Menopausal Hormone Treatments Research Articles

Effect of menopausal hormone therapy on proteins associated with senescence and inflammation.

BackgroundEstrogen may inhibit cell senescence that contributes to age‐related disorders.This study determined the effects of menopausal hormone treatments on circulating levels of markers of cell senescence.MethodsGrowth differentiation factor 15 (GDF15), tumor necrosis factor receptor 1 (TNFR1), FAS, and macrophage inflammatory protein 1α (MIP1α) were measured in serum using multiplexed bead‐based assays and compared among menopausal women participating in the Kronos Early Estrogen Prevention Study randomized to either placebo (n = 38), oral conjugated equine estrogen (oCEE, n = 37), or transdermal 17β‐estradiol (tE2, n = 34). Serum levels of the senescent markers for each treatment were compared to placebo 36 months after randomization using the Wilcoxon rank sum test.ResultsSerum levels of GDF15, TNFR1, and FAS, but not MIP1α, were lower in both the oCEE and tE2 groups compared to placebo. The difference in levels between treatment and placebo for GDF15, TNFR1, and FAS were greater for oCEE [−108 pg/mL (p = .008), −234 pg/mL (p = .0006), and −1374 pg/mL (p < .0001), respectively] than for tE2 [−76 pg/mL (p = .072), −105 pg/mL (p = .076), and −695 pg/mL (p = .036), respectively]. Additionally, TNFR1 showed a positive association with time past menopause (correlation = 0.255, p = .019).ConclusionsCirculating levels of some markers of cell senescence were lower in menopausal women treated with oCEE and tE2 compared to placebo. Differences in the magnitude of effect of the two active treatments may reflect the differences in circulating levels of estrogen metabolites due to formulation and mode of delivery. These data generate new hypotheses with regard to the effects of menopause on the biology of aging.

Effect of Natural Menopause and Hormone Therapy on Markers of Cellular Senescence

BackgroundAccumulation of senescent cells and the release of proteins from those cells contribute to aging‐related disorders. Estrogen may reduce physiological changes associated with aging through inhibition of cell senescence. This study aimed to determine the effects of menopausal hormone treatments on circulating levels of cell senescence markers.MethodsGDF 15, TNF R1, FAS, and MIP1α were measured in serum using bead‐based assays and compared among women who were within 3 years of natural menopause (mean age 52 years) participating in the Kronos Early Estrogen Prevention Study (KEEPS). Women were randomized to either placebo (n=38), oral conjugated equine estrogen (oCEE, n=37), or transdermal 17β‐estradiol (tE2, n=34). Serum levels of the senescent markers for each treatment group were compared to placebo 36 months after randomization using the Wilcoxon rank‐sum test.ResultsSerum levels of GDF 15, TNF R1, and FAS but not MIP1α were lower in both the oCEE and tE2 groups compared to placebo. However, the difference in levels between treatment and placebo were greater for oCEE [−108 pg/mL (p=0.008), −234 pg/mL (p=0.0006), and −1374 pg/mL (p&lt;.0001), respectively] than for tE2 [−76 pg/mL (p=0.072), −105 pg/mL (p=0.076), and −695 pg/mL (p=0.036), respectively].ConclusionsIn recently menopausal women, oCEE and tE2 reduced circulating levels of some markers of cell senescence. Differences in the magnitude of effect may reflect the differences in circulating levels of 17β estradiol, estrone, and sulfonated estrogens between the two active treatments.Support or Funding InformationThe research is supported by the Kronos Early Estrogen Prevention Study, NIA U54‐AG44170, and the Mayo Fnd.

Menopausal hormone therapy, blood thrombogenicity, and development of white matter hyperintensities in women of the Kronos Early Estrogen Prevention Study.

Development of white matter hyperintensities (WMH) in the brain is associated with blood thrombogenicity in recently menopausal women. This study examined the influence of menopausal hormone treatments (MHTs) on this association. Measures of blood thrombogenicity were examined in women of the Kronos Early Estrogen Prevention Study (n = 95) who had brain magnetic resonance imaging before and during the 48 months of randomization to transdermal 17β-estradiol (n = 30), oral conjugated equine estrogen (n = 29) both with progesterone for 12 days per month or placebo pills and patch (n = 36). Principal components (PCs) analysis was used to reduce the dimensionality of 14 markers of platelet activation and blood thrombogenicity. The first 5 PCs were assessed for association with treatment and changes in WMH. Within-person slopes were obtained to capture the extent of WMH change for each woman. WMH increased in all groups over the 48 months (P = 0.044). The partial effect of PC1, representing an average of six thrombogenicity variables (microvesicles derived from endothelium, leukocytes, and monocytes, and positive for tissue factor and adhesion molecules) on WMH was significant (P = 0.003). PC3, reflecting a contrast of platelet microaggregates and adenosine triphosphate secretion versus total platelet count, differed across groups (P = 0.006) with higher scores in the oral conjugated equine estrogen group. The global association between PCs and WMH increase, however, did not differ significantly by MHT (P = 0.207 for interaction between MHT and PC's). In recently menopausal women, the type of MHT did not significantly influence the association of markers of blood thrombogenicity with development of WMH in the brain.

Individualized medicine: Sex, hormones, genetics, and adverse drug reactions.

Clinically relevant adverse drug reactions differ between men and women. The underlying physiological and pharmacological processes contributing to these differences are infrequently studied or reported. As gene expression, cellular regulatory pathways, and integrated physiological functions differ between females and males, aggregating data from combined groups of men and women obscures the ability to detect these differences. This paper summarizes how genetic sex, that is, the presence of sex chromosomes XY for male or XX for female, and the influence of sex hormones affect transporters, receptors, and enzymes involved in drug metabolism. Changing levels of sex steroids throughout life, including increases at puberty, changes with pregnancy, and decreases with age, may directly and indirectly affect drug absorption, distribution, metabolism, and elimination. The direct and indirect effects of sex steroids in the form of exogenous hormones such as those used in hormonal contraceptives, menopausal hormone treatments, transgender therapy, and over‐the‐counter performance enhancing drugs may interfere with metabolism of other pharmaceuticals, and these interactions may vary by dose, formulation, and mode of delivery (oral, injection, or transdermal) of the steroid hormones. Few drugs have sex‐specific labeling or dosing recommendations. Furthermore, there is limited literature evaluating how the circulating levels of sex steroids impact drug efficacy or adverse reactions. Such research is needed in order to improve the understanding of the impact of sex hormones on pharmacological therapies, particularly as medicine moves toward individualizing treatments.

Risk factors of neurovascular ageing in women.

Biological sex and changes in sex hormones throughout life influence all aspects of health and disease. In women, changes in sex hormonal status reflect ovarian function, pregnancy and the use of exogenous hormonal treatments. Longitudinal data from defined cohorts of women will help to identify mechanisms by which the hormonal milieu contributes to cerebrovascular ageing, brain structure and ultimately cognition. This review summarises the phenotypes of three cohorts of women identified through the medical records‐linkage system of the Rochester Epidemiology Project and the Mayo Clinic Specialized Center of Research Excellence (SCORE) on Sex Differences: (i) menopausal women with histories of normotensive or hypertensive pregnancies; (ii) women who had bilateral oophorectomy ≤45 years of age; and (iii) women who experienced natural menopause and used menopausal hormone treatments for 4 years. Data from these cohorts will influence the design of follow‐up studies concerning how sex hormonal status affects neurovascular ageing in women.

The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned?

Objective:The Kronos Early Estrogen Prevention Study (KEEPS) was designed to address gaps in understanding the effects of timely menopausal hormone treatments (HT) on cardiovascular health and other effects of menopause after the premature termination of the Women's Health Initiative.Method:The KEEPS was a randomized, double-blinded, placebo-controlled trial to test the hypothesis that initiation of HT (oral conjugated equine estrogens [o-CEE] or transdermal 17β-estradiol [t-E2]) in healthy, recently postmenopausal women (n = 727) would slow the progression of atherosclerosis as measured by changes in carotid artery intima-media thickness (CIMT).Results:After 4 years, neither HT affected the rate of increase in CIMT. There was a trend for reduced accumulation of coronary artery calcium with o-CEE. There were no severe adverse effects, including venous thrombosis. Several ancillary studies demonstrated a positive effect on mood with o-CEE, and reduced hot flashes, improved sleep, and maintenance of bone mineral density with both treatments. Sexual function improved with t-E2. There were no significant effects of either treatment on cognition, breast pain, or skin wrinkling. Variants of genes associated with estrogen metabolism influenced the age of menopause and variability in effects of the HT on CIMT. Platelet activation associated with the development of white matter hyperintensities in the brain.Conclusions:KEEPS and its ancillary studies have supported the value and safety of the use of HT in recently postmenopausal women and provide a perspective for future research to optimize HT and health of postmenopausal women. The KEEPS continuation study continues to pursue these issues.

Menopausal hormone treatments and risk of cardiovascular diseases: modern view

Estrogens have a multifactorial protective effect on various components of the cardiovascular system, and postmenopause in women is associated with an increased incidence of cardiovascular disease. Admission of menopausal hormone therapy helps to reduce the risk of cardiovascular events, but the perceived benefit far outweighs the risks in cases where women begin treatment no later than at the age of 60 or 10 years after menopause. Studies have shown that the combination of estradiol and drospirenone is effective and safe in terms of preventing cardiovascular diseases. The antiandrogenic effect of drospirenone has additional metabolic effects that may be preferable in certain groups of postmenopausal patients.

Prior Menopausal Hormone Treatments And Association of Peripheral Markers of Neurovascular Unit Integrity And β‐amyloid in The Brains of Menopausal Women

BackgroundBreak down of the blood brain barrier and activation of brain cells are implicated in progression of deposition of β‐amyloid that is associated with the pathophysiology of Alzheimer's disease. A previous study from our group indicated that deposition of β‐amyloid may be reduced in the brains of menopausal women treated with transdermal 17β‐estradiol. This study aimed to determine the association of peripheral microvesicles carrying markers of cells of the neurovascular unit with β‐amyloid in the brains of menopausal women and if the association was affected by prior menopausal hormone treatments (MHT).MethodsMenopausal women previously enrolled in the Kronos Early Estrogen Prevention Study at Mayo Clinic underwent β‐amyloid positron emission tomography (PET) imaging of their brains 3 years following treatment with either placebo (PL, n=29), transdermal 17β‐estradiol (tE2; n=21), or oral conjugated equine estrogen (oCEE; n=17) for 4 years. Microvesicles (MV) were isolated from peripheral venous blood by differential centrifugation and analyzed by flow cytometry using fluorophore conjugated antibodies directed toward total tau, β‐amyloid 1‐42 (Ab1‐42), neuron specific class III β‐tubulin (Tuj1), microglia ionized calcium adaptor molecule 1(Iab‐1), glial fibrillar acid protein (GFAP), and low density lipoprotein receptor‐related protein 1. Principal components analysis was used to reduce the dimensionality of the 6 brain markers to 2 principal components (PCs). Proportional odds ordinal logistic regression analysis was used to regress deposition of β‐amyloid on the 2 PCs with and without adjustment for MHT group.ResultsNumber of blood MV positive for Ab1‐42 differed significantly among MHT groups (median [IQR]: 6.06 [2.11, 12.55] in the PL; 2.49 [0.73, 3.59] in the tE2 and 4.96 [0.83, 10.31] in the oCEE; P=0.036). The first 2 PCs explain 58% of the variance of the 6 markers. PC#1 represented a contrast between MV‐Iab‐1 and the MV‐GFAP and MV‐Tuj1. In multivariable models, brain β‐amyloid load positively associated with the first PC after adjustment for MHT (P= 0.006).ConclusionMV derived from cells of the neurovascular unit can be detected in peripheral blood, and, when combined into summary scores, showed an association with deposition of β‐amyloid in the brain that is independent of MHT.Support or Funding InformationSupported by grants from NIH P50 AG044170 and the Mayo FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Association between Cerebrovascular Reactivity and Intravascular Cellular Activation in Postmenopausal Women Following Use of Menopausal Hormone Treatments

Cerebrovascular reactivity to hypercapnia, an estimate of microvascular responses in the brain, is increased during menopausal hormone treatment (MHT) in postmenopausal women. It is unclear whether this effect of MHT continues beyond the treatment period. We hypothesized that prior MHT use would not affect cerebrovascular reactivity 3 years after treatment. In addition, we have previously shown that cerebrovascular reactivity is associated with vascular activation in postmenopausal women with elevated cardiovascular risk. We hypothesized that cerebrovascular reactivity is not associated with markers of intravascular cellular activation in postmenopausal women with low cardiovascular risk who are within 10 years of menopause. Cerebrovascular reactivity to hypercapnia was measured in 58 postmenopausal women from the Kronos Early Estrogen Prevention Study at Mayo Clinic 3 years after the cessation of MHT [oral conjugated equine estrogen (oCEE), n=15; transdermal 17β‐estradiol (tE2, n=22); or placebo (PLA, n=23)]. Cerebrovascular reactivity was estimated from the middle cerebral artery flow velocity (MCAv) response to hypercapnia. Mean arterial blood pressure (MAP) was measured continuously throughout the protocol. Fasting blood was analyzed for a set of 14 activation markers of platelet and endothelial cells, inflammation and thrombogenicity. Principal components (PC) analysis was used to reduce these measures to fewer dimensions on which the associations of intravascular cellular activation with cerebrovascular reactivity could be based. Women were 60±3 years of age with a body mass index of 28±4 Kg/m2. MAP (99±14 mmHg in PLA, 97±7 mmHg in tE2, 98±9 mmHg in oCEE; p&gt;0.90) and MCAv (60±14 cm/s in PLA, 68±20 cm/s in tE2, 71±18cm/s in oCEE; p&gt;0.16) did not differ among groups. Cerebrovascular reactivity did not differ among women based on previous MHT randomization (1.2±0.7 cm/s/mmHg in PLA, 1.4±1.0 cm/s/mmHg in tE2 and 1.7±1.0 cm/s/mmHg in oCEE; p&gt;0.17). The 14 markers of intravascular cellular activation were reduced to five PC that did not differ based on prior MHT assignment. There was no overall association of cellular activation PC with cerebrovascular reactivity. Effects of MHT on cerebral microvascular reactivity do not extend beyond the time of menopausal hormone treatment. Intravascular cellular activation does not alter cerebrovascular reactivity to hypercapnia in postmenopausal women with low cardiovascular risk profiles 3 years after the cessation of MHT.Support or Funding InformationNIH grant P50 AG44170This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impact of Menopausal Hormone Treatments on Intravascular Cellular Activation and Development of White Matter Hyperintensities in Healthy Postmenopausal Women

ObjectiveBlood thrombogenicity and vascular inflammation may influence development of white matter hyperintensities (WMH) in the brain. This study aimed to determine if menopausal hormone treatments (MHT) modified that association in recently menopausal women who were enrolled in the Kronos Early Estrogen Prevention Study (KEEPS) at Mayo Clinic.MethodsWomen (n=95) underwent MRI prior to and at 18, 36 and 48 months after randomization to either transdermal 17β‐estradiol (tE2, n=30), conjugated equine estrogen (oCEE, n=29) both with progesterone for 12 days per month or placebo pills and patch (PBO, n=36). Fasting blood was analyzed for a set of 14 activation markers of platelets and endothelial cells, inflammation, and thrombogenicity. Principal components (PC) analysis was used to reduce dimensionality of these markers, and the first 5 PC identified were then assessed for association with treatment and changes in WMH.ResultsWMH increased in all groups over the 48 months of treatment with greater increases in the oCEE compared to tE2 and PBO (P=0.015). The 5 PC explained 62% of the variation in cellular activation markers. A global test of these 5 PC revealed a borderline association with treatment group (P=0.059), with the PC reflecting total platelet count, platelet microaggregates and ATP secretion showing higher scores in the oCEE compared to the other groups (P=0.006). The change in WMH over the 48 months of MHT showed an overall association with the 5 PC (P=0.026), the most prominent of which was the first PC reflecting vascular inflammation by number of blood microveicles (MV) from activated monocytes and endothelial cells and MV positive for intercellular adhesion molecule 1 (P=0.001). There was no evidence that this association differed by MHT.ConclusionMarkers of blood thrombogenicity and inflammation may influence development of WMH in the brain but this relationship may be influenced by factors other than the type of MHT used in the KEEPS study.Support or Funding InformationNIH P50 AG44170This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of oral versus transdermal menopausal hormone treatments on self-reported sleep domains and their association with vasomotor symptoms in recently menopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS).

Objective:This study determined whether two different formulations of hormone therapy (HT): oral conjugated equine estrogens (o-CEE; 0.45 mg/d, n = 209), transdermal 17β-estradiol (t-E2; 50 μg/d, n = 201) plus cyclic progesterone (Prometrium, 200 mg) or placebo (PBO, n = 243) affected sleep domains in participants of the Kronos Early Estrogen Prevention Study.Methods:Participants completed the Pittsburgh Sleep Quality Index at baseline and during the intervention at 6, 18, 36, and 48 months. Global sleep quality and individual sleep domain scores were compared between treatments using analysis of covariance, and correlated with vasomotor symptom (VMS) scores using Spearman correlation coefficients.Results:Global Pittsburgh Sleep Quality Index scores (mean 6.3; 24% with score >8) were similar across groups at baseline and were reduced (improved sleep quality) by both HT (average change −1.27 [o-CEE] and −1.32 [t-E2]) when compared with PBO (−0.60; P = 0.001 [o-CEE vs PBO] and P = 0.002 [t-E2 vs PBO]). Domain scores for sleep satisfaction and latency improved with both HT. The domain score for sleep disturbances improved more with t-E2 than o-CEE or PBO. Global sleep scores significantly correlated with VMS severity (rs = 0.170, P < 0.001 for hot flashes; rs = 0.177, P < 0.001 for night sweats). Change in scores for all domains except sleep latency and sleep efficiency correlated with change in severity of VMS.Conclusions:Poor sleep quality is common in recently menopausal women. Sleep quality improved with both HT formulations. The relationship of VMS with domains of sleep suggests that assessing severity of symptoms and domains of sleep may help direct therapy to improve sleep for postmenopausal women.

Sex hormone therapy and progression of cardiovascular disease in menopausal women.

One of the most controversial health decisions facing women is deciding upon the use of hormonal treatments for symptoms of menopause. This brief review focuses on the historical context of use of menopausal hormone treatments (MHT), summarizes results of major observational, primary and secondary prevention studies of MHT and cardiovascular (CV) outcomes, provides evidence for how sex steroids modulate CV function and identifies challenges for future research. As medicine enters an era of personalization of treatment options, additional research into sex differences in the aetiology of CV diseases will lead to better risk identification for CV disease in women and identify whether a woman might receive CV benefit from specific formulations and doses of MHT.

Age and Long-Term Hormone Treatment Effects on the Ultrastructural Morphology of the Median Eminence of Female Rhesus Macaques

The median eminence (ME) of the hypothalamus comprises the hypothalamic nerve terminals, glia (especially tanycytes) and the portal capillary vasculature that transports hypothalamic neurohormones to the anterior pituitary gland. The ultrastructure of the ME is dynamically regulated by hormones and undergoes organizational changes during development and reproductive cycles in adult females, but relatively little is known about the ME during aging, especially in nonhuman primates. Therefore, we used a novel transmission scanning electron microscopy technique to examine the cytoarchitecture of the ME of young and aged female rhesus macaques in a preclinical monkey model of menopausal hormone treatments. Rhesus macaques were ovariectomized and treated for 2 years with vehicle, estradiol (E₂), or estradiol + progesterone (E₂ + P₄). While the overall cytoarchitecture of the ME underwent relatively few changes with age and hormones, changes to some features of neural and glial components near the portal capillaries were observed. Specifically, large neuroterminal size was greater in aged compared to young adult animals, an effect that was mitigated or reversed by E₂ alone but not by E₂ + P₄ treatment. Overall glial size and the density and tissue fraction of the largest subset of glia were greater in aged monkeys, and in some cases reversed by E₂ treatment. Mitochondrial size was decreased by E₂, but not E₂ + P₄, only in aged macaques. These results contrast substantially with work in rodents, suggesting that the ME of aging macaques is less vulnerable to age-related disorganization, and that the effects of E₂ on monkeys' ME are age specific.

Longitudinal effects of menopausal hormone treatments on platelet characteristics and cell-derived microvesicles

Activated platelets serve as a catalyst for thrombin generation and a source of vasoactive and mitogenic factors affecting vascular remodeling. Oral menopausal hormone treatments (MHT) may carry greater thrombotic risk than transdermal products. This study compared effects of oral and transdermal MHT on platelet characteristics, platelet proteins, and platelet-derived microvesicles (MV) in recently menopausal women. Platelets and MV were prepared from blood of a subset of women (n = 117) enrolled in the Kronos Early Estrogen Prevention Study prior to and after 48 months of treatment with either oral conjugated equine estrogen (0.45 mg/day), transdermal 17β-estradiol (50 µg/day), each with intermittent progesterone (200 mg/day for 12 days a month), or placebo pills and patch. Platelet count and expression of platelet P-selectin and fibrinogen receptors were similar across groups. An aggregate measure of 4-year change in vasoactive and mitogenic factors in platelet lysate, by principle component analysis, indicated significantly lower values in both MHT groups compared to placebo. Increases in numbers of tissue factor positive and platelet-derived MV were significantly greater in the transdermal compared to placebo group. MHT was associated with significantly reduced platelet content of vasoactive and mitogenic factors representing a potential mechanism by which MHT may affect vascular remodeling. Various hormonal compositions and doses of MHT could differentially regulate nuclear transcription in bone marrow megakaryocytes and non-genomic pathways in circulating platelets thus determining numbers and characteristics of circulating MV. Thrombotic risk associated with oral MHT most likely involves liver-derived inflammatory/coagulation proteins rather than circulating platelets per se.

Longitudinal Effects of Menopausal Hormone Treatments (MHT) on Platelet Characteristics and Cell‐Derived Microvesicles

ObjectiveActivated platelets serve as a catalyst for thrombin generation. Furthermore, oral MHT may carry greater thrombotic risk than transdermal products. This study compared effects of oral and transdermal MHT on platelet characteristics including platelet‐derived microvesicles (MV) in recently menopausal women.MethodsPlatelets and MV were prepared from blood of a subset of women (n=117) enrolled in the Kronos Early Estrogen Prevention Study prior to and after 4 years of treatment with either oral conjugated equine estrogen (0.45 mg, oCEE), transdermal 17β estradiol (50 µg/day, tE2), each with intermittent progesterone (200 mg/day for 12 days a month), or placebo pills and patch.ResultsPlatelet count, and activated platelet P‐selectin and fibrinogen‐binding receptor expression were similar across groups. Numbers of tissue factor positive and platelet‐derived MV increased significantly in the tE2 compared to placebo.ConclusionsFour years of MHT did not increase thrombogenic characteristics of platelets. Thrombotic risk associated with oral MHT most likely involves liver‐derived proteins than platelets per se. Differential effects of oCEE and tE2 on circulating MV may reflect the hormonal composition of the two formulations on non‐genomic pathways in circulating platelets.FundingThis work was supported by grants from the Aurora Foundation to the Kronos Longevity Research Institute, NIH HL90639, UL1TR000131, American Heart Association‐ Scientist Development Grant, AHA 08‐30503Z, American Heart Association, Grant‐in‐Aid, 12GRNT12050147, and the Mayo Foundation.

Effects of menopausal hormone treatments on prostanoid levels and platelet sensitivity to cyclic AMP activation in healthy, recently menopausal women

Estrogen modulates the prostanoids prostacyclin (PGI2) and thromboxane A2 (TXA2) which contribute to vascular hemostasis in endothelium and platelets. Estrogen decreases in women at menopause, and menopausal hormone therapy (MHT) may increase risk of thrombosis. This study aimed to determine effects of MHT on serum prostanoid levels and on prostanoid‐related platelet functions in healthy, recently‐menopausal women. Women (age 52.3±2.3 yrs; n=115) enrolled in the Kronos Early Estrogen Prevention Study (KEEPS) were randomized to either: 1) oral conjugated equine estrogen, 2) transdermal 17β estradiol each with intermittent oral progesterone or 3) placebo, for 48 months. Serum PGI2 and TXA2 levels were assessed by quantification (ng/ml) of their stable metabolites 6‐k‐PGF1α and TXB2, respectively. Initial TXB2 levels (46.9±7.5) were unchanged (P&gt;; 0.05) after 48 months in each treatment group. However, 6‐k‐PGF1α decreased from 2.1±0.2 to 1.4±0.1 at 48 months in combined groups, but was statistically significant (1.5±0.3) only in the transdermal group. Inhibition of platelet ATP secretion by PGE1 did not correlate with serum 6‐k‐PGF1α levels. These results suggest that serum PGI2 levels decrease with age in menopausal women and are unaffected by MHT. Factors other than changes in serum prostanoids may impose thrombotic risk associated with MHT. (Supported by the Aurora Fnd, NIH HL88988 and Mayo Clinic).

Association of mitogen activated protein kinase genetic polymorphism with carotid intima medial thickness (CIMT) in women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS)

Menopausal hormone treatments (MHT) may limit progression of CIMT, a measure of atherosclerosis, but pose a risk for ischemic stroke. To test candidate gene variation for an association with CIMT, DNA from 714 women participating in KEEPS, a clinical trial of MHT to prevent progression of atherosclerosis, was genotyped using custom Illumina Infinium iSelect chemistry. Single nucleotide polymorphisms (SNPs; 13,229) were genotyped within 769 genes within the anticoagulant, procoagulant, fibrinolytic or innate immunity pathways. Of these SNPs, 75 were removed due to call rate&lt;0.95, relatedness, duplication, and misidentification; 1275 were removed for quality control. There were 504 ancestry informative markers (AIM). Percent of European ancestry using AIM, age at enrollment and pulse pressure correlated positively with CIMT. Using logistic regression to adjust for these, one SNP (rs2236935 of MAP4K4 on chromosome 2) associated positively with CIMT (p‐value = 5.771e‐06). This gene encodes a protein of the serine/threonine protein kinase family involved in cytokine signaling pathways related to innate immunity, development of type II diabetes, and response to environmental stress. Whether this SNP remains associated with changes in CIMT in women randomized to hormonal treatment in KEEPS remains to be determined. (Supported by grants from the Aurora Foundation, NIH HL90639 and the Mayo Foundation)

Non-Hormonal Treatment Strategies for Vasomotor Symptoms

Hot flashes (or flushes) are the most commonly reported symptoms during the menopause transition and early postmenopausal years, particularly in Western societies; they affect 60-90% of women and can lead to significant physical discomfort and functional impairment. The emergence of hot flashes and night sweats (also known as vasomotor symptoms [VMS]) coincide with a period in life that is also marked by dynamic changes in hormone and reproductive function that interconnect with the aging process, changes in metabolism, lifestyle behaviours and overall health. Estrogen-based therapies have long been the treatment of choice for women suffering from VMS. More recent concerns over long-term safety of menopausal hormone treatments, however, have led physicians and patients to pursue non-hormonal strategies to alleviate their symptoms. In this article, we review most of the efficacy and safety data on non-hormonal treatments for VMS published over the past 20 years. We discuss the evidence for treating symptomatic women in different clinical scenarios, e.g. VMS with and without concomitant depression or VMS following the use of anti-estrogen therapies. Overall, efficacy data support the use of some psychotropic medications, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and gabapentin. Complementary and alternative methods for VMS also showed limited but promising results, although more definitive studies are warranted. Clinicians should therefore be able to tailor treatment strategies for those who are unable or unwilling to use hormones to alleviate VMS and improve overall functioning and quality of life.

Copy number of human SULT1A1 gene among newly menopausal Caucasion women

There is large variation in response to menopausal hormone treatments among women and it remains unclear as to what genetic factors might increase risk of breast cancer in women using such treatments to relieve symptoms of menopause. SULT1A1 is a ubiquitous enzyme involved in the metabolism of steroid hormones including estrogen. A number of polymorphisms in the gene for this enzyme are associated with various cancer risks and the activity level of the enzyme is correlated closely with variation in copy number of the gene. This pilot study evaluated SNP variation and copy number of SULT1A1 in a subset of women (n=156) being screened for the Kronos Early Estrogen Prevention Study (KEEPS). All participants gave written informed consent. DNA prepared from blood was genotyped for SULT1A1 copy number, rs3760091 and rs750155 from the promoter region of SULT1A1, and rs9282861 from the coding region (SULT1A1*2 variant). In this cohort, 5.2% had 1 copy of SULT1A1, 65.2% had 2 copies, 23.9% had 3 copies, and 5.8% had 4 copies. Previously reports of the allele frequency for the three SNPs did not take into account gene copy number. When copy number was taken into account, allele frequency was significantly different, a fact that will have to be taken into account in future genotype‐phenotype correlations. (Supported by grants from the Kronos Longevity Research Institute, NIH HL90639, RR24150 and GM61388.)