Fertility counselling and fertility preservation among early onset female cancer patients-A Finnish register-based study.

INTRODUCTION: Advances in multimodality cancer treatments have increased long-term survival rates for early onset cancer patients, with 5-year survival rates reaching 80% in Northern Europe. According to recent recommendations, clinicians should, as early as possible, inform cancer patients about the impact that cancer treatment may have on their fertility. Still, there is limited published data on fertility counselling (FC) and fertility preservation (FP) for cancer patients. METHODS: This register-based study used hospital records to identify female cancer patients in the hospital district (n = 192) who received FC at the age of 16-42 years between 2011 and 2019. RESULTS: Altogether, 97 (50.5%) cancer patients were eligible for FP. Of these, 55 (56.7%) underwent FP, whereas 42 (43.3%) declined. Women undergoing FP were recommended cancer treatments with a higher risk of infertility (p = 0.01), and women with breast cancer were more prone to undergo FP than women with lymphoma (p = 0.043). In FP treatment cycles, the mean number of oocytes retrieved (13.9 ± 7.7 vs. 12.0 ± 6.5, p = 0.04) and transferrable embryos (4.7 ± 2.9 vs. 3.7 ± 2.8, p = 0.002) was higher among cancer patients compared to age-matched comparisons with male or tubal factor infertility. The total mean gonadotropin dose used was higher among cancer patients (2243 ± 963 IU vs. 1679 ± 765 IU, p < 0.001). CONCLUSION: We conclude that a good ovarian response during FP can be achieved in female cancer patients.

Serum erythropoietin level is increased during stimulation for IVF but not in OHSS.

BACKGROUND: Erythropoietin (Epo) is a potent vascular growth factor that induces angiogenesis and antiapoptotic signalling. We investigated whether the development of numerous follicles and corpora lutea during in vitro fertilization (IVF) cycle affects circulating Epo levels and further, if Epo could be used as a novel marker for ovarian hyperstimulation syndrome (OHSS). METHODS: 24 women were included in the uncomplicated IVF group and 35 women in the OHSS group. Repeated blood samples from both groups were analysed for Epo, progesterone, blood haemoglobin, and creatinine. Follicular fluid from the IVF group was analysed for Epo and progesterone. Repeated measure analysis was performed for the variables and circulating Epo levels were compared between the IVF group and early OHSS. Furthermore, related growth factors, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF-1) were analysed from subgroup of women to test for correlation with Epo. RESULTS: During IVF, circulating Epo increased from natural mid-luteal phase to stimulated mid-luteal phase (median 9.5; 95% CI 7.2-13.4 IU/L and 12.5; 10.3-13.4 IU/L; p = 0.003). In cycles resulting in pregnancy, Epo level decreased 14 days after oocyte pick-up (OPU) and remained low thereafter. In cycles not resulting in pregnancy, Epo level increased again 35 days after OPU. Follicle fluid Epo concentration was 1.5 times higher than the serum concentration (median 15.4; 95% CI 10.4-19.2 IU/L vs. 10.2; 8.8-12.7; p = 0.006). There was no difference in circulating Epo concentration between early OHSS and uncomplicated IVF. Circulating Epo did not correlate with VEGF or HIF-1. CONCLUSIONS: Circulating Epo levels fluctuate during IVF cycle. We hypothesise this may suggest Epo's involvement in ovarian physiology and angiogenesis. However, Epo was not a clinical marker for OHSS.

Pre-eclampsia and cardiovascular risk: a long-term nationwide cohort study on over 120 000 Finnish women.

OBJECTIVES: To investigate the impact of pre-eclampsia on the future cardiovascular risk in Finnish women DESIGN: A registry-based nationwide controlled cohort study. SETTING: Women hospitalised for pre-eclampsia in 1969-1993 and control women with a history of normotensive pregnancies followed from the pre-eclampsia diagnosis until 2019 for cardiovascular outcomes. PARTICIPANTS: 31 688 women with and 91 726 control women without a history of pre-eclampsia. PRIMARY OUTCOME MEASURES: Incidences of and deaths from ischaemic heart disease (IHD), myocardial infarction (MI) and stroke. RESULTS: In total, 25 813 (81.5%) women had pre-eclampsia without severe features, 4867 (15.4%) had pre-eclampsia with severe features and 1006 (3.2%) women developed eclampsia. Women with a history of pre-eclampsia showed elevated risks for IHD (HR 1.52, 95% CI 1.44 to 1.59), MI (HR 1.66, 95% CI 1.52 to 1.81) and stroke (HR 1.40, 95% CI 1.32 to 1.48). The risks for death from IHD (HR 1.50, 95% CI 1.28 to 1.75), MI (1.63, 95% CI 1.30 to 2.05) and stroke (1.44, 95% CI 1.03 to 2.01) were also elevated. Pre-eclampsia with severe features or eclampsia was accompanied with 15% higher IHD risk, 19% higher MI risk and 26% higher stroke risk than pre-eclampsia without severe features. The highest risk elevations of 30% for IHD, 32% for MI and 30% for stroke were observed in women with recurrent pre-eclampsia (n=4180). CONCLUSION: Pre-eclampsia-related significant elevations in CVD risks of Finnish women with inherently high risk for these diseases were of the same magnitude as reported previously from other countries. Thus, women with a history of pre-eclampsia should be screened and treated early for modifiable cardiovascular risk factors.

Sex Steroid Hormone Analysis in Human Tear Fluid Using a Liquid Chromatography-Mass Spectrometry Method.

The marked sexual dimorphism prevalent in inflammatory/autoimmune diseases is mostly due to sex hormone actions. One common eye disease that disproportionately affects women is dry eye. Thus, our aim was to optimise our highly sensitive liquid chromatography-tandem mass spectrometry method for steroid hormone quantification in tear fluid (TF). We used tears and matched serum samples from 10 heathy individuals. Estrone, estradiol testosterone, progesterone, androstenedione, and dehydroepiandrosterone, were quantified with an HPLC coupled with a Triple Quad 5500 MS. Estrone was measured in 80% of female and 20% of male TF samples (mean ± SD, 68.9 ± 62.2 pmol/L), whereas estradiol was undetectable in tears. Progesterone was identified in half of the female tear samples (2.91 ± 3.47 nmol/L) but in none of the male samples, whereas testosterone was quantifiable only in male tears (0.24 ± 0.1 nmol/L). TF hormone levels were, on average, from 1.4% to 55% of systemic values. Estrone, progesterone, and testosterone levels in tears correlated with the matching serum samples (r = 0.82, 0.79, and 0.85, respectively), but androstenedione and dehydroepiandrosterone showed no correlations. Our LC-MS/MS method could detect five out of the six steroid hormones studied in individual human TF samples and could therefore be used to analyse the role of sex steroids in eye diseases.

Somatic Health and Psychosocial Background Among Finnish Adolescents with Gender Dysphoria Seeking Hormonal Interventions.

Purpose: Although the number of young adults suffering from gender dysphoria (GD) is increasing, reports focusing on their somatic health remain scarce. We studied the somatic health, pubertal development, psychosocial background, and interest regarding gender-affirming surgical treatment of Finnish adolescents seeking gender-affirming hormonal treatment (GAHT). Methods: In this retrospective register study at an adolescent gynecology clinic in Helsinki University Hospital, Finland we included 124 adolescents diagnosed with GD and referred to GAHT between January 1, 2011 and December 31, 2018. This cohort covered two thirds of all Finnish adolescents referred to GAHT during the follow-up. Data on the general adolescent population were obtained from the Finnish School Health Promotion (SHP) study of year 2017. Results: Most adolescents were assigned female at birth. Sex ratio increased from 1.2 in 2012 to 5.2 in 2017. One-third of the patients were overweight or obese (body mass index [BMI] >25 kg/m2). Other somatic comorbidities were rare. Interest toward reconstructive genital surgery was more common among male-to-female than female-to-male patients (80% vs. 22%, respectively, p<0.001). Depression (29%) and anxiety (19%) were common psychiatric comorbidities. Parental divorce rate (57%) was higher than in the general adolescent population in Finland (23%, p<0.001). Conclusion: Finnish adolescents diagnosed with GD-seeking GAHT have good somatic health, but a higher proportion of overweight, depression, and anxiety than the general adolescent population. Prospective follow-up of this cohort will provide an opportunity to evaluate the somatic and psychosocial outcomes and quality of life during GAHT.

Adipose tissue estrogen production and metabolism in premenopausal women.

OBJECTIVE: Although the ovaries produce the majority of estrogens in women before menopause, estrogen is also synthesized in peripheral tissues such as adipose tissue (AT). The typical female AT distribution, concentrated in subcutaneous and femoro-gluteal regions, is estrogen-mediated, but the significance of estrogen synthesis in AT of premenopausal women is poorly understood. DESIGN AND METHODS: Serum and subcutaneous and visceral AT homogenates from 28 premenopausal women undergoing non-malignant surgery were analyzed for estrone, estradiol, and serum estrone sulfate (E1S) concentrations with liquid chromatography-tandem mass spectrometry. Isotopic precursors were used to measure enzyme activities of estrone-producing steroid sulfatase and estradiol-producing 17ß-hydroxysteroid dehydrogenases (17ß-HSD). Messenger RNA (mRNA) expression levels of genes for estrogen-metabolizing enzymes were analyzed using real-time reverse transcription quantitative polymerase chain reaction. RESULTS: While estradiol was the predominant circulating active estrogen, estrone dominated in AT, with a higher concentration in visceral than subcutaneous AT (median, 2657 vs 1459 pmol/kg; P = 0.002). Both AT depots converted circulating E1S to estrone, and estrone to estradiol. Median levels of estrone were five to ten times higher in subcutaneous and visceral AT than in serum (P < 0.001) and the estradiol level in visceral AT was 1.3 times higher than in serum (P < 0.005). The local estrone concentration in visceral AT correlated positively with mRNA expression of estrone-producing enzyme aromatase (r = 0.65, P = 0.003). Waist circumference correlated positively with increased estradiol production in subcutaneous AT (r = 0.60, P = 0.039). CONCLUSIONS: Premenopausal AT demonstrated high estrogenic enzyme activity and considerable local estrogen concentrations. This may be a factor promoting female-typical AT distribution in premenopausal women.

Human adipocyte differentiation and composition of disease-relevant lipids are regulated by miR-221-3p.

MicroRNA-221-3p (miR-221-3p) is associated with both metabolic diseases and cancers. However, its role in terminal adipocyte differentiation and lipid metabolism are uncharacterized. miR-221-3p or its inhibitor was transfected into differentiating or mature human adipocytes. Triglyceride (TG) content and adipogenic gene expression were monitored, global lipidome analysis was carried out, and mechanisms underlying the effects of miR-221-3p were investigated. Finally, cross-talk between miR-221-3p expressing adipocytes and MCF-7 breast carcinoma (BC) cells was studied, and miR-221-3p expression in tumor-proximal adipose biopsies from BC patients analyzed. miR-221-3p overexpression inhibited terminal differentiation of adipocytes, as judged from reduced TG storage and gene expression of the adipogenic markers SCD1, GLUT4, FAS, DGAT1/2, AP2, ATGL and AdipoQ, whereas the miR-221-3p inhibitor increased TG storage. Knockdown of the predicted miR-221-3p target, 14-3-3γ, had similar antiadipogenic effects as miR-221-3p overexpression, indicating it as a potential mediator of mir-221-3p function. Importantly, miR-221-3p overexpression inhibited de novo lipogenesis but increased the concentrations of ceramides and sphingomyelins, while reducing diacylglycerols, concomitant with suppression of sphingomyelin phosphodiesterase, ATP citrate lyase, and acid ceramidase. miR-221-3p expression was elevated in tumor proximal adipose tissue from patients with invasive BC. Conditioned medium of miR-221-3p overexpressing adipocytes stimulated the invasion and proliferation of BC cells, while medium of the BC cells enhanced miR-221-3p expression in adipocytes. Elevated miR-221-3p impairs adipocyte lipid storage and differentiation, and modifies their ceramide, sphingomyelin, and diacylglycerol content. These alterations are relevant for metabolic diseases but may also affect cancer progression.

Plasma pentraxin 3 is higher in early ovarian hyperstimulation syndrome than in uncomplicated in vitro fertilization cycle of high-risk women.

PURPOSE: Pentraxin 3 (PTX3) is a locally secreted, quicker responsive pro-inflammatory protein than C-reactive protein (CRP). We evaluated the value of PTX3 in the prediction of ovarian hyperstimulation syndrome (OHSS), a severe complication of in vitro fertilization (IVF). METHODS: This two-year prospective follow-up study included 27 women with uncomplicated IVF-cycles (IVF group) and 31 patients diagnosed with moderate or severe early OHSS (OHSS group). PTX3 was analysed from follicular fluid (FF) and serial blood samples with enzyme-linked immunoassay and CRP with particle-enhanced immunoturbidimetric assay. The value of PTX3 and CRP in detecting OHSS was examined with receiver operating characteristic (ROC) curve analysis and expressed as the area under the curve (AUC). RESULTS: The circulating PTX3 level peaked at two days after oocyte pick-up (OPU2), and in the OHSS group the level was 1.9 times higher (P = 0.006) than in the IVF group. However, in ROC curve analysis PTX3 (AUC 0.79, best cut off 1.1 µg/L) was not superior to CRP (AUC 0.87; best cut off 9.5 mg/L) in predicting early OHSS. In the IVF group, the FF-PTX3 concentration was 15-20 times higher than in the plasma. PTX3 level at OPU2 correlated with the number of punctured follicles (r = 0.56, n = 22, P = 0.006). Triggering with human chorionic gonadotrophin or early pregnancy had no effect on PTX3 level. CONCLUSION: The elevated PTX3 concentration in OHSS at OPU2, when freeze-all embryos strategy is still possible to consider, indicates that PTX3 level could provide additional benefit in the risk assessment for early OHSS.

Use of postmenopausal hormone therapy and risk of Alzheimer's disease in Finland: nationwide case-control study.

OBJECTIVES: To compare the use of hormone therapy between Finnish postmenopausal women with and without a diagnosis for Alzheimer's disease. DESIGN: Nationwide case-control study. SETTING: Finnish national population and drug register, between 1999 and 2013. PARTICIPANTS: All postmenopausal women (n=84 739) in Finland who, between 1999 and 2013, received a diagnosis of Alzheimer's disease from a neurologist or geriatrician, and who were identified from a national drug register. Control women without a diagnosis (n=84 739), matched by age and hospital district, were traced from the Finnish national population register. INTERVENTIONS: Data on hormone therapy use were obtained from the Finnish national drug reimbursement register. MAIN OUTCOME MEASURES: Odds ratios and 95% confidence intervals for Alzheimer's disease, calculated with conditional logistic regression analysis. RESULTS: In 83 688 (98.8%) women, a diagnosis for Alzheimer's disease was made at the age of 60 years or older, and 47 239 (55.7%) women had been over 80 years of age at diagnosis. Use of systemic hormone therapy was associated with a 9-17% increased risk of Alzheimer's disease. The risk of the disease did not differ significantly between users of estradiol only (odds ratio 1.09, 95% confidence interval 1.05 to 1.14) and those of oestrogen-progestogen (1.17, 1.13 to 1.21). The risk increases in users of oestrogen-progestogen therapy were not related to different progestogens (norethisterone acetate, medroxyprogesterone acetate, or other progestogens); but in women younger than 60 at hormone therapy initiation, these risk increases were associated with hormone therapy exposure over 10 years. Furthermore, the age at initiation of systemic hormone therapy was not a decisive determinant for the increase in risk of Alzheimer's disease. The exclusive use of vaginal estradiol did not affect the risk of the disease (0.99, 0.96 to 1.01). CONCLUSIONS: Long term use of systemic hormone therapy might be accompanied with an overall increased risk of Alzheimer's disease, which is not related to the type of progestogen or the age at initiation of systemic hormone therapy. By contrast, use of vaginal estradiol shows no such risk. Even though the absolute risk increase for Alzheimer's disease is small, our data should be implemented into information for present and future users of hormone therapy.

Postmenopausal hormone therapy is accompanied by elevated risk for uterine prolapse.

OBJECTIVE: Receptors for estrogen and progesterone are present in the pelvic floor, and therefore, postmenopausal hormone therapy may affect its function. We compared the former use of estradiol-progestogen postmenopausal hormone therapy in nonhysterectomized women with a uterine prolapse surgery (N = 12,072) and control women (N = 33,704). METHODS: The women with a history of uterine prolapse operation were identified from the Finnish National Hospital Discharge Register, and the control women from the Finnish Central Population Register. The use of hormone therapy was traced from the national drug reimbursement register, and the odd ratios with 95% CIs for prolapse were calculated by using the conditional logistic regression analysis. RESULTS: The women with uterine prolapse had used hormone therapy more often than control women (N = 4,127; 34.2% vs N = 9,189; 27.3%; P < 0.005). The use of hormone therapy was accompanied by significant (23%-53%) elevations in the risk for prolapse, being higher with longer exposure. The risk elevations (33%-23%) were comparable between sole norethisteroneacetate-estradiol and sole medroxyprogesteroneacetate-estradiol therapy. The use of estradiol in combination with a levonorgestrel releasing intrauterine device was accompanied by a 52% elevation. CONCLUSIONS: The postmenopausal use of estradiol in combination with various progestogen regimens may weaken the pelvic floor, resulting in uterine prolapse. This data should be incorporated into the information given to the users of estradiol-progestogen hormone therapy.

Increased risk for stress urinary incontinence in women with postmenopausal hormone therapy.

INTRODUCTION AND HYPOTHESIS: The impact of estradiol-based hormone therapy (HT) on the incidence of stress urinary incontinence (SUI) is unknown. Therefore, we compared the use of such HT regimens and tibolone in women with and without SUI. METHODS: The women with a history of SUI operation (N = 15,002) were identified from the Finnish National Hospital Discharge Register, and the control women without such an operation (N = 44,389) from the Finnish Central Population Register. The use of HT was traced from the National Drug Reimbursement Register, and the odd ratios (ORs) with 95% confidence intervals (95% CIs) for SUI were calculated by using the conditional logistic regression analysis. RESULTS: The cases had used any HT more often than the controls. The use of systemic estradiol-only or estradiol-progestin therapy was accompanied by an increased SUI risk (OR 3.8, 95% CI: 3.6-4.0 and OR 2.7, 95% CI: 2.6-2.9 respectively). The use of estradiol with noretisterone acetate showed a higher risk of increase than that with medroxyprogesterone acetate. Age over 55 years at the initiation of systemic HT was accompanied by a higher SUI risk increase than that under 55 years of age. The use of tibolone, an estradiol + levonorgestrel-releasing intrauterine device, or vaginal estradiol also increased the risk. CONCLUSIONS: The use of HT regimens may predispose to the de novo development or worsening of pre-existing SUI. Thus, caution is needed when these regimens are prescribed to women with mild stress-related urine leakage or with established SUI risk factors.

Estrogen biosynthesis in breast adipose tissue during menstrual cycle in women with and without breast cancer.

Circulating estrogens fluctuate during the menstrual cycle but it is not known whether this fluctuation is related to local hormone levels in adipose tissue. We analyzed estrogen concentrations and gene expression of estrogen-regulating enzymes in breast subcutaneous adipose tissue in premenopausal women with (n = 11) and without (n = 17) estrogen receptor-positive breast cancer. Estrone (E1) was the predominant estrogen in premenopausal breast adipose tissue, and E1 and mRNA expression of CYP19A1 in adipose tissue correlated positively with BMI. Adipose tissue estradiol (E2) concentrations fluctuated during the menstrual cycle, similarly to the serum concentrations. In women with breast cancer median adipose tissue E1 (1519 vs. 3244, p < .05) and E2 (404 vs. 889 pmol/kg, p < .05) levels were lower in the follicular than in the luteal phase whereas in control women no significant differences were observed. In the follicular phase, mRNA expressions of HSD17B1 (median 0.06; interquartile range 0.05-0.07 vs. 0.17; 0.03-0.2, p = .010) and CYP19A1 (0.08; 0.07-0.14 vs. 0.22; 0.09-0.54, p = .025) were lower in women with breast cancer than in controls. In conclusion, the changes in adipose tissue E1 and E2 concentrations and the estrogen-regulating CYP19A1 and HSD17B1 during the menstrual cycle may be related to dysfunctional local estrogen metabolism in women with breast cancer.

Increased cardiac and stroke death risk in the first year after discontinuation of postmenopausal hormone therapy.

OBJECTIVE: The aim of the study was to evaluate the risk of cardiac and stroke deaths in women who discontinue postmenopausal hormone therapy (HT). METHODS: We analyzed the risk of death due to cardiac (n = 5,204) and cerebrovascular (n = 3,434) causes in Finnish women who discontinued systemic HT during 1994 to 2013 (n = 432,775). The risks were compared with those in the age-matched female background population and with those in age-matched HT users. Women diagnosed with cardiac or cerebrovascular events within 1 year before discontinuation of HT were excluded (n = 8,711). RESULTS: Women younger than 60 years at discontinuation of HT showed a significantly increased risk of cardiac death (after ≤5 y of HT exposure, standardized mortality ratio [SMR] 1.52, 95% CI 1.13-2.00; after >5 y of exposure, SMR 2.08, 95% CI 1.44-2.90) and stroke death (after ≤5 y of exposure, SMR 2.62, 95% CI 2.07-3.28; after >5 y of exposure, SMR 3.22, 95% CI 2.29-4.40) during the first year after treatment as compared with age-matched female background population. When compared with HT users, elevations in risks of cardiac and stroke deaths were even higher. Increased mortality risks were limited to the first post-HT year because increases in risks vanished or markedly decreased when the follow-up time was extended over more than 1 year. CONCLUSIONS: Discontinuation of postmenopausal HT may be associated with increased risk of cardiac and stroke death in the first posttreatment year. Further investigation is required to evaluate causality of the observed associations.

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

Context: In 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. Objective: We compared concentrations of and metabolic pathways producing estrone and estradiol in abdominal subcutaneous and visceral AT in postmenopausal women. Design, Setting, Patients, and Interventions: AT 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 17ß-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. Results: Estrone 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). Conclusions: Both 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.

MicroRNA-221-3p Regulates Angiopoietin-Like 8 (ANGPTL8) Expression in Adipocytes.

Context: Angiopoietin-like 8 (ANGPTL8) has been identified as a key regulator of lipid metabolism. Design: We addressed the correlation between ANGPTL8 messenger RNA (mRNA) with hallmark insulin-regulated and lipogenic genes in human adipose tissue (AT). The regulation of ANGPTL8 expression in adipocytes was studied after inflammatory challenge, and the role of microRNA (miRNA)-221-3p therein was investigated. Results: ANGPTL8 gene expression in subcutaneous AT (SAT) and visceral AT (VAT) was highly correlated with SLC2A4/GLUT4, ADIPOQ, fatty acyl synthase, and diacylglycerol O-acyltransferase 1. ANGPTL8 mRNA in human adipocytes was suppressed by the inflammatory impact of conditioned medium of lipopolysaccharide-stimulated macrophages, which markedly induced miR-221-3p. MiR-221-3p was shown to target the ANGPTL8 mRNA, and to reduce adipocyte ANGPTL8 protein expression. Analysis of SAT biopsies from 69 subjects ranging from lean to morbidly obese and of VAT of 19 female subjects biopsied during gynecologic surgery demonstrated a trend of negative correlation between ANGPTL8 and miR-221-3p. Significant negative correlation of ANGPTL8 and miR-221-3p was identified in presurgery SAT samples from 22 morbidly obese subjects undergoing bariatric surgery, but vanished after ∼2-year surgery-induced weight loss, which also resulted in a marked reduction of miR-221-3p. ANGPTL8 correlated negatively with the AT inflammatory gene phospholipase A2 G7, whereas miR-221-3p showed a significant positive correlation with this marker. Of note, no correlation was found between AT ANGPTL8 mRNA expression and plasma ANGPTL8. Conclusions: The inflammation-induced miR-221-3p regulates ANGPTL8 expression in adipocytes. This miRNA impact may become especially prominent under pathologic conditions such as morbid obesity, putatively contributing to the impaired AT lipid metabolism in metabolic disease.

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.

Context: There are conflicting data on postmenopausal hormone therapy (HT) and the risk of vascular dementia (VD) and Alzheimer's disease (AD). Objective: We analyzed the mortality risk attributable to VD or AD in women with a history of HT use. Design, Patients, Interventions, and Main Outcome Measures: Finnish 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. Results: Risk 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. Conclusion: Estradiol-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.

C-reactive protein response is higher in early than in late ovarian hyperstimulation syndrome.

OBJECTIVES: Many in vitro fertilization (IVF) complications are inflammatory by nature, some of which are even life-threatening. We evaluated the response of C-reactive protein (CRP) in IVF complications, especially in early and late ovarian hyperstimulation syndrome (OHSS), to support clinical decision making in gynecological emergency policlinics. STUDY DESIGN: In a prospective two-year study at Helsinki University Hospital, Finland, we recruited patients with IVF complications including moderate or severe OHSS (n=47 patients: 36 early and 14 late OHSS cases), or other IVF complications (n=13). As controls, we recruited women in an uncomplicated IVF cycle (n=27). Serial blood samples (CRP, blood count, platelets, albumin, estradiol, creatinine, and electrolytes) were collected from patients upon admission to the emergency polyclinic and during and after treatment on the ward, and from the controls prior, during, and after the IVF protocol. All samples were categorized according to oocyte pick-up (OPU). The statistics included comparisons between and within the study groups, and receiver-operating characteristic (ROC) curve analysis for diagnostic accuracy of CRP for early OHSS at emergency polyclinics. RESULTS: On admission, CRP did not differentiate OHSS from other IVF complications, but CRP was higher in early (median 21; IQR 8-33mg/L) than in late (6; 3-9mg/L, p=0.001) OHSS. In ROC analysis for CRP (12mg/L), the area under the curve (AUC) was 0.74 (p=0.001) with sensitivity of 69% and specificity of 71% for early OHSS. CRP was significantly higher (28; 10-46mg/L) in patients with early OHSS two days after oocyte pick-up (OPU) than in the controls (5; <3-9mg/L, p<0.001). The level normalized by 12 days, similarly to the controls. On the ward, the peak CRP was higher if early OHSS was complicated with infection (108; 49-166mg/L) than without infection (20; 8-32mg/L, p=0.001). Late OHSS was associated with hypoalbuminemia (19.6; 16.2-23.1g/L, p<0.001) and thrombocytosis (494; 427-561 E9/L, p=0.004; comparisons to early OHSS). CONCLUSIONS: Early OHSS associates with a distinct rise in CRP level beyond that induced by uncomplicated oocyte pick-up, whereas the CRP levels in late OHSS are comparable to those in the control cycles. CRP identifies, but cannot distinguish IVF complications.

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 (n = 1,578 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.

Cardiac Death Risk in Relation to the Age at Initiation or the Progestin Component of Hormone Therapies.

CONTEXT: The "window of opportunity hypothesis" refers to data indicating that conjugated equine estrogen alone or in combination with medroxyprogesterone acetate, if initiated before 60 years of age, protects the heart but endangers it if initiated later (Women's Health Initiative study). Less is known about the "window of opportunity hypothesis" with natural estradiol alone (ET) or with various progestins in combination with estradiol (EPT). OBJECTIVE: We related the death risk from coronary heart disease (CHD) in users of ET or EPT to the age at the initiation of therapy and to the progestin component of EPT. Design, Patients, Interventions, and Main Outcome Measures: Altogether, 498 105 women had used ET or EPT containing medroxyprogesterone acetate, norethisterone acetate, dydrogesterone, other progestins, or tibolone during 3.7 million person-years during 1994-2009. Women were followed from the therapy initiation to death, or to the end of year 2009. The risk of CHD death in hormone users was compared with that in the age-matched background population using standardized mortality ratio with 95% confidence intervals. RESULTS: Age younger than 60 rather than older than 60 years at the initiation of ET (standardized mortality ratio, 0.53; 95% confidence interval, 0.47-0.59 vs 0.76; 0.71-0.82), EPT with norethisterone acetate (0.45; 0.41-0.49 vs 0.74; 0.67-0.81), or tibolone (0.35; 0.26-0.47 vs 1.01; 0.67-1.46) therapy lasting for less than 5 years was associated with significantly greater decreases in the CHD death risk. A similar tendency was also seen for other EPT groups and for longer use. In all hormone users, the CHD death risk was smaller the earlier the use of ET or EPT had started (P < .05); this phenomenon was unrelated to the progestin component of EPT. CONCLUSIONS: Estradiol-based hormone therapies are accompanied with larger CHD mortality risk reductions the earlier the therapies are initiated. The progestin component of EPT does not modify this "timing effect."