Continuous Hormone Replacement Therapy Research Articles

A Novel Homozygous Mutation of Thyroid Peroxidase Gene Abolishes a Disulfide Bond Leading to Congenital Hypothyroidism.

Congenital hypothyroidism (CH) is the most prevalent congenital endocrine disorder and causes mental retardation. A male Japanese patient with first cousin marriage parents was diagnosed as CH at 10 months. He was born before introduction of mass screening for CH. With continuous thyroid hormone replacement therapy, normal thyroid hormone status was maintained until adulthood. Genetic screening of next-generation sequencing was performed at the age of 52 years, and we identified a new homozygous thyroid peroxidase (TPO) gene mutation (GRCh38.p13, chromosome 2 at position 1493997, c.1964 G>T, p.Cys655Phe). TPO is an important enzyme to produce thyroid hormone. As demonstrated by a homology analysis of TPO proteins among different species, cysteine 655 residue is highly conserved, suggesting an important role in maintaining TPO function and structure. An in silico study with three-dimensional structure of the novel mutation was performed and suggested that the mutation abolished disulfide bond between cysteines at positions 598 and 655. An in vitro functional analysis using HEK293 cells revealed that TPO activity of the mutant was significantly impaired compared with that of the wild type. Furthermore, study of immunohistochemistry showed that localization of TPO in cells did not differ between the wild type and the mutant. In conclusion, this single disulfide bond loss mutation of a new TPO homozygous mutation, p.Cys655Phe, reduced TPO activity and caused congenital hypothyroidism without affecting subcellular localization of TPO proteins.

Hormone replacement therapy and the risk of melanoma in post-menopausal women.

Is hormone replacement therapy (HRT) associated with an increased risk of melanoma skin cancer or prognostic outcomes amongst post-menopausal women? Whilst we found evidence of an association with melanoma risk, the lack of dose-response and associations observed with recent use, localised disease and intravaginal oestrogens suggests this is a non-causal association. Evidence on HRT and melanoma risk remains inconclusive, with studies providing conflicting results. Furthermore, evidence on melanoma survival is sparse, with only one previous study reporting protective associations with HRT use, likely attributable to immortal time bias. We conducted a nation-wide population-based case-control study and a retrospective cohort study utilising the Danish healthcare registries. Case-control analyses included 8279 women aged 45-85 with a first-ever diagnosis of malignant melanoma between 2000 and 2015, matched by age and calendar time to 165 580 population controls. A cohort of 6575 patients with a diagnosis of primary malignant melanoma between 2000 and 2013 and followed through 2015 was examined to determine if HRT use had an impact on melanoma survival outcomes. Based on prescriptions dispensed since 1995, ever-use of HRT was defined as having filled at least one prescription for HRT prior to the index date. In total, 2629 cases (31.8%) and 47 026 controls (28.4%) used HRT. Conditional logistic regression was used to calculate odds ratios (ORs) for melanoma risk according to HRT use, compared with non-use, adjusting for potential confounders. For cohort analyses, Cox proportional hazards models was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for second melanoma incidence and all-cause mortality associated with HRT. High use of HRT was associated with an OR of 1.21 (95% CI 1.13-1.29) for melanoma risk, with no evidence of a dose-response pattern. Results were most pronounced amongst recent high users (OR, 1.28; 95% CI 1.17-1.41), for localised disease (OR, 1.25; 95% CI 1.15-1.36) and for intravaginal oestrogen therapy (OR, 1.38; 95% CI 1.13-1.68). Compared with non-use, there was no evidence of an association for secondary melanoma for post-diagnostic new-use (fully adjusted HR, 1.56; 95% CI 0.64-3.80) or continuous HRT use (fully adjusted HR, 1.26; 95% CI 0.89-1.78). Similar associations were observed for all-cause mortality. Despite the large sample size and the use of robust population-based registries with almost complete coverage, we lacked information on some important confounders including sun exposure. Whilst we cannot rule out an association between HRT use and melanoma risk, the associations observed are also compatible with increased healthcare utilisation and thus increased melanoma detection amongst HRT users. No association between HRT use and melanoma survival outcomes was observed. This should provide some reassurance to patients and clinicians, particularly concerning the use of HRT in patients with a history of melanoma. B.M.H. is funded by a Cancer Research UK Population Research Postdoctoral Fellowship. The funding source had no influence on the design or conduct of this study. A.P. reports participation in research projects funded by Alcon, Almirall, Astellas, Astra-Zeneca, Boehringer-Ingelheim, Servier, Novo Nordisk and LEO Pharma, all with funds paid to the institution where he was employed (no personal fees) and with no relation to the work reported in this article. The other authors have no competing interests to declare. N/A.

Значення замісної гормональної терапії при ранній менопаузі

Substitution of estrogen is a proven way of correcting disorders that are associated with menopause. The question of the optimal method for the administration of estrogens, given changes in the cardiovascular system and psychological maladaptation, is controversial. The objective: to study the effect of alternative schemes of exogenous estrogen administration on the state of endothelial regulation and psychological adaptation of women with RM. Material and methods. Under observation, there were 74 patients who asked the gynecologist about the termination of menstrual function at the age of less than 40 years. Patients were divided into 3 subgroups – 25 patients of subgroup Ia received classic cyclic hormone replacement therapy, 25 subgroup Ib patients received exogenous drugs in combination oral contraceptives, 24 patients of the subgroup Ic received exogenous estrogens as transdermal patches. In all groups, the level of reactive and personality anxiety was determined prior to the start of treatment on a special scale. For the study of endothelial regulation, the activity of vascular motor expansion of the shoulder artery under the influence of hyperemia was investigated, the base diameter of the shoulder artery Db was estimated, the shoulder artery diameter after decompression Dd and the increase in the diameter of the shoulder artery after decompression,%, Δ 1. All of these indicators were studied in patients of all subgroups in 3, 6 and 12 months after initiating the administration of exogenous estrogens. The Kolmogorov-Smirnov criterion (level of psychological adaptation) and Student’s criterion (indicators of endothelial regulation) were used to assess the statistical differences between the groups. Results. Among all methods of exogenous use of estrogen, oral administration of them in a continuous mode has the most powerful positive effect on psychological adaptation – after 6 and 12 months of therapy, 52% and 76% of patients achieved a low level of situational anxiety, while 48% and 72% personal anxiety, in other subgroups, these proportions were significantly smaller (not more than 42%). The effect on endothelial dysfunction was also more pronounced in patients of the Ia subgroup – they reported a significant increase in the growth of the diameter of the brachial artery during the first year of therapy during the 6 months after starting treatment. Such changes in endothelial regulation are not the same or even the tendency towards them in the groups of other forms of administration of estrogens. Conclusions. 1. The application of different schemes of exogenous estrogen assignment has a different effect on the psychological adaptation and regulation of cardiovascular function in patients with early menopause. 2. Thus, during 6 months of treatment, 52% of patients taking estrogens in continuous hormone replacement therapy had a low level of situational anxiety, while patients taking hormonal contraceptive cyclical estrogens in only 32 % showed a low level of anxiety, and women who took exogens in the form of a transdermal patch – a lice of 25%. After 12 months, the disagreements became even higher – 76, 40, and 41.6% respectively. 3. The tendency to reduce the level of personal anxiety, outlined after 6 months of treatment, in women who received estrogens in continuous hormone therapy (48% vs. 32 and 33.3% in hormonal contraceptives and transdermal patches), became statistically probable due to year of treatment (72, 40 and 45.8% respectively). 4. In the subgroup receiving estrogens in the mode of continuous substitution hormone therapy, improvement of endothelial function in the form of increase in the growth of the diameter of the brachial artery after decompression was noted during 6 months of treatment, this trend was not found in other subgroups Key words: early menopause, situational, personality anxiety, endothelial regulation, estrogen therapy.

Human Chorionic Gonadotropin Stimulation Test in Prepubertal Children with Micropenis Can Accurately Predict Leydig Cell Function in Pubertal or Postpubertal Adolescents

Background/Aim: To evaluate the accuracy of the human chorionic gonadotropin (hCG) stimulation test in children with micropenis in predicting later Leydig cell function. Methods: We conducted a retrospective investigation of testosterone response to a 3-day hCG test (3,000 IU/m²/day) in prepuberty to indicate the need for hormone replacement therapy (HRT) in adolescence. Results: Fifty Japanese boys (range, 0.8-15.4 years of age; median, 8.9) with micropenis were enrolled. Thirty-four spontaneously developed puberty and preserved the ability of testosterone production (group 1), while 16 did not develop any pubertal signs without HRT (group 2). Serum testosterone levels after the hCG test (post-hCG T) in group 2 (range, <0.05-1.1 ng/ml; median, 0.24) were significantly lower than in group 1 (range, 0.5-8.7 ng/ml; median, 2.4; p < 0.0001). Based on true positives who required continuous HRT, the area under the receiver-operating characteristics curve for post-hCG T was 0.983 [95% confidence interval (CI), 0.90-1.00]. The post-hCG T cut-off level corresponding to the Youden index was 1.1 ng/ml (95% CI, 1.0-1.1), with a sensitivity of 100.0% (95% CI, 79.4-100.0) and a specificity of 94.1% (95% CI, 80.3-99.3). Conclusions: The hCG test in prepubertal children with micropenis can be useful for predicting Leydig cell function in pubertal or postpubertal adolescents. The post-hCG T cut-off level of 1.1 ng/ml is recommended to screen for those who will likely require HRT for pubertal development.

Health related quality of life of children and adolescents with congenital adrenal hyperplasia in Brazil.

BackgroundCongenital Adrenal Hyperplasia (CAH) is an endocrine disorder characterized by enzymatic deficiency in adrenal steroidogenesis, leading to adrenal insufficiency and hyperandrogenism. Patients need continuous hormone replacement therapy, but adequate control has proven challenging, exposing patients to undesirable consequences of both disease and treatment.ObjectiveTo evaluate the health related quality of life (HRQoL) of children and adolescents with CAH due to 21-hydroxylase deficiency.MethodsIn an analytical study, generic questionnaires, validated and translated versions, Pediatric Quality of Life Inventory 4.0 (for self-assessment of patients) and Child Health Questionnaire - PF50 (for parents) were applied and mean scores were analyzed with Student’s t-test.ResultsWe included 25 patients (19 female) with classical CAH (14 salt wasting/11 simple virilizing), mean age ± standard deviation (SD) of 11.4 ± 3.6 years (5–17.9), and their parents. Self-assessment of HRQOL showed decrease in mean scores: overall (67.8 ± 15.5 vs. 88.9 ± 7.4, p value = 0.015) and in the physical (75.2 ± 15.0 vs. 95.9 ± 5.8, p value = 0.014) and psychosocial (63.9 ± 17.8 vs. 85.0 ± 9.6, p value = 0.023) dimensions of patients, compared to healthy controls (previously published national data on children and adolescents). The assessment of the parent’s view was concordant, also showing losses in the physical (43.7 ± 8.0 vs. 55.1 ± 3.6, p value = 0.013) and psychosocial (41.9 ± 9.7 vs. 53.0 ± 7.0, p value = 0.025) dimensions. The comparison of HRQOL between subgroups 1) males versus females and 2) salt-wasting versus simple virilizing showed no significant differences.ConclusionThere seems to be a loss of HRQOL in children and adolescents with classical CAH. The self-assessment was concordant in key areas with the assessment made by their parents. No differences were observed between genders or clinical presentation of the disease.

Effect of cyclic versus continuous hormonal replacement therapy on the structure of dentate gyrus of ovariectomized adult albino rats

Effect of cyclic versus continuous hormonal replacement therapy on the structure of dentate gyrus of ovariectomized adult albino rats

Effects of transdermal and oral hormone replacement therapies on monocyte chemoattractant protein-1 levels: a randomized clinical trial

ObjectivesTo assess the effects of oral and transdermal hormone replacement therapies (HRT) on levels of important cardiovascular disease (CVD) markers, MCP-1 and homocyteine, in the early postmenopausal period. Study designSeventy-six healthy, early postmenopausal women were enrolled in the study. Patients were randomly assigned to receive oral or transdermal HRT for 6 months. The first group received continuous combined oral HRT containing 1mg 17β-estradiol and 0.5mg norethisterone acetate (n=39), and the second group received sequential transdermal HRT releasing 50μg/day estradiol alone given twice a week on days 1–14 and 50μg/day estradiol plus 0.25mg/day norethisterone acetate given twice a week on days 15–28 (n=37). Circulating levels of MCP-1 and homocysteine, along with other CVD markers, were assessed before and after treatment in all patients. ResultsThere were no significant differences between the baseline characteristics of the two groups. Baseline serum MCP-1 levels were similar between the oral and transdermal HRT groups (150.1±12.8 vs. 145.2±11.6pg/ml; P=.219). The mean MCP-1 levels did not change after 6 months of HRT in both oral (150.1±12.8 vs. 153.6±12.5pg/ml; P=.192) and transdermal HRT groups (145.2±11.6 vs. 146.1±15.1pg/ml; P=.419). Moreover, there was no significant difference between the groups in MCP-1 serum levels after 6 months of HRT. Similarly, no difference was found in serum homocyteine levels following 6 months of HRT. ConclusionsBoth oral continuous and sequential transdermal HRTs do not have significant effects on serum MCP-1 and homocyteine levels in women during the early postmenopausal period.

Comparative effects of continuous combined hormone therapy and tibolone on body composition in postmenopausal women

ObjectiveTo compare the effects of tibolone with those of continuous combined hormone replacement therapy (HT) on body composition in postmenopausal women.MethodsOne hundred and fifty postmenopausal women were enrolled in a randomized, controlled trial to compare the effects of tibolone with continuous combined HT on body composition. Patients were randomly allocated into three groups and followed for 9 months. Of the subjects included, 50 women received 2.5 mg tibolone plus one Cal+D tablet (500 mg calcium and 200 IU vitamin D) daily, 50 women received 0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate (CEE/MPA) plus one Cal+D tablet daily, and the rest (50 women) received only one Cal+D tablet and served as a control group. Body composition was evaluated with measurements of body mass index (BMI), weight, waist-to-hip ratio (WHR), fat mass and fat-free mass (FFM) before and after the intervention. Measurements of body fat mass percentage, fat mass, body fat-free mass percentage and fat-free mass (FFM) were assessed by measurement of skin-fold thickness.Results Tibolone significantly increased weight, BMI and FFM and decreased WHR after the treatment in comparison with baseline (p < 0.05). However, only weight and BMI increased significantly in the CEE/MPA group after the treatment (p < 0.05). There were significant increases in weight, BMI and fat mass in the control group after 9 months. In the comparison of the parameters after the treatment between the three groups, tibolone significantly increased FFM compared with the control and CEE/MPA groups (p < 0.01).Conclusions The effect of tibolone on body composition is favorable and therefore tibolone may be regarded as an alternative to continuous combined hormone therapy in postmenopausal women.

Hormonal management of migraine at menopause

In this review, we underline the importance of linking migraine to reproductive stages for optimal management of such a common disease across the lifespan of women. Menopause has a variable effect on migraine depending on individual vulnerability to neuroendocrine changes induced by estrogen fluctuations and on the length of menopausal transition. Indeed, an association between estrogen 'milieu' and attacks of migraine is strongly supported by several lines of evidence. During the perimenopause, it is likely to observe a worsening of migraine, and a tailored hormonal replacement therapy (HRT) to minimize estrogen/progesterone imbalance may be effective. In the natural menopause, women experience a more favourable course of migraine in comparison with those who have surgical menopause. When severe climacteric symptoms are present, postmenopausal women may be treated with continuous HRT. Even tibolone may be useful when analgesic overuse is documented. However, the transdermal route of oestradiol administration in the lowest effective dose should be preferred to avoid potential vascular risk.

Variations of Jitter and Shimmer Among Women in Menacme and Postmenopausal Women

The objective of the study was to analyze comparatively the jitter and shimmer values of spoken voice among women in menacme and menopausal women using or not hormonal replacement therapy (HRT). Forty-five women were studied, divided into the following groups: Control Group (CG), 15 women aged 20-40 years with regular menstrual cycles who did not take hormonal contraceptives; Treated Group (TG), 15 women aged 45-60 years with at least 2 years of menopause, under continuous HRT with 1 mg estradiol valerate + 90 microg norgestimate per day for at least 6 months; Untreated Group (UG), 15 women aged 45-60 years with at least 2 years of menopause who did not use HRT. Mean age was 30.3, 54.5, and 56.5 years for CG, TG, and UG, respectively. All subjects were submitted to acoustic analysis of jitter and shimmer for the sustained vowels /e/ and /i/. Mean jitter values were 0.56%, 0.64%, and 0.56% for the vowel /e/ and 0.88%, 0.79%, and 0.68% for the vowel /i/ for CG, TG, and UG, respectively. Mean shimmer values were 4.17%, 4.38%, and 4.77% for the vowel /e/ and 5.19%, 4.59%, and 5.37% for the vowel /i/ for CG, TG, and UG, respectively. There were no significant differences between the groups studied. The results obtained here by the methodology used suggest that there were no significant differences in jitter and shimmer when we assessed the sustained vowels /i/ and /e/ between menopausal women using or not HRT or between young and menopausal women treated or not.

Headache and hormone replacement therapy in the postmenopausal woman

Headache and migraine are common symptoms of the menopause, often associated with irregular periods, hot flashes, and night sweats. Perimenopausal women should routinely be asked about headache and migraine, so that they can be offered appropriate advice. If attacks are infrequent, it may be sufficient to optimize acute treatment strategies. Lifestyle changes, alone or combined with a nonprescription treatment such as isoflavones, may be considered, although evidence of efficacy is limited. In women with migraine and more severe menopause symptoms, continuous hormone replacement therapy should be considered, using a nonoral route and the lowest dose effective in controlling symptoms. For women who have contraindications to estrogen therapy or do not wish to use it, compounds that inhibit serotonin reuptake, such as venlafaxine, fluoxetine, and paroxetine, have all shown efficacy for the control of hot flashes and prevention of migraine. Gabapentin is another nonhormonal option that has clinical trial evidence of effectiveness in treating hot flashes and reducing the frequency and severity of migraine attacks. Although clonidine is licensed in several countries for migraine prophylaxis and treatment of vasomotor symptoms, any benefit from treatment is often offset by adverse events. There is evidence that hysterectomy can increase the frequency of migraine and menopause symptoms, with added morbidity and risk of mortality. Therapy should regularly be evaluated to assess its ongoing need, as hormonal triggers are self-limiting and abate after menopause.

Mucinous Cystadenocarcinoma of the Pancreas Developing During Hormone Replacement Therapy

Hormone replacement therapy (HRT) containing estrogens is generally used to relieve climacteric symptoms and to prevent osteoporosis and coronary heart disease [1], however, there has been increasing evidence of the HRT as the risk of hormone-dependent neoplasms including breast cancer [2], uterine endometrial cancer [3], ovarian cancer [4], and even lung cancer [5]. Noteworthy is mucinous cyst neoplasms (MCNs) of the pancreas, characterized by mucin-producing columnar epithelium supported by "ovarian-like" mesenchymal stroma, occur mostly in females expressing estrogen receptors [6, 7]. Although several reports regarding the closed relationship between MCNs and pregnancy [8, 9] might imply potential sex hormone-dependency of the MCNs [10], no correlation has been reported. This is the first case report of malignant MCN developing during continuous HRT after hysterectomy.

A prospective randomized comparative study of the effects of intranasal and transdermal 17 β-estradiol on postmenopausal symptoms and vaginal cytology

Investigating the adverse effects of oral hormone replacement therapy (HRT), the clinical effectiveness of alternative combinations and route of administrations. To compare the effects of intranasal and transdermal 17 beta-estradiol combined with vaginal progesterone on vasomotor symptoms and vaginal cytology. A 12-week, prospective, randomized comparative study was conducted between July 2005 and September 2006. Eighty postmenopausal women aged between 42-57 years, who had scores of > or =1.7 on the menopause rating scale-I (MRS-I) items "1-6", were randomly assigned to receive intranasal (300 microg/day, n =40) or transdermal (50 microg/day, n =40) 17 beta-estradiol continuously. All patients also received a vaginal progesterone gel twice weekly. Vasomotor symptoms were evaluated at weeks 0, 4, 8 and 12. Vaginal maturation index (VMI) was evaluated at weeks 0 and 12 of the study. The Mann-Whitney U and the Wilcoxon tests were used. P < 0.05 was regarded as significant. Thirty-two women in the intranasal and 29 women in the transdermal group completed the study. The total score of the MRS, the sum-scores of Factor 1 "HOT FLUSHES" and Factor 2 "PSYCHE" significantly decreased in both groups at week 4. Factor 3 "ATROPHY" scores significantly decreased only in the transdermal group at week 12. The VMI showed no changes within and between the two groups at the end of the study. Intranasal and transdermal 17beta-estradiol combined with vaginal progesterone gel as a continuous HRT caused a similar decrease in vasomotor symptoms but did not have any significant effect on VMI after 12 weeks of treatment in this study population.

Comparison of two forms of continuous combined hormone replacement therapy with respect to metabolic effects

To compare the metabolic effects of two frequently used continuous hormone replacement therapies. Two hundred and forty-six menopausal women, aged between 41 and 57 years were enrolled in the present study. They were randomized to receive either estrogen + 2.5 mg medroxyprogesterone acetate (CEE/MPA) or 1 mg 17 <beta> estradiol + 0.5 mg norethindrone acetate (E2/NETA). Women in group I (n = 139) and group II (n = 107) were followed up for 1 year and compared with respect to total cholesterol, triglycerides, HDL, LDL, VLDL, weight gain during this period. The basal and 12th month weight of the patients of two groups were not statistically different (P = 0.57 and P = 0.17, respectively, in the groups I and II). No changes were detected in the levels of triglycerides, HDL and VLDL, while total cholesterol (P = 0.01) and LDL (P = 0.003) levels significantly decreased in the CEE/MPA group. In group 2, total cholesterol and triglyceride levels showed no significant change, however, levels of HDL cholesterol (P = 0.001) increased and LDL (P = 0.001) and VLDL cholesterol (P = 0.006) decreased significantly. Administration of E2/NETA regimen has better results on lipid profile when compared to CEE/MPA regimen. No weight gain is recorded in E2/NETA group.

Endometrial safety, overall safety and tolerability of transdermal continuous combined hormone replacement therapy over 96 weeks: a randomized open-label study

Objectives To establish whether transdermal continuous hormone replacement therapy (HRT) with estrogen/progestogen provides adequate long-term endometrial protection in postmenopausal women over a period of 96 weeks.Methods This multicenter, randomized, open-label, parallel-group study evaluated the endometrial effects and overall safety and tolerability of a transdermal matrix patch delivering estradiol (E2) 50 µg/day and norethisterone acetate (NETA) 140 µg/day (Estalis®; patches applied twice weekly without intermediate breaks) and a once-daily oral comparator (Kliogest®; one tablet containing E2 2 mg/NETA 1 mg) in postmenopausal women. A total of 406 women with an intact uterus, aged 44–69 years, were randomized in the 48-week core phase of the study, and 239 continued into the 48-week extension phase. Subjects were randomized in the ratio 3 : 1 to transdermal or oral E2/NETA treatment.Results No cases of endometrial hyperplasia or endometrial cancer were reported with either treatment during the core or extension phase. Both treatments were generally well tolerated, with most adverse events (>90%) being mild to moderate, although minor differences in the tolerability profile were observed between treatments.Conclusions Continuous combined transdermal HRT with E2/NETA shows no evidence of an increased endometrial hyperplasia or endometrial cancer risk over a 96-week period.

Effects of two different regimens of continuous hormone replacement therapy on endometrial histopathology and postmenopausal uterine bleeding

To compare the effects of frequently used two different regimens of combined continuous hormone replacement therapy; 0.625 mg conjugated equine estrogen (CEE) + 2.5 mg medroxyprogesterone acetate (MPA) and 1 mg 17beta estradiol (E2) + 0.5 mg norethindrone acetate (NETA), on endometrial histopathology and postmenopausal uterine bleeding. Two hundred and forty-six outpatient subjects aged 41-57 years were enrolled in the study conducted at the menopause clinic between November 2003 and November 2004. One hundred and thirty-nine patients were assigned to receive 0.625 mg conjugated equine estrogen + 2.5 mg medroxyprogesterone acetate (CEE/MPA), whereas 107 patients were to receive 17beta estradiol + 0.5 mg norethindrone acetate (E2/NETA). Inclusion criteria of the study were: normal values of endometrial thickness at basal evaluation, women with intact uterus, at least 12 months of amenorrhea, normal vaginal smear, bilateral mammography and biochemical blood parameters. All women were questioned every 3 months for vaginal bleeding/spotting. Endometrial sampling was performed by Pipelle catheter in the 12th month of therapy. For the first 3 months, vaginal bleeding/spotting rate for the CEE/MPA group was 38.7%, whereas it was higher (45%) in the E2/NETA group. For the second 3-month period, vaginal bleeding/spotting frequencies were 41.1 and 37.8%, respectively. In the third 3-month period 30.6 and 29.6%, and in the fourth 3-month period, 18.5 and 12.5% of the patients reported vaginal bleeding or spotting. None of the results of endometrial sampling have shown findings of cancer histopathology. Compared to CEE/MPA regimen, E2/NETA therapy has not shown more favorable effects on postmenopausal bleeding abnormalities. Irregular endometrial proliferation was seen more with the E2/NETA regimen.

Dramatic change in prescribing of hormone replacement therapy in The Netherlands after publication of the Million Women Study: a follow-up study.

To estimate the diffusion of new safety information concerning postmenopausal hormonal replacement therapy (HRT) into prescribing practice in The Netherlands and to assess the impact of revised guidelines on the long-term treatment of HRT. Cross-sectional study. Community pharmacy dispensing data from a population of approximately 450,000 patients in the northern and eastern part of The Netherlands. Women aged 45-69 years to whom at least one HRT prescription was dispensed between 1 January 2000 and 1 January 2004. Annual and quarter prevalences of HRT and the proportion of new HRT users, switchers and continuous HRT users per quarter. The prevalence of HRT prescribing decreased significantly from 107/1000 [95% confidence interval (CI) 104, 110] in 2000 to 87/1000 (95% CI 84, 89) in 2003. The decreasing prevalence was especially evident among the younger age groups and was most pronounced among users of oestrogen/progestagen combinations. The publication of the Women Health Initiative Study (WHI) was followed by a modest decrease in prescribing of HRT, whereas prescribing of HRT declined dramatically after publication of the Million Women Study (MWS) in August 2003. Among the continuous HRT users in the 4th quarter of 2002, 55% used HRT longer than 3 years. This percentage was 53 in the 4th quarter of 2003. In contrast to the release of the WHI study results, publication of the MWS was followed by a dramatic fall in prescribing of HRT in The Netherlands. Despite the new recommendation that long-term HRT use should be discouraged, the proportion of long-term users did not change after the publication of the MWS.

Conjugated estrogen/progestagen versus tibolone hormone replacement therapy in postmenopausal women: Effects on carbohydrate metabolism and serum sex hormone-binding globulin

Objective To study the effects of different types of continuous hormone replacement therapy on carbohydrate metabolism. Method Postmenopausal women were treated with conjugated estrogens, 0.625 mg/medroxyprogesterone acetate, 2.5 or 5 mg (CEE/MPA) or tibolone 2.5 mg daily for 13 28-day cycles. Serum glucose and insulin were measured before and during a 75 g oral glucose tolerance test (OGTT) at baseline and after 3, 6 and 13 cycles and areas under the curve (AUC) were calculated. Sex hormone-binding globulin (SHBG) was measured as an additional marker of nutritional and insulin status. Results Neither CEE/MPA 2.5 mg nor tibolone had any effects on carbohydrate metabolism while AUC insulin, AUC glucose and also body mass index (BMI) increased after 13 cycles of treatment in the CEE/MPA 5 mg group. SHBG increased significantly during CEE/MPA treatment and decreased significantly during treatment with tibolone. The effects on SHBG were less pronounced in the CEE/MPA 5 mg group. Pretreatment SHBG showed significant negative correlations to BMI and to variables that may reflect a certain degree of insulin resistance, the most pronounced being fasting glucose. Changes in SHBG during treatment with tibolone were negatively correlated to pretreatment SHBG and positively to BMI, AUC insulin and fasting insulin resistance index, while no such correlations were found in the CEE/MPA groups. There were no correlations between changes in AUC insulin and AUC glucose on one hand and basal variables or treatment SHBG on the other in the CEE/MPA groups. Conclusion The effects of tibolone and CEE/MPA on carbohydrate metabolism were considered to have clinical significance only for CEE/MPA 5 mg, indicating a less favourable role of the higher progestagen dose. The results further support the important role of metabolic and insulin status in the physiological regulation of SHBG and also indicate that the suppressive effect of tibolone on circulating SHBG is mainly depends on pretreatment SHBG levels. SHBG does not reflect changes in carbohydrate metabolism during CEE/MPA treatment.

Postmenopausal hormone therapy and mammographic breast density

Objective The aim of this study was to evaluate the effects of different types of hormone replacement therapy (HRT) on mammographic density. Materials and methods In a prospective 1-year study, 103 postmenopausal women were randomized to receive tibolone 2.5 mg/die, continuous conjugated equine estrogens 0.625 mg/die plus medroxyprogesterone acetate (MPA) 5 mg/die or placebo. Mammograms were performed at baseline and after 12 months of treatment. Mammographic density was quantified according to the Wolfe classification. Results After 12 months of HRT 16 of the 35 patients (45.1%) receiving continuous combined hormonal therapy showed an increase of breast density change in the Wolfe classification. After treatment with tibolone, an up grading in breast density, according to Wolfe's classification, was found in 2 of the 43 patients (2.3%). No changes were recorded in the 25 patients of the control group. The difference between the group treated with continuous combined hormonal therapy and the control group was highly significant ( p < 0.001). The difference in breast density between patients in treatment with tibolone and the control group was not statistically significant ( p = 0.34). Discussion Continuous combination HRT may be more commonly associated with an increase of mammography density than tibolone treatment.

Investigation of abnormal uterine bleeding in perimenopausal women by hysteroscopy and endometrial biopsy

The causes of abnormal uterine bleeding (AUB) during the perimenopausal period in women receiving hormone replacement therapy (HRT) were investigated, along with the causes of postmenopausal bleeding, the efficacy of hysteroscopy in the diagnosis of endometrial pathology was investigated. The patients studied were referred to our academic gynaecological clinic during the period 1999–2003. 145 cases that had undergone hysteroscopy and endometrial biopsy for AUB during the perimenopausal period over the last four years were reviewed retrospectively. The main group (76 patients) presented AUB while they were taking sequential or continuous HRT for menopausal symptoms and to prevent osteoporosis. The control group (69 patients) presented postmenopausal bleeding. There was an increased incidence of endometrial pathology in the group receiving HRT in comparison with the control group (52.6% vs. 40.4%), but this difference was not significant. The main findings were functional endometrium (38.1%) in the group receiving HRT and atrophic endometrium (40.6%) in the control group, respectively. These differences were statistically significant between the two groups. Diagnostic hysteroscopy was performed successfully with no serious complications and was performed without anesthesia in over 30% of the patients in both groups. The incidence rates of the structural endometrial causes of AUB in perimenopausal period are similar in women taking HRT and those presenting postmenopausal bleeding. Hysteroscopy is a safe and efficient method of investigating women with AUB during the perimenopausal period. In addition, the increasing use of outpatient hysteroscopy will simplify assessments of patients presenting with AUB during the perimenopausal period.