.     

A transdermal regimen for continuous combined hormone replacement therapy in the menopause

Transdermal systems for oestrogen therapy in the menopause have become very popular. The compliance, however, is impeded by the cyclic addition of oral progestins which leads to monthly withdrawal bleeds. In this pilot study a skin patch releasing 0.05 mg oestradiol and 0.25 mg norethisterone acetate per day, which was originally designed for sequential therapy, was used in a continuous manner. Results were quite favourable. Menopausal complaints were efficiently relieved and the Kupperman score dropped from 27.6 to 5.0. Out of 10 women, 1 had mild breakthrough bleeding, and 7 patients recorded one or several spotting episodes, mainly within the first 3 treatment months. No endometrial hyperplasia was observed and there was no significant change in plasma lipids, i.e. cholesterol, triglycerides, HDL-, HDL2-, HDL3-cholesterol, LDL-cholesterol and apolipoproteins A1 and B. The regimen might be a useful alternative to oral continuous combined replacement therapy.     

Dry eye in post-menopausal women using hormone replacement therapy

PURPOSE: To evaluate the effect of hormone replacement therapy (HRT) on dry eye in post-menopausal women. METHODS: Forty post-menopausal women with dry eye (20 patients, group 1) and without dry eye (20 patients, group 2), and planning to receive HRT (estrogen plus progesterone), were recruited as the study groups. Forty age-matched untreated women were enrolled as controls (group 3 with dry eye, 5 patients; group 4 without dry eye, 35 patients). Patients having at least one of the symptoms (dryness, itching, photophobia, foreign body sensation, and tearing) together with two of the tests with positive results for dry eye (tear film break-up time (BUT), fluorescein staining of the cornea, analysis of the meibomian gland, and Schirmer I test) in both eyes were considered dry eye positive. Hormonal assay for follicle stimulating hormone, luteinizing hormone, estradiol, and free testosterone was performed. Dry eye statuses in the groups were evaluated statistically. RESULTS: Four patients with incomplete follow-up data were excluded. HRT use increased estradiol levels in the groups. Mean ages of patients (50.2+/-4.8 and 50.7+/-3.9 years, and 50.0+/-4.6 and 53.0+/-3.9 years) were similar (p=0.67). Duration of menopause in groups 1 and 2 (3.2+/-2.2 and 1.4+/-1.2 years; p=0.01), and in groups 3 and 4 (3.0+/-1.6 and 1.7+/-1.3 years; p=0.014) were different. At the third month examinations, all of the patients in group 1, and 11 patients (61.1%) in group 2 had dry eye (p=0.003). CONCLUSION: Duration of menopause and use of HRT may increase the incidence of dry eye in post-menopausal woman.     

Tissue specificity: the clinical importance of steroid metabolites in hormone replacement therapy

Metabolic activations or inactivations of estrogens, progesterone and androgens are important steps towards the understanding of the physiological and the pathological effects of these hormones in the female organism. Analysis of the tissue specific metabolic pathways of sex steroids will result in a better understanding of successful hormone replacement therapy on the one hand and of the occurrence of steroid hormone related side effects on the other hand. In this contribution we analyse the different mechanisms involved in the synthesis of tissue specific metabolites and discuss the therapeutical importance of these metabolites in hormone replacement therapy.     

Effective bleeding control and symptom relief by lower dose regimens of continuous combined hormone replacement therapy: A randomized comparative dose-ranging study

Objectives: We compared two different continuous combined hormone replacement therapy (HRT) regimens of estradiol valerate (E₂V) and medroxyprogesterone acetate (MPA) with a combination of micronized estradiol (E₂) and norethisterone acetate (NETA) to determine bleeding pattern, control of climacteric symptoms, lipid profile, endometrial and general safety in a 1-year multicenter study. Methods: 440 postmenopausal women were randomized to three treatment groups to receive: 1 mg E₂V+2.5 mg MPA; 1 mg E₂V+5 mg MPA; or 2 mg of E₂+1 mg NETA. After the first 6 months, the E₂V dose was increased to 2 mg in both E₂V/MPA groups. Information on bleeding was recorded on diaries by the women and intensity of climacteric symptoms was assessed using VAS scales. Physical and laboratory examinations, endometrial biopsy and vaginal ultrasonography were performed at baseline and follow-up visits. Results: Significantly fewer bleeding days were experienced in the first 3 months by women taking E₂V/MPA compared with women taking E₂/NETA. When the dose of E₂V was increased in the E₂V/MPA groups, an increase in maximum bleeding intensity was observed in the group receiving 2.5 mg of MPA, but not in the group taking 5 mg of MPA. All dose combinations effectively relieved climacteric symptoms and beneficial effects on the lipid profile were seen after 6 months in all groups. Tolerability and endometrial safety were good and no cases of hyperplasia were observed. More women discontinued treatment prematurely in the E₂/NETA group compared with either of the E₂V/MPA groups. The overall continuation rates ranged from 70 to 86%. Conclusions: These results confirm that lower dose combinations of continuous combined HRT are usually sufficient to control symptoms or avoid breakthrough bleeding. However, if higher E₂V dose is needed for symptom control, it should be combined with the higher dose of progestin (5 mg) to avoid bleeding disturbances. Flexible treatment regimens should be available for individualized HRT.     

Insulin-like growth factor-binding protein-1: a biochemical marker of endometrial response to progestin during hormone replacement therapy

Objectives: To compare immunohistochemical localization of insulin-like growth factor binding protein-1 (IGFBP-1) in endometrial stromal cells with endometrial morphology during three regimens of continuous combined hormone replacement therapy. Methods: Endometrial samples for morphological examination and immunohistochemical staining with monoclonal antibody against IGFBP-1 were obtained from 30 menopausal women before treatment and after 12 and 24 months of continuous combined hormone replacement therapy. All women received percutaneous estradiolgel releasing 1.5 mg estradiol daily. Regarding progestins, patients were divided into three groups: one group (n = 15) had a 20 μg/24 h levonorgestrel-releasing intrauterine device (LNG-IUD); the women in the other two groups received micronised natural progesterone either 100 mg orally (n = 7) or 100–200 mg vaginally (n = 8) daily, 25 days per calendar month. Results: Before treatment the endometrium of all women was atrophic or subatrophic and no IGFBP-1 could be detected in any of the samples which contained enough stromal cells for evaluation. After 12 and 24 months of treatment, epithelial atrophy with decidual transformation in stroma was detected in all specimens in the LNG-IUD group, and IGFBP-1 was localized in decidualized stromal cells in all samples. In the other two groups, no signs of progestin effect were detected by microscopic examination in any of the endometrial samples and IGFBP-1 staining was completely negative in all of them. Conclusion: A striking difference occurred in both morphological and biochemical response in the endometrium of women treated with LNG-IUD compared with those receiving oral or vaginal micronised progesteron during continuous combined HRT. Micronised progesterone at doses used in this study turned out to be ineffective to prevent the proliferative effect of estrogen. Immunohistochemical localization of IGFBP-1 in endometrial stromal cells strongly correlated with decidual reaction in all endometrial specimens exposed to LNG-IUD, suggesting that the immunostaining of IGFBP-1 can be used as a means of assessing the strength of progestin effect in the endometrium during HRT.     

The benefits of androgens combined with hormone replacement therapy regarding to patients with postmenopausal sexual symptoms

OBJECTIVE: To evaluate the benefits and risks of hormone replacement therapy (HRT) combined with methyltestosterone (MT) in postmenopausal women with sexual dysfunction. DESIGN: This study was a randomized, double-blind, placebo-controlled and crossover trial. Eighty-five women using HRT were divided into four treatment groups: GI-HRT plus placebo for 4 months; GII-HRT plus MT 2.5mg/day for 4 months; GIII-HRT plus placebo for 2 months and then replaced with HRT plus MT 2.5mg/day for 2 months; GIV-HRT plus MT 2.5mg/day and then replaced with HRT plus placebo for 2 months. Blood was collected at baseline, after 2 months (T1) and 4 months (T2) of treatment for hormone determinations of estradiol, FSH, total and free testosterone, GOT, GPT, glucose, total and fractions of cholesterol and triglycerides. All participants answered clinical questions and a validated questionnaire of modified McCoy's sex scale. RESULTS: The association of HRT with MT 2.5mg/day did not significantly change liver enzymes or increase cardiovascular risk factors. The patients of GII, GIIII and GIV when using MT presented amelioration of sex symptoms, mainly satisfaction and desire (p<0.01); however, GIII at T1 (1.3+/-0.3) presented similar problem score results as compared to GIII at T2 (1.5+/-0.6). CONCLUSION: All data suggest that combined HRT-androgen therapy may be beneficial for postmenopausal women receiving HRT who continue to complain of sexual difficulties or for postmenopausal women with sexual complaints who are not undergoing estrogen therapy.     

Opinion survey towards hormone replacement therapy in the prevention of coronary heart disease

Background: Observational and experimental data underscore the cardioprotective effects of hormone replacement therapy (HRT). On the other hand, the randomised trial available, the ‘Heart and Estrogen/Progestin Replacement Study (HERS)’, showed no reduced risk of coronary heart disease (CHD), using HRT. Aim: Opinion survey on the effect of HRT on CHD risk. Setting: Identification of articles on the related topic using a Medline search. Written survey of the authors’ opinion towards HRT in relation to CHD. Results: Thirty-seven of the 108 principal authors responded. Among them, respectively, 16 (43%) and seven (19%) found that HRT has favourable effects on primary and secondary prevention, two (5%) and five (14%) that it had no effect, none (0%) and four ( 11%) that it had an unfavourable effect, seven (19%) and nine (25%) that it had both favourable and unfavourable effects, and nine (25%) and ten (27%), thought that there are not enough data. Considering a risk modification superior to 20% as clinically relevant, then 57% thought that HRT has a beneficial effect of on primary prevention and 30% on secondary prevention, while none of the responders considered that HRT has unfavourable effects on primary prevention and only 2% on secondary prevention of CHD. Conclusion: Despite the negative results of the HERS study, about one-half of the responders still think that HRT has a beneficial effect on primary prevention of CHD and almost one-third on secondary prevention.     

National differences in lipid response to postmenopausal hormone replacement therapy

Objective: To compare the response of serum lipids and lipoproteins to the transdermal hormone replacement therapy (HRT) in five European countries. Methods: Five-hundred and sixty-seven healthy postmenopausal women from Belgium, Finland, the Netherlands, Sweden, and the UK received transdermal estradiol 50 μg daily for 12 months. In addition, two groups received transdermally norethisterone acetate (NETA) continuously, two groups sequentially (170 or 350 μg/day); one group received sequentially oral NETA (1 mg/day), and one group dydrogestrone (20 mg/day). Serum total cholesterol, HDL-, HDL2-, LDL-cholesterol, lipoprotein(a) (Lp(a)), and triglycerides were assessed before and at the end of treatment. Results: No significant national differences existed in the pretreatment levels of lipids and lipoproteins. Mean cholesterol, LDL, Lp(a), and triglycerides decreased during HRT, and HDL and HDL2 increased. Individual changes in responses to HRT were strongly dependent on pretreatment values. In this regard, British women differed from the others: their cholesterol, HDL, HDL2, and Lp(a) responses, when related to the pretreatment levels, were smaller than those of the others. Conclusion: A national difference discovered in response of serum lipids to HRT calls for caution in generalization of lipid data from one nation to another during HRT.     

Clinical profile of a new hormone replacement therapy containing 2 mg 17 beta-estradiol and 10 mg dydrogesterone

Objective: Patient’s acceptability, compliance, and effectiveness of a new sequential hormone replacement regimen containing 2 mg 17β-estradiol and 10 mg dydrogesterone, were assessed in a 3-month, open, multicentre study involving 110 menopausal women. Methods: A specially designed menopause score was used to assess the severity of menopausal symptoms, each symptom being graded at baseline and after 3 months on a four-point scale. Bleeding data were recorded by the patient on a diary card. Serum hormone levels including FSH, LH, E2, P, PRL, DHEA-S, T, SHBG were checked at the initial visit and at the end of the study. Results: After 3 months of treatment, all but four of the 34 climacteric symptoms investigated showed a significant improvement. There were no significant changes noted in body weight. The average duration and flow of bleeding showed no significant changes during hormone replacement therapy (HRT). There were no serious adverse events related to treatment. Conclusion: The 17β-estradiol/dydrogesterone combination HRT reduced effectively climacteric symptoms, showed no significant changes in endometrial thickness as determined by transvaginal ultrasonography and provided excellent cycle control.     

Prevalence of hormone replacement therapy in a sample of middle-aged women

A survey based on a postal questionnaire sent to a random sample of Danish women aged 40–59 yr living on the island of Fünen (n = 401, response RATE = 79%) revealed that the overall prevalence of the use of hormone replacement therapy (HRT) was 16%, the highest rate being in the 50–54 age group (21%). Among post-menopausal women the rate was 21% and it was highest of all (37%) in those who had undergone an artificial menopause. The median age at the start of treatment was 44.3 yr among the artificial menopause and 48.9 yr among the natural menopause subjects. About half of the women were treated with natural oestrogen alone and over a third with cyclic natural oestrogen in combination with progestogens.

Almost one-third of the women had consulted their doctor about climacteric complaints and two-thirds of these were current or past users of HRT. The women had ambiguous feelings towards HRT, approximately one third reporting a positive and one-third a negative attitude.     

Prevalence of hormone replacement therapy and user''s characteristics: a community survey in Japan

Objectives: It is quite recently that much interest has been paid to the benefits of hormone replacement therapy (HRT) in Japan. We conducted a community survey in Japan in 1992 to examine the prevalence of HRT use and factors related to HRT use. Methods: A total of 8791 female residents aged 45–64 years old in a city of the Gifu Prefecture, Japan, responded to the questionnaire including medical and reproductive histories, lifetime occupational history, diet, exercise, smoking and drinking habits, and use of vitamin supplements or medications. The response rate was 94.2%. Results: Overall, 2.5% of women reported current use of HRT and 6.3% had used HRT previously. The highest prevalence of current use was found among postmenopausal women with surgical menopause (4.8%). Current users were more likely to have participated in cancer screenings, and to have used vitamin supplements or calcium during the past year. Conclusions: HRT use rate was 2.5% among female residents aged 45–64 years old in a Japanese community in 1992. Current users may have more regard for their health status.     

Beneficial effect of hormone replacement therapy on weight loss in obese menopausal women

Objective: at the onset of menopause, weight-gain and the aggravation of certain cardiovascular risk factors are frequently observed. The aim of this study was to examine the metabolic effects of combined hormone replacement therapy (17β-oestradiol transdermic 50 μg for 21 days and oral medroxyprogesterone acetate 5 mg from day 10 to 21) using, in particular, indirect calorimetry. Methods: patients (21; 12 substituted and nine controls) were studied twice (3 months apart) during an oral glucose load (75 g). Results: total body weight was unaltered after 3 months in the control group, whereas a fat-loss of 2.1±0.2 kg and a decrease of the waist:hip ratio were observed in the substituted group. In the latter group, a significant increase in lipid oxidation was observed (0.58±0.06 mg/kg/min before and 0.75±0.04 mg/kg/min after substitution P<0.05), whilst total energy expenditure and thermogenesis were also increased. Glucose, lipid and protein oxidation remained stable during three months in the control group. The insulin response to an oral glucose load diminished by 30% with hormone replacemnet therapy (102.3±32.8 mμ/l versus 71.4±20.0 mμ/l). Total and LDL-cholesterol improved after hormone replacement therapy whereas plasma triglycerides were not altered. Conclusions: combined hormone replacement therapy not only prevented weight-gain, but favored weight-loss by significantly increasing lipid oxidation after 3 months of treatment. It also favourably influenced the insulin response, plasma lipids and energy expenditure.     

The incidence of breast cancer and changes in the use of hormone replacement therapy: A review of the evidence

Even though a link between hormone replacement therapy (HRT) and breast cancer has been well documented in the epidemiological literature since the 1980s, it was not until publication of the results of the Women's Health Initiative (WHI) study in 2002 and the Million Women Study in 2003 that women and doctors started reconsidering the use of HRT and sales of HRT started to drop. This paper evaluates the impact of the publication of these two landmark studies on the expected and observed changes in the incidence of breast cancer.Between 2001–2002 and 2005–2006, sharp and significant reductions in the incidence of breast cancer of up to 22% were reported in many US and European populations, temporally consistent with the drop in usage of HRT. Declines in the rates of breast cancer were strongest for 50–60-year-old women (those most likely to be current users of HRT), affected mainly ER+ and PR+ cancers (those most strongly associated with HRT use), and were largest among women with the highest pre-decline prevalence of HRT use and the sharpest decline in its use.A considerable amount of scientific evidence supports the hypothesis that the decline in the incidence of breast cancer is in large part attributable to the sudden drop in HRT use following publication of the WHI and Million Women studies. Nevertheless, the problem of how to advise women contemplating HRT use today remains. Medical relief will remain necessary for many women with menopausal complaints, and so new therapeutic options need to be explored.     

Update of the evolution of breast cancer incidence in relation to hormone replacement therapy use in Belgium

Background

Several studies reported a decrease in breast cancer (BC) incidence, subsequent to the decrease in hormone replacement therapy (HRT) use.

Aim

Although Belgium has one of the highest incidences of BC in Europe and one of the highest rates of HRT use, we were unable, in a previous study, to observe a significant association between BC incidence and HRT changes. In this updated report we added the BC data from incidence years 2007 and 2008.

Material and method

We used European standardized incidence rates for invasive BC in the age class 50–69 years for Flanders (1999–2008), Brussels and Wallonia (2004–2008), obtained from IMS Health HRT sales data (1997–2008) for Brussels, Flanders and Wallonia. The association between BC incidence and HRT use was analyzed using generalized estimating equations (GEE) in order to take into consideration the dependency between the subsequent data points.

Results

There was a significant association between the invasive BC incidence rate and estimated rate of HRT users in the previous year: p-value < 0.001.

Conclusion

Although this study is hampered by a number of limitations, these data support the idea that the drop in BC incidence can be partly attributed to the decrease in HRT use. Since HRT remains the most used medication for climacteric symptoms, we encourage the creation of a prospective registry in Europe, collecting detailed data in various European countries, in order to assess the adjusted increase in BC risk associated with HRT, which may be population and regimen dependent.     

Influence of hormone replacement therapy on proteomic pattern in serum of postmenopausal women

OBJECTIVES: Proteomics approaches to cardiovascular biology and disease hold the promise of identifying specific proteins and peptides or modification thereof to assist in the identification of novel biomarkers. METHOD: By using surface-enhanced laser desorption and ionization time of flight mass spectroscopy (SELDI-TOF-MS) serum peptide and protein patterns were detected enabling to discriminate between postmenopausal women with and without hormone replacement therapy (HRT). RESULTS: Serum of 13 HRT and 27 control subjects was analyzed and 42 peptides and proteins could be tentatively identified based on their molecular weight and binding characteristics on the chip surface. By using decision tree-based Biomarker Patternstrade mark Software classification and regression analysis a discriminatory function was developed allowing to distinguish between HRT women and controls correctly and, thus, yielding a sensitivity of 100% and a specificity of 100%. The results show that peptide and protein patterns have the potential to deliver novel biomarkers as well as pinpointing targets for improved treatment. The biomarkers obtained represent a promising tool to discriminate between HRT users and non-users. CONCLUSION: According to a tentative identification of the markers by their molecular weight and binding characteristics, most of them appear to be part of the inflammation induced acute-phase response.