Hanna Savolainen-Peltonen

17β-Estradiol and estradiol fatty acyl esters and estrogen-converting enzyme expression in adipose tissue in obese men and women.

CONTEXTnObesity is associated with increased circulating 17β-estradiol (E₂), but less is known about E₂ concentrations in adipose tissue. In addition to E₂, adipose tissue synthesizes E₂ fatty acyl esters (E₂-FAE).nnnOBJECTIVEnThe aim was to compare estrogen concentrations and expression of estrogen-converting enzymes in adipose tissue between severely obese men and women.nnnDESIGN AND SETTINGnTissue samples were obtained during elective surgery in University Central Hospital in the years 2008 through 2011.nnnPATIENTSnWe studied 14 men and 22 premenopausal women undergoing bariatric surgery and 10 control women operated for nonmalignant reasons.nnnINTERVENTIONSnPaired samples were taken from abdominal sc and visceral adipose tissue and serum and analyzed for E₂ and E₂-FAE by fluoroimmunoassay and liquid chromatography-tandem mass spectrometry. mRNA expression of genes was analyzed by quantitative PCR.nnnRESULTSnCompared with men, E₂ levels in sc adipose tissue in obese women were higher, along with higher relative mRNA expression of steroid sulfatase and 17β-hydroxysteroid dehydrogenases 1, 7, and 12. In men, E₂-FAE concentrations in adipose tissue were similar to E₂ but in women significantly lower compared with E₂. Adipose tissue E₂-FAE and serum E₂-FAE levels correlated positively in obese subjects. Serum E₂ did not significantly correlate with E₂ concentration or mRNA expression of genes in adipose tissue in obese men or women.nnnCONCLUSIONSnThe production of E₂ by the large adipose mass was not reflected by increased circulating E₂ concentrations in severely obese men or women. However, adipose tissue may contribute to concentrations of serum E₂-FAE.

Health-related quality of life in women with or without hot flashes: a randomized placebo-controlled trial with hormone therapy.

ObjectiveWe assessed the impact of hot flashes and various forms of hormone therapy on health-related quality of life and sexual well-being in recently postmenopausal women. MethodsWe prospectively interviewed 150 healthy women about hot flashes and health-related quality of life (using the Women’s Health Questionnaire and the McCoy Female Sexuality Questionnaire), menopause-related symptoms, and general health. The women were classified into those with (n = 72) and without (n = 78) hot flashes and treated for 6 months with transdermal estradiol (1 mg/d), oral estradiol (2 mg/d) with or without medroxyprogesterone acetate (5 mg/d), or placebo. ResultsAt baseline, hot flashes contributed most strongly to poor sleep (correlation coefficient r = −0.525, P < 0.0001), somatic symptoms such as muscle pains (r = −0.348, P < 0.0001), menstrual cycle–resembling complaints (r = −0.304, P < 0.0001), anxiety and fears (r = −0.283, P < 0.0001), decreased memory and concentration (r = −0.279, P = 0.001), and sexual behavior (r = −0.174, P = 0.035). The different hormone therapy regimens alleviated hot flashes equally effectively and were therefore combined into a single group for further analysis. In women with baseline flashes, hormone therapy use significantly improved the scores for sleep (0.787 [0.243] vs 0.557 [0.249], hormone therapy vs placebo, P = 0.001, at 6 mo), memory and concentration capacity (0.849 [0.228] vs 0.454 [0.301], P < 0.0001, at 6 mo), and anxiety and fears (0.942 [0.133] vs 0.826 [0.193], P = 0.005, at 6 mo). Hormone therapy use showed no significant impact on these variables in women without baseline flashes. ConclusionsHot flashes contribute differently to various variables affecting health-related quality of life shortly after menopause. Estradiol or an estradiol–medroxyprogesterone acetate combination similarly alleviates hot flashes and improves health-related quality of life in relation to elimination of hot flashes. Hormone therapy use does not confer any detectable quality-of-life benefit over placebo in women without disturbing baseline flashes.

Reduced risk of breast cancer mortality in women using postmenopausal hormone therapy: a Finnish nationwide comparative study.

Objective:Data are controversial on the impact of postmenopausal hormone therapy (HT) on breast cancer mortality. We analyzed nationwide Finnish data on breast cancer mortality risk in women using HT consisting of estradiol-only therapy (ET) or estrogen-progestogen therapy (EPT). Methods:In total, 489,105 women using HT in 1994 to 2009, traced from the nationwide reimbursement register, were followed from the HT initiation (3.3 million cumulative exposure years) to breast cancer death (nu200a=u200a1,578 women). The observed deaths were compared with those in the age-standardized background population. Results:The breast cancer mortality risk was reduced in all HT users with exposure for at most 5 years (standardized mortality ratio 0.56; CI 0.52-0.60), more than 5 to 10 years (0.46; 0.41-0.51), or more than 10 years (0.62; 0.56-0.68). A significantly larger risk reduction was detected in the 50 to 59 years age group (0.33; 0.29-0.37) compared with 60 to 69 (0.64; 0.59-0.70) or 70 to 79 (0.78; 0.69-0.87) years age groups. The death risk reductions in ET users tended to be larger in all age groups compared with EPT users, with a significant difference only in the 70 to 79 years age group (0.66; 0.57-0.76 vs 0.88; 0.77-1.00). The age at HT initiation, regardless whether ET or EPT, showed no association with breast cancer mortality. Conclusions:In the Finnish unselected population, breast cancer is fatal in 1 of 10 patients. Our data imply that this risk is prevalent in 1 of 20 patients with history of HT use. This is an important message for women considering or already using HT.

MicroRNA-192* impairs adipocyte triglyceride storage

We investigated the expression of miR-192* (miR-192-3p) in the visceral adipose tissue (VAT) of obese subjects and its function in cultured human adipocytes. This miRNA is a 3 arm derived from the same pre-miRNA as miR-192 (miR-192-5p) implicated in type 2 diabetes, liver disease and cancers, and is predicted to target key genes in lipid metabolism. In morbidly obese subjects undergoing bariatric surgery preceded by a very low calorie diet, miR-192* in VAT correlated negatively (r=-0.387; p=0.046) with serum triglyceride (TG) and positively with high-density lipoprotein (HDL) concentration (r=0.396; p=0.041). In a less obese patient cohort, the miRNA correlated negatively with the body mass index (r=-0.537; p=0.026). To characterize the function of miR-192*, we overexpressed it in cultured adipocytes and analyzed the expression of adipogenic differentiation markers as well as cellular TG content. Reduced TG and expression of the adipocyte marker proteins aP2 (adipocyte protein 2) and perilipin 1 were observed. The function of miR-192* was further investigated by transcriptomic profiling of adipocytes expressing this miRNA, revealing impacts on key lipogenic genes. A number of the mRNA alterations were validated by qPCR. Western analysis confirmed a marked reduction of the lipogenic enzyme SCD (stearoyl coenzyme A desaturase-1), the fatty aldehyde dehydrogenase ALDH3A2 (aldehyde dehydrogenase 3 family member A2) and the high-density lipoprotein receptor SCARB1 (scavenger receptor B, type I). SCD and ALDH3A2 were demonstrated to be direct targets of miR-192*. To conclude, the present data identify miR-192* as a novel controller of adipocyte differentiation and lipid homeostasis.

Steroid sulfatase activity in subcutaneous and visceral adipose tissue: a comparison between pre- and postmenopausal women

OBJECTIVEnAdipose tissue is an important extragonadal site for steroid hormone biosynthesis. After menopause, estrogens are synthesized exclusively in peripheral tissues from circulating steroid precursors, of which the most abundant is dehydroepiandrosterone sulfate (DHEAS). Our aim was to study activity of steroid sulfatase, an enzyme hydrolyzing DHEAS, and expression of steroid-converting enzyme genes in subcutaneous and visceral adipose tissue derived from pre- and postmenopausal women.nnnDESIGNnSerum and paired abdominal subcutaneous and visceral adipose tissue samples were obtained from 18 premenopausal and seven postmenopausal women undergoing elective surgery for non-malignant reasons in Helsinki University Central Hospital.nnnMETHODSnTo assess steroid sulfatase activity, radiolabeled DHEAS was incubated in the presence of adipose tissue homogenate and the liberated dehydroepiandrosterone (DHEA) was measured. Gene mRNA expressions were analyzed by quantitative RT-PCR. Serum DHEAS, DHEA, and estrogen concentrations were determined by liquid chromatography-tandem mass spectrometry.nnnRESULTSnSteroid sulfatase activity was higher in postmenopausal compared to premenopausal women in subcutaneous (median 379 vs 257 pmol/kg tissue per hour; P=0.006) and visceral (545 vs 360 pmol/kg per hour; P=0.004) adipose tissue. Visceral fat showed higher sulfatase activity than subcutaneous fat in premenopausal (P=0.035) and all (P=0.010) women. The mRNA expression levels of two estradiol-producing enzymes, aromatase and 17β-hydroxysteroid dehydrogenase type 12, were higher in postmenopausal than in premenopausal subcutaneous adipose tissue.nnnCONCLUSIONSnSteroid sulfatase activity in adipose tissue was higher in postmenopausal than in premenopausal women suggesting that DHEAS, derived from the circulation, could be more efficiently utilized in postmenopausal adipose tissue for the formation of biologically active sex hormones.

Estrogen Metabolism in Abdominal Subcutaneous and Visceral Adipose Tissue in Postmenopausal Women.

ContextnIn postmenopausal women, adipose tissue (AT) levels of estrogens exceed circulating concentrations. Although increased visceral AT after menopause is related to metabolic diseases, little is known about differences in estrogen metabolism between different AT depots.nnnObjectivenWe compared concentrations of and metabolic pathways producing estrone and estradiol in abdominal subcutaneous and visceral AT in postmenopausal women.nnnDesign, Setting, Patients, and InterventionsnAT and serum samples were obtained from 37 postmenopausal women undergoing surgery for nonmalignant gynecological reasons. Serum and AT estrone, estradiol, and serum estrone sulfate (E1S) concentrations were quantitated using liquid chromatography-tandem mass spectrometry. Activity of steroid sulfatase and reductive 17β-hydroxysteroid dehydrogenase enzymes was measured using radiolabeled precursors. Messenger RNA (mRNA) expression of estrogen-converting enzymes was analyzed by real-time reverse transcription quantitative polymerase chain reaction.nnnResultsnEstrone concentration was higher in visceral than subcutaneous AT (median, 928 vs 706 pmol/kg; P = 0.002) and correlated positively with body mass index (r = 0.46; P = 0.011). Both AT depots hydrolyzed E1S to estrone, and visceral AT estrone and estradiol concentrations correlated positively with serum E1S. Compared with visceral AT, subcutaneous AT produced more estradiol from estrone (median rate of estradiol production, 1.02 vs 0.57 nmol/kg AT/h; P = 0.004). In visceral AT, the conversion of estrone to estradiol increased with waist circumference (r = 0.65; P = 0.022), and estradiol concentration correlated positively with mRNA expression of HSD17B7 (r = 0.76; P = 0.005).nnnConclusionsnBoth estrone and estradiol production in visceral AT increased with adiposity, but estradiol was produced more effectively in subcutaneous fat. Both AT depots produced estrone from E1S. Increasing visceral adiposity could increase overall estrogen exposure in postmenopausal women.

Premenstrual symptoms in fertile age are associated with impaired quality of life, but not hot flashes, in recently postmenopausal women.

ObjectiveBecause premenstrual symptoms in fertile age resemble menopausal symptoms, many women with premenstrual symptoms fear that they have an increased risk for developing vasomotor symptoms in menopause. We investigated the impact of premenstrual symptoms on the occurrence and severity of menopausal vasomotor symptoms and quality of life. MethodsOne hundred fifty recently postmenopausal healthy women recorded hot flashes prospectively (23, none; 34, mild; 30, moderate; 63, severe), and their quality of life was assessed using the Women’s Health Questionnaire. We measured the occurrence of premenstrual symptoms in fertile age using the Premenstrual Symptoms Screening Tool and calculated a premenstrual score reflecting symptom severity. ResultsOne hundred seven women (89.2%) reported premenstrual symptoms (median score, 7.0; range, 0-38), which had impaired work efficiency or social relations in 64 women (53.3%). The occurrence of premenstrual symptoms was similar in women with and without hot flashes of different magnitudes, as the mean (SEM) premenstrual score was 7.8 (1.4) for no hot flashes, 5.0 (1.0) for mild hot flashes, 7.7 (1.3) for moderate hot flashes, and 9.4 (1.2) for severe hot flashes (P = 0.10). The severity of premenstrual symptoms failed to correlate with the severity of postmenopausal hot flashes (r = 0.087, P = 0.346). A history of premenstrual symptoms was associated with impaired memory and concentration capacity (r = −0.448, P < 0.001), depressive mood (r = −0.263, P = 0.02), sleep problems (r = −0.282, P = 0.01), and feeling less attractive (r = −0.260, P = 0.02) during the first menopausal years. ConclusionsThe occurrence of premenstrual symptoms in fertile age is associated with impaired quality of life, but not hot flashes, in recently postmenopausal women.

Vasomotor symptoms and metabolic syndrome

A vast majority of menopausal women suffer from vasomotor symptoms, such as hot flushes and night sweats, the mean duration of which may be up to 7-10 years. In addition to a decreased quality of life, vasomotor symptoms may have an impact on overall health. Vasomotor symptoms are associated with overactivity of the sympathetic nervous system, and sympathetic overdrive in turn is associated with metabolic syndrome, which is a known risk factor for cardiovascular disease. Menopausal hot flushes have a complex relationship to different features of the metabolic syndrome and not all data point towards an association between vasomotor symptoms and metabolic syndrome. Thus, it is still unclear whether vasomotor symptoms are an independent risk factor for metabolic syndrome. Research in this area is constantly evolving and we present here the most recent data on the possible association between menopausal vasomotor symptoms and the metabolic syndrome.

Lower Death Risk for Vascular Dementia Than for Alzheimer’s Disease With Postmenopausal Hormone Therapy Users

ContextnThere are conflicting data on postmenopausal hormone therapy (HT) and the risk of vascular dementia (VD) and Alzheimers disease (AD).nnnObjectivenWe analyzed the mortality risk attributable to VD or AD in women with a history of HT use.nnnDesign, Patients, Interventions, and Main Outcome MeasuresnFinnish women (n = 489,105) using systemic HT in 1994 to 2009 were identified from the nationwide drug reimbursement register. Of these women, 581 died of VD and 1057 of AD from 1998 to 2009. Observed deaths in HT users with <5 or ≥5 years of exposure were compared with deaths that occurred in the age-standardized female population. Furthermore, we compared the VD or AD death risk of women who had started HT at <60 vs ≥60 years of age.nnnResultsnRisk of death from VD was reduced by 37% to 39% (<5 or ≥5 years of exposure) with the use of any systemic HT, and this reduction was not associated with the duration or type (estradiol only or estradiol-progestin combination) of HT. Risk of death from AD was not reduced with systemic HT use <5 years, but was slightly reduced (15%) if HT exposure exceeded 5 years. Age at systemic HT initiation (<60 vs ≥60 years) did not affect the death risk reductions.nnnConclusionnEstradiol-based HT use is associated with a reduced risk of death from both VD and AD, but the risk reduction is larger and appears sooner in VD than AD.

New evidence for cardiac benefit of postmenopausal hormone therapy

Abstract Coronary artery disease (CAD) is still the most common killer of western women. Coronary arteries, expressing estrogen receptors, are a target for estrogen action. Prior to the Women’s Health Initiative (WHI) study, postmenopausal hormone therapy (HT) was widely advocated for primary prevention of CAD, but such use was criticized after the WHI publication. However, new data accumulated in the USA and in Europe indicate that the use of estradiol-based HT regimens does not endanger the heart, but rather, it significantly reduces the incidence of CAD events and mortality. This effect may be related to the presence of hot flushes before HT initiation, because they may indicate a greater responsiveness of the cardiovascular system to HT. To get maximal cardioprotective efficacy of HT, a woman should initiate HT as soon as symptoms occur, and preferably within the first 10 postmenopausal years. Recent guidelines for optimal use of HT recommend pauses of HT at 1–2-year intervals to see whether hot flushes and other symptoms still persist. However, new data question the safety of this policy, because acute withdrawals of estradiol from the circulation may predispose to potentially fatal CAD events. All these data support modernized guidelines for optimal HT use.