Manheim1998   Manheim K, Ahlm H, Milsom I, Svensson A. Transdermal oestrogen reduces daytime blood pressure in hypertensive women. J Hum Hypertension 1998;12:323-7.

The aim of this study was to investigate the acute effects of transdermally administered 17-beta-oestradiol on ambulatory blood pressure (BP) in hypertensive, postmenopausal women. Thirteen postmenopausal women with ongoing treatment for hypertension were included in this placebo-controlled, double-blind cross-over study. Ambulatory recordings of BP and heart rate were performed during 24 h on two occasions, separated by at least 1 week, after application of a patch containing either 100 microg per 24 h 17-beta-oestradiol or placebo. Serum oestradiol was increased (P 0.001) during active treatment (139.2 +/- 21.1 pg/ml) compared with the baseline postmenopausal levels recorded during placebo (40.5 +/- 2.2 pg/ml). No rise in BP was found in office BP or during ambulatory recordings. Daytime BP pressure was acutely reduced by approximately 3 mm Hg during the 24 h of treatment with oestrogen (SBP n.s., DBP P 0.05), without any change in heart rate. Nocturnal dipping in SBP and DBP was present during placebo conditions, and there were no signs of an increase in dipping during treatment with 17-beta-oestradiol. This study supports previous evidence that hormone replacement therapy is safe in hypertensive women. The data in the present study also imply an acute, but small reduction of daytime BP due to transdermal oestrogen in hypertensive, postmenopausal women. Furthermore oestrogen did not blunt or increase the dipping phenomena during the night in these women.

Olsson1999   Olsson R, Mattson LA, Obrant K, Mellstrom D. Estrogen-progestogen therapy for low bone mineral density in primary biliary cirrhosis. Liver 1999;19:188-92.

AIMS/BACKGROUND: Patients with primary biliary cirrhosis (PBC) often have osteoporosis of the high-turnover type, suggesting that estrogen could have a beneficial effect. However, the cholestatic potential of estrogen could imply a risk of increased cholestasis in a disease characterized by cholestasis. The aim of the present study was to test whether hormone replacement therapy (HRT) could be used to increase bone mineral density (BMD) in PBC patients with osteoporosis, without causing deterioration of the liver function. METHODS: Nine female PBC patients with osteoporosis and one with osteopenia were offered HRT for two years. The change in BMD was compared to the change in ten age-matched female PBC patients who had less severe or no osteopenia and who did not receive HRT. Liver function tests were checked at six-month intervals. RESULTS: HRT patients showed a statistically significant increase in lumbar spine BMD and total body BMD whereas control patients showed a significant decrease in lumbar and total body BMD. In contrast to the controls, HRT patients also showed a decrease in truncal fat (-3.8%). Neither of the groups showed any statistically significant changes in the liver function tests. CONCLUSIONS: HRT is safe and effective in female PBC patients with osteoporosis.

Smith1998   Smith MA, Fine JA, Barnhill RL, Berwick M. Hormonal and reproductive influences and risk of melanoma in women. Int J Epidemiol 1998;27:751-7.

BACKGROUND: Evidence linking female hormones to the development of malignant melanoma has been contradictory. The purpose of this study was to examine the risk of melanoma in relation to exogenous and endogenous hormonal variables in women, including oral contraceptives, replacement oestrogens, pregnancy, and menopause. METHODS: Hormonal and reproductive factors were evaluated using data from a personal-interview population-based case-control study of melanoma in women conducted in Connecticut during 1987-1989. Caucasian female incident invasive melanoma cases (n = 308) were confirmed by standardized histopathological review. Caucasian female controls (n = 233) were selected by random digit dialling and frequency-matched on age. Data were analysed using multivariate logistic regression. RESULTS: Ever being pregnant, age at first pregnancy, current use of replacement oestrogens, ever use of oral contraceptives, duration of use of oral contraceptives, and age at first use of oral contraceptives were not associated with melanoma. Among other variables, cases were more than twice as likely as controls to report a single pregnancy lasting  6 months, but this association lacked a dose-response relationship. Menopause and body mass index were not independently associated with risk of melanoma. However, this analysis did suggest that menopause and body mass index may be interactive risk factors. Melanoma cases were three times more likely than controls to be obese and report natural menopause when compared to thin/acceptable premenopausal women (OR = 3.00, 95% CI: 1.03-8.73). CONCLUSIONS: These data do not provide strong evidence that hormonal and reproductive factors are associated with risk of melanoma in women, although the few positive results should be explored further.

Mackie1999   Mackie RM. Pregnancy and exogenous hormones in patients with cutaneous malignant melanoma. Curr Opin Oncol 1999;11:129-31.

In this article, recent literature is reviewed with regard to possible hormonal influences on susceptibility to melanoma and prognosis once melanoma is developed. At the present time, there is little data to suggest that melanoma and pregnancy interact as far as prognosis is concerned for patients with stage 1 and stage 2 disease. Recent data have provided further reassurance that oral contraceptives are safe for patients who have had melanoma, and more data is required before a definitive statement can be made regarding hormone replacement therapy for women who have had stage 1 or 2 melanoma adequately treated.

Ross2000   Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl cancer Inst 2000;92:328-32.

BACKGROUND: Hormone replacement therapy (HRT) given as unopposed estrogen replacement therapy (ERT) gained widespread popularity in the United States in the 1960s and 1970s. Recent prescribing practices have favored combination HRT (CHRT), i.e., adding a progestin to estrogen for the entire monthly cycle (continuous combined replacement therapy (CCRT)) or a part of the cycle (sequential estrogen plus progestin therapy (SEPRT)). Few data exist on the association between CHRT and breast cancer risk. We determined the effects of CHRT on a woman’s risk of developing breast cancer in a population-based, case-control study. METHODS: Case subjects included those with incident breast cancers diagnosed over 4(1/2) years in Los Angeles County, CA, in the late 1980s and 1990s. Control subjects were neighborhood residents who were individually matched to case subjects on age and race. Case subjects and control subjects were interviewed in person to collect information on known breast cancer risk factors as well as on HRT use. Information on 1897 postmenopausal case subjects and on 1637 postmenopausal control subjects aged 55-72 years who had not undergone a simple hysterectomy was analyzed. Breast cancer risks associated with the various types of HRT were estimated as odds ratios (ORs) after adjusting simultaneously for the different forms of HRT and for known risk factors of breast cancer. All P values are two-sided. RESULTS: HRT was associated with a 10% higher breast cancer risk for each 5 years of use (OR(5) = 1.10; 95% confidence interval (CI) = 1.02-1.18). Risk was substantially higher for CHRT use (OR(5) = 1.24; 95% CI = 1.07-1.45) than for ERT use (OR(5) = 1. 06; 95% CI = 0.97-1.15). Risk estimates were higher for SEPRT (OR(5) = 1.38; 95% CI = 1.13-1.68) than for CCRT (OR(5) = 1.09; 95% CI = 0. 88-1.35), but this difference was not statistically significant. CONCLUSIONS: This study provides strong evidence that the addition of a progestin to HRT enhances markedly the risk of breast cancer relative to estrogen use alone. These findings have important implications for the risk-benefit equation for HRT in women using CHRT.

Schairer2000   Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000;283:485-91.

CONTEXT: Whether menopausal hormone replacement therapy using a combined estrogen-progestin regimen increases risk of breast cancer beyond that associated with estrogen alone is unknown. OBJECTIVE: To determine whether increases in risk associated with the estrogen-progestin regimen are greater than those associated with estrogen alone. DESIGN: Cohort study of follow-up data for 1980-1995 from the Breast Cancer Detection Demonstration Project, a nationwide breast cancer screening program. SETTING: Twenty-nine screening centers throughout the United States. PARTICIPANTS: A total of 46355 postmenopausal women (mean age at start of follow-up, 58 years). MAIN OUTCOME MEASURE: Incident breast cancers by recency, duration, and type of hormone use. RESULTS: During follow-up, 2082 cases of breast cancer were identified. Increases in risk with estrogen only and estrogen-progestin only were restricted to use within the previous 4 years (relative risk (RR), 1.2 (95% confidence interval (CI), 1.0-1.4) and 1.4 (95% CI, 1.1-1.8), respectively); the relative risk increased by 0.01 (95% CI, 0.002-0.03) with each year of estrogen-only use and by 0.08 (95% CI, 0.02-0.16) with each year of estrogen-progestin-only use among recent users, after adjustment for mammographic screening, age at menopause, body mass index (BMI), education, and age. The P value associated with the test of homogeneity of these estimates was .02. Among women with a BMI of 24.4 kg/m2 or less, increases in RR with each year of estrogen-only use and estrogen-progestin-only use among recent users were 0.03 (95% CI, 0.01-0.06) and 0.12 (95% CI, 0.02-0.25), respectively. These associations were evident for the majority of invasive tumors with ductal histology and regardless of extent of invasive disease. Risk in heavier women did not increase with use of estrogen only or estrogen-progestin only. CONCLUSION: Our data suggest that the estrogen-progestin regimen increases breast cancer risk beyond that associated with estrogen alone.

Schairer2000a   Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000;283:485-91.

CONTEXT: Whether menopausal hormone replacement therapy using a combined estrogen-progestin regimen increases risk of breast cancer beyond that associated with estrogen alone is unknown. OBJECTIVE: To determine whether increases in risk associated with the estrogen-progestin regimen are greater than those associated with estrogen alone. DESIGN: Cohort study of follow-up data for 1980-1995 from the Breast Cancer Detection Demonstration Project, a nationwide breast cancer screening program. SETTING: Twenty-nine screening centers throughout the United States. PARTICIPANTS: A total of 46355 postmenopausal women (mean age at start of follow-up, 58 years). MAIN OUTCOME MEASURE: Incident breast cancers by recency, duration, and type of hormone use. RESULTS: During follow-up, 2082 cases of breast cancer were identified. Increases in risk with estrogen only and estrogen-progestin only were restricted to use within the previous 4 years (relative risk (RR), 1.2 (95% confidence interval (CI), 1.0-1.4) and 1.4 (95% CI, 1.1-1.8), respectively); the relative risk increased by 0.01 (95% CI, 0.002-0.03) with each year of estrogen-only use and by 0.08 (95% CI, 0.02-0.16) with each year of estrogen-progestin-only use among recent users, after adjustment for mammographic screening, age at menopause, body mass index (BMI), education, and age. The P value associated with the test of homogeneity of these estimates was .02. Among women with a BMI of 24.4 kg/m2 or less, increases in RR with each year of estrogen-only use and estrogen-progestin-only use among recent users were 0.03 (95% CI, 0.01-0.06) and 0.12 (95% CI, 0.02-0.25), respectively. These associations were evident for the majority of invasive tumors with ductal histology and regardless of extent of invasive disease. Risk in heavier women did not increase with use of estrogen only or estrogen-progestin only. CONCLUSION: Our data suggest that the estrogen-progestin regimen increases breast cancer risk beyond that associated with estrogen alone.

Erb2000   Erb A, Brenner H, Gunther KP, Sturmer T. Hormone replacement therapy and patterns of osteoarthritis: baseline data from the Ulm Osteoarthritis Study. Ann Rheum Dis 2000;59:105-9.

OBJECTIVES: It has been suggested that hormone replacement therapy (HRT) may protect against osteoarthritis (OA). The aim of this paper was to assess the association between HRT and radiographically defined patterns of OA. METHODS: 475 consecutive women aged 50 years or older (mean age 66.1) who underwent hip or knee joint replacement because of advanced OA in four hospitals in south west Germany were enrolled in a cross sectional study. Participants underwent a standardised interview including detailed history of medication use and a physical examination. Furthermore, radiographs of the joint being replaced and of the contralateral joint as well as of both hands were obtained. Patients were categorised as having bilateral or unilateral OA according to the presence or absence of radiographic OA in the contralateral joint. If radiographic OA of different hand and finger joint groups was present, participants were categorised as having generalised OA (GOA). Logistic regression was used to estimate odds ratios and their 95% confidence intervals for the association between HRT and bilateral or GOA while adjusting for potential confounders. RESULTS: Fifty five women (11.6%) were using HRT. The median duration of use was 5.4 years. The prevalence of bilateral and GOA was similar among users of ORT (86.3% and 27.5%, respectively) and among non-users of HRT (88.7% and 35.7%, respectively). After adjustment for potential confounding factors, the odds ratios (95% confidence intervals) of bilateral OA and GOA among HRT users compared with non-users was 1.21 (0.48, 3.03) and 1. 21 (0.53, 2.74), respectively. CONCLUSION: Despite limited generalisability because of the selective study sample, these data do not support the hypothesis that HRT acts as a systemic protective factor against OA.

BarrettConnor1999b   Barrett-Connor E. Postmenopausal estrogen therapy and selected (less-often-considered) disease outcomes. Menopause 1999;6:14-20.

OBJECTIVE: To review the association between postmenopausal estrogen therapy and chronic conditions not usually considered in risk-benefit reviews. DESIGN: Ten-year literature review (1989-1998) of case series and epidemiologic studies with risk estimates and 95% confidence intervals. RESULTS: Osteoarthritis and rheumatoid arthritis, the most extensively studied conditions, show no consistent association with hormone therapy. Two studies of systemic lupus erythematosus show a nearly three-fold increased risk apparent after 2 or more years of hormone therapy. Single studies suggest an increased risk of pancreatitis, asthma, and Raynaud’s syndrome. Evidence for a reduced risk of diabetes mellitus is not compelling. Cataracts and migraine are either increased or decreased by hormone therapy. Among the associations considered here, only an increased risk of gallbladder disease and venous thromboembolic disease have been confirmed in clinical trials of hormone replacement therapy. CONCLUSIONS: Further studies are needed.

Wetterberg1995a   Wetterberg L, Olsson MB, Alm-Agvald I. Estrogen treatment caused attacks of porphyria. Lakartidingen 1995;92:2197-8,2201.

Two female patients with acute intermittent porphyria, who received oestrogen skin pads as supplementary treatment for postmenopausal discomfort, developed severe psychiatric disorders with persistent confusion, aggression and paranoid reactions. Some decades earlier they had reacted with symptoms of acute porphyria following oral contraceptive usage. There is well documented evidence of the advisability of restrictiveness in the use of oestrogens in conjunction with acute porphyria, particularly in cases of patients with a history of hormone-related symptoms of acute porphyria. The putative mechanisms by means of which oestrogens may exert effects on neurotransmitters and peptides are discussed in the article. The authors would be grateful to hear from colleagues abroad who have treated patients with similar symptoms following postmenopausal treatment with oestrogens.

BarrettConnor1999a   Barrett-Connor E. Postmenopausal estrogen therapy and selected (less-often-considered) disease outcomes. Menopause 1999;6:14-20.

OBJECTIVE: To review the association between postmenopausal estrogen therapy and chronic conditions not usually considered in risk-benefit reviews. DESIGN: Ten-year literature review (1989-1998) of case series and epidemiologic studies with risk estimates and 95% confidence intervals. RESULTS: Osteoarthritis and rheumatoid arthritis, the most extensively studied conditions, show no consistent association with hormone therapy. Two studies of systemic lupus erythematosus show a nearly three-fold increased risk apparent after 2 or more years of hormone therapy. Single studies suggest an increased risk of pancreatitis, asthma, and Raynaud’s syndrome. Evidence for a reduced risk of diabetes mellitus is not compelling. Cataracts and migraine are either increased or decreased by hormone therapy. Among the associations considered here, only an increased risk of gallbladder disease and venous thromboembolic disease have been confirmed in clinical trials of hormone replacement therapy. CONCLUSIONS: Further studies are needed.

Lindamer1997   Lindamer LA, Lohr JB, Harris MJ, Jeste DV. Gender, estrogen and schizophrenia. Psychopharmacol Bull 1997;33:221-8.

Most of the evidence to support an association between estrogen and psychosis is indirect and comes from clinical studies of gender differences in schizophrenia and from studies of fluctuating levels of psychopathology in different phases of the menstrual cycle. Our data, as well as those of other investigators, suggest a significantly later age at onset of schizophrenia in women than in men. There is somewhat more direct evidence from animal studies indicating that estrogen modulates dopamine systems in a manner similar to neuroleptics, although there are some inconsistencies in the literature. Few studies have examined the effects of estrogen administration in conjunction with neuroleptics on psychotic symptoms. We present a case report of a postmenopausal women with schizophrenia who had an improvement in positive symptoms with estrogen replacement therapy. Long-term double-blind treatment studies are needed to investigate the effects of estrogen on psychotic symptoms in women with schizophrenia.

MatuszkiewiczRowinska1999   Matuszkiewicz-Rowinska J, Skorzewska K, Radowicki S et al. The benefits of hormone replacement therapy in premenopausal women with oestrogen deficiency on haemodialysi. Nephrol Dial Transplant 1999;14:1238-43.

BACKGROUND: Impaired sexual function is an important cause of depression in uraemic females. Hyperprolactinaemia is frequent, and often associated with decreased serum oestradiol concentration, which can significantly contribute to accelerated bone loss. The aim of the study was to evaluate the effect of hormone replacement therapy (HRT) on sexual function, serum 17beta-oestradiol and prolactin, and bone mineral density (BMD) in pre-menopausal women undergoing haemodialysis. METHODS: Among 63 women on haemodialysis, aged 18-45 years, 23 with secondary amenorrhoea and serum oestradiol  30 pg/ml were enrolled into the 1 year study. They were divided into: group I (n = 13) treated with transdermal oestradiol with cyclic addition of noretisterone acetate, and control group II (n = 10). BMD was measured with dual energy X-ray absorptiometry (DEXA). RESULTS: No important changes in sexual function and hormonal profile were observed in the control group, whereas in all women from group I the treatment induced regular menses and a marked improvement of libido and sexual activity. Serum 17beta-oestradiol increased after the first month from 20.5 11.7 to 46.8 13.6 pg/ml (P  0.001) and remained at that level until the end of the study, accompanied by a decrease of serum prolactin (from 1457 1045 to 691 116 mIU/ml after 12 months; P  0.001). In group I, the treatment induced an increase in BMD, although significant only in L2-L4 (P  0.05), whereas in group II a mild insignificant decrease was observed. However, a comparison of BMD values after 12 months in both groups revealed marked (P  0.01-P  0.05) differences at all studied sites. CONCLUSIONS: Transdermal HRT allows sustained physiological serum oestradiol concentrations in pre-menopausal women with oestrogen deficiency on haemodialysis, with the restoration of regular menses and a marked improvement in their sexual function. The treatment inhibits bone demineralization and can play an important role in the prevention of early osteoporosis in this group of patients.

Fraenkel1998   Fraenkel L, Zhang Y, Chaisson CE, Evans SR, Wilson PWF, Felson DT. The association of estrogen replacement therapy and the Raynaud phenomenon in postmenopausal women. Ann Intern Med 1998;129:208-11.

BACKGROUND: Hormonal factors may play an important role in the pathophysiology of the Raynaud phenomenon. Experimental studies have shown an increased vasoconstrictor response to estrogen, a response that can be prevented by the addition of progesterone. OBJECTIVE: To measure the association between estrogen replacement therapy (alone and with progesterone) and the Raynaud phenomenon. DESIGN: Cross-sectional study. SETTING: Framingham Offspring Study. PARTICIPANTS: 497 postmenopausal women. MEASUREMENTS: Prevalence of the Raynaud phenomenon according to hormone use. Covariates measured included age, body mass index, smoking, alcohol consumption, and beta-blocker use. RESULTS: Forty-nine women were classified as having the Raynaud phenomenon (9.9%). The prevalence of this phenomenon was 8.4% among women who did not receive estrogen, 19.1% among women receiving estrogen alone, and 9.8% among women receiving estrogen plus progesterone. The adjusted odds ratio for the Raynaud phenomenon was 2.5 (95% CI, 1.2 to 5.3) for unopposed estrogen and 0.9 (CI, 0.3 to 2.6) for estrogen plus progesterone, with nonusers as the reference group. CONCLUSIONS: Unopposed estrogen therapy was associated with the Raynaud phenomenon in postmenopausal women. This association was not present in women who were receiving combined hormone therapy.

A0581   Ginsburg J, Hardiman P, What do we know about the pathogenesis of the menopausal hot flush?. In: Sitruk-Ware R, Utian WH (eds) The menopause and hormonal replacement therapy. Facts and contoversies. Marcel Dekker Inc 1991:15-46

A0282   McFarland KF, Boniface ME, Hornung CA, Earnhardt W, Humphries JO, Risk factors and noncontraceptive estrogen use in women with and without coronary disease.. Am-Heart-J. 1989 Jun; 117(6): 1209-14

To evaluate the risk factors for coronary disease, 345 women, aged 35 to 59 years, who had undergone coronary arteriography for suspected coronary disease completed a mail questionnaire, telephone interview, or both. Two hundred eight women with angiographically normal coronary arteries constituted the control group, and 137 with a 70% or more occlusion of one or more coronary vessels were classified as having severe coronary occlusive disease. Age-adjusted odds of severe coronary disease based on the logistic regression model for the risk factors evaluated were as follows: smoking, 5.73 (p less than 0.001); diabetes, 5.09 (p less than 0.001); cholesterol level greater than 240 mg/dl, 2.35 (p less than 0.05); a parental history of death from heart disease before age 60 years, 2.03 (p less than 0.05); and estrogen use for 6 months or longer, 0.50 (p less than 0.01). There were no differences with regard to the presence of obesity and a history of hypertension in women with and without coronary disease. These data support the hypothesis that use of noncontraceptive estrogen significantly reduces the risk of severe coronary disease, whereas smoking, an elevated cholesterol level, and a parental history of heart disease all increase the risk of ischemic heart disease in women.

A0582   McKinlay SM, Jefferys M, The menopausal syndrome.. Br-J-Prev-Soc-Med. 1974 May; 28(2): 108-15

A0262a   Oldenhave JM, Well-being and sexuality in the climacteric.. Academisch Proefschrift Utrecht 1991

A0031   Furuhjelm M, Karlgren E, Carlstrom K, The effect of estrogen therapy on somatic and psychical symptoms in postmenopausal women.. Acta-Obstet-Gynecol-Scand. 1984; 63(7): 655-61

The effect of oral estrogen replacement therapyupon somatic and psychical disturbances and sexuality wasstudied in a double-blind investigation in 48 postmeno-pausalwomen using hormone preparations with two differentlevels of micronized estradiol-17 (E2) as active estrogencomponent. The patients were treated for 8 months infour 2-month periods with two preparations containing1-2 mg of E2 (Trisekvens(r) and Estrofema), with one preparationcontaining 1-4 mg of E2 (Trisekvensa(r) forte) andwith a placebo preparation. Investigations performed beforeand during treatment included general clinical chemicalanalysis, serum levels of FSH, LH and E2 and evaluation ofthe patients’ somatic and psychical disturbances and sexuality.The patients were classified into three subgroups accordingto their pretreatment scores for mental distress and/or depression: severe (group I), moderate (group II), or no(group III) mental distress and/or depression. No significant differences between the three subgroups were found inpretreatment values from the general clinical chemical analysis or the hormone assays. Estrogen treatment significantlyreduced S-total cholesterol values in all three subgroups; otherwise no significant effects were revealed by the generalchemical analysis. During the period of optimalwellbeing, serum E2 levels corresponded to luteal phase values. The gonadotropin levels, although depressed by approx. 50%, were still within the postmenopausal range. There were no significant differences between the two subgroups in hormone levels obtained during optimal estrogen treatment.Twenty-one patients had the best test resultswhen treated with the larger dose (Trisekvens(r) forte) and 23with the smaller dose (Trisekvens(r) and Estrofem) and 4during placebo treatment. The dose of estrogen did notsignificantly influence the hormone values found during optimalestrogen treatment. Vasomotoric and physical symptomsimproved appreciably during estrogen treatment whencompared with placebo or pretreatment scores. A certain placebo effect was noted for physical symptoms, which may be attributed to persisting effects of previous active estrogentreatment. The psychical symptoms too improved considerably during estrogen treatment, although placebo effectswere also noted. In 10 patients, detrimental effects on psychicalsymptoms were observed during active estrogen treatment.Hormone analysis revealed very high E2 and low gonadotropin levels in these patients, which must therefore be considered as overtreated. In one patient with premeno-pausaldepression periods and in 3 who surreptitiously tooktranquillizers during the treatment period, no effects. ofestrogens upon the psychical symptoms were observed. Tbesexuality of the patients did not improve during estrogentreatment.The authors stress the need to individuale the dosage inestrogen replacement therapy.

A0033   Ditkoff EC, Crary WG, Cristo M, Lobo RA, Estrogen improves psychological function in asymptomatic postmenopausal women.. Obstet-Gynecol. 1991 Dec; 78(6): 991-5

Estrogen treatment of postmenopausal women has been suggested to improve mood and psychological function. However, this remains controversial because previous studies involved heterogeneous groups, were not double blind, and included women who were also experiencing somatic symptoms that were relieved by estrogen. A randomized double-blind study was carried out comparing the effects of placebo and conjugated equine estrogens (0.625 and 1.25 mg) on psychological function over 3 months in 36 asymptomatic women, aged 45-60. The tests included the Minnesota Multiphasic Personality Inventory-168, the Profile of Adaptation to Life, and the Beck Depression Inventory. Memory was assessed directly by the Wechsler Adult Intelligence Scales, measuring both digit span and digit symbol. All women were well-adjusted psychologically. The income management scale of the Profile of Adaptation to Life improved (P less than .05) with estrogen, as did the Beck Depression Inventory (P less than .05), but these results were not dose-related. Memory assessed prospectively by the Wechsler Adult Intelligence Scales was not affected significantly. These results suggest that estrogen use may improve the overall quality of life in postmenopausal women.

A0583   Dennerstein L, Mood and menopause.. In: Sitruk-Ware R, Utian WH (eds) The menopause and hormonal replacement therapy. Facts and contoversies. Marcel Dekker Inc 1991:101-18

A0384   Hage JC, Benedek Jaszmann LJ. A study of the effects of premarin cream in the post-menopausal woman. Curr. Therap. Res. 1983; 33: 925

For treatment of menopausal atrophic vaginitis, vaginal application of 1 gm (0.625 mg) of Premarin Cream daily for two weeks seems to be sufficient, as more than 90% of the patients were free from complaints, with significant improvements in the vaginal maturation index. No significant changes occurred in estradiol, luteinizing hormone, follicle-stimulating hormone, and prolactin plasma levels.

A0377   Nilsson K, Heimer G, Low-dose oestradiol in the treatment of urogenital oestrogen deficiency - a pharmacokinetic and pharmacodynamic study.. Maturitas. 1992 Oct; 15(2): 121-7

Twenty-four postmenopausal women with vaginal atrophy due to oestrogen deficiency were treated with 17 beta-oestradiol administered as vaginal tablets containing 10 and 25 micrograms, respectively, in a slow-release system (Vagifem, Novo Nordisk, Denmark). All the women were treated for 2 weeks with each dose in a double-blind, cross-over study. Plasma concentrations of unconjugated oestradiol and unconjugated oestrone were measured at regular intervals for 24 h on days 1 and 14 of each treatment regimen. Cytological and clinical evaluations of the vaginal and urethral epithelium were also carried out. Initially, when the epithelium was still atrophic, dose-dependent absorption of oestradiol was demonstrated. After 14 days of treatment maturation of the vaginal epithelium was seen with both regimens and the absorption of oestradiol then declined significantly on both the 10 and the 25 micrograms dose. Oestrone levels remained unchanged and gonadotrophin levels were unaffected during treatment. Vaginal cytology showed maturation on both the 10 and the 25 micrograms dose, whereas urethral cytology showed a reduction in parabasal cells that was significant only on 25 micrograms. Clinical and subjective improvement was apparent on both doses and acceptance of treatment was good.

A0048   Semmens JP, Tsai CC, Semmens EC, Loadholt CB, Effects of estrogen therapy on vaginal physiology during menopause.. Obstet-Gynecol. 1985 Jul; 66(1): 15-8

Vaginal physiology was evaluated in 23 postmenopausal women before estrogen replacement therapy and at 1, 3, 6, 12, 18, and 24 months while receiving conjugated equine estrogens (Premarin). Reversal of hormonal levels (17 beta-estradiol, gonadotropins) and vaginal cytology occurred within one month. Vaginal pH levels significantly decreased from a baseline mean of 5.2 to a level of 4.2 at 24 months (P less than .05). Women who were sexually active showed a greater decline in pH levels than did women who were sexually inactive. Maximum increases in amount of vaginal fluid and potassium levels were observed after three months of therapy. Vaginal blood flow and vaginal electropotential difference were significantly increased over baseline values at one month and again at 12 months (P less than .05) with a slow progressive improvement continuing throughout 24 months of estrogen replacement therapy. This study provides documented laboratory evidence to suggest that restoration of vaginal tissue function requires 18 to 24 months and explains why dyspareunia may persist in the early months of replacement therapy despite hormonal and cytologic return to premenopausal values.

A0586   Mettler L, Olsen PG, Long-term treatment of atrophic vaginitis with low-dose oestradiol vaginal tablets.. Maturitas. 1991 Dec; 14(1): 23-31

Fifty-one post-menopausal women suffering from symptoms of oestrogen deficiency-derived atrophic vaginitis were treated intravaginally with two therapeutic regimens based on doses of 25 micrograms 17 beta-oestradiol (E2) in an open, controlled study. All the patients received treatment daily for 2 weeks by way of induction therapy. They were then randomly allocated to either once-weekly (17 patients) or twice-weekly (34 patients) vaginal administration for a further 50 weeks as maintenance treatment. Endometrial histopathology was evaluated before and after 1 year of treatment. The effects on symptoms and oestrogen/gonadotrophin levels were determined before and after 2, 12, 24, 36 and 52 weeks of therapy. Nine women continued twice-weekly treatment for a further year, meaning that they underwent treatment for a total period of 2 years. Endometrial biopsies were obtained after 2 years of treatment. All the pretreatment endometrial biopsies indicated an atrophic endometrium. One patient out of the 14 who completed 1 year of therapy in the group treated once weekly showed weak proliferation of the endometrium, while the other 13 had an atrophic endometrium. In the group treated twice weekly, 2 out of the 31 patients who completed the study showed weak proliferation of the endometrium. The other 29 had an atrophic endometrium. All 9 women who received treatment for 2 years had an atrophic endometrium at the end of the treatment period. The twice-weekly dosage regimen gave complete relief of symptoms in almost all patients, whereas the majority of the patients in the group treated once weekly still had mild symptoms. No adverse effects were reported.(ABSTRACT TRUNCATED AT 250 WORDS)

A0061   Hilton P, Tweddell AL, Mayne C. Oral and Intravaginal Estrogens Alone and in Combination with Alpha-Adrenergic Stimulation in Genuine Stress Incontinence . Int Urogynecol J 1990;1:80-6

This second article on the subject of estrogen and phenylpropanolamine (PPA) therapy in postmenopausal women deals with both oral and intravaginal estrogen therapy. This study was also well-designed as a double-blind placebo-controlled investigation. Vaginal estrogen therapy was found to be more effective than oral estrogen therapy, particularly in the management of diurnal and nocturnal frequency. This effect was enhanced by the addition of PPA. Stress incontinence was improved in all treatment groups and maximal when vaginal estrogen was combined with PPA. Urodynamic parameters did not change in accordance with clinical improvements. Further studies are needed to address the reasons why such discordance exists between clinical symptom improvement an corresponding change in urodynamic data.

A0587   Bhatia NN, Bergman A, Karram MM, Effects of estrogen on urethral function in women with urinary incontinence.. Am-J-Obstet-Gynecol. 1989 Jan; 160(1): 176-81

In a prospective study, 2 gm of conjugated estrogen vaginal cream was administered daily for a total of 6 weeks in a group of 11 postmenopausal women with urodynamically proved genuine stress incontinence. Midurethral cytologic studies and a complete clinical and urodynamic evaluation were performed twice at 6-week intervals. Clinically, six of the 11 patients (54.5%) were cured or improved significantly after estrogen treatment, whereas the other five patients (45.5%) were clinically unchanged. The favorable clinical response correlated with urodynamic findings of increased urethral closure pressure and improved abdominal pressure transmission to the proximal urethra (p less than 0.05); in the patients who had a poor clinical response to estrogens, no significant changes in urethral dynamics were noted. Changes in urethral cytologic findings also correlated well with clinical and urodynamic findings. Patients with a favorable response to estrogen showed a maturation change from transitional to intermediate squamous epithelium (p less than 0.02), whereas nonresponders showed no significant changes in urethral cells.

A0063   Brandberg A, Mellstrom D, Samsioe G, Low dose oral estriol treatment in elderly women with urogenital infections.. Acta-Obstet-Gynecol-Scand-Suppl. 1987; 140: 33-8

Forty-one female geriatric in-patients with recurrent urogenital infections took partin a cross-over intervention study with oral estriol as an alternative to antibiotics.After one month of treatment with a dosage of 3 mg/day the vaginal flora of all patientsshowed a dominance of Lactobacilli, whereas without estriol treatment theflora was of a fecal type in two-third of the cases. In all women the atrophic vaginalmucosa became restored and well vascularised.Antibiotics were given 16 times more often during the period without estriol treat-ment.It is concluded that treatment with estriol:- restores the normal premenopausal vaginal flora and mucosa- prevents urogenital infections and disorders in postmenopausal women.

A0066   Castelo Branco C, Duran M, Gonzalez Merlo J, Skin collagen changes related to age and hormone replacement therapy.. Maturitas. 1992 Oct; 15(2): 113-9

A total of 76 nulliparous women who had been hospitalized for minor operations, classified according to age group (by decade from 20s to 60s) and 118 postmenopausal women randomly allocated to one of four groups were studied. In all, 312 skin biopsies were taken from the lower abdomen at 0 and 12 months and the skin collagen changes noted. Collagen content decreased significantly with age beyond the 40s (P  0.001) and after the menopause (P  0.01). The decrease was preventable by the use of hormone replacement therapy. All the therapeutic regimens induced increases in skin collagen content, whereas in the control group a significant decrease was observed (P  0.05).

A0075   Volpe A, Lucenti V, Forabosco A, Boselli F, Maietta Latessa A, Pozzo P, Petraglia F, Genazzani AR. Oral discomfort and hormone replacement therapy in the post-menopause . Maturitas 1990;13:1-5

We evaluated the incidence of oral discomfort in post-menopausal women and the efficacy of hormone replacement therapy in patients complaining of such symptoms. Two studies were performed. In the first, we compared oral discomfort and oral mucosa smears in 47 patients receiving replacement therapy and in 40 untreated post-menopausal women. In the second, the efficacy of hormone replacement therapy with oestriol vaginal cream (22 patients) or conjugated oestrogens plus norethisterone acetate (10 patients) was evaluated. In the first study, oral exfoliative cytology showed a similar maturation index and volume in both groups. In the second, hormone replacement therapy improved subjective and objective symptoms in 12 out of 22 patients treated with oestriol and in 7 out of 10 patients treated with conjugated oestrogens plus norethisterone. These data suggest that oestrogen deficiency can be considered a possible cause of oral discomfort in some post-menopausal patients and that oestrogen replacemnt therapy may improve subjective symptoms.

A0488   Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D, Hormone replacement therapy and endometrial cancer risk: a meta-analysis.. Obstet-Gynecol. 1995 Feb; 85(2): 304-13

OBJECTIVE: To assess the association of unopposed estrogen or estrogen plus progestin and the risk of developing endometrial cancer or dying of that disease. DATA SOURCES: A literature search of English-language studies was performed using MEDLINE, a review of bibliographies, and consultations with experts. METHODS OF STUDY SELECTION: We identified 30 studies with adequate controls and risk estimates. DATA EXTRACTION AND SYNTHESIS: Risk estimates were extracted by two authors and summarized using meta-analytic methods. The summary relative risk (RR) was 2.3 for estrogen users compared to nonusers (95% confidence interval CI 2.1-2.5), with a much higher RR associated with prolonged duration of use (RR 9.5 for 10 or more years). The summary RR of endometrial cancer remained elevated 5 or more years after discontinuation of unopposed estrogen therapy (RR 2.3). Interrupting estrogen for 5-7 days per month was not associated with lower risk than daily use. Users of unopposed conjugated estrogen had a greater increase in RR of developing endometrial cancer than users of synthetic estrogens. The risk for endometrial cancer death was elevated among unopposed estrogen users (RR 2.7, 95% CI 0.9-8.0). Among estrogen plus progestin users, cohort studies showed a decreased risk of endometrial cancer (RR 0.4), whereas case-control studies showed a small increase (RR 1.8). CONCLUSIONS: Endometrial cancer risk increases substantially with long duration of unopposed estrogen use, and this increased risk persists for several years after discontinuation of estrogen. Although not statistically significant, the risk of death from endometrial cancer among unopposed estrogen users is increased, similar to the increased risk of developing the disease. Data regarding risk for endometrial cancer among estrogen plus progestin users are limited and conflicting.

A0509   Ettinger B, Golditch IM, Friedman G, Gynecologic consequences of long-term, unopposed estrogen replacement therapy.. Maturitas. 1988 Dec; 10(4): 271-82

We evaluated the gynecologic risks of unopposed, long-term estrogen use in postmenopausal women. Our medical record review showed that unopposed estrogen users (mean dose, 0.9 mg of conjugated estrogens) had a significantly higher (P less than 0.001) incidence of abnormal vaginal bleeding, curettage, hysterectomy, and endometrial cancer. The ratios of occurrence of these events among users compared with non-users were 7.8, 4.9, 6.6 and 7.7. The prevalence of hysterectomy reached 28.2% of users compared with 5.3% of non-users, and endometrial carcinoma developed in 9.9% of users compared with 1.4% of non-users.

Ettinger1998   Ettinger B, Li DK, Klein R. Unexpected vaginal bleeding and associated gynecologic care in postmenopausal women using hormone replacement therapy: comparison of cyclic versus continuous combined schedules. Fertil Steril 1998;69:865-9.

OBJECTIVE: To measure gynecologic resources required to care for women who have unexpected vaginal bleeding while using hormone replacement therapy (HRT). DESIGN: A retrospective cohort study based on review of medical records. SETTING: A large health maintenance organization. PATIENT(S): We studied 284 women using continuous combined HRT and 306 women receiving cyclic HRT. MAIN OUTCOME MEASURE(S): We noted episodes of unexpected vaginal bleeding and associated clinic visits and gynecologic procedures recorded during a mean follow-up period of 2 years. RESULT(S): Among women using cyclic HRT for the first time, 38.3% had or = 1 visit for unexpected bleeding and 12.3% had or = 1 endometrial biopsy. Among women starting continuous combined HRT, 41.6% had or = 1 visit for unexpected bleeding and 20.1% had or = 1 endometrial biopsy. After adjusting for potential confounding variables, we found that recipients of cyclic and continuous combined HRT had similar risks of unexpected bleeding and endometrial biopsy. However, among women continuing HRT for 2 years, those using the continuous combined regimen had somewhat lower rates of unexpected bleeding (22.3 events per 100 patient-years) and endometrial biopsy (10.3 events per 100 patient-years) than those using the cyclic regimen (37.8 episodes of unexpected bleeding per 100 patient-years and 13.9 endometrial biopsies per 100 patient-years). CONCLUSION(S): Unexpected vaginal bleeding and the gynecologic resources required to manage it decreased after 2 years in women using continuous combined HRT but did not decline among those using cyclic HRT.

VandeWeijer1998   Van de Weijer PHM, Barentsen R, Kenemans P. Women’s expectations and acceptance of cyclic induced HRT bleeds. Maturitas 1998;30:257-63.

OBJECTIVES: To assess women’s expectations and acceptance of cyclic induced HRT bleeds before and after their participation in a 1-year study and to compare the impact of these cyclic bleeds with that of previous menstrual bleeds. METHODS: A structured bleeding questionnaire was used to gather information: at baseline (before screening) on previous menstrual cycle patterns and accompanying discomfort, oral contraceptive use, current smoking habits, parity and the acceptance, preferences and expectations regarding HRT-induced bleeds. Women with amenorrhoea of 6 months or more and FSH levels (35 IU/l then received a daily oral dose of 1 mg 17 beta-oestradiol on days 1-28, combined with either 5 or 10 mg dydrogesterone on days 15-28, for 12 months (13 cycles of 28 days). At the end of their participation, women were again interviewed about their actual experiences with HRT-induced bleeds. RESULTS: One hundred and fifty-four women completed the questionnaire at baseline and 141 (including 131 completers) responded at the end. At baseline, 82% indicated to be pleased that menstruation had ceased, but nevertheless 94% stated that return of periods would be acceptable. At the end, 91% still found the occurrence of cyclic bleeds acceptable; this mostly depended on the perceived benefits outweighing the discomfort. Of the women who actually experienced bleeds (101) 60% regarded discomfort and blood loss less than during their previous menstrual cycles. A regular cycle pattern was considered more important than modest flow and short duration. CONCLUSIONS: In contrast to other studies, the acceptance of renewed vaginal bleeds in our study was high.

Greendale1998   Greendale GA, Reboussin BA, Hogan P et al. Symptom relief and side effects of postmenopausal hormones: results from the postmenopausal estrogen/progestin interventions trial. Obstet Gynecol 1998;92:982-8.

OBJECTIVE: To assess pair-wise differences between placebo, estrogen, and each of three estrogen-progestin regimens on selected symptoms. METHODS: This was a 3-year, multicenter, double-blind, placebo-controlled trial in 875 postmenopausal women aged 45-64 years at baseline. Participants were assigned randomly to one of five groups: 1) placebo, 2) daily conjugated equine estrogens, 3) conjugated equine estrogens plus cyclical medroxyprogesterone acetate, 4) conjugated equine estrogens plus daily medroxyprogesterone acetate, and 5) conjugated equine estrogens plus cyclical micronized progesterone. Symptoms were self-reported using a checklist at 1 and 3 years. Factor analysis reduced 52 symptoms to a set of six symptom groups. RESULTS: In intention-to-treat analyses at 1 year, each active treatment demonstrated a marked, statistically significant, protective effect against vasomotor symptoms compared with placebo (odds ratios ORs 0.17-0.28); there was no additional benefit of estrogen-progestin over estrogen alone. Only progestin-containing regimens were significantly associated with higher levels of breast discomfort (OR 1.92-2.27). Compared with placebo, women randomized to conjugated equine estrogens reported no increase in perceived weight. Those randomized to medroxyprogesterone acetate reported less perceived weight gain (OR 0.61-0.69) than placebo. Anxiety, cognitive, and affective symptoms did not differ by treatment assignment. Analyses restricted to adherent women were not materially different than those using intention-to-treat, except that women adherent to medroxyprogesterone acetate and micronized progesterone regimens reported fewer musculoskeletal symptoms (OR 0.62-0.68). CONCLUSION: These results confirm the usefulness of post-menopausal hormone therapy for hot flashes, show convincingly that estrogen plus progestin causes breast discomfort, and demonstrate little influence of postmenopausal hormones on anxiety, cognition, or affect.

A0224a   Marsh MS, Whitcroft S, Whitehead MI, Paradoxical effects of hormone replacement therapy on breast tenderness in postmenopausal women.. Maturitas. 1994 Aug; 19(2): 97-102

We have studied the effect of HRT on breast tenderness in 61 postmenopausal women randomised to oral or transdermal sequential HRT. An untreated reference group of 29 postmenopausal women was studied concurrently. A questionnaire concerning breast tenderness was administered before and after 10, 12 and 24 weeks of treatment (n = 60) and on 3 occasions at 3-month intervals in the reference group (n = 28). In 10 women with frequent tenderness at baseline, HRT resulted in a reduction at 10 weeks (P  0.05), which was maintained at 24 weeks (P  0.05). In contrast, 10 women with infrequent tenderness before treatment reported worsening of tenderness at the 10-week visit (P  0.01 for transdermal, P  0.05 for oral), which was not significantly different from the baseline thereafter. These 10 women were older (P  0.05), and further from the menopause (P  0.05) than the remaining 40 women who did not develop more frequent tenderness. No significant changes occurred in the reference group. HRT may cause transient breast tenderness, especially in older women and those furthest from the menopause. Paradoxically, it may relieve this symptom in women who have breast tenderness prior to treatment. Breast tenderness should not be considered a contraindication to HRT.

A0224b   Marsh MS, Whitcroft S, Whitehead MI, Paradoxical effects of hormone replacement therapy on breast tenderness in postmenopausal women.. Maturitas. 1994 Aug; 19(2): 97-102

We have studied the effect of HRT on breast tenderness in 61 postmenopausal women randomised to oral or transdermal sequential HRT. An untreated reference group of 29 postmenopausal women was studied concurrently. A questionnaire concerning breast tenderness was administered before and after 10, 12 and 24 weeks of treatment (n = 60) and on 3 occasions at 3-month intervals in the reference group (n = 28). In 10 women with frequent tenderness at baseline, HRT resulted in a reduction at 10 weeks (P  0.05), which was maintained at 24 weeks (P  0.05). In contrast, 10 women with infrequent tenderness before treatment reported worsening of tenderness at the 10-week visit (P  0.01 for transdermal, P  0.05 for oral), which was not significantly different from the baseline thereafter. These 10 women were older (P  0.05), and further from the menopause (P  0.05) than the remaining 40 women who did not develop more frequent tenderness. No significant changes occurred in the reference group. HRT may cause transient breast tenderness, especially in older women and those furthest from the menopause. Paradoxically, it may relieve this symptom in women who have breast tenderness prior to treatment. Breast tenderness should not be considered a contraindication to HRT.

A0484   Gambrell Jr., RD. Management of hormone replacement therapy side effects. Menopause 1994;1:67-72

Side effects of hormone replacement therapy (HRT) may keep a significant number of women from continuation of therapy. These include breast tenderness; edema or bloating; premenstrual syndrome (PMS)-like symptoms such as headache, irritability, depression, and lethargy; and withdrawal bleeding. With the many different progestogens and regimens available, therapy should be individualized to meet the patient’s need. Each has its advantages and disadvantages, but it is sometimes possible to eliminate withdrawal bleeding. The continuous combined method of HRT may not be fully endometrium protective because cases of endometrial cancer are beginning to surface. There is increasing evidence that added progestogen may even protect the bones and the breast. When adequate dosages of estrogen are given, there is no adverse effect of HRT on lipids and lipoproteins over the long term. Side effects from added progestogens may be severe in a small percentage of women. However, by adding a mild diuretic, changing the type, dosage, route of administration, or the regimen, usually a progestogen can be found for symptom-free hormone replacement. Key Words: Hormone replacement therapy-Estrogen-Progestogen.

A0725a   Wren BG, The breast and the menopause.. Clin Obstet Gynaecol 1996;10:433-47

Stadberg1996   Stadberg E, Mattson LA, Uvebrant M. 17beta-estradiol and norethisterone acetate in low doses as continuous combined hormone replacement therapy. Maturitas 1996;23:31-9.

OBJECTIVES: To evaluate low doses of 17 beta-estradiol (E2) and norethisterone acetate (NETA) as continuous combined hormone replacement therapy (HRT) in their effects on vasomotor symptoms, bleeding episodes, endometrial histology and mastalgia. METHOD: Sixty postmenopausal women were randomly allocated to three treatment groups and were given 1 mg E2 and 0.25 mg NETA (A), 1 mg E2 and 0.5 mg NETA (B) and 2 mg E2 and 1.0 mg NETA (C) in daily doses. The treatment period was 1 year. RESULTS: A similar statistically significant reduction of climacteric symptoms (P 0.05) was found in all groups. Bleedings, mainly as spottings, occurred most commonly during the first treatment months. Fewer bleeding episodes and a higher percentage of amenorrhea was noted in group B compared to the other groups but did not reach statistical significance. All endometrial biopsies showed atrophy. Women in group A and B had less severe mastalgia (P 0.05) compared to group C, given higher doses of steroids. CONCLUSION: Postmenopausal women taking 1 mg of E2 plus 0.5 mg NETA as continuous combined HRT reported a marked reduction of climacteric complaints and good bleeding control. No endometrial proliferation was detected after 1 year of treatment. This type of therapy may be beneficial especially for elderly women, in whom bleeding may be annoying.

Colacurci1998   Colacurci N, Mele D, De Franciscis P, Costa V, Fortunato N, De Seta l. Effects of tibolone on the breast. Eur J Obstet Gynecol Repr Biol 1998;80:235-8.

OBJECTIVE: to evaluate the effect of hormone replacement therapy and tibolone on the breast. STUDY DESIGN: prospective, controlled, randomized study. SETTING: Outpatient Menopause Clinic of the Second University of Naples. PARTICIPANTS: forty four women in spontaneous menopause without any risk factor for breast cancer were randomly allocated to three groups: 15 patients (group A) were treated with transdermal oestrogens 50 microg, 2 patches/week for 3 weeks per month, plus acetate nomegestrolo per os 5 mg/die for 12 days per cycle, 17 patients (group B) were treated with tibolone 2.5 mg/die. Twelve patients not given any medication represented the control group (group C). METHODS: at the time of recruitment and after at least 12 months of therapy the patients were subjected to a questionnaire aimed at quantifying the slight, moderate or severe presence of the tension/mastodynia symptoms and to a mammographic test to assess the parenchymal pattern according to a quantitative method: type 1 (less than 25% of mammary gland covered by dense tissue), type 2 (from 25% to 75% of total glandular area covered by dense tissue), type 3 (more than 75% of mammary parenchyma covered by dense tissue). Statistical analysis was carried out by means of Fisher’s exact test. RESULTS: after at least 12 months of treatment in Group A 5 out of 15 patients (33%) showed a trend of increase in mammographic density not statistically significant (P=0.22) when compared with group B in which one patient showed a swift from type 1 to type 2 and another from type 2 to type 3. The analysis of tension/mastodynia symptoms revealed a significantly difference between the two groups (P=0.02): in group A mastodynia appeared in three previously asymptomatic women and increased in five women, with a total increase in the symptomatology in 8 out of 15 patients (53.3%), in group B only in one case (5%) mastodynia turned from slight to moderate. CONCLUSION: in postmenopausal women oestroprogestogenic replacement therapy may be associated with an increase in mammographic density and with the onset or increase in mastodynia. On the contrary tibolone does not seem to affect normostructured mammas and may be considered a first-rate replacement therapy in case of mammas showing particular density or benign mastopathies.

A0450   Davis GF, Winter Jr, L. Cumulative irritation study of placebo transdermal estrogen patches. Curr. Therap. Res. 1987; 42: 712

A 21-day cumulative irritation study was performed using primary occlusive patch testing to evaluate the irritation potential of transdermal estrogen patches. Estraderm 0.05 placebo patches, minus the active ingredient of estradiol, were tested against control adhesive patches of comparable size in 55 white women over 40 years of age, who returned twice weekly for reading and reapplication of patches. Test and control patches were applied by fixed (new patch was reapplied over the same site each time and the patch was changed) and rotated (the new patch was applied to a different site each time the patch was changed) methods of application to three different areas of the trunk (i.e., abdomen, lower back, and buttocks) for a total of 12 patch sites per subject. The study was completed by 53 subjects, with a total of 1,908 readings taken for the test patches and 1,908 readings for the control patches. There were no significant differences in the number or severity of the reactions of the test versus control patches. For the estradiol placebo test sites, application to the buttocks produced significantly less irritation than did application to the abdomen and lower back. Further, skin irritation was significantly lower when patches were rotated rather than fixed, irrespective of body area. The authors conclude that application of estradiol patches to the mid-gluteus maximus area of the buttocks and avoiding reapplication directly over the previous site should minimize the incidence and severity of skin irritation.

A0279a   Grodstein F, Colditz GA, Stampfer MJ, Postmenopausal hormone use and cholecystectomy in a large prospective study. Obstet-Gynecol. 1994 Jan; 83(1): 5-11

OBJECTIVE: To examine the association between postmenopausal hormone use and cholecystectomy. METHODS: A prospective cohort study was performed, with follow-up every 2 years. Participants were 54,845 postmenopausal United States nurses, who reported both hormone use and cholecystectomy on mailed questionnaires. RESULTS: Cholecystectomy was reported by 1750 women during 8 years of follow-up. After adjusting for confounding factors, women currently using postmenopausal hormones were at an increased risk of cholecystectomy (relative risk RR 2.1, 95% confidence interval CI 1.9-2.4) compared to never-users. For current users, the risk of cholecystectomy increased with increasing duration of hormone use (RR 2.6, 95% CI 2.2-3.1 for 10 years or more) and higher doses of estrogen (RR 2.4, 95% CI 2.0-2.9 for users of 1.25 mg or more). Although the risk for past hormone users decreased substantially in women who had discontinued use 1-2.9 years ago (RR 1.6, 95% CI 1.2-2.0), a small risk persisted for women who had stopped taking hormones 5 or more years previously (RR 1.3, 95% CI 1.1-1.6). However, after controlling for time since last use, duration of past use had little or no effect on the risk of cholecystectomy (RR 1.4 and RR 1.7 for past users of less than 2 years and 10 or more years’ duration, respectively). CONCLUSION: Women using postmenopausal hormones are at an increased risk of cholecystectomy. Women and their physicians should consider the spectrum of risks and benefits when deciding whether to take hormones.

Mamdani2000b   Mamdani MM, Tu K, Van Walraven C, Austin PC, Naylor CD. Postmenopausal estrogen replacement therapy and increased rates of cholecystectomy and appendectomy. Can Med Ass J 2000;162:1421-4.

BACKGROUND: Several studies have indicated that estrogen may prime inflammatory and nociceptive pathways, leading to symptoms that mimic cholecystitis. We set out to confirm the relation between recent estrogen use and cholecystectomy in postmenopausal women and to test the novel hypothesis that a similar relation exists for appendectomy. METHODS: We developed a retrospective cohort using prescribing and surgical procedure information from health administrative databases for approximately 800,000 female residents of Ontario who were over 65 years of age between July 1, 1993, and Mar. 31, 1998. We compared the incidence of cholecystectomy and appendectomy among women recently prescribed estrogen replacement therapy, levothyroxine and dihydropyridine calcium-channel antagonists (DCCA) using age-adjusted Cox proportional hazards models. Patients were followed for a mean of 540 (standard deviation (SD) 449) days. RESULTS: Compared with women taking DCCA, those who had recently begun taking estrogen were significantly more likely to undergo cholecystectomy (age-adjusted risk ratio (aRR) 1.9, 95% confidence interval (CI) 1.6-2.2) and appendectomy (aRR 1.8, 95% CI 1.1-3.0). No significant difference in either outcome measure was found between the levothyroxine users and the DCCA users. INTERPRETATION: This study identifies an increased risk of cholecystectomy and appendectomy among postmenopausal women who have recently begun estrogen replacement therapy.

A0280a   Van Erpecum KJ, Van Berge Henegouwen GP, Verschoor L, Stoelwinder B, Willekens FL, Different hepatobiliary effects of oral and transdermal estradiol in postmenopausal women.. Gastroenterology. 1991 Feb; 100(2): 482-8

Estrogen-replacement therapy is important for the prevention of postmenopausal osteoporosis. However, oral synthetic and conjugated estrogens increase biliary cholesterol saturation index and risk of gallstone disease. To examine whether transdermal estrogen administration could avoid these adverse effects, 17 postmenopausal women were treated with transdermal estradiol (Estraderm TTS; Ciba-Geigy, Arnhem, The Netherlands), 100 micrograms/day for 4 weeks, and after 1 month without therapy, with oral estradiol (Progynova; Schering, Weesp, The Netherlands), 2 mg/day for 4 weeks. The increase in the serum estradiol level was much higher during transdermal than oral estradiol administration. On the contrary, the increase in the serum estrone level was much more pronounced during oral treatment. Both modes of treatment led to a similar reduction of urinary calcium excretion. A highly significant decrease in serum phosphate levels was found during transdermal therapy. Biliary cholesterol saturation index did not change during transdermal therapy (mean +/- SEM, 1.25 +/- 0.06 before and 1.22 +/- 0.07 at the end of transdermal therapy; P = NS). A slight increase in cholesterol saturation index that did not reach statistical significance was found during oral therapy (1.28 +/- 0.09 before and 1.36 +/- 0.09 during oral treatment). However, the subgroup of women with strong increases in serum estrone levels during oral estradiol therapy (greater than 0.5 pmol/mL; n = 8) generally had increased biliary cholesterol saturation index, a decrease in relative percentage chenodeoxycholic acid in bile, and increased serum sex hormone-binding globulin levels during oral treatment. Cholesterol monohydrate crystals were never found in duodenal biles during either treatment. This study indicates that transdermal estradiol does not induce lithogenic bile. On the contrary, oral estradiol leads to lithogenic bile in a subgroup of women with strong increases in serum estrone levels during oral treatment.

Writinggroup1995   Writing group of the PEPI trial. Effect of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995;273:199-208.

OBJECTIVE-To assess pairwise differences between placebo, unopposed estrogen, and each of three estrogen/progestin regimens on selected heart disease risk factors in healthy postmenopausal women. DESIGN-A 3-year, multicenter, randomized, double-blind, placebo-controlled trial. PARTICIPANTS-A total of 875 healthy postmenopausal women aged 45 to 64 years who had no known contraindication to hormone therapy. INTERVENTION-Participants were randomly assigned in equal numbers to the following groups: (1) placebo; (2) conjugated equine estrogen (CEE), 0.625 mg/d; (3) CEE, 0.625 mg/d plus cyclic medroxyprogesterone acetate (MPA), 10 mg/d for 12 d/mo; (4) CEE, 0.625 mg/d plus consecutive MPA, 2.5 mg/d; or (5) CEE, 0.625 mg/d plus cyclic micronized progesterone (MP), 200 mg/d for 12 d/mo. PRIMARY ENDPOINTS-Four endpoints were chosen to represent four biological systems related to the risk of cardiovascular disease: (1) high-density lipoprotein cholesterol (HDL-C), (2) systolic blood pressure, (3) serum insulin, and (4) fibrinogen. ANALYSIS-Analyses presented are by intention to treat. P values for primary endpoints are adjusted for multiple comparisons; 95% confidence intervals around estimated effects were calculated without this adjustment. RESULTS-Mean changes in HDL-C segregated treatment regimens into three statistically distinct groups: (1) placebo (decrease of 0.03 mmol/L (1.2 mg/dL)); (2) MPA regimens (increases of 0.03 to 0.04 mmol/L (1.2 to 1.6 mg/dL)); and (3) CEE with cyclic MP (increase of 0.11 mmol/L (4.1 mg/dL)) and CEE alone (increase of 0.14 mmol/L (5.6 mg/dL)). Active treatments decreased mean low-density lipoprotein cholesterol (0.37 to 0.46 mmol/L (14.5 to 17.7 mg/dL)) and increased mean triglyceride (0.13 to 0.15 mmol/L (11.4 to 13.7 mg/dL)) compared with placebo. Placebo was associated with a significantly greater increase in mean fibrinogen than any active treatment (0.10 g/L compared with -0.02 to 0.06 g/L); differences among active treatments were not significant. (truncated)

Hulley1998a   Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280-605-13.

CONTEXT: Observational studies have found lower rates of coronary heart disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has not been confirmed in clinical trials. OBJECTIVE: To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease. DESIGN: Randomized, blinded, placebo-controlled secondary prevention trial. SETTING: Outpatient and community settings at 20 US clinical centers. PARTICIPANTS: A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years. INTERVENTION: Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n = 1380) or a placebo of identical appearance (n = 1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end of 3 years. MAIN OUTCOME MEASURES: The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also considered. RESULTS: Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard (RH), 0.99; 95% confidence interval (CI), 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P .001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38). CONCLUSIONS: During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. (truncated)

A0493   Smith RN, Holland EF, Studd JW, The symptomatology of progestogen intolerance.. Maturitas. 1994 Feb; 18(2): 87-91

It is common for women receiving oestrogen replacement therapy to experience adverse symptoms whilst taking cyclical progestogen. This study highlights the similarity of these symptoms to those experienced in pre-menstrual syndrome and confirms that the Moos Menstrual Distress Questionnaire is an appropriate tool for future research. The data also indicate that progestogens vary in the type of symptoms they cause. Norethisterone is more likely to cause symptoms from the Moos pain symptom cluster than either medroxyprogesterone or dydrogesterone, but is less likely to cause negative affect symptom cluster symptoms. The relative levels of oestrogen and progestogen may influence the severity of progestogenic symptoms.

A0481   Lip GY, Beevers M, Churchill D, Beevers DG, Hormone replacement therapy and blood pressure in hypertensive women.. J-Hum-Hypertens. 1994 Jul; 8(7): 491-4

There remains anxiety about the use of hormone replacement therapy (HRT) in postmenopausal women with hypertension. We therefore conducted a prospective open study of sequential changes in BP in 75 women referred to our hypertension clinic who required HRT for amelioration of menopausal symptoms. There were no significant differences in mean systolic or diastolic BPs following the introduction of HRT over a median follow-up time of 14 months (interquartile range 8-32 months), despite a significant rise in mean body weight for individual patients which was statistically significant at three, nine and 12 months following the introduction of HRT. No differences in BP were seen in relation to type of menopause, ethnic origin, history of previous pregnancy-induced hypertension or the type of HRT preparation used. Our data suggest that HRT is safe in hypertensive women who should not therefore be denied this therapy if they have menopausal symptoms, although careful supervision is necessary.

A0717c   Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S, Risk of venous thromboembolism in users of hormone replacement therapy.. Lancet 1996;348:977-80

Background The association between current use of oralcontraceptives and increased risk of venousthromboembolism (VTE) has been firmly established.Although data-sheets for hormone replacement therapy(HRT) carry similar warnings as regards VTE, evidence of anassociation is inconclusive. We carried out a hospital-basedcase-control study to investigate whether current use ofHRT is associated with VTE.Methods We screened all women aged 45-64 years admitted to hospitals in the area of the Oxford RegionalHealth Authority with a suspected diagnosis of VTE betweenFebruary, 1993, and December, 1994. We recruited 81 cases of idiopathic VTE and 146 hospital controls withdisorders of eyes, skin, ears, respiratory and alimentarytracts, kidneys, bones, and joints, and trauma; controls werematched to cases for age-group and date and district ofadmission. To increase the study power, an additional 22cases of idiopathic VTE and 32 hospital controls admittedbefore February, 1993, were recruited retrospectively.Participants were questioned about medical andgynaecological history, use of oral contraceptives and HRT,use of other drugs within the previous 3 months, andlifestyle and socioeconomic characteristics. Detaileddiagnostic data were extracted from the notes of eligiblecases. Matched analyses, adjusted for body-mass index,socioeconomic group, and history of varicose veins, wereundertaken by conditional logistic regression.Findings 44 (42.7%) cases and 44 (24.7%) controls were current users of HRT. The adjusted odds ratio for VTE incurrent users of HRT compared with non-users (never-usersand past users combined) was 3.5 (95% Cl 1.8-7.0;p  0.001). No association was found with past use, and riskappeared to be highest among short-term current users(adjusted likelihood ratio test of trend in odds ratios acrossdifferent durations of current use, p = 0.011).Interpretation Current HRT use is associated with risk ofVTE. The increased risk may be concentrated in new users. The number of extra cases appears to be only about one in5000 users per year. These findings need to be weighedagainst the probable benefits of long-term treatment,including reductions in risks of osteoporotic fracture andcoronary heart disease, and the probable modest increasein risk of breast cancer.

A0718c   Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM, Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens.. Lancet 1996;348:981-3

Background At the request of researchers in the UK, weconducted a case-control study to explore the relationbetween use of postmenopausal oestrogen hormonereplacement therapy (HRT) and idiopathic venousthromboembolism (VTE).Methods The study was based on information derived fromGroup Health Cooperative of Puget Sound for the period1980 to 1994. Women aged 50-74 years admitted tohospital for idiopathic VTE were identified from hospitalrecords. The diagnosis of idiopathic VTE was validated fromthe clinical record. Women who had medical conditionspredisposing to VTE (a history of VTE or cancer, recenttrauma, or surgery) were excluded as cases. Four controlsubjects matched to each case by age, duration ofCooperative membership, and calendar time were identifiedfrom the base population. Various potential risk factorswere recorded based on record review;Findings An initial analysis of 42 cases and 168 matchedcontrols yielded a matched relative ridk estimate of 3.6(95% Cl 1.6-7.8) for current users of oestrogens comparedwith non-users. There was a substantial effect of dailyoestrogen dose. The matched relative risk estimates foroestrogen users of 0.325 mg, 0.625 mg, and 1.25 mg ormore daily were 2.1, 3.3, and 6.9, respectively. Body-massindex was independently associated with the risk of VTE butdid not materially confound the relation of oestrogen andVTE. The absolute risk of idiopathic VTE is estimated to below (0.9x10^-4 woman-years) in non-users of oestrogen; therisk in current users is estimated at 3.2x10^-4 woman-years.Interpretation The risk of idiopathic VTE is about threetimes higher among current users of replacementoestrogens than among non-users. However, the absoluterisk is low for both groups and accounts for only a modestincrease in morbidity.

A0719c   Grodstein F, Stampfer MJ, Goldhaber SZ et al, Prospective study of exogenous hormones and risk of pulmonary embolism in women.. Lancet 1996;348:983-7

Background Current use of oral contraceptives (OCs)consequent pulmonary embolism (PE). Little is knownabout residual effects of past OC use. Furthermore, fewepidemiological studies have assessed the relationbetween postmenopausal use of hormones and thromboticdisease.MethodsIn this prospective study information was obtained through questionnaires sent every 2 years(1976-92) to 112593 women aged 30-55 in 1976. Weexcluded women with previously diagnosed cardiovasculardisease or cancer in 1976 and at the beginning of each subsequent 2-year follow-up period.Findings From self-reports and medical records, wedocumented 123 cases of primary PE (no identifiedantecedent cancer. trauma. surgery, or immobilisation).Current users of postmenopausal hormones had anincreased risk of primary PE (relative risk adjusted formultiple risk factors 2.1 95% Cl 1.2-3.81). However, pastuse showed no relation to PE (1.3 0,7-2.41). In currentusers of OCs the risk of primary PE was about twice that innon-users (2.2 0.8-5.9), but this finding was based ononly five cases who were current OC users. Users of OCs inthe past had no increase in risk of PE (O.8 0.5-1.2).These relations were consistent irrespective of cigarettesmoking status.Interpretation Primary PE was uncommon in this cohort.The risk was increased by current though not past use ofpostmenopausal hormones or OCs.

A0720c   Vandenbroucke JP, Helmerhorst FM, Risk of venous thrombosis with hormone replacement therapy.. Lancet 1996;348:972

A0261a   Neri I, Granella F, Nappi R, Manzoni GC, Facchinetti F, Genazzani AR, Characteristics of headache at menopause: a clinico-epidemiologic study.. Maturitas. 1993 Jul; 17(1): 31-7

The prevalence and characteristics of primary headaches in a large sample of postmenopausal women were investigated. Seventy-six out of 556 women (13.7%) were affected by headache of either the migraine or tension type. In 82% of cases onset had preceded the menopause. The postmenopausal course of headaches with a premenopausal onset differed according to type of headache and type of menopause. Indeed, while migraine improved in almost two-thirds of cases, tension-type headache worsened or did not change in 70% of cases. However, in women who had undergone surgical ovariectomy, the natural course of migraine was worse than in those who had a physiological menopause (P = 0.003). Among the symptoms covered by the Kuppermann Index, only anxiety and insomnia were correlated with headache. The favourable course of migraine in the postmenopausal period can be attributed primarily to the absence of variations in sex hormone levels although psychological factors also seem to play a fundamental role.

A0267a   Somerville BW, The role of estradiol withdrawal in the etiology of menstrual migraine.. Neurology. 1972 Apr; 22(4): 355-65