The association of hormone therapy with blood pressure control in postmenopausal women with hypertension: a secondary analysis of the Women's Health Initiative clinical trials.

OBJECTIVE: The objective of this study was to assess the effect of menopausal hormone therapy (HT) on blood pressure control in postmenopausal women with hypertension. METHODS: The Women's Health Initiative HT clinical trials were double-blinded, randomized, placebo-controlled studies of women aged 50 to 79 years testing the effects of HT (conjugated equine estrogens [CEE, 0.625 mg/d] or CEE + medroxyprogesterone acetate [MPA; 2.5 mg/d]) on risks for coronary heart disease and invasive breast cancer, the primary outcomes for efficacy and safety, respectively. This secondary analysis of the Women's Health Initiative HT trials examined a subsample of 9,332 women with hypertension (reported ever taking pills to treat hypertension or were taking antihypertensive medication) at baseline. Blood pressure was measured at baseline and up to 10 annual follow-up visits during the planned study phase. Antihypertensive medications were inventoried at baseline and years 1, 3, 6, and 9 during the study, and self-reported during extended follow-up: 2009-2010 and 2012-2013, which occurred median of 13 and 16 years after randomization, respectively. The intervention effect was estimated through year 6. Cumulative follow-up included all visits. RESULTS: Compared with placebo, CEE-alone had significantly ( P = 0.02) higher systolic blood pressure (SBP) by mean (95% confidene interval [CI]) = 0.9 (0.2-1.5) mm Hg during the intervention phase. For cumulative follow-up, the CEE arm was associated with increased SBP by mean (95% CI) = 0.8 (0.1-1.4) mm Hg ( P = 0.02). Furthermore, CEE + MPA relative to placebo was associated with increased SBP by mean (95% CI) = 1.8 (1.2-2.5) mm Hg during the intervention phase ( P < 0.001). For cumulative follow-up, the CEE + MPA arm was associated with increased SBP by mean (95% CI) = 1.6 (1.0-2.3) mm Hg ( P < 0.001). The mean number of antihypertensive medications taken at each follow-up visit did not differ between randomization groups during the intervention or long-term extended follow-up of 16 years. CONCLUSION: There was a small but statistically significant increase in SBP in both CEE-alone and CEE + MPA arms compared with placebo during both the intervention and cumulative follow-up phases among postmenopausal women with hypertension at baseline. However, this increase in SBP was not associated with an increased antihypertensive medication use over time among women randomized to HT compared with placebo.

The association between incidentally found breast arterial calcification on routine screening mammography and the development of coronary artery disease and stroke: results of a 10-year prospective study.

OBJECTIVE: The objective of this study is to assess whether the presence of breast arterial calcifications (BACs) found on routine mammography is prospectively associated with the development of cardiovascular disease (CVD) events after 10 years of follow-up. METHODS: Women presenting for screening mammography were enrolled in this prospective cohort. Baseline data were collected including history of CVD and CVD risk factors. Mammograms were assessed for the presence or absence of BAC. Participants completed questionnaires 10 years after baseline that assessed the development of CVD (coronary artery disease [CAD] and stroke) and CVD risk factors. RESULTS: Of the 1,995 participants who enrolled at baseline, complete 10-year follow-up data were available for 1,039; of those, 114 (11.0%) were BAC-positive and 925 (89.0%) were BAC-negative at baseline. After controlling for age, BAC-positive women were more likely to develop CAD (odds ratio, 3.14; 95% confidence interval, 1.86-5.27; P < 0.001) compared with BAC-negative women after 10 years of follow-up. After controlling for age, BAC-positive women were more likely to have had a stroke (odds ratio, 5.10; 95% CI, 1.82-14.30) compared with BAC-negative women after 10 years. CONCLUSIONS: The presence of BAC on routine screening mammography was associated with a significantly increased risk of developing CAD and stroke after 10 years of follow-up. Additional large prospective, population-based studies are needed to confirm BAC as a predictor of future CVD events and its utility in stratifying a woman's risk of CVD.

The severity of individual menopausal symptoms, cardiovascular disease, and all-cause mortality in the Women's Health Initiative Observational Cohort.

OBJECTIVE: The aim of this study was to examine the association between common menopausal symptoms (MS) and long-term cardiovascular disease (CVD) and all-cause mortality. METHODS: In an observational cohort of 80,278 postmenopausal women with no known CVD at baseline from the Women's Health Initiative, we assessed individual MS severity (mild vs none; moderate/severe vs none) for night sweats, hot flashes, waking up several times at night, joint pain or stiffness, headaches or migraines, vaginal or genital dryness, heart racing or skipping beats, breast tenderness, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating. Outcomes included total CVD events (primary) and all-cause mortality (secondary). Associations between specific MS, their severity, and outcomes were assessed during a median of 8.2 years of follow-up. All results were multivariable adjusted, and individual associations were Bonferroni corrected to adjust for multiple comparisons. A machine learning approach (least absolute shrinkage and selection operator) was used to select the most parsimonious set of MS most predictive of CVD and all-cause mortality. RESULTS: The severity of night sweats, waking up several times at night, joint pain or stiffness, heart racing or skipping beats, dizziness, feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating were each significantly associated with total CVD. The largest hazard ratio (HR) for total CVD was found for moderate or severe heart racing or skipping beats (HR, 1.55; 95% confidence interval [CI], 1.29-1.86). The individual severities of heart racing or skipping beats, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating were associated with increased all-cause mortality. Moderate or severe dizziness had the largest HR (1.58; 95% CI, 1.24-2.01). Multiple symptom modeling via least absolute shrinkage and selection operator selected dizziness, heart racing, feeling tired, and joint pain as most predictive of CVD, whereas dizziness, tremors, and feeling tired were most predictive of all-cause mortality. CONCLUSION: Among postmenopausal women with no known CVD at baseline, the severity of specific individual MS was significantly associated with incident CVD and mortality. Consideration of severe MS may enhance sex-specific CVD risk predication in future cohorts, but caution should be applied as severe MS could also indicate other health conditions.

Large Retroperitoneal Hematoma: A Rare Intraoperative Complication of Total Vaginal Hysterectomy.

Retroperitoneal (RP) hematoma is a rare complication of total vaginal hysterectomy. A 45-year-old female G4P3013 with a history of abnormal uterine bleeding refractory to treatment by endometrial ablation and stress urinary incontinence underwent total vaginal hysterectomy, bilateral salpingectomy, bilateral uterosacral ligament suspension, anterior colporrhaphy, and cystoscopy. After the hysterectomy the left uterine artery pedicle was hemostatic; however, the patient became hemodynamically unstable and anemic. Laparoscopy revealed a stable zone III RP hematoma. Intraoperative observation revealed no further expansion of the hematoma. Left iliac angiography and aortography revealed there was no extravasation from the uterine arteries and gonadal vessels. Four days post-operative abdominal CT showed a stable hematoma. Hemodynamic instability resolved over the post-operative course. RP hematoma must be included in the differential for the evaluation of acute intraoperative hemodynamic instability with an unclear source.

Safety assessment of compounded non-FDA-approved hormonal therapy versus FDA-approved hormonal therapy in treating postmenopausal women.

OBJECTIVE: To assess the safety and serum estradiol (E2) and total testosterone (T) concentrations in postmenopausal women treated with Pellet Hormonal Therapy (PHT) and Food and Drug Administration approved Hormonal Therapy (FHT). METHODS: A total of 539 postmenopausal women were identified, including 384 on PHT and 155 on FHT. Data extracted from medical records include demographics, indication for hormone therapy, treatment duration, side effects, serum E2 and T levels, and frequency of laboratory follow-up. RESULTS: The incidence of overall side effects was significantly higher in PHT compared with FHT (221 [57.6%] vs 23 [14.8%], P < 0.00001, odds ratio [95% CI] =8.0[4.5-14.2]). When examining women with an intact uterus prior to hormone therapy initiation, 55.3% (136/246) on PHT vs 15.2% (12/79) on FHT had at least one episode of abnormal uterine bleeding (P < 0.0001, odds ratio [95% CI] = 7.9[3.6-17.0]). Furthermore, a significantly higher proportion of women on PHT (20.3% [50/246]), compared with 6.3% (5/79) on FHT, had a hysterectomy (P = 0.036, odds ratio [95% CI] = 3.2[1.1-9.3]). Both mean (SD, Min-Max) peak E2 (pg/mL) and peak T (ng/dL) are significantly higher in the PHT group than those in the FHT group (E2: 237.70 [168.55, 10-1,111] vs 93.45 [130.77, 5.5-465.8], T: 194.04 [84.94, 4.3-599] vs 15.59 [19.52, 0.2-70], P < 0.00001). Of those on PHT, four women had E2 level > 1,000 pg/mL and nine women with T level > 400 ng/dL. CONCLUSION: Women on PHT had a significantly higher incidence of side effects than FHT as well as a significantly higher supraphysiological level of peak E2 and T during the treatment.

The severity of vasomotor symptoms and number of menopausal symptoms in postmenopausal women and select clinical health outcomes in the Women's Health Initiative Calcium and Vitamin D randomized clinical trial.

OBJECTIVE: This study evaluated whether vasomotor symptom (VMS) severity and number of moderate/severe menopausal symptoms (nMS) were associated with health outcomes, and whether calcium and vitamin D (CaD) modified the risks. METHODS: The Women's Health Initiative CaD study was a double blind, randomized, placebo-controlled trial, which tested 400 IU of 25-hydroxyvitamin-D and 1,000 mg of calcium per day in women aged 50 to 79 years. This study included 20,050 women (median follow-up of 7 y). The outcomes included hip fracture, colorectal cancer, invasive breast cancer, all-cause mortality, coronary heart disease, stroke, cardiovascular death, and total cardiovascular disease (CVD). MS included: hot flashes, night sweats, dizziness, heart racing, tremors, feeling restless, feeling tired, difficulty concentrating, forgetfulness, mood swings, vaginal dryness, breast tenderness, migraine, and waking up several times at night. Associations between VMS severity and nMS with outcomes were tested. RESULTS: No association between VMS severity and any outcome were found. In contrast, nMS was associated with higher stroke (hazard ratio [HR] 1.40 95% confidence interval [CI] 1.04-1.89 for ≥ 2 MS vs none; HR 1.20 95% CI 0.89-1.63 for 1 MS vs none, P trend = 0.03) and total CVD (HR 1.35, 95% CI, 1.18-1.54 for ≥ 2 MS vs none; HR 0.99, 95% CI, 0.87-1.14 for 1 MS vs none P trend < 0.001). CaD did not modify any association. CONCLUSION: Severity of VMS was not associated with any outcome. Having ≥2 moderate or severe MS was associated with an increased risk for CVD. The number of moderate/severe MS may be a marker for higher CVD risk. : Video Summary:http://links.lww.com/MENO/A669.

Video Summary:http://links.lww.com/MENO/A669.

Women's Health Initiative clinical trials: potential interactive effect of calcium and vitamin D supplementation with hormonal therapy on cardiovascular disease.

OBJECTIVE: Data in humans and nonhuman primates have suggested a possible synergistic effect of vitamin D and calcium (CaD) and estrogen on the cardiovascular disease (CVD) risk factors. Using randomized trial data we explored whether the effect of menopausal hormone therapy (HT) on CVD events is modified by CaD supplementation. METHODS: A prospective, randomized, double-blind, placebo-controlled trial was implemented among postmenopausal women in the Women's Health Initiative. A total of 27,347 women were randomized to the HT trials (0.625 mg/d of conjugated equine estrogens [CEE] alone for women without a uterus vs placebo; or 0.625 mg of CEE in addition to 2.5 mg of medroxyprogesterone acetate daily [CEE + MPA] for women with a uterus vs placebo). After 1 year, 16,089 women in the HT trial were randomized to the CaD trial and received either 1,000 mg of elemental calcium carbonate and 400 IU of vitamin D3 daily or placebo. The mean (SD) duration of follow-up after CaD randomization was 6.2 (1.3) years for the CEE trial and 4.6 (1.1) years for the CEE + MPA trial. CVD and venous thromboembolism events evaluated in this subgroup analysis included coronary heart disease, stroke, pulmonary embolism, all-cause mortality, plus select secondary endpoints (total myocardial infarction, coronary revascularization, deep venous thrombosis, cardiovascular death, and all CVD events). Time-to-event methods were used and models were fit with a Cox proportional hazards regression model. RESULTS: In the CEE trial, CaD significantly modified the effect of CEE on stroke (P interaction = 0.04). In the CaD-placebo group, CEE's effect on stroke was harmful (hazard ratio [95% confidence interval] = 2.19[1.34-3.58]); however, it was neutral in the CaD-supplement group (hazard ratio [95% confidence interval] = 1.07[0.66-1.73]). We did not observe significant CEE-CaD interactions for coronary heart disease, total CVD events, or any of the remaining endpoints. In the CEE + MPA trial, there was no evidence that the effect of CEE + MPA on any of CVD endpoints was modified by CaD supplementation. CONCLUSIONS: CaD did not consistently modify the effect of CEE therapy or CEE + MPA therapy on CVD events. However, the increased risk of stroke due to CEE therapy appears to be mitigated by CaD supplementation. In contrast, CaD supplementation did not influence the risk of stroke due to CEE + MPA.

Assessment of NAMS members' prescription patterns of hormone therapy before and after the 2016 NAMS Annual Meeting.

OBJECTIVE: Hormone therapy (HT) prescription patterns have varied enormously over time and across specialties. The present study attempts to look at practice variation in specific controversial scenarios and to determine if attendance at The North American Menopause Society (NAMS) 2016 Annual Meeting, where the draft of the 2017 NAMS HT Position Statement was presented, had any impact on members' HT prescribing patterns. METHODS: An anonymous survey with 11 case scenarios was sent to all NAMS members before and after the 2016 NAMS Annual Meeting. Pre- and postmeeting responses were pooled into a single cohort. For those who responded to both surveys, only the postmeeting survey responses were included in the cohort. The impact of attendance at the 2016 NAMS Annual Meeting was investigated by comparing paired responses with "controversial questions" between pre- and postmeeting surveys in the matched population who either attended the 2016 NAMS Annual Meeting (intervention arm) or did not (control arm). "Controversial questions" were defined as those where 25% to 75% of responders answered "YES" to a question. McNemar's test was applied to analyze paired responses using SAS statistical software, with P ≤ 0.05 being considered statistically significant. RESULTS: A total of 1,786 NAMS members were surveyed before and after the 2016 NAMS meeting, 234 (13%) completed the premeeting survey, 166 (9%) completed the postmeeting survey, and 52 completed both surveys. Of the 52, 27 attended the 2016 NAMS Annual Meeting and 25 did not. The pooled cohort contains 348 responses which represents a 20% response rate. Six complex case scenarios with "controversial questions" were identified from the pooled cohort and reexamined in the intervention and control arm, respectively. In the intervention arm, significant changes toward being more likely to prescribe HT in guideline-consistent cases were noted in four out of six cases, whereas significant changes in HT use were not seen in any of six complex cases in the control arm. CONCLUSIONS: NAMS members' prescribing patterns of HT vary in complex clinical scenarios. After the 2016 NAMS Annual Meeting where a draft of the 2017 NAMS HT Position Statement was presented and discussed, in four challenging and complex clinical situations a significant number of practitioners changed their prescription patterns toward prescribing HT which was consistent with the new guideline.

Transvaginal ultrasound training for the obstetrics and gynecology resident: A multisite randomized controlled trial of educational DVD.

PURPOSE: Residents in obstetrics and gynecology are deemed to be proficient in transvaginal ultrasound (TVUS) upon graduation, although TVUS education in residency is not standardized. The objective of this study is to assess for improvement in TVUS knowledge among residents after viewing an educational DVD. METHODS: This is a multisite prospective randomized controlled trial using an educational DVD ("Gynecology: Beginners Only"), compared to routine education. All participants completed a pretest on TVUS images and principles. The intervention group repeated the test after DVD viewing. During the trial, performing and logging TVUS examinations were encouraged. All enrolled residents repeated the test 6-10 months later. RESULTS: Fifty-seven residents completed the study with a mean pretest score of 9.7 (1st year resident 9.8, 2nd year resident 9.6, 3rd year resident 10.1, 4th year resident 9.4, P = .763), with a mean of 31.5 TVUS examinations logged prior to intervention. The mean score in the intervention group (n = 34) improved significantly after viewing (11.2, P < 0.003). This improvement did not persist 6-10 months later on a follow-up quiz (mean 10.7, P = .894). At completion of the study, participants logged an average of 56.7 TVUS examinations. CONCLUSION: An educational DVD is easily implemented and demonstrates short-term benefit. Exploration of different teaching modalities in development of a comprehensive training program may improve long-term retention.

Long-acting reversible contraception in adolescents in Sub-Saharan Africa: evidence from demographic and health surveys.

OBJECTIVE: To explore (1) long-acting reversible contraception (LARC) use and (2) future contraceptive preferences in Sub-Saharan African adolescents as undesired pregnancies in Sub-Saharan African adolescents are associated with significant maternal/neonatal morbidity. METHODS: Nationally-representative Demographic and Health Surveys (USAID) obtained informed consent and interviewed 45,054 adolescents, including 19,561 (43.4% of total) sexually active adolescents (aged 15-19) from 18 least developed Sub-Saharan African nations regarding contraception (years 2005-2011, response rate 89.8-99.1% for all women interviewed). Frequencies and percentages of contraceptive use, prior pregnancies, and unwanted births were reported. Categorical variables were analyzed through χ2 and unadjusted and binary logistic regression, adjusted for confounders, evaluated LARC use. RESULTS: A majority of sexually active adolescents were not using contraception (n = 16,165 non-users; 82.6% of all sexually active adolescents). Many (n = 8465, 43.3% of sexually active adolescents) interviewed already had at least one child, with 31.5% (n = 2646) of those with previous children reporting the pregnancy was not wanted at the time it occurred. Sexually active adolescents using contraception (n = 3384) used LARCs (injectable contraception, implants, or intrauterine devices; 29.8%, n = 1007) barrier contraceptives (31.9%), oral contraceptives (10.9%), and other methods (27.4%). Adolescents using LARCs were more likely to be urban [OR 1.76 (95% CI 1.39-2.22)], to have been visited by a family planning worker in the last 12 months [OR1.62 (95% CI 1.24-2.11)], and to have visited a health facility in the past 12 months [OR1.84 (95% CI 1.53-2.21)]. Injectable contraception was the most preferred (39.9%, n = 3036) future method by sexually-active non-contracepting adolescents who were asked about future methods (n = 7605) compared to other methods. An unfortunate percentage of adolescents surveyed cannot read (35.7%, n = 16,084). CONCLUSION: A majority of sexually-active adolescents in Sub-Saharan Africa are not using contraception and are desirous of doing so. Offering LARCs during post-abortive or postpartum care with particular focus on rural adolescents may reduce undesired pregnancy and subsequent morbidity/mortality. Educational materials should limit printed information as many teens are unable to read.

Gynecologic Screening for Men in an OBGYN Resident Community Outreach Clinic: The Transgender Care Experience.

OBJECTIVE: The aim of the study was to promote the importance of providing gynecologic screening for transgender men (TGM) who desire to keep their female organs. MATERIALS AND METHODS: In June 2015, the Women's Health Center (WHC) at Reading Hospital was approached to become a resource for transgender (TG) patients in our community. This also presented the opportunity to develop an educational program for OBGYN residents/providers in TG healthcare. From June 2015 to August 2016, we educated ourselves, established standards of care, collaborated with other services, and reached out to the community we represent. We present our experience in creating this specialty clinic as well as our first 16 months of experiential data to help other facilities meet the needs of this community. RESULTS: The primary outcome was the establishment of a comprehensive service for TG patients in our community. From August 2016 to December 2017, a total of 27,516 patient visits were conducted in WHC, 67 (0.2%) were TG patient visits with an average age of 33 years. Of 67, 16 (23.9%) were TGM and 51 (76.1%) were transgender women (TGW) visits, representing a total of 20 new TG patients including 9 (45%) TGM and 11 (55%) TG women. A total of 5 (55.6%) of 9 TGM received vaginal/cervical cytology screening. Sexually transmitted infection screenings were performed in 14 (70%) TG patients versus 6,689 (40.7%) in a non-TG WHC population. CONCLUSIONS: Servicing the transgender community is an important aspect of care for OBGYN providers. Our data suggest that TGM have similar gynecologic needs to the rest of our clinic population.

Depression may be a risk factor for coronary heart disease in midlife women <65 years: A 9-year prospective cohort study.

OBJECTIVE: Depression has been suggested as a risk factor for coronary heart disease (CHD). However, whether the risk may be affected by age is unknown. We seek to assess the difference in long-term CHD risk between younger (<65) and older (≥65) women with depressive symptoms. METHODS: Between June and August 2004, 1995 women presenting for routine mammography were enrolled to the primary study on breast arterial calcification. In 2005 (year 2), each woman completed a validated depression screening questionnaire. A similar questionnaire was mailed to each participant at year 4, 5, and 10 to obtain follow-up data (demographic and CHD risk factors) and record any change in CHD status. RESULTS: Of 1084 women who returned surveys at year 10, 998 had no history of CHD and answered depression screening questions at year 2 as well as questions about CHD events at year 10. Of 185 out of 998 (18.5%) who had positive depression screening at year 2, 24 (13.0%) developed ≥1 CHD events by year 10, which is significantly higher than the incidence of 6.5% (53/813) in control group (p < 0.001). With CHD risk factors including age adjusted in a logistic regression model, depression was the only significant predictive factor for CHD in women aged <65 (OR = 6.56, 95% CI 1.07-40.09, p = 0.042). However, in women aged ≥65, age was the only significant predictive factor for CHD. CONCLUSION: A history of depression may increase the risk of CHD over 9 years of follow-up, and more prominently in midlife women aged <65 years.

Diagnostic accuracy of FRAX in predicting the 10-year risk of osteoporotic fractures using the USA treatment thresholds: A systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to conduct a systematic review and meta-analysis on the performance of the WHO's Fracture Risk Assessment (FRAX) instrument in predicting 10-year risk of Major Osteoporotic Fractures (MOF) and Hip Fractures (HF), using the USA treatment thresholds, in populations other than their derivation cohorts. DESIGN: EMBASE and MEDLINE database were searched with search engine PubMed and OVID as well as Google Scholar for the English-language literature from July 2008 to July 2016. Limiting our search to articles that analyzed only MOF and/or HF as an outcome, 7 longitudinal cohorts from 5 countries (USA, Poland, France, Canada, New Zealand) were identified and included in the meta-analysis. SAS NLMIXED procedure (SAS v 9.3) was applied to fit the Hierarchical Summary Receiver Operating Characteristics (HSROC) model for meta-analysis. Forest plot and HSROC plot was generated by Review Manager (RevMan v 5.3). RESULTS: Seven studies (n=57,027) were analyzed to assess diagnostic accuracy of FRAX in predicting MOF, using 20% as the 10-year fracture risk threshold for intervention, the mean sensitivity, specificity, and diagnostic odds ratio (DOR) along with their 95% confidence intervals (CI) were 10.25% (3.76%-25.06%), 97.02% (91.17%-99.03%) and 3.71 (2.73-5.05), respectively. For HF prediction, using 3% as the 10-year fracture risk threshold, six studies (n=50,944) were analyzed. The mean sensitivity, specificity, and DOR along with their 95% confidence intervals (CI) were 45.70% (24.88%-68.13%), 84.70% (76.41%-90.44%) and 4.66 (2.39-9.08), respectively. CONCLUSIONS: Overall, using the 10year intervention thresholds of 20% for MOF and 3% for HF, FRAX performed better in identifying patients who will not have a MOF or HF within 10years, than those who will. A substantial number of patients who developed fractures, especially MOF within 10years of follow up, were missed by the baseline FRAX assessment.

Effects of Calcium, Vitamin D, and Hormone Therapy on Cardiovascular Disease Risk Factors in the Women's Health Initiative: A Randomized Controlled Trial.

OBJECTIVE: To analyze the treatment effect of calcium+vitamin D supplementation, hormone therapy, both, and neither on cardiovascular disease risk factors. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled trial among Women's Health Initiative (WHI) participants. The predefined primary outcome was low-density lipoprotein cholesterol (LDL-C). RESULTS: Between September 1993 and October 1998, a total of 68,132 women aged 50-79 years were recruited and randomized to the WHI-Dietary Modification (n=48,835) and WHI-Hormone Therapy trials (n=27,347). Subsequently, 36,282 women from WHI-Hormone Therapy (16,089) and WHI-Dietary Modification (n=25,210) trials were randomized in the WHI-Calcium+Vitamin D trial to 1,000 mg elemental calcium carbonate plus 400 international units vitamin D3 daily or placebo. Our study group included 1,521 women who participated in both the hormone therapy and calcium+vitamin D trials and were in the 6% subsample of trial participants with blood sample collections at baseline and years 1, 3, and 6. The average treatment effect with 95% confidence interval, for LDL-C, compared with placebo, was -1.6, (95% confidence interval [CI] -5.5 to 2.2) mg/dL for calcium+vitamin D alone, -9.0 (95% CI -13.0 to -5.1) mg/dL for hormone therapy alone, and -13.8 (95% CI -17.8 to -9.8) mg/dL for the combination. There was no evidence of a synergistic effect of calcium+vitamin D+hormone therapy on LDL-C (P value for interaction=.26) except in those with low total intakes of vitamin D, for whom there was a significant synergistic effect on LDL (P value for interaction=.03). CONCLUSION: Reductions in LDL-C were greater among women randomized to both calcium+vitamin D and hormone therapy than for those randomized to either intervention alone or to placebo. The treatment effect observed in the calcium+vitamin D+hormone therapy combination group may be additive rather than synergistic. For clinicians and patients deciding to begin calcium+vitamin D supplementation, current use of hormone therapy should not influence that decision. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00000611.

A design thinking approach to primary ovarian insufficiency.

Most clinicians are not prepared to provide integrated personal care to address all the clinical needs of women with primary ovarian insufficiency. Design thinking is an engineering methodology used to develop and evaluate novel concepts for systems operation. Here we articulate the need for a seamlessly integrated mobile health system to support genomic research as well as patient care. We also review the pathophysiology and management of primary ovarian insufficiency. Molecular understanding regarding the pathogenesis is essential to developing strategies for prevention, earlier diagnosis, and appropriate management of the disorder. The syndrome is a chronic disorder characterized by oligo/amenorrhea and hypergonadotropic hypogonadism before age 40 years. There may be significant morbidity due to: 1) depression and anxiety related to the loss of reproductive hormones and infertility; 2) associated autoimmune adrenal insufficiency or hypothyroidism; and 3) reduced bone mineral density and increased risk of cardiovascular disease related to estrogen deficiency. Approximately 5% to 10% of women with primary ovarian insufficiency conceive and have a child. Women who develop primary ovarian insufficiency related to a premutation in FMR1 are at risk of having a child with fragile X syndrome, the most common cause of inherited intellectual disability. In most cases of spontaneous primary ovarian insufficiency no environmental exposure or genetic mechanism can be identified. As a rare disease, the diagnosis of primary ovarian insufficiency presents special challenges. Connecting patients and community health providers in real time with investigators who have the requisite knowledge and expertise would help solve this dilemma.