Can a healthy endothelium influence the cardiovascular effects of hormone replacement therapy?

Emerging clinical and observational evidences suggest that estrogen confers physiologic benefits that are receptor mediated and depend on the integrity and functional status of the endothelium within the coronary vasculature. In postmenopausal women, estrogen replacement therapy (ERT) and hormone replacement therapy (HRT) regimens can enhance the lipoprotein panel; blunt the expression of numerous cytokines, chemokines, and other proinflammatory mediators of endothelial injury and vascular smooth muscle cell proliferation; up-regulate endothelial nitric oxide synthase activity and nitric oxide production; and augment fibrinolysis potential and vasodilator capacity (diminish arterial resistance). Advancing age and atherosclerotic injury to the vessel wall tend to deplete estrogen receptors, compromise endothelial function, promote thrombus formation, and thus potentially diminish the efficacy of ERT and HRT. Therefore, optimizing the clinical benefits of these regimens in postmenopausal women depends largely on promoting a healthy endothelium through life-style modifications that diminish coronary risk.     

Does hormone replacement therapy influence retinal microvascular caliber?

Previous population-based data suggest that retinal arteriolar diameter is wider in women than in men. Estrogen exposures could account for this difference. To evaluate the effects of HRT on small blood vessels, we assessed the relationship between use of hormone replacement therapy (HRT) and retinal microvascular diameter in older women in the Blue Mountains Eye Study baseline population (n = 1993, age >/= 49 years). Information on HRT use was recorded by trained interviewers. A computer-assisted program measured retinal vessel diameters from digitized photographs. Average arteriolar diameter was calculated as the central retinal arteriolar equivalent (CRAE); the lowest quintile of CRAE was considered generalized arteriolar narrowing. Of the 1897 women with complete data, 79 (4%) were premenopausal and 315 (17%), 224 (12%), and 1279 (67%) were current, past, and never HRT users, respectively. Among women aged < 65 years, multivariate-adjusted mean CRAE for the four groups was 196, 198, 201, and 200 microm (P < 0.0001), respectively. Among postmenopausal women >/= 65 years, multivariate-adjusted mean CRAE was 187, 188, 191 microm (P < 0.0001), respectively, for current, past, and never users. Current HRT users were 40% more likely than never users to have generalized arteriolar narrowing (95% confidence interval 1.0-2.1). It appears that the use of HRT in older women may not have any long-term vasodilatory effects on retinal arterioles. These data do not support our hypothesis that exogenous estrogen exposures account for observed wider retinal arteriolar diameters in women.     

Does hormonal therapy have any benefit for bleeding angiodysplasia?

Sixty-four patients took part in a cohort study measuring the efficacy of daily hormonal therapy in diminishing intestinal bleeding from small bowel angiodysplasia. Thirty patients received 5-10 mg norethynodrel either with mestranol, 0.075-0.15 mg (24 patients) or with conjugated estrogens, 0.625 mg (six patients). The cohort group consisted of 34 patients who either refused hormonal therapy (six patients) or were diagnosed early in our experience, before the resurgence of hormonal therapy (28 patients). Mean follow-up was 15.6 months (range 2-31 months) for the treated group and 13.4 months (range 1-23 months) for the untreated group. In addition, the change in monthly transfusion requirement with therapy was analyzed ("within group" analysis). Fifty percent (15 of 30) of the treated group required no further transfusion during therapy, while 44% (15 of 34) of the untreated group required no further therapy (not significant). During therapy, the mean monthly transfusion requirement of packed red blood cells in the treated group was not significantly different from that found before therapy (1.5 vs. 2.2 units, NS) or from that of the control group (1.5 vs. 1.6 units, NS). The findings do not support the use of hormonal therapy for bleeding from small intestinal angiodysplasia.     

Who should receive hormone replacement therapy?

Coronary heart disease is the leading cause of death in women in the United States and increases dramatically in postmenopausal women. The following review summarizes the known benefits and risks of hormone replacement therapy and gives recommendations for use of hormone replacement in women. Estrogen may play a role in preventing the development of atherosclerosis in women by raising levels of HDL cholesterol, lowering levels of LDL cholesterol and lipoprotein (a), lowering levels of fibrinogen and plasminogen activator inhibitor-1, dilating coronary arteries, preventing the oxidation of LDL cholesterol, decreasing the proliferation and migration of smooth muscle cells, and decreasing the production of inflammatory cell activators. These anti-atherogenic effects of estrogen may translate into clinical benefits. A meta-analysis of 31 studies yielded a 44% reduction in the risk of coronary heart disease in women taking estrogen alone. Unopposed estrogen is associated with an increased risk of endometrial cancer; therefore, progestin is added to estrogen in women with an intact uterus. Less is known about the effect of the combination of estrogen and a progestin on the risk of coronary heart disease. Estrogen is also beneficial in the prevention of osteoporosis; however, long-term use of estrogen alone and estrogen in combination with progestin may increase the risk for breast cancer. Mathematical modeling predicted that women with no risk for cardiovascular disease, cancer, or osteoporosis may gain 0.9 years of life with the use of estrogen alone; women with risk factors for cardiovascular disease can expect to gain 1.5 years of life; and women with coronary heart disease at the age of 50 can expect to gain 2.1 years of life. The current American College of Physicians recommendations for hormone replacement are as follows: (1) All women should be considered; (2) women with a hysterectomy should receive estrogen alone; (3) women at risk for, or with, coronary heart disease are most likely to benefit from estrogen; with an intact uterus, progestin must be added; (4) risks of estrogen may outweigh benefits in women at increased risk for breast cancer. Definitive guidelines for the treatment of women must await the results of randomized clinical trials in the ongoing Women's Health Initiative. These will not be available for several years, and until then any recommendations for women will have to be judged from estimates of risk rather than of benefit from reduction of risk. The decision whether to initiate estrogen replacement in postmenopausal women is one that still needs to be made on an individual patient basis.Supported by NHLBI grant HL 02626. Dr. Welty is the 1995 recipient of the Alpha Phi Foundation Award.     

Anterior pituitary hormone replacement therapy—a clinical review

This clinical review summarizes current approaches to diagnosis and treatment of anterior pituitary hormone deficiency. The diagnostic value of endocrine function tests and replacement strategies for hydrocortisone, thyroxine, sex steroids, and growth hormone replacement are reviewed. Female androgen deficiency syndrome and the current role of DHEA and testosterone replacement in women are also discussed.     

Does the addition of fibrates to statin therapy have a favorable risk to benefit ratio?

Statins effectively lower low-density lipoprotein cholesterol levels and the risk of cardiovascular disease (CVD) events, and because of this they have become a standard treatment for dyslipidemia and atheroprevention. Unfortunately, statin monotherapy may fail to normalize high triglycerides and low high-density lipoprotein cholesterol, and it prevents only a minority of CVD events. Further treatment of lipid disorders that remain after statin monotherapy should help reduce the residual CVD risk. Fibrate monotherapy lowers high triglyceride levels, raises low high-density lipoprotein cholesterol, and reduces CVD risk; therefore, fibrates are recommended as an adjunct to statins for treatment of residual dyslipidemia and residual CVD risk. This review provides an update on the benefits and risks of fibrate monotherapy and addresses the benefits and risks of adding fibrates to statins.     

Does the type of hormone replacement therapy affect lipoprotein (a), homocysteine, and C-reactive protein levels in postmenopausal women?

BACKGROUND: The results of studies evaluating the effect of hormone replacement therapy (HRT) on the cardiovascular risk raise many controversies. This may be related to both the type of treatment used and the disregard of additional risk factors. OBJECTIVE: The objective of the study was to evaluate the effect of natural estrogens taken transdermally and synthetic estrogens taken orally on the concentrations of lipoprotein (a) [Lp(a)], homocysteine, and C-reactive protein (CRP) in healthy women in the early postmenopausal period. Material The study was conducted on 61 healthy women with average age of 52.3 +/- 4.1 years, in the postmenopausal period, who were randomly assigned to 3 groups depending on the type and route of administration of the products. Group I (n = 24) was administered transdermal estrogens (micronized 17beta-estradiol; Systen, Janssen-Cilag, Switzerland) and progesterone in the second phase of the cycle. Group II (n = 21) was administered oral hormones (Cyclo-Menorette). Group III (n = 16), serving as a control, included women taking placebo in the form of patches. In each group, therapeutic cycles took 22 days and were followed by a treatment-free interval of 7 to 10 days for a 3-month period. RESULTS: After 3 months of treatment, Lp(a) and homocysteine levels were not significantly different from the baseline, irrespective of the route of administration of estrogens or placebo. Both forms of HRT used indicate significant difference in changes of CRP concentration during 3 months of administration (analysis of variance P = .0356). CRP concentration values increased in the group of women using oral HRT from 1.22 to 2.68 mg/L. In the group of women using oral therapy, significantly more cases (61%) of increase in CRP concentration compared with 39% in the transdermal HRT group (chi(2) P = .015) were observed. CONCLUSIONS: On the basis of our observations, it appears that in women in the early postmenopausal stage with normal initial concentrations of Lp(a) and homocystein, the form of therapy used has no influence on values of these parameters. The 2 forms of HRT therapy differ in effect, which is expressed as a change in CRP concentration. A tendency to increase CRP values when using oral HRT is observed, while such an effect is not observed in case of transdermal therapy after 3 months.     

Shouldn't adults with growth hormone deficiency be offered growth hormone replacement therapy?

Growth hormone as therapy for adults with growth hormone deficiency has not been universally accepted by endocrinologists who treat adult patients. The following are addressed in this commentary: the evidence on safety and efficacy in the literature supporting the idea that growth hormone should be offered as replacement therapy to adults who are growth hormone deficient; common concerns of the average prescribing endocrinologist, including the purported association between insulin-like growth factor-I and malignant neoplasms and quality-of-life issues with long-term therapy; and controversial subjects, such as differences in dosing for adults versus children and diagnostic issues. This analysis should encourage reluctant practitioners to at least consider growth hormone replacement therapy for patients with definite growth hormone deficiency--that is, patients with symptomatic panhypopituitarism.     

Does physical therapy still have a place in the treatment of ankylosing spondylitis?

PURPOSE OF REVIEW: To review studies of various physical therapy programs in ankylosing spondylitis and identify their benefits and potential indications in the treatment of this disease. RECENT FINDINGS: Various exercise and physical therapy programs have been evaluated in clinical studies. Home exercise programs have been shown to improve symptoms, mobility, function and overall quality of life. Formal physical therapy under the supervision of a physical therapist has been shown to improve posture, fitness, mobility, function and mood. Water therapy may improve symptoms, function and overall sense of health. Inpatient rehabilitation may provide rapid short-term improvement in pain and stiffness, mobility, function and quality of life for patients with severe active disease. SUMMARY: Despite the advances in the pharmacological therapy of ankylosing spondylitis, physical therapy remains an essential part of the management plan. Even though data are not sufficient to determine which specific physical therapy program should be recommended, physicians should implement such nonpharmacological therapy as part of a comprehensive management strategy for this disease. All patients should receive instructions on proper posture and home exercises and be encouraged to perform water exercises if they can. Formal physical therapy and, in most severe cases, inpatient rehabilitation may be of benefit to select patients with ankylosing spondylitis.     

What is the cardioprotective role of hormone replacement therapy?

A very large body of literature has yielded strong biologic and mechanistic plausibility for the consistent observational findings that estrogen is cardioprotective. Recently completed randomized, controlled trials have been interpreted as challenging the doctrine that hormone replacement is cardioprotective for postmenopausal women. However, other than the Estrogen in the Prevention of Atherosclerosis Trial, none of the currently completed (and no ongoing) randomized, controlled trials have appropriately tested the hypothesis generated from observational data that estrogen replacement is cardioprotective. This mainly results from the fact that randomized, controlled trials have not tested the same pattern and type of hormone use in the same population of women observed in the epidemiologic studies. On the other hand, recently completed randomized, controlled trials provide important but limited information concerning the clinical use of a specific regimen of hormone replacement for the prevention of cardiovascular disease in a particular population of postmenopausal women. Observations made from epidemiologic studies will have to be appropriately tested in randomized, controlled trials before any real conclusions can be drawn as to whether hormone replacement is cardioprotective.     

Should progestins be blamed for the failure of hormone replacement therapy to reduce cardiovascular events in randomized controlled trials?

Many observational studies and experimental and animal studies have demonstrated that estrogen replacement therapy (ERT) or hormone replacement therapy (HRT) (estrogen plus progestin) significantly reduces the risk of coronary heart disease. Nonetheless, recent randomized controlled trials demonstrated some trends toward an increased risk of cardiovascular events rather than a reduction of risk. Recently, both the HRT and ERT arms of the Women's Health Initiative (WHI) study were terminated early because of an increased/no incidence of invasive breast cancer, increased incidence of stroke, and increased trend/no protective effects of cardiovascular disease. We discuss the controversial effects of HRT and ERT on cardiovascular system and provide a hypothesis that the failure of HRT and ERT in reducing the risk of cardiovascular events in postmenopausal women might be because of the stage of their atherosclerosis at the time of initiation of HRT or ERT.