Christine L. Hitchcock

What is the role of non-invasive measurements of atherosclerosis in individual cardiovascular risk prediction?

Primary prevention of CVD (cardiovascular disease) is mainly based on the assessment of individual cardiovascular risk factors. However, often, only the most important (conventional) cardiovascular risk factors are determined, and every level of risk factor exposure is associated with a substantial variation in the amount of atherosclerosis. Measuring the effect of risk factor exposure over time directly in the vessel might (partially) overcome these shortcomings. Several non-invasive imaging techniques have the potential to accomplish this, each of these techniques focusing on a different stage of the atherosclerotic process. In this review, we aim to define the current role of various of these non-invasive measurements of atherosclerosis in individual cardiovascular risk prediction, taking into account the most recent insights about validity and reproducibility of these techniques and the results of recent prospective outcome trials. We conclude that, although the clinical application of FMD (flow-mediated dilation) and PWA (pulse wave analysis) in individual cardiovascular risk prediction seems far away, there may be a role for PWV (pulse wave velocity) and IMT (intima-media thickness) measurements in the near future.

Oral micronized progesterone for vasomotor symptoms--a placebo-controlled randomized trial in healthy postmenopausal women.

ObjectiveThe aim of this study was to compare oral micronized progesterone (progesterone) with placebo as therapy for postmenopausal hot flushes and night sweats (vasomotor symptoms [VMS]). MethodsHealthy volunteer community women 1 to 10 years since final menstruation were recruited for a randomized double-blind placebo-controlled trial of progesterone (300 mg daily at bedtime) between 2003 and 2009 and were screened for clinical, physical, or laboratory evidence of cardiovascular risks (nonsmoking, moderate body mass index [<35 kg/m2], normal lipids, electrocardiogram, nondiabetic). Women recorded daily frequency and severity (1-4) of VMS in the Daily Menopause Diary during run-in (4 wk) and intervention (12 wk). Average daily VMS score (day frequency × day severity + night frequency × night severity) during final 28 therapy days was the primary outcome, analyzed by therapy, with run-in score as covariate. ResultsRandomized participants were 133 healthy community women with VMS, ages 44 to 62 years, with a mean (SD) VMS score of 17.0 (10.4) at run-in (VMS frequency 6.8 [3.2] episodes/d). Women were randomized to progesterone (n = 75) or placebo (n = 58); analysis included all with VMS data at run-in and on therapy (n = 68 and 46, respectively). The VMS scores of women taking progesterone were better than placebo (mean adjusted difference, −4.3 (95% CI, −6.6 to −1.9), with mean reductions of 10.0 (95% CI, −12.0 to −8.1) and 4.4 (95% CI, −6.6 to −2.2) in the progesterone and placebo arms, respectively. Discontinuation with adverse events was 9% (progesterone, 8; placebo, 4), with no serious cases. ConclusionsOral micronized progesterone is effective for treatment of hot flushes and night sweats in healthy women early in postmenopause.

Negative Spinal Bone Mineral Density Changes and Subclinical Ovulatory Disturbances—Prospective Data in Healthy Premenopausal Women With Regular Menstrual Cycles

Subclinical ovulatory disturbances (anovulation or short luteal phases within normal-length menstrual cycles) indicate lower progesterone-to-estrogen levels. Given that progesterone plays a bone formation role, subclinical ovulatory disturbances may be associated with bone loss or less than expected bone gain. Our purpose was to perform a meta-analysis of prospective studies in healthy premenopausal women to determine the overall relationship of subclinical ovulatory disturbances to change in bone mineral density. Two reviewers independently identified from serial literature searches 6 studies meeting inclusion criteria: a 2-year study in 114 young adult women, 2006-2009, Vancouver, Canada; a 2-year study in 189 premenopausal women, 2000-2005, Toronto, Canada; a single-cycle study in 14 young women, 1996-1997, Melbourne, Australia; an 18-month study in 53 women, 1990-1995, Santa Clara, California; a 4-year study in 27 women, 1988-1995, Vancouver, Canada; and a 1-year study in 66 women, 1985-1988, Vancouver, Canada. This meta-analysis included a combined sample size of 473 observations in 436 premenopausal women studied over 1-4 years and aged 14-47 years. The percentage of women with ovulatory disturbances varied significantly from 13% to 82%. Women with more frequent ovulatory disturbances had more negative percentage changes in spine bone mineral density (weighted mean difference = -0.86; P = 0.040) for random-effects analysis. There was significant heterogeneity among these 6 studies (I(2) = 80%). In summary, these data show that regularly menstruating women with more frequent ovulatory disturbances experience more negative changes in bone (approximately -0.9% per year). These cycles with silent estrogen/progesterone imbalance may be clinically important.

Hot flushes and night sweats differ in associations with cardiovascular markers in healthy early postmenopausal women.

ObjectiveThe aim of this study was to evaluate the associations between vasomotor symptoms ([VMS] hot flushes or flashes and night sweats) and markers of cardiovascular risk. MethodsHealthy postmenopausal women in a randomized controlled trial of progesterone for VMS recorded VMS frequency in the Daily Menopause Diary for 28 days at baseline. Accepted risks for cardiovascular disease were measured: body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), blood pressure (BP), endothelial function by venous occlusion plethysmography, fasting lipids, glucose, high-sensitivity C-reactive protein, albumin, and D-dimer. Relationships between risk variables and VMS frequency (24 h, day and night) were assessed by univariate and multivariate robust regressions with adjustment for age and WHtR. ResultsData were available for 145 healthy, nonsmoking women without heart disease, hypertension, or diabetes who were 1 to 11 years past their final menstruation and were aged 43 to 65 years, with a mean (SD) BMI of 25.0 (2.9) kg/m2 and WC of 79.1 (7.1) cm. Anthropometric variables (BMI, WC, and WHtR) were significantly negatively associated with total (24-h day) VMS frequency and with day VMS but not with night VMS frequency. Systolic BP decreased with greater 24-hour VMS frequency, and both systolic and diastolic BPs were inversely related to day but not night VMS frequency. Albumin was positively associated with night VMS frequency but not with day or 24-hour VMS frequency. Other variables showed little association with VMS frequency. ConclusionsHot flushes, but not night sweats, were associated with lower cardiovascular risk factors in these healthy postmenopausal women. Future research should differentiate night sweats from hot flushes.

Fluid Retention over the Menstrual Cycle: 1-Year Data from the Prospective Ovulation Cohort

We report menstrual and mid-cycle patterns of self-reported “fluid retention” in 765 menstrual cycles in 62 healthy women. Self-reported “fluid retention,” commonly described as bloating, is one element of the clinical assessment and diagnosis of premenstrual symptoms. These daily diary data were collected as part of an observational prospective one-year study of bone changes in healthy women of differing exercise characteristics. Ovulation was documented by quantitative basal temperature analysis, and serum estradiol and progesterone levels were available from initial and final cycles. Fluid retention scores (on a 0–4 scale) peaked on the first day of menstrual flow (mean ± SE : 0.9 ± 0.1), were lowest during the mid-follicular period, and gradually increased from 0.22 ± 0.05 to 0.50 ± 0.09 over the 11 days surrounding ovulation. Mid-cycle, but not premenstrual, fluid scores tended to be lower in anovulatory cycles (ANOVA P = 0.065), and scores were higher around menstruation than at midcycle (P < 0.0001). Neither estradiol nor progesterone levels were significantly associated with fluid retention scores. The peak day of average fluid retention was the first day of flow. There were no significant differences in womens self-perceived fluid retention between ovulatory and anovulatory cycles.

Progesterone for hot flush and night sweat treatment - effectiveness for severe vasomotor symptoms and lack of withdrawal rebound

A controlled trial recently showed that oral micronized progesterone (Progesterone, 300 mg at h.s. daily) was effective for vasomotor symptoms (VMS) in 133 healthy early postmenopausal women. Here, we present subgroup data in women with severe VMS (50 VMS of moderate–severe intensity/wk) and also 1-mo withdrawal study outcomes. Women with severe VMS (n = 46) resembled the full cohort but experienced 10 VMS/d of 3 of 4 intensity. On therapy, the progesterone VMS number (#) decreased significantly more than placebo # to 5.5/day (d) versus 8/d (ANCOVA −2.0 95% CI: −3.5 to −0.4). Just after trial mid-point, a withdrawal substudy (D/C) was added – 56 women were invited and 34 (61%) took part (progesterone 17; placebo 17). Those in the D/C cohort resembled the whole cohort. On stopping, VMS gradually increased – at D/C week 4, on progesterone, VMS daily # reached 78% and significantly less than baseline (−3.0 to −0.8) but placebo VMS # did not differ from run-in. In summary, progesterone is effective for severe VMS and does not cause a rebound increase in VMS when stopped. That progesterone may be used alone for severe VMS and unlike estrogen does not appear to cause a withdrawal rebound increases VMS treatment options.

Detecting evidence of luteal activity by least-squares quantitative basal temperature analysis against urinary progesterone metabolites and the effect of wake-time variability

OBJECTIVE To assess computerised least-squares analysis of quantitative basal temperature (LS-BT) against urinary pregnanediol glucuronide (PdG) as an indirect measure of ovulation, and to evaluate the stability of LS-QBT to wake-time variation. STUDY DESIGN Cross-sectional study of 40 healthy, normal-weight, regularly menstruating women aged 19-34. Participants recorded basal temperature and collected first void urine daily for one complete menstrual cycle. Evidence of luteal activity (ELA), an indirect ovulation indicator, was assessed using Kassams PdG algorithm, which identifies a sustained 3-day PdG rise, and the LS-QBT algorithm, by determining whether the temperature curve is significantly biphasic. Cycles were classified as ELA(+) or ELA(-). We explored the need to pre-screen for wake-time variations by repeating the analysis using: (A) all recorded temperatures, (B) wake-time adjusted temperatures, (C) temperatures within 2h of average wake-time, and (D) expert reviewed temperatures. RESULTS Relative to PdG, classification of cycles as ELA(+) was 35 of 36 for LS-QBT methods A and B, 33 of 34 (method C) and 30 of 31 (method D). Classification of cycles as ELA(-) was 1 of 4 (methods A and B) and 0 of 3 (methods C and D). Positive predictive value was 92% for methods A-C and 91% for method D. Negative predictive value was 50% for methods A and B and 0% for methods C and D. Overall accuracy was 90% for methods A and B, 89% for method C and 88% for method D. The day of a significant temperature increase by LS-QBT and the first day of a sustained PdG rise were correlated (r=0.803, 0.741, 0.651, 0.747 for methods A-D, respectively, all p<0.001). CONCLUSION LS-QBT showed excellent detection of ELA(+) cycles (sensitivity, positive predictive value) but poor detection of ELA(-) cycles (specificity, negative predictive value) relative to urinary PdG. Correlations between the methods and overall accuracy were good and similar for all analyses. Findings suggest that LS-QBT is robust to wake-time variability and that expert interpretation is unnecessary. This method shows promise for use as an epidemiological tool to document cyclic progesterone increase. Further validation relative to daily transvaginal ultrasound is required.

Ovulation disturbances and mood across the menstrual cycles of healthy women

We examined the cyclicity of negative mood relative to ovulation and ovulation disturbances in Menstrual Cycle Diary© data collected daily during a 1-year study of ovulation, exercise, and bone change. A validated quantitative basal temperature-based methodology was used to determine the onset of the luteal phase. ‘Feeling depressed’, ‘feeling anxious’, and ‘feeling angry/frustrated’ were scored on a scale of 0 (absent) to 4 (very intense). Mood scores were examined over two 15-day intervals centered on either ovulation/midpoint, or on the onset of flow. Data were available from 765 cycles of 62 healthy and initially ovulatory women with a mean age of 33.9 ± 5.4 years. Of 739 cycles that could be classified, 532 (72%) were normally ovulatory, 185 (25%) were ovulatory with a short (<10 day) luteal phase, and 22 (3%) were anovulatory. Minor cyclic mood changes were present in both ovulatory and anovulatory menstrual cycles. In anovulatory cycles, mood tended to be more variable but less negative, with a time course that differed from that in ovulatory cycles. Mood scores did not differ based on luteal phase length or with hormone levels. Patterns and mechanisms of mood change in very symptomatic women appear to be essentially amplifications of normal experiences.

Progesterone Therapy, Endothelial Function and Cardiovascular Risk Factors: A 3-Month Randomized, Placebo-Controlled Trial in Healthy Early Postmenopausal Women

Background Progesterone is effective treatment for hot flushes/night sweats. The cardiovascular effects of progesterone therapy are unknown but evidence suggests that premenopausal normal estradiol with also normal progesterone levels may provide later cardiovascular protection. We compared the effects of progesterone to placebo on endothelial function, weight, blood pressure, metabolism, lipids, inflammation and coagulation. Methods and Results We conducted a randomized, double-blind, 3-month placebo-controlled trial of progesterone (300 mg daily) among 133 healthy postmenopausal women in Vancouver, Canada from 2003–2009. Endothelial function by venous occlusion plethysmography was a planned primary outcome. Enrolled women were 1–11 y since last menstruation, not using hormones (for >6 months), non-smoking, without diabetes, hypertension, heart disease or their medications. Randomized (1∶1) women (55±4 years, body mass index 25±3) initially had normal blood pressure, fasting lipid, glucose and electrocardiogram results. Endothelial function (% forearm blood flow above saline) was not changed with progesterone (487±189%, n = 18) compared with placebo (408±278%, n = 16) (95% CI diff [−74 to 232], P = 0.30). Progesterone (n = 65) and placebo (n = 47) groups had similar changes in systolic and diastolic blood pressure, resting heart rate, weight, body mass index, waist circumference, total cholesterol, low-density lipoprotein cholesterol and triglyceride levels. High-density lipoprotein was lower (−0.14 mmol/L, P = 0.001) on progesterone compared with placebo. Fasting glucose, hs-C-reactive protein, albumin and D-dimer changes were all comparable to placebo. Framingham General Cardiovascular Risk Profile scores were initially low and remained low with progesterone therapy and not statistically different from placebo. Conclusions Results indicate that progesterone has short-term cardiovascular safety. Endothelial function, weight, blood pressure, waist circumference, inflammation and coagulation were unchanged as were lipids except for HDL-C. The statistically significant decrease in HDL-C levels was not clinically important (based on lack of Cardiovascular Risk Profile change). Trial Registration ClinicalTrials.gov NCT00152438

Elements of the Menstrual Suppression Debate

In this article I review common arguments and frameworks used by participants in the debate about extended use of combined hormonal contraceptives (CHCs; usually oral contraceptive pills) for menstrual suppression. I examine the way in which menstruation is described and the scope of risks considered. I consider the role of the pharmaceutical industry, personal and clinical experience, and concerns about the contraceptive effectiveness of contraceptive formulations with lower doses. I also address public consequences of the debate, including the possibility of inciting a pill scare, and increasing product awareness and off-label practice.