Article

Surgical and pharmacological reassignment: influence on transsexual cardiovascular risk profile

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  • Hospital "F. Perinei" Altamura (BA) - ASL BARI
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Abstract

Introduction: The aim was to evaluate and stratify early cardiovascular risk of transsexuals undergone pharmacological and/or surgical gender reassignment. Methods: Fifty-six transsexuals were divided into two groups: 1- undergone gonadectomy (orchiectomy for trans women and hystero-annessiectomy for trans men); group 2- hormone replacement therapy alone. All underwent carotid artery intima-media thickness (C-IMT) and flow-mediated vasodilation (FMD) of brachial artery evaluations. Results: FMD was lower in patients undergone gonadectomy as compared to not- surgically treated patients (Group 1: 5.711 vs Group 2: 7.339, p < 0.0001). Mean C-IMT was higher in group 1 than group 2 (group 1: 0.733 vs group 2: 0.582). The duration of hormone therapy correlates positively with mean C-IMT (B = 0.001) and negatively with FMD (%) (B = - 0.007). Conclusions: Cardiovascular risk, which is expressed in terms of endothelial (FMD) and morphological (C-IMT) dysfunction, increases in subjects undergoing gonadectomy as compared to those receiving cross-sex reassignment therapy alone.

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... 70 Furthermore, people who are TGD who had undergone gender-affirming surgery and were receiving hormone therapy had reduced brachial artery flowmediated dilation compared with women and men who are transgender who had not undergone surgery but who were taking hormone therapy. 71 In secondary analyses, the results remained the same when separating by gender identity. However, the sample sizes in the surgery group likely lacked the power to detect differences. ...
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Book
1 Neuroendocrine Regulation of Gonadal Function.- 2 Hormonal Control of Folliculogenesis.- 3 Androgen Transport and Plasma Levels in the Normal Female.- 4 The Pathologic Anatomy of Polycystic Ovarian Disease.- 5 Genetics of Polycystic Ovarian Disease.- 6 Pathophysiology of Polycystic Ovarian Disease.- 7 Clinical Features of Polycystic Ovarian Disease.- 8 Hyperprolactinemia and Polycystic Ovarian Disease.- 9 Laboratory Diagnosis and Differential Diagnosis of Polycystic Ovarian Disease.- 10 Treatment of Polycystic Ovarian Disease.- 11 Hypothesis and Summary.- References.
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Chapter
The original description of the syndrome which bears the names of Stein and Leventhal (880) emphasized the association of amenorrhea, hirsuitism and sterility with enlarged polycystic ovaries. They established specific criteria for the diagnosis of their syndrome that included bilaterally enlarged ovaries, normal urinary 17-ketosteroid excretion and absence of virilization. These criteria were established as a basis for their selection of patients for bilateral ovarian wedge resection (521,876,878,879). Using the classic description of patients originally de-scribed in 1935, Stein (874), in 1964, reported only 108 patients who conformed to the original description. In this strictly defined group he was able to report a 95% return to ovulatory cycles and an 85% conception rate following bilateral ovarian wedge resection. Subsequent reports by numerous investigators have emphasized that enlarged ovaries are not necessarily present, nor is infertility or anovulation always present (347,349,852,905,909,945).
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Most patients with polycystic ovarian disease (PCOD) have inappropriately elevated LH re-lease and low or a low normal FSH secretion, namely, an elevated LH/FSH ratio (24,39,74, 138, 202, 203, 242, 302, 327, 332, 434, 443, 529, 530, 647, 711, 733, 742, 830, 934, 973, 998,1015,1028,1029). The mean normal mid- follicular LH/FSH ratio is 1.3 (1.0–1.6) (24, 39,332). The high circulating LH level is maintained by exaggerated pulsatile LH discharge, either in the form of enhanced amplitude or increased frequency (oscillations) (Fig. 6-1) (39, 742,973). The serum LH has no consistent pat-tern in magnitude or interval in PCOD (473). Daily LH excursions are frequently so great that they may resemble those of normal cycling women, or to the magnitude seen in a spontaneous mid-cycle LH surge (1015). It has been demonstrated that surges of LH in patients with polycystic ovaries may be preceded by a rapid increase of endogenous circulating E2 (1015).
Article
CONTEXT: Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain. OBJECTIVE: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States. DESIGN: Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998. INTERVENTIONS: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). MAIN OUTCOMES MEASURES: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. RESULTS: On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years. CONCLUSIONS: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.
Article
Objective: To assess the effect of estrogen replacement therapy on endothelium-dependent vasodilation in postmenopausal women. Design: Double-blind, placebo-controlled, crossover trial. Setting: University medical center. Patients: 13 postmenopausal women aged 44 to 69 years (average age, 55±7 years). Intervention: Patients were randomly assigned to receive placebo, oral estradiol at a dose of 1 mg/d, and oral estradiol at a dose of 2 mg/d. Each treatment phase lasted 9 weeks. Measurements: High-resolution ultrasonography was used to measure vascular reactivity in a peripheral conduit vessel, the brachial artery
Article
Estrogens are secreted primarily by the ovaries and placenta, by the testes in men and also produced by peripheral steroidogenic conversion. The 3 major naturally occurring estrogens are: 17β-estradiol (E2), estrone and estriol, of which E2 is the predominant and most active. The actions of E2 are mediated by at least 3 different receptors - the classical ERs (ERα and ERβ) and G-protein coupled receptor 30 (GPR30). E2 signaling in cardiomyocytes involves ERα- and ERβ-independent pathways, and treatment with the E2 receptor antagonists (Selective Estrogen Receptor Modulators- SERMs), which are agonists of GPR30, inhibits cardiac cell growth. Effects of E2 in preventing endothelial dysfunction, a prerequisite of atherosclerosis, are well recognized. Atherosclerosis involves interaction between the cells of the arterial wall endothelial cells (EC) and vascular smooth muscle cell (VSMC), as well as migration of macrophages into wall tunica media. It is predominantly developed at sites with abnormally high shear stress, such as bifurcations or branching of arteries, initiated by an injury to the endothelium and exposure to atherogenic lipids and toxins, such as those contained in tobacco smoke or infectious agents. Animal studies have shown effects of E2 in preventing atherosclerosis, inflammation and endothelial or vascular dysfunction. Gender differences along this pathogenic pathway have been also described. We review the data from the available animal and human studies, which focus on anti-atherogenic effects of E2. These studies represent evidence, albeit indirect, for an inhibitory effect of E2 on the progression of coronary artery atherosclerosis.
Article
Purpose of review: Oestrogens are important modulators of lipid metabolism, inflammation and vascular homeostasis. Endogenous oestrogens contribute to the low prevalence of atherosclerotic vascular disease in premenopausal women with intact ovarian function, and cessation of oestrogen production following menopause increases cardiovascular risk. Orally administered oestrogens such as postmenopausal hormone therapy increase HDL and reduce LDL cholesterol levels, and they increase triglyceride levels. Current guidelines do not recommend postmenopausal hormone therapy for cardiovascular prevention. Recent findings: Recent clinical studies have suggested potential benefits of natural oestrogen or selective oestrogen receptor modulators on cardiovascular outcomes, effects that are associated with lipid profile improvements. In contrast to earlier studies such as the Women's Health Initiative, the Heart and Estrogen/Progestin Replacement Study or the Estrogen Replacement and Atherosclerosis trial, in which investigators used hormone mixtures derived from horse urine (misleadingly named 'conjugated oestrogens' with unknown activity on oestrogen receptors), triphasic oestrogen therapy started early after menopause as primary prevention study protocol improved outcome. New studies suggest therapeutic potential of natural oestrogens and certain selective oestrogen receptor modulators to reduce coronary artery disease risk in postmenopausal women. Summary: Endogenous oestrogens are important regulators of lipid metabolism and inhibit inflammation, vascular cell growth and plaque progression in premenopausal women. The recent trials warrant further studies, which should also determine how much of the potential benefits are due to improvements of lipid metabolism.
Article
Lack of estrogen is a cause of cardiovascular disease in men and postmenopausal women. We examined the effects of estrogen receptor (ERs) activation/inactivation on endothelial cells subjected to tumor necrosis factor (TNF) α, which is involved in vascular disease pathogenesis. Endothelial nitric oxide synthase (eNOS) and matrix metalloproteinases (MMP) 9 expression, as well as protein kinase B (PKB) activation were evaluated as markers of endothelial dysfunction. The TNF-α induces eNOS and MMP-9 expression and PKB activation. The ER activation by apigenin, a nonsteroidal compound with estrogen-like activity mediated through ER binding-dependent pathways, counteracts these effects. These effects are reversed by classic (ER-α and ER-β) and nonclassic (G-protein-coupled receptor) ER inhibitors (ICI182 780 and pertussis toxin, respectively). Our data suggest that ER activation counteracts endothelial dysfunction induced by TNF-α. The use of ER activators, such as apigenin, may represent a strategy to prevent vascular disease associated with endothelial dysfunction, while avoiding the feminizing effects of estrogens.
Article
The exact mechanism of estrogen in cardiovascular disease is not fully understood. As estrogen receptors (ERs), the peroxisome-proliferator-activated-receptor-γ (PPARγ) belongs to the family of ligand activated nuclear receptors regulating atheroprotective genes. The aim of this project was to investigate whether vascular effects of estrogen are mediated via PPARγ-regulation in the vascular compartment. Estrogen deficient ovariectomized wildtype-mice (OVX) displayed significant reduction of PPARγ-expression in aortic tissue compared to wildtype-mice with intact ovarian function (Sham). Hormone replacement with subdermal 17ß-estradiol pellets significantly increased vascular PPARγ-expression in ovariectomized female wildtype-mice (OVX/E2). Analogous to wildtype-mice, estrogen-deficient OVX ApoE(-/-)-mice had low vascular PPARγ-expression associated with ROS generation, endothelial dysfunction and atherogenesis. Estrogen replacement (OVX/E2) rescued vascular PPARγ-expression, reduced ROS generation, monocyte recruitment, atherosclerotic lesion formation and improved endothelial function. Inhibition of PPARγ by GW9662, a specific PPARγ-antagonist reduced 17ß-estradiol mediated vascular effects (OVX/E2+GW9662). Finally, despite estrogen deficiency treatment with pioglitazone (OVX+pioglitazone), a selective PPARγ-agonist, compensates deterioration of vascular morphology and function. 17ß-estradiol regulates vascular PPARγ-expression in wildtype- and ApoE(-/-)-mice. The presented data demonstrate the fundamental relevance of PPARγ as downstream target of 17ß-estradiol-related anti-inflammatory and atheroprotective effects within the vascular wall independent of its cardiovascular risk factor modifications.
Article
Estrogens protect the vascular system in women, but its effect in men is unclear. We evaluated the impact of estrogen on the male cardiovascular system. Of 140 Chinese males, 55 (aged 61.2 ± 3.5) were cases and 60 (aged 59.5 ± 4.6) were controls. Compared with the control group, only serum estradiol ([E2]; P < .01) levels but not testosterone ([T]; P = .21) were significantly lower in the cases. Linear and multiple regression analysis showed that serum T was positively associated with triglycerides ([TG]; r = .439, P < .01) and d-dimer (r = .258, P < .05) but negatively associated with high-density lipoprotein cholesterol (HDL-C) levels (r = -.267, P < .05) and C-reactive protein (CRP; r = -.214, P < .05). Estradiol was highly associated with TG (r = .783, P < .01) and HDL-C (r = .515, P < .01) but was negatively related with low-density lipoprotein cholesterol (LDL-C; P < .05), total cholesterol/HDL-C (P < .05), CRP (P < .01), and d-dimer (P < .01). In conclusion, serum E2 and T levels affect coronary heart disease risk factors in males.
Article
Endogenous testosterone has been shown to provide a protective role in the development of cardiovascular diseases in men. This study investigated the changes of testosterone level and its relationship to the severity of coronary artery stenosis in middle-aged men with coronary artery disease (CAD). Serum testosterone concentration was measured in 87 middle-aged men patients with CAD including stable angina pectoris (SAP), unstable angina pectoris (USAP) and acute myocardial infarction (AMI). All patients underwent coronary angiography and the severity of coronary stenosis was estimated by the Gensini coronary score. The patients with the severity of coronary artery stenosis of less than 50% served as control group. The levels of testosterone in SAP group (488.2 ± 96.8ng/dl), USAP group (411.6 ± 128.6ng/dl) and AMI group (365.3 ± 116.6ng/dl) were significantly lower than that in control group (562.8 ± 110.2ng/dl) (all p<0.05). When compared with another group among SAP, USAP and AMI groups, the level of testosterone in the AMI group was the lowest, the USAP group was the median while the SAP group was the highest (all p<0.05). There was a significant correlation between angiographic Gensini score and testosterone level (n=87, r=-0.513, p<0.05). Multiple regression analysis found that testosterone and BMI were independent predictors for CAD (testosterone: odds ratio 0.311, 95% confidence interval 0.174-0.512; BMI: odds ratio 1.905, 95% confidence interval 1.116-2.973). The present study showed that middle-aged male patients with CAD present a lower level of serum testosterone and the testosterone level was negatively correlated with the severity of coronary artery stenosis.
Article
Men die of coronary artery disease (CAD) more often than women. There is evidence that testosterone either is neutral or has a beneficial effect on male cardiovascular disease. The role of oestrogens in male CAD has been less studied. This study was carried out with the purpose of evaluating the relationship between sex hormone levels and CAD. Case-control study. Men (aged 40-70) submitted to coronary angiography. A 70% occlusion of at least one major coronary artery defined the cases; subjects with ≤ 50% occlusion constituted the control group. Blood samples were collected for total testosterone (TT), oestradiol, luteinizing hormone, follicle-stimulating hormone, sex hormone-binding globulin, lipid profile and albumin measurements. Bioavailable and free testosterone, free androgen index (FAI) and free oestrogen index (FEI) were calculated. Oestradiol and TT levels were examined as terciles, based on the whole study population. Of the 140 patients included, 72 were cases and 68 were controls. The baseline characteristics of the two groups were similar, except for the older age and lower LDL-C in the cases. Oestradiol and FEI but not total, bioavailable and free testosterone and FAI correlated positively with CAD. After adjustments for potential confounders, oestradiol remained statistically significant. The prevalence of CAD was significantly higher in the 3rd than in the 1st tercile of oestradiol. In this study, men with CAD had higher oestradiol and FEI levels. Additional studies are needed to clarify the direction of causality and possible underlying mechanisms.
Article
The prevalence of polycystic ovary syndrome (PCOS) is estimated to be nearly 10% among reproductive-age women. PCOS may represent the largest underappreciated segment of the female population at risk of cardiovascular disease. Clinicians providing care to women of childbearing age must recognize the presenting clues, including irregular menses, hirsutism, alopecia, hyperandrogenemia, and obesity. The pathophysiology of PCOS is complex, involving the hypothalamus-pituitary-ovarian axis, ovarian theca cell hyperplasia, hyperinsulinemia, and a multitude of other cytokine- and adipocyte-driven factors. Cardiac risk factors associated with PCOS have public health implications and should drive early screening and intervention measures. There are no consensus guidelines regarding screening for cardiovascular disease in patients with PCOS. Fasting lipid profiles and glucose examinations should be performed regularly. Carotid intimal medial thickness examinations should begin at age 30 years, and coronary calcium screening should begin at age 45 years. Treatment of the associated cardiovascular risk factors, including insulin resistance, hypertension, and dyslipidemia, should be incorporated into the routine PCOS patient wellness care program.
Article
To summarize the available evidence on the cardiovascular effects of cross-sex steroid use in transsexuals. We searched relevant electronic databases and sought additional references from experts. Eligible studies reported on cardiovascular events, venous thromboembolism, blood pressure and fasting serum lipids. Data were extracted in duplicate. We used the random-effects model to estimate the pooled weighted mean difference (WMD) and 95% confidence intervals (CIs). We found 16 eligible studies, mostly uncontrolled cohorts of varied follow-up durations (1471 male-to-female (MF) and 651 female-to-male (FM) individuals). In the MF individuals, cross-sex hormone use was associated with a statistically significant increase in fasting serum triglycerides without changes in the other parameters (WMD = 23.39 mg/dl; 95% CI = 4.82-41.95). In the FM individuals, there was a similar increase of triglycerides (WMD = 31.35 mg/dl; 95% CI = 7.53-55.17) and a reduction of high density lipoprotein (HDL)-cholesterol (WMD = -6.09 mg/dl; 95% CI = -11.44 to -0.73). There was a statistically significant but clinically trivial increase in systolic blood pressure (WMD = 1.74 mmHg; 95% CI = 0.21-3.27). Analyses were associated with significant heterogeneity across studies. There were very few reported cardiovascular events (deaths, strokes, myocardial infarctions or venous thromboembolism), more commonly among MF individuals. Very low quality evidence, downgraded due to methodological limitations of included studies, imprecision and heterogeneity, suggests that cross-sex hormone therapies increase serum triglycerides in MF and FM and have a trivial effect on HDL-cholesterol and systolic blood pressure in FM. Data about patient important outcomes are sparse and inconclusive.
Article
Polycystic ovary syndrome (PCOS) is associated with a clustering of metabolic and cardiovascular risk factors. Insulin resistance is implicated as the major player in the metabolic abnormalities and contributes to the increased cardiovascular risk associated with the syndrome. However, androgen excess appears to participate as an independent parameter, which further aggravates the cardiovascular and metabolic aberrations in affected women with PCOS. The resultant impact of hyperandrogenemia possibly acquires clinical significance for women's health in the context of PCOS, particularly since recent data support an increased incidence of coronary artery disease and of cardiovascular events directly related to androgen levels in women with the syndrome.
Article
A patient developed benign nodular hyperplasia of the liver after long-term, high-dose estrogen therapy. A 10.5-cm benign liver nodule appeared after three years of high-dose estrogen therapy and was resected. Fourteen months later, while still receiving estrogen, a 4.5-cm nodule and multiple small nodules were seen on angiography. Four months after estrogen was discontinued, the larger liver nodule disappeared and the smaller ones decreased.
Article
The effect of postmenopausal estrogen therapy on the risk of cardiovascular disease remains controversial. Our 1985 report in the Journal, based on four years of follow-up, suggested that estrogen therapy reduced the risk of coronary heart disease, but a report published simultaneously from the Framingham Study suggested that the risk was increased. In addition, studies of the effect of estrogens on stroke have yielded conflicting results. We followed 48,470 postmenopausal women, 30 to 63 years old, who were participants in the Nurses' Health Study, and who did not have a history of cancer or cardiovascular disease at base line. During up to 10 years of follow-up (337,854 person-years), we documented 224 strokes, 405 cases of major coronary disease (nonfatal myocardial infarctions or deaths from coronary causes), and 1263 deaths from all causes. After adjustment for age and other risk factors, the overall relative risk of major coronary disease in women currently taking estrogen was 0.56 (95 percent confidence interval, 0.40 to 0.80); the risk was significantly reduced among women with either natural or surgical menopause. We observed no effect of the duration of estrogen use independent of age. The findings were similar in analyses limited to women who had recently visited their physicians (relative risk, 0.45; 95 percent confidence interval, 0.31 to 0.66) and in a low-risk group that excluded women reporting current cigarette smoking, diabetes, hypertension, hypercholesterolemia, or a Quetelet index above the 90th percentile (relative risk, 0.53; 95 percent confidence interval, 0.31 to 0.91). The relative risk for current and former users of estrogen as compared with those who had never used it was 0.89 (95 percent confidence interval, 0.78 to 1.00) for total mortality and 0.72 (95 percent confidence interval, 0.55 to 0.95) for mortality from cardiovascular disease. The relative risk of stroke when current users were compared with those who had never used estrogen was 0.97 (95 percent confidence interval, 0.65 to 1.45), with no marked differences according to type of stroke. Current estrogen use is associated with a reduction in the incidence of coronary heart disease as well as in mortality from cardiovascular disease, but it is not associated with any change in the risk of stroke.
Article
A study in vitro of specimens of human aortic and common carotid arteries was carried out to determine the feasibility of direct measurement (i.e., not from residual lumen) of arterial wall thickness with B mode real-time imaging. Measurements in vivo by the same technique were also obtained from common carotid arteries of 10 young normal male subjects. Aortic samples were classified as class A (relatively normal) or class B (with one or more atherosclerotic plaques). In all class A and 85% of class B arterial samples a characteristic B mode image composed of two parallel echogenic lines separated by a hypoechoic space was found. The distance between the two lines (B mode image of intimal + medial thickness) was measured and correlated with the thickness of different combinations of tunicae evaluated by gross and microscopic examination. On the basis of these findings and the results of dissection experiments on the intima and adventitia we concluded that results of B mode imaging of intimal + medial thickness did not differ significantly from the intimal + medial thickness measured on pathologic examination. With respect to the accuracy of measurements obtained by B mode imaging as compared with pathologic findings, we found an error of less than 20% for measurements in 77% of normal and pathologic aortic walls. In addition, no significant difference was found between B mode-determined intimal + medial thickness in the common carotid arteries evaluated in vitro and that determined by this method in vivo in young subjects, indicating that B mode imaging represents a useful approach for the measurement of intimal + medial thickness of human arteries in vivo.
Article
A retrospective study of 40 female-to-male transsexuals was performed to investigate the frequency of endocrine dysfunction prior to hormonal treatment with testosterone. Two patients had laparoscopic evidence of polycystic ovarian disease (PCOD) prior to androgen treatment. Nine additional subjects had clinical evidence of PCOD, including ultrasonographic evidence of multicystic and enlarged ovaries in three patients and/or evidence of hirsutism and oligomenorrhea associated with increased androgen levels and/or an increased plasma luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratio. Two subjects had evidence of gonadal dysgenesis. Plasma levels of testosterone, prolactin, LH/FSH ratio, and dehydroepiandrosterone sulfate were significantly increased in 30 female transsexuals prior to testosterone treatment when compared to normal adult female controls studied in the early follicular phase of the menstrual cycle. These data indicate that female transsexuals have an increased incidence of endocrine dysfunction (32.5%) which should be investigated prior to hormonal treatment.
Article
This article deals with some aspects of the interaction between natural and synthetic female sex hormones and the liver. Because of the close structural relationship between some progestogens and anabolic steroids the effect of the latter compounds on the liver is also reviewed. The following effects of anabolic steroids, progesterone, synthetic progestogens, estrogens, compounds with estrogenic activity and oral contraceptives on liver are discussed in greater detail: Effect on morphology including light and electron microscopic changes; effect on bile secretion, with special emphasis on cholestatic effects; effect on biochemistry of the liver cell with special regard to enzyme induction, the drug-metabolizing enzyme system of the liver cell, porphyrin metabolism and changes in mitochondrial enzymes. Jaundice and porphyria due to steroids are also discussed, and the close connection between recurrent (intrahepatic cholestatic) jaundice of pregnancy and jaundice due to oral contraceptives is emphasized. The metabolism of female sex hormones in liver disease is briefly reviewed. In the general discussion the main topics are: Effect of oral contraceptives on the liver, the mechanism of the cholestatic effect of steroids, possible genetical defects involved and the likely connection between the metabolism of hormonal steroids and the formation of gallstones in women.
Article
Vital statistics and epidemiologic studies in Great Britain and the U.S. have shown that among nonpregnant women of reproductive age who are not using OCs (oral contraceptives) the risks of myocardial infarction and stroke increase substantially with age and in the presence of such risk factors as cigarette smoking and hypertension. The same statistics and studies show that OCs multiply instead of adding to the effects of age and these other risk factors. The pathogenesis of myocardial infarction that is attributable to OCs involves the effects of current use which are unrelated to duration and which disappear when OCs are discontinued and the effects of past use which are related to duration of use and which persist when OCs are discontinued. OCs are known to elevate blood pressure and decrease glucose tolerance slightly in most women. The net effect on high-density-lipoprotein cholesterol depends on the composition of the specific OC compounds. Among women under 35 who do not smoke the risks of death associated with OC cardiovascular effects are lower than the risks associated with complications of pregnancy and risks associated with other methods of contraception. Over 35 the risk of OC-related mortality rises substantially. For smokers the risk is even greater. Introduction of the very low dose estrogenic compounds may reduce these risks. Screening of susceptible high-risk women may also reduce OC-associated mortality.
Article
Current information suggests that oral contraceptives increase both the risk of overt venous thromboembolic disease and the occurrence of subclinical venous thromboembolic disease, primarily by increasing the size of the intravenous clots formed in response to endothelial injury or other stimuli that lead to thrombin formation. This effect appears to be primarily due to the estrogenic component of oral contraceptives, to involve decreased antithrombin III activity, and probably to be exacerbated in women who do not have an appropriate increase in fibrinolytic activity in response to increased intravenous clotting.
Article
To assess the effect of estrogen replacement therapy on endothelium-dependent vasodilation in postmenopausal women. Double-blind, placebo-controlled, crossover trial. University medical center. 13 postmenopausal women aged 44 to 69 years (average age, 55 +/- 7 years). Patients were randomly assigned to receive placebo, oral estradiol at a dose of 1 mg/d, and oral estradiol at a dose of 2 mg/d. Each treatment phase lasted 9 weeks. High-resolution ultrasonography was used to measure vascular reactivity in a peripheral conduit vessel, the brachial artery. Endothelium-dependent vasodilation was determined by measuring the change in brachial artery diameter during increases in flow induced by reactive hyperemia. Endothelium-independent vasodilation was measured after sublingual nitroglycerin was administered. Flow-mediated, endothelium-dependent vasodilation of the brachial artery was greater when patients received estradiol (13.5% and 11.6% for 1-mg and 2-mg doses, respectively) than when patients received placebo (6.8%; P < 0.05 for each dose compared with placebo). In contrast, estrogen administration had no effect on endothelium-independent vasodilation as assessed by sublingual nitroglycerin. Short-term estrogen replacement therapy improves flow-mediated endothelium-dependent vasodilation in postmenopausal women. This improvement may be mediated by a direct effect of estrogen on vascular function or may be induced through modification of lipoprotein metabolism.
Article
Most epidemiologic studies of cardiovascular disease in postmenopausal women suggest that estrogen-replacement therapy has a protective effect. The effects of the use of estrogen combined with progestin are less well studied. To examine the associations of hormone-replacement therapy with concentrations of plasma lipids and hemostatic factors, fasting serum concentrations of glucose and insulin, and blood pressure, we studied 4958 postmenopausal women participating in a population-based investigation. Using cross-sectional data, we classified the women into four groups according to their use of hormone-replacement therapy: current users of estrogen alone, current users of estrogen with progestin, nonusers who had formerly used these hormones, nonusers who had never used them. Current users had higher mean levels of high-density lipoprotein cholesterol, its subfractions high-density lipoprotein2 and high-density lipoprotein3, and apolipoprotein A-I than nonusers and lower mean levels of low-density lipoprotein cholesterol, apolipoprotein B, lipoprotein(a), fibrinogen, antithrombin III, and fasting serum glucose and insulin. However, current users of estrogen alone had higher triglyceride, factor VII, and protein C levels than either nonusers or current users of estrogen with progestin. After making certain assumptions, we estimated that the findings, if causal, would translate into a reduction of 42 percent in the risk of coronary heart disease in users of hormones as compared with nonusers. Women using estrogen with progestin would have an even greater estimated benefit. A randomized trial is needed to eliminate possible selection biases in our observational study that are related to the prescription of replacement hormones. Nevertheless, hormone-replacement therapy appears to be associated with a favorable physiologic profile, which probably mediates its protective effects on cardiovascular disease. The use of estrogen combined with progestin appears to be associated with a better profile than the use of estrogen alone.
Article
Estrogen therapy in postmenopausal women has been associated with a decreased risk of heart disease. There is little information, however, about the effect of combined estrogen and progestin therapy on the risk of cardiovascular disease. We examined the relation between cardiovascular disease and postmenopausal hormone therapy during up to 16 years of follow-up in 59,337 women from the Nurses' Health Study, who were 30 to 55 years of age at base line. Information on hormone use was ascertained with biennial questionnaires. From 1976 to 1992, we documented 770 cases of myocardial infarction or death from coronary disease in this group and 572 strokes. Proportional-hazards models were used to calculate relative risks and 95 percent confidence intervals, adjusted for confounding variables. We observed a marked decrease in the risk of major coronary heart disease among women who took estrogen with progestin (multivariate adjusted relative risk, 0.39; 95 percent confidence interval, 0.19 to 0.78) or estrogen alone (relative risk, 0.60; 95 percent confidence interval, 0.43 to 0.83), as compared with women who did not use hormones [corrected]. However, there was no significant association between stroke and use of combined hormones (multivariate adjusted relative risk, 1.09; 95 percent confidence interval, 0.66 to 1.80) or estrogen alone (relative risk, 1.27; 95 percent confidence interval, 0.95 to 1.69). The addition of progestin does not appear to attenuate the cardioprotective effects of postmenopausal estrogen therapy.
Article
This study sought to examine the effects of long-term estrogen therapy on vascular function in male to female transsexuals and to compare the findings with those observed in men and premenopausal women. Gender differences in coronary artery disease have largely been attributed to the beneficial effects of estrogen on vascular function and plasma lipids in women. However, the effects of estrogen on the male vasculature have not been widely studied. We compared the effects of estrogen on vascular function in 14 male to female transsexuals, 14 age-matched men and 15 premenopausal women. Flow-mediated vasodilation and response to nitroglycerin were assessed in the brachial artery using noninvasive ultrasound. Flow-mediated vasodilation was similar in transsexuals and women but greater than that in men ([mean +/- SE] 11.5 +/- 1.3% and 9.4 +/- 1.1% vs. 5.2 +/- 1.0% respectively, p < 0.005). Responses to nitroglycerin were also greater in transsexuals and women than in men (21.6 +/- 1.7% and 21.0 +/- 0.9% vs. 14.5 +/- 1.2%, respectively, p = 0.0005). These differences persisted even after adjusting for vessel size. Despite similar total cholesterol levels, transsexuals had high density lipoprotein cholesterol levels similar to those in women and greater than those observed in men (1.76 +/- 0.12 and 1.82 +/- 0.11 mmol/liter vs. 1.35 +/- 0.07 mmol/liter, respectively, p < 0.005). Moreover, triglyceride levels were greater in transsexuals than in men and women, and low density lipoprotein cholesterol (LDL-C) particle size was smaller (25.7 +/- 0.2 nm vs. 26.2 +/- 0.1 and 26.6 +/- 0.1 nm, respectively, p = 0.0001). Serum testosterone (an index of estrogen therapy in transsexuals) was markedly suppressed in transsexuals and similar to that in women. Univariate analysis revealed that there was a strong inverse correlation between serum testosterone and flow-mediated vasodilation (r(s) = -0.48, p < 0.005). Multivariate analysis revealed that the best combination of predictors of flow-mediated vasodilation was serum testosterone, vessel size and LDL-C (R2 = 0.3, p < 0.005). Long-term estrogen therapy appears to improve vascular function in male to female transsexuals and occurs despite higher triglyceride levels and the presence of small, dense LDL-C. The beneficial effects of estrogen are not gender specific or solely mediated through endothelium-derived nitric oxide.
Article
We have previously shown that chronic estrogen therapy improves endothelium-dependent vasodilation in the resistance vessels of biological males. Whether this is nitric oxide (NO) mediated and whether estrogen improves metabolic vasodilation is unknown. Resting forearm blood flow (FBF), ACh-induced vasodilation, and functional hyperemic blood flow (exercise) were assessed before and after the inhibition of NO with N(G)-monomethyl-L-arginine (L-NMMA) in 15 male-to-female transsexuals prescribed estrogen and in 14 age-matched males. Resting FBF was similar in the two groups and was similarly (P = 0.44) but significantly reduced by 48% after infusion of L-NMMA (P < 0.0001). The ACh dose-response relationship was shifted upward and to the left in the transsexual compared with the male group (P < 0.01). After the inhibition of NO, however, the difference in the ACh dose-response curve between the two groups was abolished (P = 0.15). Peak functional hyperemic blood flow was similar for the two groups (P = 0.94). L-NMMA produced a significant (P < 0.01) but similar (P = 0.64) reduction in peak hyperemia in the two groups. The volume of blood repaid to the forearm 1 and 5 min after exercise was also reduced by L-NMMA (P < 0.0001); however, there were no differences between the two groups. This suggests that ACh-mediated NO-dependent vasodilation may be more sensitive to the effects of chronic estrogen than exercise-induced vasodilation. Long-term estrogen does not appear to improve exercise-induced metabolic vasodilation in biological males, despite the fact that NO contributes to this process.
Article
Endothelial function is thought to be an important factor in the pathogenesis of atherosclerosis, hypertension and heart failure. In the 1990s, high-frequency ultrasonographic imaging of the brachial artery to assess endothelium-dependent flow-mediated vasodilation (FMD) was developed. The technique provokes the release of nitric oxide, resulting in vasodilation that can be quantitated as an index of vasomotor function. The noninvasive nature of the technique allows repeated measurements over time to study the effectiveness of various interventions that may affect vascular health. However, despite its widespread use, there are technical and interpretive limitations of this technique. State-of-the-art information is presented and insights are provided into the strengths and limitations of high-resolution ultrasonography of the brachial artery to evaluate vasomotor function, with guidelines for its research application in the study of endothelial physiology.
Article
Cross-sex hormone treatment is an important component in medical treatment of transsexual people. Endocrinologists are often faced with designing treatment recommendations. Although guidelines from organizations, such as the Harry Benjamin International Gender Dysphoria Association, have been helpful, management remains complex and experience guided. We discuss the range of treatment used by transsexual people, the rationale behind these, and the expectation from such treatment. Recommendations from seven clinical research centers treating transsexual people are discussed. In addition, self-reported hormonal regimens from 25 male-to-female transsexual people and five female-to-male transsexual people are reported. Finally, the potential adverse effects of cross-sex hormone treatment of transsexual people are reviewed. In light of the complexity of managing treatment goals and adverse effects, the active involvement of a medical doctor experienced in cross-sex hormonal therapy is vital to ensure the safety of transsexual people.