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'DOES THE DISCONTINUATION OF MENOPAUSAL HORMONE THERAPY AFFECT A WOMAN'S CARDIOVASCULAR RISK?' ANDREW M. KAUNITZ, MD; JOANN E. MANSON, MD, DRPH; AND CYNTHIA A. STUENKEL, MD (EXAMINING THE EVIDENCE; DECEMBER [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajog.2005.02.084 Byline: Mervi Vaisanen-Tommiska, Tomi S. Mikkola, Olavi Ylikorkala Abstract: The cells of the human uterine cervix synthesize nitric oxide, which may be a factor in cervical ripening. We studied the effect of misoprostol on cervical nitric oxide release in nonpregnant and pregnant women. Author Affiliation: Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland Article History: Received 29 November 2004; Revised 8 February 2005; Accepted 8 February 2005

Background: Hysterectomy rates are decreasing in many countries, and virtual reality simulators bring new opportunities into residents’ surgical education. The objective of this study was to evaluate the effect of training in laparoscopic hysterectomy module with virtual reality simulator on surgical outcomes among residents performing their first laparoscopic hysterectomy. Methods: This randomized study was carried out at the Department of Obstetrics and Gynecology in Helsinki University Hospital and Hyvinkää Hospital. We recruited twenty residents and randomly signed half of them to train ten times with the laparoscopic hysterectomy module on a virtual reality simulator, while the rest represented the control group. Their first laparoscopic hysterectomy was video recorded and assessed later by using the Objective Structured Assessment of Technical Skills (OSATS) forms and Visual Analog Scale (VAS). The scores and surgical outcomes were compared between the groups. Results: The mean OSATS score for the Global Rating Scale (GRS) was 17.0 (SD 3.1) in the intervention group and 11.2 (SD 2.4) in the control group (p= 0.002). The mean procedure-specific OSATS score was 20.0 (SD 3.3) and 16.0 (SD 2.8) (p= 0.012), and the mean VAS score was 55.0 (SD 14.8) and 29.9 (SD 14.9) (p= 0.001). Operative time was 144 min in the intervention group and 165 min in the control group, but the difference did not reach statistical significance (p= 0.205). There were no differences between the groups in blood loss or direct complications. Conclusion: Residents training with a virtual reality simulator prior to the first laparoscopic hysterectomy seem to perform better in the actual live operation. Thus, a virtual reality simulator hysterectomy module could be considered as a part of laparoscopic training curriculum.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajog.2007.10.804 Byline: Pauliina Tuomikoski (a), Kristiina Aittomaki (b), Tomi S. Mikkola (a), Anne Ropponen (a), Olavi Ylikorkala (a) Keywords: hormone therapy; hyaluronic acid; intrahepatic cholestasis of pregnancy; liver disease Abstract: Intrahepatic cholestasis of pregnancy predisposes women to liver disorders years after affected pregnancy. We compared the basal levels and responses of hyaluronic acid, a marker of liver fibrosis, and liver transaminases to postmenopausal hormone therapy in women with (n = 20) and without (n = 20) a history of intrahepatic cholestasis of pregnancy. Author Affiliation: (a) Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland (b) Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland. Article History: Received 27 March 2007; Revised 3 July 2007; Accepted 13 October 2007 Article Note: (footnote) This study was supported by an unrestricted research grant from the Ida Montini Foundation and the Paivikki and Sakari Sohlberg Foundation., Cite this article as: Tuomikoski P, Aittomaki K, Mikkola TS, et al. Effect of oral and transdermal hormone therapy on hyaluronic acid in women with and without a history of intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol 2008;198:375.e1-375.e5.

Background: Gynecological surgery and resident education have changed during recent decades, thus impacting surgical training. Training on simulators must begin before operating on patients. The objective of this study was to evaluate the effect of a simple curriculum on the surgical outcome of the participants’ first operative laparoscopy. Methods: This randomized prospective interventional study was carried out in Helsinki University Hospital and Hyvinkää Hospital. We recruited twenty junior residents in Obstetrics and Gynecology, of which half formed a control group and the rest completed the intervention with a theoretical and a practical part. The participants’ first laparoscopic salpingectomy was assessed from video recordings by using Objective Structured Assessment of Technical Skills (OSATS) forms and the Numeric Rating Scale (NRS). The surgical outcome and assessed scores were compared between the groups. Results: We found no differences in operative time, blood loss, or complications, nor in OSATS or NRS scores. In the intervention group, participants with the weakest performances in the simulator, seemed to benefit from the training program more than the participants with the best performances (skill level elevation 29.2–31.6% vs. 21.1–23.3%, respectively). The participants with the best performances in the simulator were scored among the best in the recorded operations as well. Conclusion: In this study, we found no difference in the surgical outcome between the groups. However, the participants with low starting levels in the simulator could elevate their skill levels more, though they did not reach the skill level of those with a high starting level. Consequently, we found elevation in skills levels in the simulator tasks, but not in the surgical outcome. Likely, our simple training program with a fixed number of repetitions was insufficient to reach a plateau in the learning curve, and thus the training program in such a curriculum should be proficiency based.

Apical objective and subjective outcomes were sustained after 5 years in women operated on for apical compartment prolapse by the Uphold Vaginal Support System.

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.

Reduction in the number of gynecological operations has made resident training more difficult in gynecological surgery. We used electronic educational material to supplement traditional apprentice model in resident surgical education. Our aim was to evaluate effectiveness of a web-based course in knowledge gaining among residents with various levels of clinical experience.

There are conflicting data on postmenopausal hormone therapy (HT) and the risk of vascular dementia (VD) and Alzheimer's disease (AD).

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.”

Context:Current guidelines recommend annual discontinuation of postmenopausal hormone therapy (HT) to evaluate whether a woman could manage without the treatment. The impact of HT on cardiovascular health has been widely studied, but it is not known how the withdrawal of HT affects cardiovascular risk.Objective:We evaluated the risk of cardiac or stroke death after the discontinuation of HT.Design, Patients, Interventions, and Main Outcome Measures:Altogether 332 202 Finnish women discontinuing HT between 1994 and 2009 (data from National Reimbursement register) were followed up from the discontinuation date to death due to cardiac cause (n = 3177) or stroke (n = 1952), or to the end of 2009. The deaths, retrieved from the national Cause of Death Register, were compared with the expected number of deaths in the age-standardized background population. In a subanalysis we also compared HT stoppers with HT users.Results:Within the first posttreatment year, the risk of cardiac death was significantly elevated (standardized mortality ratio; 95% confidence interval 1.26; 1.16–1.37), whereas follow-up for longer than 1 year was accompanied with a reduction (0.75; 0.72–0.78). The risk of stroke death in the first posttreatment year was increased (1.63; 1.47–1.79), but follow-up for longer than 1 year was accompanied with a reduced risk (0.89; 0.85–0.94). The cardiac (2.30; 2.12–2.50) and stroke (2.52; 2.28–2.77) death risk elevations were even higher when compared with HT users. In women who discontinued HT at age younger than 60 years, but not in women aged 60 years or older, the cardiac mortality risk was elevated (1.94; 1.51–2.48).Conclusions:Increased cardiovascular death risks question the safety of annual HT discontinuation practice to evaluate whether a woman could manage without HT.

Because 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.

We 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.

Recent data have indicated that menopausal hot flashes may be a determinant for cardiovascular health. Therefore, we studied the impact of hot flashes on insulin resistance, one of the most powerful markers of cardiovascular health, in recently postmenopausal women.

The aim of this study was to assess whether aerobic training affects menopausal symptoms in recently postmenopausal sedentary women.

The aim of the study was to compare the responses of heart rate variability (HRV) with hormone therapy in recently postmenopausal women with and without vasomotor hot flashes.

The aim of this study was to investigate whether cardiovascular autonomic reactivity and risk profile are associated with the frequency and severity of hot flashes in recently postmenopausal women.

Menopausal hot flashes may affect vascular function and perhaps explain conflicting data on cardiovascular disease (CVD) between observational and randomized hormone therapy (HT) studies. We prospectively assessed hot flash status in recently postmenopausal women and related it to a number of biochemical vascular surrogate markers for CVD.

Isoflavones may display beneficial health effects in postmenopausal women. We studied in a clinical trial whether isolated isoflavone treatment in postmenopausal women could affect reverse cholesterol transport as evaluated by adenosine triphosphate-binding cassette A1- (ABCA1), dependent cholesterol efflux from macrophages. In addition, various serum lipid and lipoprotein parameters were investigated. Furthermore, we separately assessed equol-producing and non-equol-producing women.

Based on the low cardiovascular risk in Asian populations, phytoestrogens are believed to provide vascular benefits. To elucidate the mechanisms behind the possible cardiovascular effects of phytoestrogens, we evaluated reverse cholesterol transport by assessing the capacity of serum to promote cholesterol efflux in postmenopausal women treated with isolated isoflavones.

Objective: Labetalol reduces blood pressure primarily by blocking alpha-and beta-receptors, but other mechanisms of action may also be possible. We studied the effects of labetalol on the synthesis of vasodilatory prostacyclin (PGI2) and vasoconstrictory endothelin-1 (ET-1) by cultured human umbilical vein endothelial cells (HUVECs). We also studied the effect of oral labetalol treatment on PGI, and thromboxane A2 (TxA.2) production in preeclamptic patients.Methods: HUVECs were incubated in the absence (control) and presence of labetalol (10-8-10-5 mol/L) and the release of PGI-, as measured by its metabolite 6-keto-PGF1α, and that of ET-1, were assessed by radioimmuno- assays. Because the presence of serum strongly affects endothelial cell function, we studied the effect of labetalol in HUVECs incubated with or without serum. In the in vivo part of the study, urine samples collected before and during oral labetalol intake were assessed for 2,3-dinor-6-keto-PGF, a metab-olite of PGI.1α and for 2,3-dinor-thromboxane-B., a metabolite of TxA,2 with high-pressure liquid chromatography and radioimmunoassay.Results: HUVECs incubated in the presence of serum (10%) produced 8 times more 6-keto-PGFloi and 5 times more ET-1 than HUVECs incubated without serum. Labetalol (10-8-10-5 mol/L) did not affect the production of PGL, although the highest labetalol level (not achievable in vivo, 10-5 mol/L) was accompanied by a drop in PG1-, release in both serum-free (- 21%) and serum conditions (- 14%); this was probably a sign of toxic effect. Labetalol caused no consistent change in the release of ET-1 in HUVECs. Oral labetalol treatment did not affect urinary excretion of PGI, and TxA., metabolites.Conclusions: No clinically relevant effects of labetalol were found on endothelial cell PG1-, or ET-1 production. Labetalol at therapeutic doses and concentrations does not affect the production of vasoactive PGI2 and TxA2 in preeclamptic patients.

Objectives: Vasodilatory nitric oxide (NO) is evidently a factor in pregnancy physiology and perhaps also in preeclampsia. Human umbilical vein endothelial cells (HUVECs) express the calcium-dependent NO synthase (NOS), whereas the scanty data on the expression of the inducible isoform of NOS (iNOS) are discrepant. We have previously shown that HUVECs can express iNOS and now further characterize the regulation of iNOS induction in freshly isolated HUVECs in vitro. In addition, we study whether iNOS mRNA expression is induced in vivo in preeclampsia.Study Design: Freshly isolated HUVECs from normal pregnancies were treated with proinflammatory cytokines, and inducible NO production was detected by measurement of nitrate and nitrite accumulation in the media. The expression of iNOS mRNA in these cells was detected by the reverse transcriptase-polymerase chain reaction. In addition, HUVECs from preeclamptic (n = 9) and normal (n = 11) pregnancies were lyzed immediately after delivery and assayed for iNOS mRNA.Results: The cytokine treatment of HUVECs led to consistent expression of iNOS mRNA and NO synthesis. Dexamethasone blunted both the expression of iNOS mRNA and the production of NO, whereas NOS inhibitor NG-methyl-L-arginine merely suppressed the release of NO. No iNOS mRNA could be detected under basal conditions in HUVECs from preeclamptic or control patients.Conclusions: HUVECs are able to express iNOS after cytokine-stimulation in vitro, but this pathway was not activated in preeclampsia.

Optimal vascular homeostasis requires efficient control of both proliferation and elimination of vascular endothelial cells. Programmed cell death, or apoptosis, is the main mechanism controlling cell elimination, and it is an essential component of vascular formation. Human vascular endothelial cells die in vitro, if prevented from obligatory survival factors like growth factors or attachment and cell spreading, but very little is known about the mechanisms controlling endothelial cell elimination. Signaling from the extracellular matrix affects the behavior and functions of human umbilical vein endothelial cells (HUVECs), and we have recently demonstrated the beneficial effects of plating on the reconstituted extracellular matrix Matrigel™, on the inducible nitric oxide production of freshly isolated HUVECs. In this work we observed that cultured HUVECs formed typical capillary-like structures on Matrigel, but unexpectedly, after 24–48 hours their viability was gradually lost. Viability was measured with an assay based on mitochondrial reduction of reagent XTT. No decrease in viability was seen in freshly isolated HUVECs or in cultured fibroblasts during this time. It is known that cells often turn into apoptosis if they receive conflicting information from their surroundings, and apparently signaling from Matrigel to HUVECs, while at their in vitro proliferating phenotype, resulted in launching of the apoptotic machinery. Thus, proliferating and differentiated phenotypes of endothelial cells seemed to have different sensitivity to signals that induce apoptosis. J. Cell. Physiol. 176:92–98, 1998. © 1998 Wiley-Liss, Inc.

Cultured human umbilical vein endothelial cells (HUVECs) are a widely used model to study the regulation of endothelial production of vasoactive substances such as endothelin-1 (ET-1) and prostacyclin (PGI2) in human. As even short term culturing is known to affect the function of many cell types, we studied whether there are differences in the production of ET-1 and PGI2between freshly isolated HUVECs and HUVECs cultured for two passages, and whether variation in cell density affects the production of ET-1 and PGI2by these cells. At confluency, freshly isolated HUVECs produced only from one-tenth to one-fifth of ET-1, but 46-86 times more PGI2 (p < 0.001), when compared to respective productions by similar amounts of cultured HUVECs. When the cell density of freshly isolated HUVECs was lowered either by diluting the cell suspension or by plating the same amount of cells on different size wells, the production of ET-1 increased: lowering cell density to one-tenth led to 18 fold increase in ET-1 production (p < 0.001). PGI2production was not affected by cell density. Thus our data imply that the production of both ET-1 and PGI2are differently regulated in freshly isolated and cultured HUVECs, and that cell density is an important determinant in the regulation of ET-1 production.

To determine if hormone replacement therapy (HRT) modifies the ability of plasma or serum to regulate the synthesis of vasodilatory prostacyclin and that of vasoconstrictive endothelin-1 by cultured human umbilical vein endothelial cells.

ObjectivesTo compare the use of hormone therapy between Finnish postmenopausal women with and without a diagnosis for Alzheimer’s disease.DesignNationwide case-control study.SettingFinnish national population and drug register, between 1999 and 2013.ParticipantsAll 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.InterventionsData on hormone therapy use were obtained from the Finnish national drug reimbursement register.Main outcome measuresOdds ratios and 95% confidence intervals for Alzheimer’s disease, calculated with conditional logistic regression analysis.ResultsIn 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).ConclusionsLong 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.