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Aris Bechlioulis,
Katerina K Naka, Sophia N Kalantaridou,
Anthoula Chatzikyriakidou,
Odysseas Papanikolaou,
Apostolos Kaponis,
Konstantinos Vakalis,
Patra Vezyraki,
Konstantina Gartzonika,
Anestis Mavridis,
Ioannis Georgiou,
Lampros K Michalis
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ABSTRACT: Hormone therapy (HT) has been suggested to improve vascular function and inflammation in menopausal women, although not consistently. We aimed to investigate the effects of HT on endothelial function and inflammation, especially sCD40L, in early menopausal women, and the effect of common estrogen receptor (ER) polymorphisms on vascular responses to HT.
Eighty-four early menopausal women (<3 years in menopause) with menopausal complaints eligible for HT. Forty women received transdermal 17β-estradiol plus cyclical micronized progesterone for 3 months while 44 did not (controls).
Brachial artery flow-mediated dilation (FMD) and vascular inflammation markers (sICAM, sP-Selectin and sCD40L). Genetic polymorphisms of ERα (PvuII 454-397T>C and XbaI 454-351A>G) and ERβ (AluI 1730A>G) were also assessed.
The two groups did not differ at baseline. Following HT, vasomotor complaints' severity, blood pressure, LDL, sCD40L, sICAM and sP-Selectin decreased and FMD increased compared to controls (P<0.05 for all). ERβ AluI A allele presence was the most important independent predictor of HT-induced increase in FMD while ERα XbaI A allele was the only independent predictor of decrease in sCD40L.
Short-term HT in early menopausal women improved endothelial function and inflammation. Specific ER polymorphisms that were found to be main determinants of HT-induced effects on endothelium could identify subgroups of women who may benefit the most from HT.
Maturitas 04/2012; 71(4):389-95. · 2.77 Impact Factor
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Aris Bechlioulis,
Katerina K Naka, Sophia N Kalantaridou,
Apostolos Kaponis,
Odysseas Papanikolaou,
Patra Vezyraki,
Theofilos M Kolettis,
Antonis P Vlahos,
Konstantina Gartzonika,
Anestis Mavridis,
Lampros K Michalis
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ABSTRACT: Menopause has been related to an increased atherosclerotic risk. Presence and severity of hot flushes in menopausal women have been associated with impaired endothelial function and advanced subclinical atherosclerosis.
The objective of the study was to evaluate the effect of menopausal transition on vascular inflammation indices and investigate the association of hot flush severity with these indices in early menopausal women.
This was a cross-sectional study that included 120 early menopausal women (age range 42-55 yr, <3 yr in menopause) recruited from the menopause outpatient clinic of an academic hospital and 24 age-matched premenopausal women (controls).
Serum high-sensitivity C-reactive protein, P-selectin, and soluble CD40 ligand (sCD40L) levels were measured.
P-selectin and sCD40L were increased in early menopausal compared with control women (P = 0.006 and P = 0.02 respectively), whereas high-sensitivity C-reactive protein levels did not differ (P = 0.4) between the groups. Hot flush severity was the most important independent predictor of P-selectin levels (P = 0.011) in early menopausal women. Women with moderate/severe/very severe hot flushes had increased P-selectin compared with women with no/mild hot flushes or controls (P < 0.05 for both). The sCD40L levels were also higher in menopausal women with moderate/severe/very severe hot flushes compared with controls (P = 0.03) but did not differ significantly compared with women with no/mild hot flushes (P = 0.2).
Increased indices of vascular inflammation in early menopausal compared with age-matched premenopausal women may indicate a higher atherosclerotic risk. Increased severity of hot flushes was associated with adverse changes in vascular inflammation, further supporting the emerging role of hot flushes in cardiovascular prognosis in these women.
The Journal of clinical endocrinology and metabolism 03/2012; 97(5):E760-4. · 6.50 Impact Factor
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European Journal of Clinical Investigation 03/2012; 42(10):1146. · 3.02 Impact Factor
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European Journal of Clinical Investigation 03/2012; 42(3):231-2. · 3.02 Impact Factor
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ABSTRACT: Sperm flow cytometry (SFC) was used to evaluate the association of sperm chromatin condensation and ploidy with fertilization, embryo development, pregnancy and abortion rates following IVF.
Conventional semen analysis was performed in one hundred fifty men, as well as SFC analysis, after acridine orange and propidium iodide staining, for the evaluation of sperm maturity and ploidy respectively. Conventional IVF was performed in all couples.
Couples with low percentages of mature spermatozoa presented with lower fertilization rates (p < 0.005), lower rates of grade A embryos (p < 0.003) and lower pregnancy rates (p < 0.006), compared to couples with high percentages of mature spermatozoa. Couples with low total aneuploidy rates presented with higher fertilization rates (p < 0.007), higher rates of grade A embryos (p < 0.004) and higher pregnancy rates (p < 0.003), compared to couples with high total aneuploidy rates.
Sperm chromatin condensation and ploidy constitute critical parameters for the evaluation of semen samples before IVF and for the identification of cases in need of ICSI application.
Journal of Assisted Reproduction and Genetics 07/2011; 28(10):885-91. · 1.84 Impact Factor
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ABSTRACT: Combined oral contraceptives are used in polycystic ovary syndrome (PCOS) women for the treatment of hyperandrogenism and menstrual cycle disturbances.
To assess the effect of ethinylestradiol and cyproterone acetate (EE/CA) on endothelial function in young, non-obese PCOS women in a pilot study.
Thirteen young, non-obese PCOS women (20.9 ± 3.7 years, 23.0 ± 4.0 kg/m(2)) received 35 mcg EE & 2 mg CA for 6 months. Fourteen age- and body mass index (BMI)-matched healthy women served as controls. Endothelial function assessed by brachial artery flow-mediated dilation (FMD), indices of hyperandrogenism, and insulin resistance were studied at baseline and 6-month follow-up.
FMD was impaired in PCOS compared to control women (4.67 ± 2.38% vs. 10.12 ± 3.19%, p < 0.001), but increased significantly following EE/CA (9.99 ± 2.11%, p < 0.001 vs. baseline), reaching normal values (p = NS vs. controls). EE/CA also significantly decreased hyperandrogenism indices and increased total and HDL cholesterol and triglycerides (p < 0.05 vs. baseline). The only independent predictor of treatment-induced FMD improvement in PCOS women was the decrease in free androgen index.
Treatment with combination of estrogens and antiandrogens reverses endothelial dysfunction in young, non-obese PCOS women mainly via improving hyperandrogenism. Further research is needed to investigate whether this treatment may also reduce cardiovascular risk in these women.
Gynecological Endocrinology 02/2011; 27(9):615-21. · 1.58 Impact Factor
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Katerina K Naka, Sophia N Kalantaridou,
Maria Kravariti,
Aris Bechlioulis,
Nikolaos Kazakos,
Karim A Calis,
Antonis Makrigiannakis,
Christos S Katsouras,
George P Chrousos,
Agathocles Tsatsoulis,
Lampros K Michalis
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ABSTRACT: To compare the effect of two different insulin sensitizers, metformin and pioglitazone, on endothelial function in women with polycystic ovary syndrome (PCOS).
Prospective randomized study.
University Hospital endocrinology outpatient clinic.
Young women with PCOS (aged 23.3±4.9 years).
Patients were assigned randomly to no treatment (n=14), metformin 850 mg two times per day (n=15), and pioglitazone 30 mg daily (n=14) for 6 months. Healthy age- and body mass index-matched women served as controls (n=14).
Brachial artery flow-mediated dilation was studied at baseline and 6 months.
Women with PCOS had higher insulin resistance and hyperandrogenism indices and lower flow-mediated dilation compared with controls. The three groups of women with PCOS did not differ at baseline. No differences were observed at follow-up in women who received no treatment. Metformin and pioglitazone improved flow-mediated dilation to a similar extent, restoring it to normal values at 6 months. Both insulin sensitizers induced favorable changes in insulin resistance and hyperandrogenism indices in women with PCOS. Independent predictors of flow-mediated dilation improvement at 6 months were treatment with insulin sensitizers and reduction in insulin resistance.
In young women with PCOS, treatment with metformin or pioglitazone for 6 months induces a similar beneficial effect on endothelial function; this may be partially attributed to an improvement in insulin resistance. Further research is needed to investigate whether treatment with insulin sensitizers in women with PCOS also reduces cardiovascular risk.
Fertility and sterility 01/2011; 95(1):203-9. · 3.97 Impact Factor
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ABSTRACT: Life exists by establishing a balanced equilibrium, called homeostasis, constantly challenged by adverse stimuli, called stressors. In response to these stimuli, a complex neurohormonal reaction exerted by the activation of the so-called stress system is initiated. The latter is activated in a coordinated fashion, leading to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chance for survival. The stress system suppressive effects on female reproduction involve suppression of the hypothalamic-pituitary-ovarian axis at the hypothalamic, pituitary, ovarian, and uterine levels. Experimental and human data suggest that adverse prenatal stimuli, of either maternal or fetal origin, acting in the developing embryo in utero, can lead to the development of short- and long-term health disorders. These include preterm birth of the offspring, low birth weight, and the development of adult diseases ranging from the metabolic syndrome to several neurodevelopmental disorders.
Annals of the New York Academy of Sciences 09/2010; 1205:69-75. · 3.15 Impact Factor
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Aris Bechlioulis, Sophia N Kalantaridou,
Katerina K Naka,
Anthoula Chatzikyriakidou,
Karim A Calis,
Antonis Makrigiannakis,
Odysseas Papanikolaou,
Apostolos Kaponis,
Christos Katsouras,
Ioannis Georgiou,
George P Chrousos,
Lampros K Michalis
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ABSTRACT: Context: The effect of early menopause on indices of vascular function has been little studied. Objective: The objective of the study was to investigate the effect of early menopause on indices of subclinical atherosclerosis and identify predictors of those indices in early menopausal women. Design, Setting, and Participants: This was a cross-sectional study that included 120 early menopausal women (age range 42-55 yr, <3 yr in menopause) recruited from the menopause outpatient clinic of an academic hospital and 24 age-matched premenopausal women. Main Outcome Measures: Brachial artery flow-mediated dilation (FMD) and common carotid intima-media thickness (IMT) were studied. Estrogen receptor (ER)-alpha (rs2234693 T-->C and rs9340799 A-->G) and ERbeta (rs4986938 A-->G) polymorphisms were studied in menopausal women. Results: FMD was significantly lower in early menopausal women compared with controls (5.43 +/- 2.53 vs. 8.74 +/- 3.17%, P < 0.001), whereas IMT did not differ between groups (P > 0.8). Severity of hot flushes was the most important independent predictor for FMD (P < 0.001) in menopausal women. Women with moderate/severe/very severe hot flushes had impaired FMD in contrast to women with no/mild hot flushes or controls. Women with no/mild hot flushes did not differ compared with controls. Age and systolic blood pressure were the main determinants of IMT (both P = 0.004). ER polymorphisms were not associated with vascular parameters. Conclusions: Impairment of endothelial function is present in the early menopausal years, whereas carotid IMT is not affected. Severity of hot flushes is the main determinant of endothelial dysfunction in early menopausal women. The studied ER polymorphisms do not offer important information on vascular health in early menopause.
The Journal of clinical endocrinology and metabolism 03/2010; 95(3):1199-206. · 6.50 Impact Factor
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ABSTRACT: The incidence of cardiovascular disease is low in healthy premenopausal women and increases with age especially after the menopause; this difference has been attributed to the loss of endogenous estrogen. Atherosclerosis is a chronic inflammatory condition of the vascular wall that may result in an acute clinical event by inducing plaque rupture/ erosion leading to thrombosis. A growing body of evidence suggests that the spectrum of the effects of estrogen on vascular pathophysiology is complex and may depend largely on the state of vascular pathology. In relatively healthy vessels, estrogen prevents the development and progression of atherosclerotic lesions, while in the presence of established atherosclerotic plaques, estrogen fails to inhibit the progression of atherosclerosis or may even trigger cardiovascular events. The mechanisms responsible for this are not yet fully elucidated. It is possible that postmenopausal estrogen/ progestogen therapy may be beneficial in perimenopausal and early menopausal women prior to atherosclerotic plaque formation, but it may not prevent progression of atherosclerotic plaques and acute cardiovascular events in older women with cardiovascular risk factors or women with established atherosclerosis. Various formulations, doses and routes of hormone therapy administration as well as the genetic background of women should also be taken into account when considering the benefit-to-risk ratio of hormone therapy use.
Current Vascular Pharmacology 02/2010; 8(2):249-258. · 2.90 Impact Factor
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[show abstract]
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ABSTRACT: The incidence of cardiovascular disease is low in healthy premenopausal women and increases with age especially after the menopause; this difference has been attributed to the loss of endogenous estrogen. Atherosclerosis is a chronic inflammatory condition of the vascular wall that may result in an acute clinical event by inducing plaque rupture/erosion leading to thrombosis. A growing body of evidence suggests that the spectrum of the effects of estrogen on vascular pathophysiology is complex and may depend largely on the state of vascular pathology. In relatively healthy vessels, estrogen prevents the development and progression of atherosclerotic lesions, while in the presence of established atherosclerotic plaques, estrogen fails to inhibit the progression of atherosclerosis or may even trigger cardiovascular events. The mechanisms responsible for this are not yet fully elucidated. It is possible that postmenopausal estrogen/progestogen therapy may be beneficial in perimenopausal and early menopausal women prior to atherosclerotic plaque formation, but it may not prevent progression of atherosclerotic plaques and acute cardiovascular events in older women with cardiovascular risk factors or women with established atherosclerosis. Various formulations, doses and routes of hormone therapy administration as well as the genetic background of women should also be taken into account when considering the benefit-to-risk ratio of hormone therapy use.
Current Vascular Pharmacology 02/2010; 8(2):249-58. · 2.90 Impact Factor
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Journal of Molecular Medicine 01/2008; 85(12):1347-9. · 4.67 Impact Factor
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ABSTRACT: To assess sexual function in women with spontaneous 46,XX primary ovarian insufficiency after at least 3 months of a standardized hormone replacement regimen.
Cross-sectional cohort, controlled.
National Institutes of Health Clinical Research Center.
Women with primary ovarian insufficiency (n = 143) and regularly menstruating controls (n = 70).
Self-administered questionnaires, 100 microg/day E(2) patch, oral medroxyprogesterone acetate 10 mg for 12 days each month for patients.
Derogatis Interview for Sexual Function Self-Report (DISF-SR).
Women with primary ovarian insufficiency had significantly lower DISF-SR composite scores compared with control women. Their serum total testosterone levels were significantly correlated with DISF-SR composite score, although this accounted for only 4% of the variance in this measure. Patients with testosterone levels below normal tended to have lower DISF-SR composite scores. Of patients with primary ovarian insufficiency, 9 of 127 (7%) scored below the second percentile on the composite sexual function score, compared with 1 of 49 control women (2%).
As assessed by the DISF-SR, sexual function is in the normal range for most young women with 46,XX spontaneous primary ovarian insufficiency who are receiving physiologic E(2) replacement. However, as a group, these young women score significantly lower on this sexual function scale than control women.
Fertility and sterility 11/2007; 90(5):1805-11. · 3.97 Impact Factor
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Postgraduate Obstetrics & Gynecology. 10/2007; 27(19):1–7.
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ABSTRACT: To systematically review evidence of the association between fibrinolytic defects and recurrent miscarriage.
MEDLINE, EMBASE, and references of retrieved articles (last update September 2006) were used.
Studies comparing the prevalence of fibrinolytic defects in patients with recurrent miscarriage and control women were reviewed. Of 111 potentially relevant studies, data from 14 were integrated with meta-analytic techniques and were presented as odds ratios (ORs).
Plasminogen activator inhibitor-1 4G/5G polymorphism (OR 1.65, 95% confidence interval [CI] 0.92-2.95) and increased plasminogen activator inhibitor activity were not significantly associated with recurrent miscarriage, although the latter showed profound heterogeneity across studies. Although factor XII C46T polymorphism is not associated with recurrent miscarriage (OR 1.07, 95% CI 0.52-2.22), factor XII deficiency is significantly associated (five studies, 1,096 women; OR 18.11, 95% CI 5.52-59.39), with minimal heterogeneity across studies. Factor XIII Val34Leu and Tyr204Phe polymorphisms were not associated with recurrent miscarriage (OR 1.24, 95% CI 0.46-3.34 and OR 2.61, 95% CI 0.45-15.16, respectively). There were no eligible studies found for the rest of the factors searched (urokinase-type plasminogen activator, tissue-type plasminogen activator, kallicrein, a2-antiplasmin, a2-macroglobulin, thrombin-activated thrombolysis inhibitor, and factor XI). Only a small minority of studies ascertained miscarriage according to specific criteria, and none of the studies provided equal examination for confounders in cases and controls.
Factor XII deficiency is associated with recurrent miscarriage. Data on the other factors either fail to show association or are quite limited.
Obstetrics and Gynecology 06/2007; 109(5):1146-55. · 4.73 Impact Factor
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ABSTRACT: To compare the prevalence of five common thrombophilic polymorphisms and their combination in women with recurrent miscarriage and a control group.
Genomic analysis using polymerase chain reaction (PCR) was carried out in patients with two or more miscarriages and controls for Factor V Leiden, Factor V A1299H (HR2), Factor II G20210A, MTHFR C677T and MTHFR A1298C. Secondary analyses were made for number of miscarriages and gestational age at miscarriage.
None the mutations was associated with significantly increased risk for recurrent miscarriage. The prevalence of combined thrombophilias (4/88 versus 2/88) did not increase the risk for miscarriage (OR 2.04, 95% CI 0.36-11.47). Although virtually all patients with thrombophilia had miscarriages<or=10 weeks, statistical significance was not reached due to the small size of the >10 weeks' subgroup. There was no difference in the distribution of Factor V Leiden (P=1.000), FII G20210A (P=0.652), and MTHFR C677T (P=0.869) between patients with two and three or more miscarriages, whereas MTHFR A1298C was more common among patients with two miscarriages (P=0.017).
Combinations of the five thrombophilic mutations studied are an uncommon event with heterogeneous pattern and they do not significantly increase the risk for miscarriage.
American journal of reproductive immunology (New York, N.Y.: 1989) 03/2007; 57(2):133-41. · 3.05 Impact Factor
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ABSTRACT: The fundamental process of implantation involves a series of steps leading to effective cross-talk between invasive trophoblast cells and the maternal endometrium. The molecular interactions at the embryo-maternal interface during the time of blastocyst adhesion and subsequent invasion are not fully understood. Embryonic trophoblast and maternal decidual cells produce corticotropin-releasing hormone (CRH) and express Fas ligand (FasL), a proapoptotic cytokine. Fas and its ligand are pivotal in the regulation of immune tolerance. Trophoblast and decidual CRH play crucial roles in implantation, as well as in the anti-rejection process that protects the fetus from the maternal immune system, primarily by killing activated T cells through Fas-FasL interaction. The potential use of CRH antagonists is presently under intense investigation. CRH antagonists have been used experimentally to elucidate the role of CRH in blastocyst implantation and invasion, early fetal immunotolerance, and premature labor.
Critical Reviews in Clinical Laboratory Sciences 02/2007; 44(5-6):461-81. · 5.25 Impact Factor
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ABSTRACT: Corticotropin-releasing hormone (CRH), a 41 amino acid peptide, is an important regulatory molecule synthesized by neurons of the parvocellular and magnocellular hypothalamic paraventricular nuclei. It acts as the major physiologic corticotropin (ACTH) secretagogue. The CRH gene is located in humans on chromosome 8. The CRH hormone family has at least four ligands, two receptors (CRH-R1 and CRH-R2), and a binding protein (CRHbp). CRH is the principal regulator of the hypothalamic-pituitary-adrenal axis. Furthermore, CRH has been identified in most female reproductive tissues including the uterus, the placenta, and the ovary. CRH produced in the endometrium may participate in decidualization, implantation, and early maternal tolerance to semiallograft embryo. Placental CRH may participate in the physiology of pregnancy, in late pregnancy complications such as preterm labor and preeclampsia, and also in the onset of parturition. Ovarian CRH is involved in follicular maturation, ovulation, and luteolysis. Increased levels of unbound placental CRH may be responsible for the hypercortisolism of the second half of pregnancy. This hypercortisolism is followed by a transient suppression of hypothalamic CRH secretion in the postpartum period. This may explain the depressive states frequently observed in the postpartum period.
Annals of the New York Academy of Sciences 01/2007; 1092:310-8. · 3.15 Impact Factor
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ABSTRACT: To determine whether women with 46,XX spontaneous premature ovarian failure have lower serum free-T levels than do control women.
Cross-sectional.
National Institutes of Health Clinical Research Center.
Women with 46,XX spontaneous premature ovarian failure (n = 130).
Evaluation while off any estrogen therapy and then again after receiving a standardized hormone regimen. Regularly menstruating control women (n = 65) were sampled during the midfollicular phase.
Serum total T by RIA after extraction and column chromatography, free T by equilibrium dialysis, and sex hormone-binding globulin by immunoradiometric assay.
While off estrogen therapy patients had a median serum free-T concentration that was statistically significantly lower than controls (2.2 vs. 3.3 pg/mL). This dropped significantly lower to 1.9 pg/mL while the patients were on physiologic transdermal E(2) therapy. This is despite the fact that sex hormone-binding globulin levels did not change. While on E(2) therapy, 13% of women (95% confidence interval, 7.9%-20.3%) had serum free-T levels below the lower limit of normal (<1.1 pg/mL).
As a group, young women with 46,XX spontaneous premature ovarian failure have reduced circulating free-T levels, both during an interval off of estrogen therapy and while on physiologic transdermal E(2) therapy.
Fertility and sterility 11/2006; 86(5):1475-82. · 3.97 Impact Factor
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ABSTRACT: Implantation of the blastocyst into the endometrium is a delicately controlled process and a prerequisite for the furtherance of the mammalian species. A complex network of molecules is involved in preparing both the endometrium and blastocyst for a successful interaction. However, the exact molecular steps are poorly understood. Studies so far have shown that disruption of certain pathways results in fertility defects. Impaired implantation is currently considered to be the most important limiting factor for the establishment of viable pregnancies in assisted reproduction. It is expected that elucidating the molecular background of the process will enable accurate diagnosis and effective treatment of infertility.
Trends in Endocrinology and Metabolism 08/2006; 17(5):178-85. · 8.11 Impact Factor
