Clinical and personal relationships between oral contraceptive and hormone replacement therapy use among US women physicians

OBJECTIVE: To examine relationships between a history of oral contraceptive (OC) use and current use of or intention to use hormone replacement therapy (HRT). DESIGN: The Women Physicians' Health Study examined a stratified random sample of US women MDs, aged 30 to 70 years (4,501 respondents; a 59% response rate). RESULTS: Among postmenopausal physicians who previously used OCs, current HRT use was significantly associated ( < 0.05) with being younger, living somewhere besides the East Coast, being sexually active, being an obstetrician/gynecologist, having no history of breast cancer, having a longer use of OCs, and being posthysterectomy. Among premenopausal physicians, intended future HRT use was significantly associated with being white, being an obstetrician/gynecologist, being in good health, living somewhere besides the East Coast, being a longer user of OCs, and having more extensive, recent continuing medical education. Among women who had taken both OCs and HRT, there were no significantly elevated rates in any of the 15 health conditions we examined (after controlling for family history). Postmenopausal physicians who took HRT (and premenopausal OC-using physicians intending to take HRT) were significantly more likely to counsel their patients on HRT use. Among post-OC HRT-users, 44% counseled their postmenopausal female patients on HRT at least yearly versus 22% of post-OC HRT-nonusers (74% v 45% among such primary care physicians). CONCLUSIONS: Physicians' personal OC/HRT use may strongly affect their patient counseling practices. HRT use after OC use was not associated with any obvious increases in examined diseases in this population.     

Impact of hormone replacement therapy on endogenous estradiol metabolism in postmenopausal women

OBJECTIVES: Changes in estradiol metabolism may play a role in the pathophysiology of different diseases, of special interest being an increase in D-ring over A-ring metabolites for the risk of breast cancer. In the present work we investigated the effect of exogenous estradiol therapy on endogenous estradiol metabolism in postmenopausal women. METHODS: Three different studies were carried out in 126 women: in study A the women were treated for 4 weeks either with oral or with transdermal 17beta-estradiol, in study B for 4 weeks with oral or transdermal 17beta-estradiol sequentially combined with oral or transdermal norethisterone acetate, and in study C for 12 weeks either with oral 17beta-estradiol or with an oral continuous combination of 17beta-estradiol with the new progestin dienogest. As main representatives of the A- and D-ring metabolism, 2-hydroxyestrone (2-OHE1) and 16 alpha-hydroxyestrone (16-OHE1), respectively, were measured in 8 h night urine using enzyme immunoassay technique. RESULTS: Oral estradiol treatment resulted in a significant higher excretion of estradiol metabolites compared to transdermal treatment. Neither oral nor transdermal estradiol induced a significant change in the ratio of 16-OHE1 to 2-OHE1. The addition of oral or transdermal norethisterone acetate to estradiol did not alter on average the endogenous estradiol metabolism, although in individual patients a significant increase in 16-OHE1 metabolism was observed only with oral norethisterone. The continuous oral addition of dienogest did not lead to any significant change in estradiol metabolism. CONCLUSIONS: These results indicate that oral estradiol replacement therapy enhances the quantity of circulating estradiol metabolites. This may have a more negative impact on estrogenic target cells as compared to transdermal application. Progestin addition to estradiol replacement therapy seems to have no major impact on endogenous estradiol metabolism. Further studies, however, are necessary to evaluate the progestin effect in possible pre-disposed patients.     

Lidocaine pharmacokinetics in postmenopausal women on hormone therapy

OBJECTIVE: The study was designed to evaluate the effect of hormone therapy (HT) preparations containing 17beta-estradiol and micronized progesterone administered orally and transdermally on the pharmacokinetics of lidocaine, a probe drug that is metabolized by liver oxidative pathways involving cytochrome P-450 1A2 and 3A4 (CYP1A2 and CYP3A4). DESIGN: The study was carried out in 18 postmenopausal women divided into two groups administered HT for 6 months: group 1, 17beta-estradiol (orally) and micronized progesterone sublingually; and group 2, 17beta-estradiol (transdermally) and micronized progesterone sublingually. Pharmacokinetic study with intravenous lidocaine (1 mg/kg) and blood sampling during 360 minutes from injection was performed before the HT initiation and after 3 and 6 months of HT. RESULTS: Pharmacokinetic parameters of lidocaine demonstrated accelerated drug elimination in women on oral HT after 3 months. A significant reduction of area under the curve by 15.0% (P < 0.05), shortening of t(1/2) by 15.2% (P < 0.05), increase of lambda(z) by 10.0% (P < 0.05), and Cl/BW by 14.3% (P < 0.05) were observed. In contrast, transdermal administration of HT did not influence pharmacokinetic parameters of the drug. The effects of oral HT were not seen 6 months after the start of HT. CONCLUSION: HT can influence the pharmacokinetics of lidocaine, ie, its hepatic metabolism, through CYP3A4 and CYP1A2. The effect depends on the route of administration and therapy duration.     

Hemostatic markers in healthy postmenopausal women during intranasal and oral hormone therapy: a randomized trial

OBJECTIVE: To study changes in the hemostatic balance during intranasal compared with oral administration of 17beta-estradiol (E2) and norethisterone (NET) or NET acetate in postmenopausal women. A wide range of markers of coagulation and fibrinolysis associated with coronary artery disease was tested. DESIGN: In a two-center, randomized, double-blind, comparative trial, 90 healthy postmenopausal women (aged 56.6 +/- 4.7 y) received daily continuous combined hormone therapy, either E2/NET 175 microg/275 mug intranasally as a spray (n = 47) or E2/NET acetate 1 mg/0.5 mg orally as a capsule (n = 43) for 1 year. Hemostatic markers were measured in blood samples taken at baseline and after 12, 24, and 52 weeks of treatment. RESULTS: After 52 weeks of treatment, changes in the intranasal group in markers of coagulation-fibrinogen (-1.3%), factor VII activity (-14.0%), and prothrombin fragment 1 + 2 (+5.8%)-were significantly less (P < 0.05) than the changes in the oral group for these parameters (-6.5%, -20.3%, and +19.0%, respectively). Changes in activated factor VII did not differ between the groups. Neither group showed significant changes in thrombin-antithrombin complex. In the intranasal group, decreases in markers of fibrinolysis-tissue-type plasminogen activator (-10.4%) and plasminogen activator inhibitor-1 antigen (-13.8%)-were significantly less (P < 0.05) than the decreases in the oral group (-17.8% and -38.0%, respectively). A decrease in plasminogen activator inhibitor-1 activity and increases in D-dimer and plasmin-alpha2-antiplasmin complex did not differ between the groups. No differences were found between the groups in homocysteine, which overall was unaltered in both groups. CONCLUSIONS: During intranasal E2/NET therapy, changes in the coagulatory and fibrinolytic markers were to some extent less than those observed during oral therapy.     

Vaginal microflora in postmenopausal women on hormone replacement therapy

To study the spectrum of vaginal microflora in postmenopausal women on hormone replacement therapy (HRT) and to compare the efficacy of Papanicolaou (Pap) smears with other methods for their detection. Eighty postmenopausal women were recruited for the study. These included 40 women who had attained spontaneous and were on HRT (User 1); 20 hysterectomised women on only estrogen therapy (User 2) and 20 controls (Non users). Their clinical data was recorded and specimens were collected for vaginal cultures (for aerobic bacteria and fungi), vaginal pH, Gram stain and Pap stain on cervical-vaginal smears and toluidine blue on wet smears. Vaginal pH was significantly lower in Users as compared to Non users. Lactobacilli and Gardnerella were more frequently isolated from Users while Bacteroides and E. coli were more common in Non users. Cultures were significantly more sensitive than Gram stained direct vaginal smears in detection of aerobic bacteria; however, Candida could be detected on Gram stain alone in all the cases. Frequency of detection of organisms significantly improved by application of Gram stain to the cervico-vaginal smears. However, clinically relevant organisms like Candida, Gardnerella and Mobiluncus could be identified on Pap smears alone in >50% cases. Lactobacilli could be readily identified in Pap smears in 98% cases. Wet mounts could detect cocci more easily as compared to Pap smears. Altered vaginal microbial profile in post menopausal women receiving HRT may cause bacterial and fungal vaginitis. Although culture studies remain the gold standard to detect these microorganisms, Pap and Gram stains and wet smears provide useful supplements and may be used as alternative procedures especially in resource limited settings lacking adequate culture facilities.     

Effects of transdermal and oral postmenopausal hormone therapy on vascular function: a randomized, placebo-controlled study in healthy postmenopausal women

OBJECTIVE: To compare the effect of transdermal and oral estrogen therapy, the latter with or without the addition of gestodene, on plasma concentrations of markers of endothelial function and on ultrasonographic parameters of vascular function in healthy postmenopausal women. DESIGN: In a 15-month, randomized, double-blind, placebo-controlled study, 152 healthy hysterectomized postmenopausal women received daily doses of placebo (n = 49), 50 microg of transdermal 17ss-estradiol (tE2, n = 33), 1 mg of oral E2 (oE2, n = 37), or 1 mg of oral estradiol combined with 25 microg of gestodene (oE2+ G, n = 33) for 13 cycles of 28 days, followed by four washout cycles with placebo in each group. At baseline and in cycles 4, 13, and 17, we measured plasma levels of endothelial markers and ultrasonographic markers of vascular function (pulsatility index [PI] and, at baseline and cycle 13, arterial stiffness). RESULTS: Compared with placebo, we found reductions in soluble vascular cell adhesion molecule (oE2, P < 0.01; oE2+ G, P < 0.001), sE-selectin (oE2 + G, P < 0.05), von Willebrand factor (tE2, P < 0.05), and divergent effects in PI and stiffness parameters in the carotid artery. We found no effect on PI in the retinal and femoral arteries, or on stiffness parameters in the femoral and brachial artery. CONCLUSIONS: Oral hormone therapy reduced plasma levels of adhesion molecules, whereas transdermal estrogen therapy reduced von Willebrand factor. Effects on ultrasonographic parameters of vascular function in the carotid artery were inconclusive.     

The association between hormone therapy use and changes in strength and body composition in early postmenopausal women

OBJECTIVE: To prospectively examine potential differences in upper- and lower-body muscle strength, lower-body power, lean muscle mass, total body fat, intra-abdominal fat, and energy expenditure (METS) variables in early postmenopausal women. Measurements were taken at baseline and 12 months. DESIGN: Prospective, 1-year non-randomized [self-selected hormone therapy (HT) and non-HT-replaced], longitudinal study with participation from 136 normally active, early [14.2 +/- 9.8 mo past menopause (51.1 +/- 3.0 y) mean age +/- SD] postmenopausal women. Total body fat mass, lean mass, and bone mass were assessed by dual-energy x-ray absorptiometry (Hologic), METS (6-mo activity recall questionnaire) upper- and lower-body peak force by isokinetic dynamometry (KinCom 500H, Chattex Corp.), and leg power by the Bassey Power Rig (Nottingham, UK). RESULTS: We observed no significant differences in central adipose tissue, total fat mass, lean muscle mass, strength, or lower limb power. However, estrogen did promote a maintenance affect in bone mineral density at the spine and total hip and an increase in greater trochanter bone mineral density (P < 0.01) in the estrogen-replaced group. CONCLUSION: Our findings suggest that HT does not play a role in either increasing or maintaining strength, lean muscle mass, lower limb power, or the attenuation of increases in total body or abdominal fat, at least in this group of postmenopausal women during the initial years of menopause     

Estrogens,hormone therapy,and hippocampal volume in postmenopausal women

The brain atrophies in late life. However, there are many factors that either magnify or mitigate the rate of atrophy. Loss of estrogens during menopause and administration of hormone therapy have both been hypothesized as sources of individual variation in the prevalence of cortical and subcortical atrophy and loss of cognitive function in late adulthood. In this review we critically summarize and assess the extant rodent and human neuroimaging studies that examine the link between estrogens and hippocampal morphology and function and focus predominantly on human studies of the hippocampus in postmenopausal women. Several cross-sectional studies report that the size of the hippocampus is larger in women receiving hormone therapy while several other cross-sectional studies report either negligible effects or smaller volumes in women receiving hormone therapy. We suggest that these differences might be caused by the variation between studies in the age of the samples studied, the duration of therapy, and the age at which hormone therapy is initiated. Unfortunately, all of the human studies reviewed here are cross-sectional in nature. With the lack of well-controlled randomized trials with neuroimaging measures on postmenopausal women both before and after some exposure interval, the effect of hormone therapy on hippocampal atrophy will remain equivocal and poorly understood.     

Endometrial bleeding in postmenopausal women: with and without hormone therapy

The aim of this study was to present a review of the potential mechanisms involved in the occurrence of endometrial bleeding in postmenopausal women using hormone therapy. Selected literature on the incidence of bleeding in postmenopausal women using estrogen progestogen therapy was reviewed. The incidence of spotting and bleeding in women using continuous-combined hormone therapy was presented. Relevant articles related to the role of angiogenic factors and vasculogenesis in the endometrium, endometrial leukocytes, and endometrial metalloproteinases were used for the review. The cause or etiology of endometrial bleeding with hormone therapy is unknown. Several options are known to alter angiogenesis or be involved in tissue remodeling during normal menstruation. Vascular endothelial growth factor and thrombospondin-1 are proangiogenic and antiangiogenic factors that could cause dysfunction in vasculogenesis that could result in blood vessel fragility and bleeding. The role of pericytes in maintaining vessel morphology and integrity is discussed. Endometrial leukocytes and metalloproteinases are involved in normal menstruation, but their role in postmenopausal bleeding is not clear suggesting involvement of mechanisms in the bleeding. There is limited information on clinical investigation into the etiology of postmenopausal bleeding associated with hormone therapy. The major cause of hormone therapy-related bleeding is unknown. Alterations in angiogenic factors that could result in vascular dysfunction and vessel breakdown provide a working hypothesis as to the potential cause of vessel breakdown.     

Ultra low-dose hormone replacement therapy and bone protection in postmenopausal women

OBJECTIVES: The aim of the present study was to evaluate the effects of low doses of hormone replacement therapy (HRT) in normal young postmenopausal women. METHODS: In an open trial healthy, non-obese postmenopausal women received for 2 years a low-dose continuous combined HRT (LD-HRT) containing 1mg estradiol+0.5 mg norethisterone acetate each pill for 28 days, or 0.5 mg of 17beta-estradiol and 0.25 mg of norethisterone acetate (Ultra low dose, Ultra-LD-HRT) along with 1000 mg of calcium per day. Control group consisted of women receiving only 1000 mg of calcium per day, for 2 years. Menopausal symptoms were evaluated by the Green climacteric scale for the first 12 weeks of the study while bleeding profiles, bone mineral density (BMD) and bone turnover were assessed for 24 months. RESULTS: LD-HRT and Ultra-LD-HRT were effective in reducing menopausal clinical symptoms. In the control group, BMD significantly (P<0.05) decreased at the spine (-2.8+/-0.2%), and femoral neck (-2.8+/-0.7%). In LD-HRT treated group BMD showed a significant (P<0.05) increase at the spine (5.2+/-0.7%), and femoral neck (2.8+/-0.4%) after 24 months. In the Ultra-LD-HRT treated women spine and femoral neck BMD showed a significant (P<0.05) increase (2.0+/-0.3 and 1.8+/-0.3%, respectively) after 24 months. In these women treated with LD-HRT and Ultra-LD-HRT the BMD values were significantly (P<0.05) different from those measured in calcium-treated women. CONCLUSIONS: LD-HRT and Ultra-LD-HRT can alleviate subjective symptoms providing an effective protection against the postmenopausal decrease of BMD.     

Anticardiolipin antibodies during hormone replacement therapy in healthy postmenopausal women

Objective: The aim of the study was to investigate IgG and IgM anticardiolipin (aCL) antibodies in the course of hormone replacement therapy (HRT).

Subjects and methods: Thirty clinically healthy postmenopausal women with no history of previous thrombotic events or autoimmune disease were divided in two groups: control group (n=12, mean age 52.9±4.5 years, and 6.2±3.6 years duration of amenorrhea) and a second group (n=18, mean age 53.6±3.5 years, and 5.7±4.5 years of amenorrhea) who were allocated to HRT, containing 2 mg 17-beta estradiol plus 1 mg norethisterone acetate daily for 6 months. ACL antibodies of IgG and IgM isotype were assessed using ELISA and the Kupperman menopausal index (KI) was calculated at baseline and after 3 and 6 months of treatment. Results: HRT had a beneficial effect on climacteric symptoms, evaluated by KI (baseline versus 3rd month and 3rd month versus 6th month, P<0.001). The KI did not change in the control group. The values of IgG at the three studied periods did not change significantly and were 14.1±4.2, 13.1±4.9 and 13.4±3.7 in the HRT group and 12.7±3.1, 13.7±1.8 and 13.1±3.8 GPL, respectively, in the control group. IgM aCL antibodies increased during HRT and were as follows: 7.7±4.8 at baseline, 12.9±5.6 at 3rd month and 9.3±3.2 MPL at 6th month. In the control group, IgM were 8.0±2.8; 7.9±2.3 and 7.1±2.3 MPL, respectively. The differences between the two groups were significant at the third and the 6th month (P<0.01 and P<0.05). Conclusion: These data suggest that HRT is associated with elevation of IgM ACA in healthy postmenopausal women. As IgG aACA are considered more pathogenic, it seems unlikely that the early prothrombogenic effects of HRT can be assigned to ACA.     

Progestogens and venous thromboembolism among postmenopausal women using hormone therapy

Hormone therapy (HT) is the most effective treatment for correcting menopausal symptoms after menopause. HT initially consisted of estrogens alone and progestogens were secondly added to estrogens for preventing the risk of endometrial cancer associated to estrogens use. Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is a major harmful effect of HT. It is now well known that oral and transdermal estrogens are differentially associated with VTE risk but progestogens may be another important determinant of the thrombotic risk among HT users. Both randomized controlled trials and meta-analysis of observational studies suggested that the VTE risk was higher among users of estrogens plus progestogens than among users of estrogens alone. With respect to the different pharmacological classes of progestogens, there is evidence for a deleterious effect of medroxyprogesterone acetate on VTE risk. In addition, observational studies showed that norpregnane derivatives were significantly associated with an increased VTE risk whereas micronized progesterone could be safe with respect to thrombotic risk. The effect of tibolone on VTE risk remains uncertain. In conclusion, progestogens may have differential effects on VTE risk according to the molecules and therefore represent an important potential determinant of the thrombotic risk among postmenopausal women using estrogens.     

Depression and endogenous melatonin in postmenopausal women

BACKGROUND: Previous reports on melatonin secretion in depression are numerous but conflicting. There are very few studies relating the duration of the nocturnal melatonin peak to depression, and the results of those studies have been equivocal. METHODS: We studied mood disorders and urinary melatonin excretion in 382 postmenopausal women. Psychiatric diagnoses and global assessment of functioning (GAF) scores were determined based on a Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). Urinary 6-sulfatoxymelatonin (6-SMT) samples were collected for two 24-h periods at home. RESULTS: A positive family history of depression was significantly related to a longer duration of 6-SMT excretion. There were marginally significant associations between current major depression and delayed offset of 6-SMT excretion and between later acrophase and lifetime major depression, even with control for age, ethnicity, season, and several medications. LIMITATIONS: The subjects were studied in their home environments, where light effects were not controlled. Data were restricted to postmenopausal women, including a limited number of subjects with current major depression. CONCLUSIONS: These results suggest that there might be a familial vulnerability in the endogenous melatonin signal in subjects prone to depression, and an abnormality in the duration of the melatonin signal in those with current major depression.     

Influence of oral contraceptive use on bone density in climacteric women

The aim of the study was to investigate the influence of long-term administration of oral contraceptives on bone density in climacteric women. The existence of a correlation between long-term use and bone density was confirmed.     

Sleep deprivation, cognitive performance, and hormone therapy in postmenopausal women

OBJECTIVE: To study the effects of sleep deprivation on cognitive performance in postmenopausal women and to evaluate whether hormone therapy (HT) has a modifying effect on coping. DESIGN: Twenty-six postmenopausal women, aged 58 to 72 years (mean 64 years), volunteered for the study (HT users, n = 16; nonusers, n = 10). They spent four consecutive nights in the sleep laboratory. The cognitive tests were performed three times: after the baseline night, after one night of sleep deprivation, and after the rebound night. The cognitive measures included visual episodic memory, visuomotor performance, verbal attention, and shared attention. RESULTS: The practice effect typically occurring in cognitive tests was blunted during sleep deprivation, which indicated deterioration of performance. At rebound, performance improved in visual episodic memory (immediate recall P < 0.01; delayed recall P < 0.05), visuomotor performance (P < 0.001), verbal attention (P < 0.0001), and shared attention (P < 0.05). HT users performed better than nonusers in the visual episodic memory test (P < 0.05) and in one of three subtests of shared attention (cancellation P = 0.040). Otherwise hormone therapy did not influence the results. CONCLUSIONS: In postmenopausal women, sleep deprivation impaired visual functions and attention. However, this effect was not prolonged because after one rebound night the performance was improved, compared with baseline. Hormone therapy did not modify the cognitive performance during sleep deprivation.