Projected Implications of Overturning Roe v Wade on Abortion Training in U.S. Obstetrics and Gynecology Residency Programs.

In June 2022, the U.S. Supreme Court is expected to issue a decision on Dobbs v Jackson Women's Health Organization, a direct challenge to Roe v Wade. A detailed policy analysis by the Guttmacher Institute projects that, if Roe v Wade is overturned, 21 states are certain to ban abortion and five states are likely to ban abortion. The Accreditation Council for Graduate Medical Education requires access to abortion training for all obstetrics and gynecology residency programs. We performed a comprehensive study of all accredited U.S. obstetrics and gynecology residency programs to assess how many of these programs and trainees are currently located in states projected to ban abortion if Roe v Wade is overturned. We found that, of 286 accredited obstetrics and gynecology residency programs with current residents, 128 (44.8%) are in states certain or likely to ban abortion if Roe v Wade is overturned. Therefore, of 6,007 current obstetrics and gynecology residents, 2,638 (43.9%) are certain or likely to lack access to in-state abortion training. Preparation for the reversal of Roe v Wade should include not only a recognition of the negative effects on patient access to abortion care in affected states, but also of the dramatic implications for obstetrics and gynecology residency training.

The potential use of lactate blockers for the prevention of COVID-19 worst outcome, insights from exercise immunology.

Following the decline in Physical Activity (PA) due to COVID-19 restrictions in the form of government mandated lockdowns and closures of public spaces, the modulatory effect of physical exercise on immunity is being heavily revisited. In an attempt to comprehend the wide discrepancy in patient response to COVID-19 and the factors that potentially modulate it, we summarize the findings relating PA to inflammation and immunity. A distinction is drawn between moderate intensity and high intensity physical exercise based on the high lactate production observed in the latter. We hypothesize that, the lactate production associated with high intensity anaerobic exercise is implicated in the modulation of several components of the innate and adaptive immunity. In this review, we also summarize these immunomodulatory effects of lactate. These include increasing serum IL-6 levels, the main mediator of cytokine storms, as well as affecting NK cells, Macrophages, Dendritic cells and cytotoxic T-lymphocytes. The implications of high lactate levels in athletic performance are highlighted where athletes should undergo endurance training to increase VO2 max and minimize lactate production. Tumor models of hypoxia were also reported where lactate levels are elevated leading to increased invasiveness and angiogenesis. Accordingly, the novel lactate blocking strategy employed in cancer treatment is evaluated for its potential benefit in COVID-19 in addition to the readily available beta-blockers as an antagonist to lactate. Finally, we suggest the diagnostic/prognostic purpose of the elevated lactate levels that can be determined through sweat lactate testing. It is the detrimental effect of lactate on immunity and its presence in sweat that qualify it to be used as a potential non-invasive marker of poor COVID-19 outcome.

Possible molecular and paracrine involvement underlying the pathogenesis of COVID-19 cardiovascular complications.

Coronavirus disease 2019 (COVID-19) has been declared a pandemic on 11 March 2020 by the WHO. Despite being mainly a respiratory virus, cardiac complications have been described. These range from sudden cardiac death to subtle diastolic dysfunction after recovery from COVID-19. The commonest cardiac presentation to date is acute heart failure resulting from biventricular or left ventricular hypokinesis and elevation of cardiac troponins. It has been shown that COVID-19 downregulates angiotensin-converting enzyme-2, which has protective effects on the endothelium and cardiomyocytes. It has also been proven that COVID-19 induces a state of hypercytokinaemia, some cytokines such as interleukin-1 and interleukin-6 have an injurious effect on the myocardium and endothelium, respectively. Such pathogenic mechanisms might play a crucial role in induction of cardiomyocyte injury and impaired myocardial perfusion probably through coronary endothelial dysfunction. The understanding and linking of such mechanisms might help in tailoring drug repurposing for treatment or prophylaxis of COVID-19 cardiovascular complications.

Common variations in the genes encoding C-reactive protein, tumor necrosis factor-alpha, and interleukin-6, and the risk of clinical diabetes in the Women's Health Initiative Observational Study.

BACKGROUND: Circulating concentrations of high-sensitivity C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) have been associated with an increased risk of diabetes. METHODS: To examine the roles of genetic variation in the genes encoding CRP, TNF- α, and IL-6 in the development of diabetes, we conducted a prospective case-control study nested within the Women's Health Initiative Observational Study. We followed 82 069 postmenopausal women (50-79 years of age) with no history of diabetes for incident diabetes for a mean follow-up of 5.5 years. We identified 1584 cases and matched them with 2198 controls with respect to age, ethnicity, clinical center, time of blood draw, and length of follow-up. We genotyped 13 haplotype-tagging single-nucleotide polymorphisms (tSNPs) across 2.3 kb of the CRP (C-reactive protein, pentraxin-related) gene, 16 tSNPs across 2.8 kb of the TNF (tumor necrosis factor) gene, and 14 tSNPs across 4.8 kb of the IL6 [interleukin 6 (interferon, beta 2)] gene. Plasma concentrations of TNF-α receptor 2 (TNF-α-R2) and IL-6 were measured. RESULTS: After adjusting for matching factors, confounding variables, and multiple comparisons, we found 8 variants in the TNF gene to be associated with plasma TNF-α-R2 concentrations in white women (q < 0.05). After adjusting for multiple comparisons (q > 0.05), we found no association of any IL6 gene variant with plasma IL-6 concentration, nor did we find any significant associations between any SNPs among these 3 genes and diabetes risk (q > 0.05). CONCLUSIONS: We found modest associations between TNF variants and circulating concentrations of TNF-α-R2. Common variants of the CRP, TNF, and IL6 genes were not significantly associated with risk of clinical diabetes in postmenopausal women.

Relations of dietary magnesium intake to biomarkers of inflammation and endothelial dysfunction in an ethnically diverse cohort of postmenopausal women.

OBJECTIVE: Although magnesium may favorably affect metabolic outcomes, few studies have investigated the role of magnesium intake in systemic inflammation and endothelial dysfunction in humans. RESEARCH DESIGN AND METHODS: Among 3,713 postmenopausal women aged 50-79 years in the Women's Health Initiative Observational Study and free of cardiovascular disease, cancer, and diabetes at baseline, we measured plasma concentrations of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), turnor necrosis factor-alpha receptor 2 (TNF-alpha-R2), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and E-selectin. Magnesium intake was assessed using a semiquantitative food frequency questionnaire. RESULTS: After adjustment for age, ethnicity, clinical center, time of blood draw, smoking, alcohol, physical activity, energy intake, BMI, and diabetes status, magnesium intake was inversely associated with hs-CRP (P for linear trend = 0.003), IL-6 (P < 0.0001), TNF-alpha-R2 (P = 0.0006), and sVCAM-1 (P = 0.06). Similar findings remained after further adjustment for dietary fiber, fruit, vegetables, folate, and saturated and trans fat intake. Multivariable-adjusted geometric means across increasing quintiles of magnesium intake were 3.08, 2.63, 2.31, 2.53, and 2.16 mg/l for hs-CRP (P = 0.005); 2.91, 2.63, 2.45, 2.27, and 2.26 pg/ml for IL-6 (P = 0.0005); and 707, 681, 673, 671, and 656 ng/ml for sVCAM-1 (P = 0.04). An increase of 100 mg/day magnesium was inversely associated with hs-CRP (-0.23 mg/l +/- 0.07; P = 0.002), IL-6 (-0.14 +/- 0.05 pg/ml; P = 0.004), TNF-alpha-R2 (-0.04 +/- 0.02 pg/ml; P = 0.06), and sVCAM-1 (-0.04 +/- 0.02 ng/ml; P = 0.07). No significant ethnic differences were observed. CONCLUSIONS: High magnesium intake is associated with lower concentrations of certain markers of systemic inflammation and endothelial dysfunction in postmenopausal women.

Relation of genetic variation in the gene coding for C-reactive protein with its plasma protein concentrations: findings from the Women's Health Initiative Observational Cohort.

BACKGROUND: Although common genetic variants of the CRP gene (C-reactive protein, pentraxin related) have been associated with plasma concentrations of high-sensitivity CRP (hsCRP) in several cohorts of European Americans, relatively few studies have comprehensively assessed this association in well-characterized multiethnic populations. METHODS: In a case-control study of diabetes nested in the Women's Health Initiative Observational Cohort, we comprehensively evaluated the association of genetic variation in CRP with plasma hsCRP concentrations. Thirteen haplotype-tagging single-nucleotide polymorphisms (tSNPs) were identified and subsequently genotyped in 3782 postmenopausal women. RESULTS: The allele frequencies for these tSNPs and the haplotype blocks defined by these tSNPs varied significantly by ethnic group (P < 0.0001). Consistent with prior studies of whites, rs3093068, rs1130864, and rs1417938 were significantly associated with higher hsCRP concentrations (geometric-mean increase per minor-allele change, 1.20-1.25 mg/L), and rs1205 and rs1800947 were significantly associated with lower hsCRP values (decrease of 1.28-1.48 mg/L). The associations with rs3093068 and rs1205 appeared to be stronger in Asians/Pacific Islanders than in whites (geometric-mean increase, 1.65 mg/L vs 1.25 mg/L, respectively). Minor alleles at rs3093075 and rs3093059 were associated with substantially increased hsCRP concentrations, whereas rs1800947 was associated with lower hsCRP values. All haplotype-based association results tended to be consistent with the associations seen with single CRP SNPs. CONCLUSIONS: Our large multiethnic case-control study of postmenopausal women provides evidence that common genetic variants in the CRP gene are substantially associated with plasma hsCRP concentrations in this case-control subcohort. The data also suggest ethnic variations in these associations.

Serum levels of soluble vascular cell adhesion molecule-1, tumor necrosis factor-alpha, and interleukin-6 in in vitro fertilization cycles.

OBJECTIVE: To assess whether gonadotropin-induced changes in E(2) alter serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) and proinflammatory cytokines. DESIGN: Prospective collection of serum in patients undergoing IVF. SETTING: University hospital. PATIENT(S): Twenty-four infertile women. INTERVENTION(S): Serum collection at baseline, in the mid and late follicular phases, at oocyte retrieval, and in the mid and late luteal phases. MAIN OUTCOME MEASURE(S): Samples were assayed for sVCAM-1, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and E(2). RESULT(S): The VCAM-1 was maximally suppressed in the luteal phase. Luteal sVCAM-1 levels correlated [1] positively with the patient's age, units of gonadotropins, day 3 FSH levels and [2] negatively with [a] the follicular, retrieval, and luteal E(2) levels and [b] the number of preovulatory follicles and oocytes retrieved. Similar correlations were noted in the late luteal phase. Serum TNF-alpha reached a peak in the mid-follicular phase and a nadir in the luteal phase. The TNF-alpha levels at retrieval correlated [1] positively with the patient's age and [2] negatively with E(2) and number of preovulatory follicles and retrieved oocytes. The IL-6 levels were suppressed in the follicular phase and correlated negatively with E(2) levels. CONCLUSION(S): Changes in E(2) levels seen during gonadotropin stimulation significantly alter VCAM-1 expression and induce changes in serum IL-6 and TNF-alpha levels.

FTO polymorphisms are associated with obesity but not diabetes risk in postmenopausal women.

The FTO gene was recently identified as a susceptibility locus for both obesity and type 2 diabetes by whole-genome association analyses of several European populations. We tested for an association between FTO risk alleles and obesity and diabetes in a well-characterized multiethnic cohort of postmenopausal women in the United States. We genotyped two most significantly associated single-nucleotide polymorphisms (SNPs) (rs9939609 and rs8050136) in intron 1 of FTO gene in a nested case-control study of 1,517 diabetes cases and 2,123 controls from the Women's Health Initiative-Observational Study (WHI-OS). The allelic frequencies of either rs9939609 or rs8050136 differed widely across four ethnic groups. The frequency of the rare allele A of rs9939609 among controls was much lower in Asians/Pacific Islanders (17%) than in blacks (45%), whites (40%), and Hispanics (31%). We found significant associations of rs9939609 with BMI and waist circumference in white and Hispanic women, but not among black and Asian/Pacific Islander women. On average, each copy of the risk-allele A at rs9939609 was significantly associated with 0.45 kg/m(2) increase in BMI (95% confidence interval (CI): 0.16-0.74; P = 0.004) and 0.97 cm increase in waist circumference (95% CI: 0.21-0.65; P = 0.0002). Similar results were observed for rs8050136. However, we found no significant genetic associations with diabetes risk, either within the full study sample or in any ethnic group. In conclusion, common genetic variants in the intron 1 of FTO gene may confer a modest susceptibility to obesity in an ethnicity-specific manner, but may be unlikely to contribute to a clinically significant diabetes risk.

Estrogen therapy and coronary-artery calcification.

BACKGROUND: Calcified plaque in the coronary arteries is a marker for atheromatous-plaque burden and is predictive of future risk of cardiovascular events. We examined the relationship between estrogen therapy and coronary-artery calcium in the context of a randomized clinical trial. METHODS: In our ancillary substudy of the Women's Health Initiative trial of conjugated equine estrogens (0.625 mg per day) as compared with placebo in women who had undergone hysterectomy, we performed computed tomography of the heart in 1064 women aged 50 to 59 years at randomization. Imaging was conducted at 28 of 40 centers after a mean of 7.4 years of treatment and 1.3 years after the trial was completed (8.7 years after randomization). Coronary-artery calcium (or Agatston) scores were measured at a central reading center without knowledge of randomization status. RESULTS: The mean coronary-artery calcium score after trial completion was lower among women receiving estrogen (83.1) than among those receiving placebo (123.1) (P=0.02 by rank test). After adjustment for coronary risk factors, the multivariate odds ratios for coronary-artery calcium scores of more than 0, 10 or more, and 100 or more in the group receiving estrogen as compared with placebo were 0.78 (95% confidence interval, 0.58 to 1.04), 0.74 (0.55 to 0.99), and 0.69 (0.48 to 0.98), respectively. The corresponding odds ratios among women with at least 80% adherence to the study estrogen or placebo were 0.64 (P=0.01), 0.55 (P<0.001), and 0.46 (P=0.001). For coronary-artery calcium scores of more than 300 (vs. <10), the multivariate odds ratio was 0.58 (P=0.03) in an intention-to-treat analysis and 0.39 (P=0.004) among women with at least 80% adherence. CONCLUSIONS: Among women 50 to 59 years old at enrollment, the calcified-plaque burden in the coronary arteries after trial completion was lower in women assigned to estrogen than in those assigned to placebo. However, estrogen has complex biologic effects and may influence the risk of cardiovascular events and other outcomes through multiple pathways. (ClinicalTrials.gov number, NCT00000611.)

Insulin sensitivity and insulin secretion determined by homeostasis model assessment and risk of diabetes in a multiethnic cohort of women: the Women's Health Initiative Observational Study.

OBJECTIVE: The homeostasis model assessment (HOMA), based on plasma levels of fasting glucose and insulin, has been widely validated and applied for quantifying insulin resistance and beta-cell function. However, prospective data regarding its relation to diabetes risk in ethnically diverse populations are limited. RESEARCH DESIGN AND METHODS: Among 82,069 women who were aged 50-79 years, free of cardiovascular disease or diabetes, and participating in the Women's Health Initiative Observational Study, we conducted a nested case-control study to prospectively examine the relations of HOMA of insulin resistance (HOMA-IR) and beta-cell function (HOMA-B) with diabetes risk. During a median follow-up period of 5.9 years, 1,584 diabetic patients were matched with 2,198 control subjects by age, ethnicity, clinical center, time of blood draw, and follow-up time. RESULTS: Baseline levels of fasting glucose, insulin, and HOMA-IR were each significantly higher among case compared with control subjects, while HOMA-B was lower (all P values <0.0001). After adjustment for matching factors and diabetes risk factors, all four markers were significantly associated with diabetes risk; the estimated relative risks per SD increment were 3.54 (95% CI 3.02-4.13) for fasting glucose, 2.25 (1.99-2.54) for fasting insulin, 3.40 (2.95-3.92) for HOMA-IR, and 0.57 (0.51-0.63) for HOMA-B. While no statistically significant multiplicative interactions were observed between these markers and ethnicity, the associations of both HOMA-IR and HOMA-B with diabetes risk remained significant and robust in each ethnic group, including whites, blacks, Hispanics, and Asians/Pacific Islanders. When evaluated jointly, the relations of HOMA-IR and HOMA-B with diabetes risk appeared to be independent and additive. HOMA-IR was more strongly associated with an increased risk than were other markers after we excluded those with fasting glucose > or = 126 mg/dl at baseline. CONCLUSIONS: High HOMA-IR and low HOMA-B were independently and consistently associated with an increased diabetes risk in a multiethnic cohort of U.S. postmenopausal women. These data suggest the value of HOMA indexes for diabetes risk in epidemiologic studies.

Serum levels of soluble vascular cell adhesion molecule-1 are decreased in women receiving oral contraceptives compared with normally menstruating women: implications in atherosclerosis.

OBJECTIVE: The primary objective was to assess whether short-term changes in estradiol (E2), such as those observed in the menstrual cycle, alter serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), and whether VCAM-1 expression is suppressed in long-term users of exogenous estrogens. The secondary objective was to assess the association, if any, between inflammatory cytokines and expression of sVCAM-1. DESIGN: Prospective collection of serum samples in healthy volunteers. SETTING: University hospital. PATIENTS(S): Thirty-one normally menstruating women and 37 oral contraceptive (OC) users. Interventions included serum collection in the early follicular, late follicular, and midluteal phases of the menstrual cycle and once in oral contraceptive users. MAIN OUTCOME MEASURE(S): Samples were assayed for sVCAM-1, tumor necrosis factor alpha (TNF-alpha), and interleukin (IL)-6 by enzyme-linked immunoabsorbent assay (ELISA). Estradiol (E2) was measured by radioimmunoassay (RIA). RESULT(S): Oral contraceptive users had significantly lower serum levels of sVCAM-1 compared with normally menstruating women. No significant change was noted in the mean values of sVCAM-1 throughout the menstrual cycle, despite the significant change in 17beta-estradiol levels. Throughout the menstrual cycle, a significant correlation was noted between the serum levels of TNF-alpha and sVCAM-1. The serum levels of IL-6 correlated with those of sVCAM-1 in the late follicular and midluteal phase of the cycle. Similar correlations were observed in OC users. CONCLUSION(S): Long-term exposure to exogenous estrogens suppresses serum levels of sVCAM-1. Short-term changes in endogenous estrogens, as observed during the menstrual cycle, may not alter VCAM-1 expression; TNF-alpha and IL-6 may play a role in the regulation of VCAM-1 expression in vivo.

17-epiestriol, an estrogen metabolite, is more potent than estradiol in inhibiting vascular cell adhesion molecule 1 (VCAM-1) mRNA expression.

17-beta estradiol (17-beta E(2)) attenuates the expression of vascular cell adhesion molecule 1 (VCAM-1) in vivo at physiological levels (pg/ml), whereas supraphysiological concentrations of 17-beta E(2) (ng/ml) are required in vitro. We assessed whether a metabolite of estrogen, which could only be generated in vivo, might be a more potent inhibitor of VCAM-1 expression and thereby explain this discrepancy. We report here that 17-epiestriol, an estrogen metabolite and a selective estrogen receptor (ER) beta agonist, is approximately 400x more potent than 17-beta E(2) in suppressing tumor necrosis factor (TNF) alpha-induced VCAM-1 mRNA as well as protein expression in human umbilical vein endothelial cells. Genistein, an ERbeta agonist, at low concentrations (1 and 10 nm) also suppressed TNFalpha-induced VCAM-1 mRNA expression. These actions of 17-epiestriol and genistein were significantly attenuated in the presence of the estrogen receptor antagonist ICI-182780. Other estrogenic compounds such as ethinyl estradiol and estrone did not have any effect on TNFalpha-induced VCAM-1 expression at the concentrations tested. We further show that, 1) 17-epiestriol induces the expression of endothelial nitric-oxide synthase mRNA and protein, 2) 17-epiestriol prevents TNFalpha-induced migration of NFkappaB into the nucleus, 3) N(G)-nitro-l-arginine methyl ester, an inhibitor of NO synthesis, abolishes 17-epiestriol-mediated inhibition of TNFalpha-induced VCAM-1 expression and migration of NFkappaB from the cytoplasm to the nucleus. Our results indicate that 17-epiestriol is more potent than 17-beta E(2) in suppressing TNFalpha-induced VCAM-1 expression and that this action is modulated at least in part through NO.

Medroxyprogesterone acetate does not antagonize estrogen-induced increases in endothelium-dependent vasodilation: potential clinical implications.

OBJECTIVE: Determine the effect of combined 17beta-estradiol benzoate (E2) and medroxyprogesterone acetate (MPA) administration on endothelium-dependent vasorelaxation to acetylcholine (ACh). DESIGN: Prospective, ex vivo study. SETTING: Academic research laboratory. ANIMAL(S): Mature female rats. INTERVENTION(S): Ovariectomized rats received one of the following interventions daily for 3 days: [1] corn oil via IM injection, [2] E2 (20 microg/kg IM), or [3] E2 (20 microg/kg IM) and MPA (10 mg/kg IM). MAIN OUTCOME MEASURE(S): Basal release of nitric oxide (NO) and endothelium-dependent and endothelium-independent vasodilation from thoracic aortas obtained from each group. RESULT(S): Estradiol treatment potentiated the endothelium-dependent relaxation to ACh when compared with the control group. Administration of MPA with E2 did not antagonize the beneficial effect of E2 on endothelium-dependent relaxation. Estradiol treatment alone or in combination with MPA did not affect endothelium-independent vasodilation as compared with the case of the control group. Administration of E2 resulted in increased basal NO release (assessed indirectly by measuring the constrictor response to N(G)-nitro-L-arginine [methyl ester (L-NAME)]) when compared with the case of the control group, and the addition of MPA to E2 did not alter the effect of E2 on basal NO release. CONCLUSION(S): Estradiol potentiates endothelium-dependent relaxant responses and increases basal endothelial NO release. Medroxyprogesterone acetate does not antagonize these effects of E2.

Testosterone attenuates expression of vascular cell adhesion molecule-1 by conversion to estradiol by aromatase in endothelial cells: implications in atherosclerosis.

We previously reported that testosterone attenuated atherogenesis in LDLR(-/-) male mice, and that this effect of testosterone was most likely caused by its conversion to estradiol. Estradiol inhibits vascular cell adhesion molecule-1 (VCAM-1) expression, and expression of VCAM-1 is one of the early events in atherogenesis. We assessed the cellular mechanism(s) involved by which testosterone attenuates atherogenesis. We evaluated whether testosterone inhibited TNFalpha-induced VCAM-1 expression via its conversion to estradiol by the enzyme aromatase in human umbilical vein endothelial cells (HUVEC). Aromatase mRNA was dedected by reverse transcription-PCR in these cells. Testosterone (30 nM-1 microM) attenuated VCAM-1 mRNA expression in a concentration-dependent manner. The non aromatizable androgen, dihydrotestosterone, had no effect on VCAM-1 mRNA expression. Testosterone was less effective in attenuating VCAM-1 expression in the presence of anastrozole, an inhibitor of aromatase, indicating that testosterone inhibited VCAM-1 via conversion to estradiol. Estradiol also attenuated VCAM-1 mRNA expression, but this action was not abolished in the presence of anastrozole, indicating that anastrozole itself did not modulate VCAM-1 mRNA expression. The effect of testosterone on VCAM-1 mRNA expression was inhibited in the presence of the estrogen receptor antagonist, ICI-182780. Testosterone also attenuated TNFalpha-induced VCAM-1 protein expression, and this attenuation was abolished in the presence of anastrozole. In conclusion, testosterone inhibited VCAM-1 mRNA and protein expression in HUVEC by its conversion to estradiol via the enzyme aromatase present in the endothelial cells. Results from our study may help explain the mechanism by which testosterone may have beneficial effects on the cardiovascular system.

Noninvasive assessment of coronary microcirculatory function in postmenopausal women and effects of short-term and long-term estrogen administration.

BACKGROUND: Estrogen improves endothelial function in the coronary conduit vessels of animals; however, its effects on the coronary microcirculation have not been studied completely in humans. METHODS AND RESULTS: We measured myocardial blood flow (MBF) with a PET scan at rest, during cold pressor testing (CPT), and during dipyridamole hyperemia in 54 postmenopausal women without coronary artery disease. Of these, 23 were not and 31 women were taking long-term hormone replacement therapy (HRT) using estrogen either alone or with a progestogen. Each group was subdivided by coronary risk factors (RFs). Twelve young healthy women served as controls. In women not taking HRT, MBF measurements were repeated after 25 mg of conjugated equine estrogens IV. Neither short estrogen nor long-term HRT affected MBF at rest in women with and without RFs. Dipyridamole MBF was attenuated only in the women with RF who were not taking HRT. Short-term estrogen and long-term HRT did not reverse the abnormal response. MBF responses to CPT were abnormal in women not taking HRT, regardless of RFs (20+/-15% versus 32+/-21%) and remained unchanged after short-term estrogen administration. Long-term HRT normalized the response to CPT only in women without RF (53+/-22% versus 59+/-36% in the young women; NS). MBFs were similar for women on estrogen alone or estrogen plus a progestogen, regardless of presence or absence of RFs. CONCLUSION: Menopause is associated with abnormal CPT (an indirect measure of endothelial function), which can be reversed by long-term HRT only when RFs are absent. Progestogens do not antagonize this effect. Long-term HRT may therefore be useful in the primary prevention of coronary artery disease in women without RFs.