Management and Long-Term Follow-Up of Hyperparathyroidism in Multiple Endocrine Neoplasia Type 1: Single Center Experience.

BACKGROUND: Primary hyperparathyroidism (PHPT) in the most common and earliest manifestation of multiple endocrine neoplasia type-1 (MEN1). Epidemiological data have been reported in MEN1 patients but data on long-term follow-up focusing on PHPT are scarce. METHODS: In this retrospective cohort study, we included patients diagnosed with MEN1-related PHPT that were under regular follow-up in our institution. RESULTS: Data on 68 patients (39 males), with a mean age at MEN1-diagnosis of 39 ± 13.06 years, were analyzed. Pancreatic neuroendocrine tumors were encountered in 82% (71% nonsecreting) followed by pituitary adenomas in 66% (49% nonsecreting). Mean age at PHPT diagnosis was 35.2 ± 4.0 years. Parathyroidectomy was performed in 57 patients (82.3%), of whom 56% achieved long-term remission, while 12.2% and 31.5% had persistent and recurrent disease, respectively (median follow-up of 4 years; range 1-21 years). Cinacalcet restored serum calcium levels in 33.8%, both as first and as a second line treatment. Permanent hypoparathyroidism occurred in 19.2%. MEN1 pathogenic variants were identified in 77.2% of the tested individuals, but no genotype-phenotype associations were reported. CONCLUSIONS: MEN1-related PHPT involves a multiglandular disease and its management remains a therapeutic challenge, as recurrent disease can develop even after 20 years of follow-up. Prolonged follow-up of these patients at referral centers is critical for their optimal management.

CYP A-204C polymorphism is associated with subclinical atherosclerosis in postmenopausal women.

OBJECTIVE: To assess the association of common polymorphisms involved in lipoprotein oxidation, platelet activation, and cholesterol and homocysteine metabolism with subclinical atherosclerosis and indices of endothelial function and arterial elasticity in healthy postmenopausal women. DESIGN: The study investigated 84 healthy postmenopausal women recruited from the Menopause Clinic of the 2nd Department of Obstetrics and Gynecology, University of Athens, Aretaieion Hospital. The following polymorphisms were genotyped: apolipoprotein B 3500, apolipoprotein E (E2/E3/E4), cholesterol 7 alpha-hydroxylase A-204C (CYP A-204C), cholesterol ester transfer protein B1/B2, glycoprotein IIIa leu33pro, integrin beta 3 PLA1/PLA2, plasminogen activator inhibitor 1 4G/5G, paraoxonase 1 gln192 arg, and methylenetetrahydrofolate reductase ala222val. Ultrasound examination aimed to assess the presence of atherosclerotic plaque and to measure intima-media thickness in the carotid and femoral arteries and to estimate the augmentation index, brachial flow-mediated dilatation, and radial and femoral pulse-wave velocity. RESULTS: The cholesterol 7 alpha-hydroxylase A-204C polymorphism was positively associated with the presence of atherosclerotic plaque (P = 0.004) and carotid and femoral intima-media thickness (P = 0.047 and P = 0.025, respectively). CONCLUSIONS: The CYP A-204C polymorphism was positively associated with subclinical atherosclerosis in healthy postmenopausal women. It remains to be clarified whether the presence of these polymorphisms may be valuable in assessing the inherent risk among postmenopausal women.

Circulating leptin and ghrelin are differentially influenced by estrogen/progestin therapy and raloxifene.

BACKGROUND: Leptin and ghrelin are increasingly being recognized as cardiotropic hormones, promoting or inhibiting the atherosclerotic process, respectively. Apoptosis may be one pathway through which the actions of these hormones are mediated. Sex hormones are reported to influence the secretion and action of ghrelin and leptin. OBJECTIVE: To evaluate (1) the association of circulating ghrelin and leptin with selected markers of receptor-mediated apoptosis and (2) the effect of estrogen monotherapy, low dose estrogen-progestin therapy, tibolone and raloxifene on serum ghrelin and leptin in healthy postmenopausal women. METHODS: Eighty eight postmenopausal women aged 44-62 years were randomly allocated to daily (1) conjugated equine estrogens 0.625 mg (CEE), (2) 17beta-estradiol 1mg plus norethisterone acetate 0.5 mg (E(2)/NETA), (3) tibolone 2.5mg, (4) raloxifene HCl 60 mg or (5) no treatment. Serum markers of apoptosis sFas, Fas-ligand (Fas-L) and caspase-1 were measured at baseline. Serum leptin and ghrelin were measured at baseline and at 3 months. RESULTS: Body Mass Index (BMI) and estradiol levels correlated positively, while FSH correlated negatively with serum leptin (BMI: r=0.646, p=0.005, estradiol: r=0.432, p=0.001, FSH: r=-0.401, p=0.002). Insulin levels associated positively with circulating leptin (r=0.394, p=0.011) and negatively with circulating ghrelin (r=-0.401, p=0.009). Serum leptin decreased significantly in E2/NETA group (baseline: 2.882+/-0.76 ng/ml, 3 months: 2.687+/-0.66 ng/ml, p=0.043), while it increased significantly in the raloxifene group (baseline: 2.671+/-0.54 ng/ml, 3 months: 2.839+/-0.47 ng/ml). Ghrelin levels decreased significantly only in the raloxifene group (baseline: 1634+/-592 pg/ml, 3 months: 1408+/-534 pg/ml). CONCLUSION: Apoptosis may be a pathway through which leptin exerts a pro-atherogenic effect. Low dose HT may act cardioprotectively by decreasing leptin levels in healthy recently menopaused women.

Circulating chemoattractants RANTES, negatively related to endogenous androgens, and MCP-1 are differentially suppressed by hormone therapy and raloxifene.

BACKGROUND: The cardinal role of chronic inflammation in the development of atherosclerosis is increasingly being recognized. Estrogens may prevent the evolution of atherosclerosis by suppressing immune response. Furthermore, the conflicting reports on the cardiovascular effects of hormone therapy between observational and clinical trials have triggered interest on the effect of alternative therapies on the cardiovascular system. OBJECTIVE: The aim of this study was to assess the effect of estrogen, estrogen-progestin, tibolone and raloxifene therapy on circulating markers of chemotaxis in healthy postmenopausal women. METHODS: Eighty-eight postmenopausal women aged 44-62 years were randomly allocated to daily: (1) conjugated equine estrogens 0.625 mg (CEE), (2) 17beta-estradiol 1mg plus norethisterone acetate 0.5mg (E(2)/NETA), (3) tibolone 2.5mg, (4) raloxifene HCl 60 mg or (5) no treatment. Serum monocyte chemoattractant protein-1 (MCP-1) and regulated upon activation, normal T-cell expressed and secreted (RANTES) were measured at baseline and at 3 months. RESULTS: Endogenous testosterone and free androgen index (FAI) correlated negatively, while SHBG correlated positively with serum RANTES (testosterone: r=-0.27, p=0.033; FAI: r=-0.43, p=0.004: SHBG: r=0.34, p=0.026). Serum MCP-1 decreased significantly in the CEE group (baseline 125.3+/-51 pg/ml, 3 months 84.5+/-36.1 pg/ml, p=0.043), while no difference was detected between baseline and post-treatment levels in the other groups. Furthermore, a significant decrease in serum RANTES was observed at the end of 3 months only in the E2/NETA and the raloxifene group (E2/NETA baseline 8690.6+/-3880.0 pg/ml, 3 months 6894.0+/-1720.0 pg/ml, p=0.007; raloxifene baseline 9042.4+/-3765.6 pg/ml, 3 months 6718.1+/-2366.2 pg/ml, p=0.011). CONCLUSION: Endogenous androgens may suppress chemotactic response. Postmenopausal hormone therapy and raloxifene may inhibit the expression of chemoattractant molecules and thus attenuate inflammation. The relevance of these findings in terms of clinically established caridoprotection remains to be clarified.

Differential effect of hormone therapy and tibolone on lipids, lipoproteins, and the atherogenic index of plasma.

The aim of our study was to assess the effect of various regimens and doses of hormone therapy and tibolone on the Atherogenic Index of Plasma (AIP). A total of 519 postmenopausal women attending our menopause clinic were studied in a prospective design. Women with climacteric symptoms were randomly assigned to receive 1 of the following regimens: tibolone 2.5 mg, conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA), 17beta-estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA), or 17beta-estradiol 1 mg plus norethisterone acetate 0.5 mg (low E2/NETA). Serum parameters were assessed at baseline and after 6 months and included total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoprotein A1 and apolipoprotein B. The AIP was assessed as the log (triglycerides [mmol/L]/HDL-C [mmol/L]). CEE/MPA treatment associated with lower mean LDL-C but higher mean triglyceride levels (-15.5 mg/dL +/- 3.6, P = 0.0001; 12.6 mg/dL +/- 4.8, P = 0.01). Furthermore, CEE/MPA treatment resulted in higher AIP levels (0.073 +/- 0.021, P = 0.001). On the contrary, both E2/NETA regimens and tibolone associated with lower mean triglyceride and HDL-C levels (E2/NETA, triglycerides: -9.8 mg/dL +/- 5.0, P = 0.049; HDL-C: -4.9 mg/dL +/- 1.8, P = 0.01, low E2/NETA triglycerides: -12.5 mg/dL +/- 4.1, P = 0.003; HDL-C: -4.7 mg/dL +/- 1.3, P = 0.001; tibolone, triglycerides: -21.9 mg/dL +/- 2.7, P = 0.0001; HDL-C: -12.7 mg/dL +/- 1.1, P = 0.0001). None of the 3 regimens had any effect on AIP. The effect of a particular regimen of hormone therapy on the lipid-lipoprotein profile differs depending on the parameter assessed. The use of unified markers such as AIP will be helpful in evaluating the overall effect of lipid-lipoprotein modulation on the cardiovascular system. In fact, the concurrent assessment of the therapy effect on both LDL-C and AIP may be more dependable in evaluating the cardiovascular impact of a given regimen.

Endogenous sex hormones and risk factors for atherosclerosis in healthy Greek postmenopausal women.

OBJECTIVE: To assess the association between endogenous sex hormones and risk factors for atherosclerosis in healthy postmenopausal women. DESIGN: Cross-sectional study in a university menopause clinic. METHODS: Serum sex hormones and lipid-lipoprotein profile, arterial pressure, homocysteine and insulin resistance, measured by the homeostasis model assessment of insulin resistance (HOMA-IR), were assessed in 598 healthy postmenopausal women not on hormone therapy. RESULTS: Compared with women in the lowest testosterone quartile (Q), women in the highest testosterone quartile had higher total cholesterol (Q1: 225.2 +/- 41.3 vs Q4: 246.2 +/- 38.4 mg/dl, P < 0.01), low-density lipoprotein (LDL)-cholesterol (Q1: 146.9 +/- 37.2 vs Q4: 171.8 +/- 35.3 mg/dl, P < 0.001), atherogenic index of plasma (AIP) (Q1: -0.224 +/- 0.238 vs Q4: -0.087 +/- 0.254, P < 0.01), apolipoprotein B (ApoB) (Q1: 100.7 +/- 23.1 vs Q4: 113.9 +/- 23.8 mg/dl, P < 0.001) and higher high-density lipoprotein (HDL)-cholesterol (Q1: 60.7 +/- 14.5 vs Q4: 52.9 +/- 13.0 mg/dl, P < 0.01). Accordingly, women in the highest free androgen index (FAI) quartile had higher AIP (Q1: -0.232 +/- 0.254 vs Q4: -0.078 +/- 0.243, P < 0.001) and ApoB (Q1: 102.4 +/- 25.5 vs Q4: 114.2 +/- 25.8 mg/dl, P < 0.01) and lower HDL-cholesterol (Q1: 62.0 +/- 15.7 vs Q4: 51.9 +/- 11.6 mg/dl, P < 0.001) and apolipoprotein A (Q1: 159.6 +/- 25.6 vs Q4: 147.9 +/- 24.1 mg/dl, P < 0.01) compared with women in the lowest FAI quartile. These differences remained significant after adjustment for age, body mass index (BMI), insulin resistance and social habits. The free estrogen index (FEI) exhibited similar associations to the FAI. HOMA-IR showed an independent positive association with total testosterone (Q1: 2.00 +/- 1.36 vs Q4: 2.66 +/- 1.60, P < 0.01), FAI (Q1: 1.70 +/- 1.12 vs Q4: 3.04 +/- 1.66, P < 0.001) and FEI (Q1: 1.70 +/- 0.91 vs Q4: 3.08 +/- 1.77, P < 0.001). CONCLUSIONS: Increased androgenicity in healthy postmenopausal women is associated with an unfavorable cardiovascular risk profile. High endogenous estradiol is related to a pro-atherogenic lipid profile, an association which may, in part, be mediated by insulin resistance.

The effect of low dose hormone therapy on mammographic breast density.

OBJECTIVES: To evaluate the effect of two standard and one low dose continuous hormone therapy regimens on mammography. METHODS: One hundred and thirty-two non-hysterectomized postmenopausal women were randomly allocated either to conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA, n=38), 17beta-estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA, n=44) or 17beta-estradiol 1 mg plus norethisterone acetate 0.5 mg (low E2/NETA, n=50). Treatment was continuous and the study period lasted 12 months. Main outcome measures were the changes according to Wolfe classification between baseline and 12-month mammograms. RESULTS: Five (13.2%) women in the CEE/MPA group showed an increase in breast density. Fourteen (31.8%) women on E2/NETA and 6 (12.2%) on low E2/NETA treatment revealed an increase in breast density. No woman exhibited an involution of fibroglandular tissue. CONCLUSIONS: Different hormone therapy regimens have a variable impact on breast density probably depending on the steroid used. Low dose hormone therapy associates with significantly lesser increase in breast density.