Oral Estrogen Replacement Therapy Research Articles

Psoralen and Isopsoralen, Two Estrogen-Like Natural Products from Psoraleae Fructus, Induced Cholestasis via Activation of ERK1/2.

With the increasing use of oral contraceptives and estrogen replacement therapy, the incidence of estrogen-induced cholestasis (EC) has tended to rise. Psoralen (P) and isopsoralen (IP) are the major bioactive components in Psoraleae Fructus, and their estrogen-like activities have already been recognized. Recent studies have also reported that ERK1/2 plays a critical role in EC in mice. This study aimed to investigate whether P and IP induce EC and reveal specific mechanisms. It was found that P and IP increased the expression of esr1, cyp19a1b and the levels of E2 and VTG at 80 μM in zebrafish larvae. Exemestane (Exe), an aromatase antagonist, blocked estrogen-like activities of P and IP. At the same time, P and IP induced cholestatic hepatotoxicity in zebrafish larvae with increasing liver fluorescence areas and bile flow inhibition rates. Further mechanistic analysis revealed that P and IP significantly decreased the expression of bile acids (BAs) synthesis genes cyp7a1 and cyp8b1, BAs transport genes abcb11b and slc10a1, and BAs receptor genes nr1h4 and nr0b2a. In addition, P and IP caused EC by increasing the level of phosphorylation of ERK1/2. The ERK1/2 antagonists GDC0994 and Exe both showed significant rescue effects in terms of cholestatic liver injury. In conclusion, we comprehensively studied the specific mechanisms of P- and IP-induced EC and speculated that ERK1/2 may represent an important therapeutic target for EC induced by phytoestrogens.

FRI268 Late Onset Polyglandular Autoimmune Syndrome Type 2

Abstract Disclosure: M.S. Nicholson: None. A. Barnett: None. A 66-year old white female was admitted for weakness, acute kidney injury, and hypotension. This is her 3rd hospital or ER visit in the last 12 months for similar complaints. She has a 25 year history of type 2 diabetes on insulin and oral therapy and 30 year history of hypothyroidism on levothyroxine 75 mcg daily. She was on oral estrogen replacement therapy for post-menopausal symptoms with a hysterectomy in her early 50s. She has a sister with type 2 diabetes on oral meds and hypothyroidism. She has a brother with type 1 diabetes. Her serum sodium was 135 mmol/L (135-145), potassium was 5.4 mEq/L (3.5 -5.1), and calcium was 9.2 (8.5-10.1). Her Creatinine was 1.2 with a GFR of 48. A random cortisol in the ED was 9.2 (no ref range). Blood pressure was low and she was tachycardic and her weight was 68 kg. She was a well developed female with a a tanned complexion. Areas of vitiligo were noted on her arms. A cosyntropin stimulation test was done midday with a baseline, 30, and 60 minute cortisol levels of 9.2, 8.8, and 9.3 respectively. Baseline ACTH was 877.6 pg/mL (7.2-63.6). Her TSH was 4.09 mIU/mL (0.358-3.74) and free T4 was 1.29 ng/dL (0.76-1.46). DHEA-S was 14 mcg/dL (13-130). She was started on stress dose steroids with rapid improvement in BP, hyponatremia, and symptoms. GAD-65 antibodies were above 250 IU/mL and 21-hydroxylase antibodies were positive. Her TPO antibodies were negative. Non-insulin diabetes medications were stopped and she was discharged home after stabilization on prednisone 5 mg daily and fludrocortisone 0.1 mg daily. This patient has an atypical presentation of polyglandular autoimmune syndrome type 2 (PAS2). She presented with an Addisons crisis at the age of 66. She was already diagnosed with hypothyroidism and insulin requiring diabetes and evidence of vitiligo. A majority of patients with PAS2 are female and present in their 20s to 40s with primary adrenal insufficiency and primary hypothyroidism. Her initial manifestation was hypothyroidism and then diabetes and vitiligo with adrenal insufficiency many years later. Her random cortisol was not suppressed and this lead to a delay in her diagnosis. This was likely due to oral estrogen therapy raising cortisol-binding globulin. Her elevated baseline ACTH and lack of response to ACTH stimulation confirmed her diagnosis of primary adrenal insufficiency. An ACTH stimulation test was repeated as an outpatient with similar response. This case highlights the importance of provocative testing for adrenal disorders and testing for autoimmune causes of endocrine disorders when patients are not responding as expected. Presentation: Friday, June 16, 2023

Systematic search for the UBA1 mutation in men after a first episode of venous thromboembolism: A monocentric study

Systematic search for the UBA1 mutation in men after a first episode of venous thromboembolism: A monocentric study

Drugs Associated With Ischemic Stroke: A Review for Clinicians.

Certain drugs may increase the risk of ischemic stroke (IS). Our goal was to review associations between frequently used drugs and IS. We created an initial list of frequently used drugs to search Pubmed/MEDLINE from 1966 to 2020 and reviewed phase III and IV data, case series, and drug authorities' safety warnings to assess a potential association with IS. Drugs were grouped according to the World Health Organization Anatomical Therapeutic Chemical Classification System. Predefined criteria were applied to establish a level of evidence for an association, from A (high level of evidence of association) to E (high level of evidence of absence of association). In addition, we assessed relative risks and reviewed potential mechanisms of IS facilitation. We assessed 81 drugs or drug classes from 11 World Health Organization Anatomical Therapeutic Chemical Groups. We identified a high level of association for erythropoietin, combined contraceptives, oral estrogen replacement therapy, bevacizumab, tamoxifen, and antipsychotics and a moderate level for ponatinib, nilotinib, darunavir, and gonadotropin-releasing hormone agonists. Drug dose and treatment duration may modify the risk. For a substantial number of drugs, we found no association, and for others, there were insufficient data to categorize risk. We identified a high level of association of IS with a limited number of drugs, a potential association with some, and a lack of data for others. The summarized information may help clinicians to estimate the contribution of a drug to an IS, to better assess drug benefit-risk ratios, and to support decisions about using specific drugs.

Treatment of the adult growth hormone deficiency syndrome with growth hormone: What are the implications for other hormone replacement therapies for hypopituitarism?

When initiating growth hormone replacement therapy, it is important to consider a patient's other pituitary hormone replacement medications, as adjustments are often necessary. Growth hormone therapy can increase the metabolism of hydrocortisone or endogenous cortisol, unmasking borderline ACTH deficiency and leading to the development of adrenal insufficiency and adrenal crisis. In addition, growth hormone can enhance the metabolism of thyroxine to triiodothyronine, uncovering borderline TSH deficiency. In many patients, thyroid hormone replacement therapy must be started, or the dose of levothyroxine must be increased. Oral estrogen replacement therapy leads to a state of relative growth hormone resistance, and the dose of GH may need to be increased substantially. Physicians have long been cognizant of the fact that adding a new prescription medication may lead to important drug-drug interactions. Starting growth hormone therapy may lead to hormone-hormone interactions that can pose serious complications for the hypopituitary patient unless the interaction of growth hormone on other pituitary hormone systems is understood.

Epidemiology of gallbladder cancer.

According to GLOBOCAN 2018 data, gallbladder cancer (GBC) accounts for 1.2% of all global cancer diagnoses, but 1.7% of all cancer deaths. Only 1 in 5 GBC cases in the United States is diagnosed at an early stage, and median survival for advanced stage cancer is no more than about a year. The incidence of the disease is increasing in the developed world. Gallstones, biliary cysts, carcinogen exposure, typhoid, and Helicobacter pylori infection, and abnormal pancreaticobiliary duct junctions are all risk factors, many of which account for its geographical, ethnic and sex distribution. Genetics also plays a strong role, as about a quarter of GBC cases are considered familial, and certain ethnicities, such as Native Americans, are at far higher risk for the neoplasm. Prevention includes weight loss, vaccination against and treatment of bacterial infections, early detection and elimination of polyps and cysts, and avoidance of oral estrogen replacement therapy.

Estrogen Receptor β as a Prognostic Marker of Tumor Progression in Colorectal Cancer with Familial Adenomatous Polyposis and Sporadic Polyps

The incidence of colorectal cancer (CRC) is lower in women than in men, and sex steroids can be considered contributing factors because oral contraception usage and estrogen replacement therapy are associated with decreased risk. Conversely, colorectal polyp development in familial adenomatous polyposis (FAP) begins during puberty. The objectives were to evaluate the relationship between the expression of these hormone receptors and adenoma-carcinoma progression, CRC stage and overall survival. We studied 120 A.C. Camargo Cancer Center patients diagnosed with either FAP-associated or spontaneous adenomatous polyps or CRC to determine the immunohistochemical expression levels of estrogen receptor (ER)-α, ER-β and the progesterone and androgen receptors (480 analyses). The ER-β expression levels differed between the groups: the group with FAP polyps had lower ER-β expression than that of the sporadic polyp group. With transformation of the sporadic polyps to cancer, there was a considerable decrease in ER-β expression (from 90% with strong expression to 80% with absent or weak expression) (p<0.001). The ER-β expression was lower in T3/T4 tumors than in T1/T2 tumors (p=0.015). The 5-year overall survival of CRC patients positively expressing ER-β exceeded that of patients without detectable expression levels (74.8% vs. 44.3%, respectively; p=0.035). There was no significant expression of the androgen or progesterone receptor or ER-α among the groups. Differences in ER-β expression represent a potential mechanism through which estrogen might alter the susceptibility to colon cancer, thereby confirming the possibility of a protective role of estrogen against colorectal carcinogenesis.

Effect of estrogen replacement therapy on bone and cardiovascular outcomes in women with turner syndrome: a systematic review and meta-analysis.

Patients with Turner syndrome have adverse bone and cardiovascular outcomes from chronic estrogen deficiency. Hence, long-term estrogen replacement therapy is the cornerstone treatment. The estimates of its effect and optimal use, however, remain uncertain. We aimed to summarize the benefits and harms of estrogen replacement therapy on bone, cardiovascular, vasomotor and quality of life outcomes in patients with Turner syndrome. A comprehensive search of four databases was performed from inception through January 2016. Randomized clinical trials and observational cohort studies studying the effect of estrogen replacement therapy in patients with Turner syndrome under the age of 40 were included. Independently and in duplicate reviewers selected studies, extracted data and assessed risk of bias. Subgroup analyses were based on route of administration and type of estrogen formulation. Twenty-five studies at moderate to high risk of bias (12 randomized trials, 13 cohort studies) with 771 patients were included. Using random-effects models, estrogen replacement therapy showed an increase in bone mineral density [weighted mean change from baseline 0.09 g/cm2 (0.04-0.14)] that differed by type of estrogen but not route of administration. Oral estrogen replacement therapy showed a higher increase in high density lipoprotein cholesterol levels when compared to transdermal [weighted mean difference 9.33 mg/dl (4.82-13.85)] with no significant effect on other lipid fractions. The current evidence suggests possible benefit of estrogen replacement therapy on bone mineral density and high density lipoprotein cholesterol. Whether this improvement translates into changes in patient important outcomes (cardiovascular events or fractures) remains uncertain. Larger randomized clinical trials with direct comparisons on patient important outcomes are necessary.

Persistency with estrogen replacement therapy among hysterectomized women after the Women’s Health Initiative study

ABSTRACTObjectives Many women are reluctant to undergo estrogen replacement therapy (ERT) and discontinue the treatment within 12 months. The aim of this study was to investigate the persistence rates of ERT in hysterectomized women over the past decade, reflecting changes in the post-Women's Health Initiative (WHI) era.Methods We analyzed 8045 patients receiving ERT from 2004 to 2013 using the Disease Analyzer database.Results After 12 months of follow-up, only 24.6% of patients receiving 1 mg and 24.5% of patients receiving 2 mg of oral ERT were still on treatment (p < 0.0001). The persistency rate of patients receiving <50 μg of transdermal ERT was 28.6% compared to 33.5% for patients receiving >50 μg within the 12 months of follow-up. ERT that began in 2007–2009 was associated with a higher discontinuation rate (hazard ratio 1.06, p = 0.0660) than ERT that began in 2010–2013 (hazard ratio 0.88, p = 0.0001).Conclusions Our results indicate low persistency rates in women on ERT irrespective of the dose as well as the route of administration. However, a decrease in discontinuation rates was found when comparing women in the early vs. late post WHI era.

Short-term estrogen replacement therapy reduces platelet marker levels in Malaysian postmenopausal women

In healthy postmenopausal women (PMW) increased platelet activation has been associated with adverse cardiovascular events. There is much debate about the relationship between platelet function and serum estradiol level in PMW. This study assessed the effect of short-term oral estrogen replacement therapy (ERT) on platelet activation markers (CD62P and PAC-1) and its correlation with age and body mass index (BMI) among healthy PMW. A prospective intervention study was conducted at Hospital University Sains Malaysia, involving 48 healthy PMW who were evaluated for platelet activation marker levels as determined by flow cytometry, before and after two weeks of oral ERT with 0.625 mg of conjugated equine estrogen once daily. The pre- and post-ERT platelets activation markers difference was analysed by paired t-test. The pre-ERT, mean ± SD percentage levels of CD62P and PAC-1 were significantly reduced from 7.00 ± 5.91 and 41.75 ± 26.85 to 3.05 ± 2.47 and 20.86 ± 19.02, respectively, after two weeks of ERT (P value < 0.001). The correlation of platelet activation markers was significant with estradiol but not with age and BMI. Short-term ERT leads to reduction in platelet activity, which might contribute to protection against cardiovascular diseases in healthy PMW.

Osteoporosis in anorexia nervosa

Anorexia nervosa is a condition associated with reduced bone mass and increased bone fragility, for which there is no known effective treatment. Anorexia nervosa usually has its onset during adolescence, the critical time when peak bone mass is accrued. Low bone mass is caused by reduced bone formation, as well as accelerated bone resorption. The etiology is multifactorial and includes poor nutrition, low bodyweight, sex hormone deficiency and hypercortisolism. Weight gain and resumption of menses is accompanied by some improvement in bone mass, but may not restore it to normal levels. Oral estrogen-replacement therapy is not effective in increasing bone mass in this disorder. The bisphosphonates, used in conjunction with nutritional rehabilitation and weight gain, have shown promise, but concerns about safety have limited their use. The aim of this article is to highlight recent recommendations regarding the assessment of fracture risk in children and adolescents, summarize the evidence for low bone mass and increased fracture risk in anorexia nervosa, and discuss approaches to the management of low bone mass in this disorder.

C-C4-04: Trends in Breast Cancer Incidence in a Setting of Increased Mammography Screening and Decreased Use of Oral Estrogen Replacement Therapy

Barbara G Silverman, MD, MPH, Nava Sieglemann-Danieli, MD and Ehud S Kokia, MD Barbara G Silverman, MD, MPH, Maccabi Healthcare Services; Nava Sieglemann-Danieli, MD, Maccabi Healthcare Services; Ehud S Kokia, MD, Maccabi Healthcare Services

The Effect of Temporary Elevated 17 B Estradiol (E2) Levels On the Coagulation System as Measured by D-Dimer in Women Undergoing in Vitro Fertilization.

Abstract 4004Poster Board III-940 BackgroundHyperestrogenic conditions of long duration such as pregnancy, use of oral contraceptives and estrogen replacement therapy have been related to alterations in the coagulation parameters and are considered as risk factors for increased incidence of thromboembolic events. In vitro fertilization (IVF) involves the use of exogenous hormones to achieve cycle control, stimulate the ovaries, and support implantation. During this process the 17 B estradiol (E2) levels change from minimal to supraphysiological levels in the same patient over several weeks. The ovarian stimulation usually continues for 8-14 days and as a result the estrogen levels are high for a relatively short time. D-dimer, a fibrin degradation product, is a marker of hypercoagulable states and of endogenous fibrinolysis. Quantitative D-dimer testing is routinely used in clinical management for its high negative predictive value in suspected venous thromboembolism, especially, in an emergency room setting. There are several reports of progressive increase of D- dimer levels (>0.5 ng/ml) during normal pregnancy and there have been reports of thromboembolic complications in patients undergoing IVF. Therefore, patients undergoing IVF present an opportunity to study isolated estrogen effects on the coagulation system. ObjectiveThe aim of our study was to evaluate the effect of short term elevated estrogen blood levels on the coagulation system as measured by D-dimer in women undergoing IVF. Methods62 healthy women under age of 40, who were scheduled to undergo IVF were included in the study. Induction of ovulation was performed in all patients with standard long protocol using GnRH agonist. Blood samples were obtained at baseline, maximum down regulation (E2<200 pmol/l) and on the day of oocyte retrieval. Plasma D-dimer level was measured by VIDAS ELISA assay according to the hematology laboratory standard protocol. D-dimer level below 500 ng/ml was considered a normal value. Results47/62 recruited subjects met the protocol requirements. The mean age of the participants was 28.6 years (range 20-39) and their mean BMI was 26 (range 18-38). Serum E2 concentrations (mean ±SD) on down regulation day and at oocyte retrieval day were 125±36 and 6549 ±3803 pmol/L respectively. Plasma D-dimer level (mean ±SD) on down regulation day and at oocyte retrieval day was 208 ±84 and 245±129 ng/ml respectively. There was a 21% increase in D-dimer (p<0.024) in the entire group. There was a statistically significant increase in D-dimer level in women with BMI >30 as compared to women with BMI <30 (38.5%/ 18.8%; p=0.06). However, in none of the groups did the level of D-dimer exceed the normal cut off value. There was no correlation between E2 levels and the level of D-dimer. Pregnancy rate was 47.5% per transfer and there was no significant correlation between pregnancy rate and the level of D-dimer. ConclusionIn our study of healthy women undergoing IVF, we found that short term exposure to supraphysiological level of E2 for induction of ovulation caused a significant increase in D-dimer level; however, it remained within the normal value. We conclude that short term exposure to supraphysiological level of E2 did not affect thromboembolic status as expressed by D -dimer levels. This may not apply to states of long term exposure to elevated E2. The finding of positive correlation of levels of D-dimer with BMI may indicate that overweight women undergoing IVF treatment may have a contributing risk factor for thromboembolic events. Further studies of larger groups are warranted to confirm our findings. Disclosures:No relevant conflicts of interest to declare.

GH replacement in adults: interactions with other pituitary hormone deficiencies and replacement therapies

Severe GH deficiency (GHD) in adults has been described as a clinical entity. However, some of the features associated with GHD could be due to unphysiological and inadequate replacement of other pituitary hormone deficiencies. This may be true for glucocorticoid replacement that lacks a biomarker making dose titration and monitoring difficult. Moreover, oral estrogen replacement therapy decreases IGF1 levels compared with the transdermal route, which attenuates the responsiveness to GH replacement therapy in women. In addition, in untreated female hypogonadism, oral estrogen may augment the features associated with GHD in adult women. Important interactions between the hormones used for replacing pituitary hormone deficiency occur. Introducing GH replacement may unmask both an incipient adrenal insufficiency and central hypothyroidism. Therefore, awareness and proper monitoring of these hormonal interactions are important in order to reach an optimal replacement therapy. This review will focus on the complex hormonal interactions between GH and other pituitary hormones in GHD and in GH replacement.

Effects of estrogen replacement therapy on estrogen receptor expression and immunoregulatory cytokine secretion in surgically induced menopausal women

To investigate the effect of oral and transdermal estrogen replacement therapy (ERT) on the expression of different estrogen receptor (ER) subtypes and the secretion of immunoregulatory cytokines, we performed a clinical investigation on previously healthy women who had undergone a total hysterectomy and bilateral salpingo-oopherectomy. These women were randomly distributed into two groups: an oral ERT group and transdermal ERT group. Before and after ERT, the serum levels of estradiol (E 2) and follicle stimulating hormone (FSH) were measured, ERα and ERβ expression of peripheral blood T lymphocytes was tested, and secretion of specific immunoregulatory cytokines (IFNγ, IL-2 and IL-4) by T lymphocytes was examined. Our results confirm that for both groups, the serum E 2 level was increased after ERT ( P < 0.01) and the serum FSH level was decreased after ERT ( P < 0.01), with no significant difference in hormone levels between the two groups. ERα expression by T lymphocytes was significantly higher after ERT than before ( P < 0.01) in both groups. Levels of type 1 cytokines (IL-2 and IFNγ), which were secreted by T helper 1 (Th1), after ERT were substantially decreased. The level of type 2 cytokine (IL-4), which were secreted by T helper 2 (Th2), was significantly increased after ERT ( P < 0.01 for the oral group and P < 0.05 for the transdermal group). In summary, both oral and transdermal ERT increased serum E 2 levels, decreased serum FSH levels and relieved the effects of peri-menopausal symptoms. These data suggest that both oral and transdermal ERT act to improve the balance of Th1/Th2 cytokines by the effects of estrogen potentially acting in T lymphocytes mainly through ERα.

Endogenous sex hormones and C‐reactive protein in healthy postmenopausal women

Oral oestrogen replacement therapy increases levels of C-reactive protein (CRP). CRP is an established strong predictor of cardiovascular events. It is unknown whether endogenous oestrogen levels are associated with CRP. We therefore studied the relationship between endogenous sex hormones and CRP in healthy postmenopausal women emphasizing the role of body composition as peripheral fat is both a main source of oestrogen production after menopause and an endocrine tissue with inflammatory activities. The study population comprised 889 women participating in the PROSPECT study, an ongoing population-based cohort study. Information on risk factors was collected by questionnaires and clinical examination. Endogenous sex hormone levels and CRP were measured with double antibody radio immuno assay (RIA) from fasting plasma samples. In this cross-sectional study, associations between risk factors and lnCRP were studied using linear regression models. Increases in oestrone and free oestradiol levels and the free androgen index were related to an increase in lnCRP of 1.19, 1.23 and 1.21 mg dL(-1) respectively. Body mass index (BMI), waist circumference and physical activity were strongly related to CRP levels, independent of age and other cardiovascular risk factors. Levels of all sex steroids but dehydroepiandrostenedione decreased with age. In age-adjusted analyses, an increase in waist circumference or BMI by one quartile was associated with a 1.28-fold and 1.26-fold increase in CRP. The relationship between endogenous hormones and CRP was modestly attenuated but remained highly significant after adjustment for body composition, physical activity and other traditional cardiovascular risk factors. Our findings show that in postmenopausal women high levels of endogenous oestrogenic and androgenic sex steroids coincide with high CRP levels. This was only explained in part by markers of body composition or intra-abdominal fat.

Oral but not transdermal estrogen replacement therapy changes the composition of plasma lipoproteins

The role of hormone replacement therapy and estrogen replacement therapy (ERT) in cardiovascular disease prevention has not been unambiguously defined yet. The metabolic effects of estrogens may vary depending upon the route of administration. Therefore, we compared the impact of unopposed oral or transdermal ERT on plasma lipids and lipoproteins in 41 hysterectomized women. This was an open-label, randomized, crossover study (with 2 treatments and 2 periods). The 41 hysterectomized women were randomized to receive oral or transdermal 17 β-estradiol in the first or second of two 12-week study periods. Plasma lipid and lipoprotein levels were assayed before and after each treatment using standard automated methods. Lipid content of lipoprotein subclasses was assessed by sequential ultracentrifugation. The atherogenic index of plasma (AIP) was calculated as log(triglyceride [TG]/high-density lipoprotein [HDL] cholesterol). The difference between the 2 forms of administration was tested using a linear mixed model. The change from baseline for each of the forms was tested using paired t test. Oral ERT resulted in a significant increase in HDL cholesterol and apolipoprotein A-I levels, whereas it significantly decreased total and low-density lipoprotein (LDL) cholesterol and increased TG concentrations. Transdermal ERT had no such effect. Oral ERT led to a significant TG enrichment of HDL (0.19 ± 0.06 vs 0.27 ± 0.07 mmol/L, P < .001) and LDL particles (0.23 ± 0.08 vs 0.26 ± 0.10 mmol/L, P < .001) compared with baseline, whereas transdermal therapy did not have any effect on lipoprotein subclasses composition. The difference between the 2 treatments was statistically significant for HDL-TG and LDL-TG (0.27 ± 0.07 vs 0.19 ± 0.05 mmol/L, P < .001 and 0.26 ± 0.10 vs 0.22 ± 0.07 mmol/L, P< .001, respectively). The transdermal but not oral ERT significantly reduced the AIP compared with baseline (−0.17 ± 0.26 vs −0.23 ± 0.25, P = .023), making the difference between the therapies statistically significant (−0.23 ± 0.25 vs −0.18 ± 0.22, P = .017). Oral administration of ERT resulted in TG enrichment of LDL and HDL particles. Transdermal ERT did not change the composition of the lipoproteins and produced a significant improvement of AIP. Compared with transdermal ERT, orally administered ERT changes negatively the composition of plasma lipoproteins.

Effect of Intranasal Estrogen on Vocal Quality

The objective of this study was to evaluate the effect of intranasal estrogen therapy on female vocal quality. Thirty-two women who had surgically induced menopause were included into the study group and examined through hall year for this study. Estrogen treatment was proposed to all of the patients. Twenty-three of them accepted the treatment protocols including oral (n=12) (2mg estradiol; Estrofem; Novo Nordisk, Denmark) and intranasal (n=11) (300 mc g 17beta-estradiol; Aerodiol; Servier, Chambray-les-Tours, France) form of estrogen. The rest of patients refused estrogen treatment and those patients constituted the control group (n=9). Vocal changes were evaluated with Voice Handicap Index (VHI) and acoustic analysis of voice variations (fundamental frequency [F0], SD F0, jitter, shimmer, normalized voice energy, and harmonics-to-noise ratio) at baseline and after 1-year follow-up. According to VHI, while voice improvement was not clear in oral estrogen group, it was significant at intranasal estrogen group. Voice quality in patients treated with hormone replacement therapy (HRT) was significantly higher than patients without HRT. But between two treatment groups, there were no any statistical discrepancy. According to acoustic analysis, vocal stability among the women who use HRT was significantly better than those who did not use. Intranasal estrogen exerted the most significant effects on vocal stability. The data of our study support that voice undergoes changes in lack of estrogen in surgically induced menopausal women. Taken together with the relevant studies, while oral estrogen replacement therapy shows a favorable influence on voice quality, it seems to be more pronounced with intranasal estrogen than oral form.

Hormone replacement therapy and cardiovascular disease: the case for a randomized controlled trial.

The menopause is associated with an increased risk of developing cardiovascular disease. Oestrogen may influence various metabolic pathways which contribute to the pathogenesis of cardiovascular disease, and observational studies suggest that in postmenopausal women oral oestrogen replacement therapy confers some protection against coronary heart disease and to a lesser extent against stroke. What is not clear is the magnitude of the cardioprotective effect and the overall balance of long-term benefits and hazards. Research is also required to establish the relative effects of oestrogen replacement therapy and combined or opposed hormone replacement therapy (HRT) where progestogen is added to counter the proliferative action of oestrogen on the endometrium. A large randomized controlled trial is the only way to provide accurate estimates of the cardioprotective effect of HRT and of other long-term benefits and hazards. Feasibility studies undertaken through the UK Medical Research Council (MRC) General Practice Research Framework show that such a trial is acceptable to patients and their doctors. Recruitment and withdrawal rates indicate that a trial of sufficient size to show a 25% reduction in cardiovascular disease with 90% power at the 1% level would be feasible. The full trial is costly and it is proposed that the UK collaborates with other countries in a major international trial to complement the Women's Health Initiative trial in the USA. Feasibility studies in Europe are underway, the design and scientific rationale for the trial have been approved by the UK MRC and it is hoped that recruitment to the full-scale trial can begin soon.

Computer-assisted image analysis of breast fine needle aspiration in a randomized chemoprevention trial of fenretinide vs. placebo in HRT users

Background Digital nuclear morphometric analysis can capture subtle differences along neoplastic progression. Studies showed different profiles from normal to cancer lesions. Our goal is to utilize this method as biomarker in chemoprevention trials. Methods Postmenopausal women were randomized to oral (CEE) or transdermal (E2) estrogen replacement therapy (ERT) in association with fenretinide or placebo. Ultrasound-guided fine needle aspiration (FNA) was performed at baseline and after 12 months in a subset of subjects. Results Ten samples were analyzed by karyometry. E2 compared with CEE increased nuclear area ( p=0.01). A similar pattern was observed for other DNA content and chromatin texture features. Fenretinide vs. placebo, increased nuclear area and shape while decreased slope, peak and entropy. Conclusion Preliminary results indicate that nuclear morphometry is feasible on FNA samples. ERT and fenretinide induced significant karyometric changes. These results support further investigation of this procedure as surrogate biomarker in chemoprevention trial.