Jane L. Lukacs

Black cohosh has central opioid activity in postmenopausal women: Evidence from naloxone blockade and positron emission tomography neuroimaging

Objective: To test whether black cohosh (BC) exhibits an action on the central endogenous opioid system in postmenopausal women. Design: This was a mechanistic study conducted in the same individuals of luteinizing hormone pulsatility with a saline/naloxone challenge (n = 6) and positron emission tomography with [11C]carfentanil, a selective &mgr;-opioid receptor radioligand (n = 5), before and after 12 weeks of unblinded treatment with a popular BC daily supplement. Results: BC treatment for 12 weeks at a standard dose (Remifemin, 40 mg/day) had no effect on spontaneous luteinizing hormone pulsatility or estrogen concentrations. With naloxone blockade, there was an unexpected suppression of mean luteinizing hormone pulse frequency (saline vs naloxone = 9.0 ± 0.6 vs 6.0 ± 0.7 pulses/16 h; P = 0.056), especially during sleep when the mean interpulse interval was prolonged by approximately 90 minutes (saline night interpulse interval = 103 ± 9 min vs naloxone night interpulse interval = 191 ± 31 min, P = 0.03). There were significant increases in &mgr;-opioid receptor binding potential in the posterior and subgenual cingulate, temporal and orbitofrontal cortex, thalamus, and nucleus accumbens ranging from 10% to 61% across brain regions involved in emotional and cognitive function. In contrast, binding potential reductions of lesser magnitude were observed in regions known to be involved in the placebo response (anterior cingulate and anterior insular cortex). Conclusions: Using two different challenge paradigms for the examination of central opioid function, a neuropharmacologic action of BC treatment was demonstrated in postmenopausal women.

Differential associations for menopause and age in measures of vitamin K, osteocalcin, and bone density: a cross-sectional exploratory study in healthy volunteers.

Objective: To distinguish the effects of midlife aging from early postmenopause on vitamin K measures, bone formation biomarkers, and bone density. Design: Cycling older volunteers (CO; 40-52 years, n = 19) were compared to cycling young (CY; 20-30 years, n = 21) and untreated, age-matched women in the early postmenopause years (EPM; 40-52 years, mean years PM = 2.8 ± 0.5, n = 19). We assessed sex steroids, vitamin status (phylloquinone, 25-hydroxyvitamin D, retinol), osteocalcin (OC), percentage of undercarboxylated osteocalcin (%ucOC), and bone mineral density (BMD) at the spine and hip with dual-energy x-ray absorptiometry. Results: CO women had similar estradiol and vitamin status as CY women, but lower OC (0.64 ± 0.04 vs 0.97 ± 0.08 nmol/L, P = 0.01) and BMD at the total hip (1.0038 ± 0.032 vs 1.1126 ± 0.030g/cm2, P = 0.02). In the two older groups, BMD was similar at all sites, but OC was elevated in the EPM women (1.10 ± 0.10 vs 0.64 ± 0.04 nmol/L, EPM vs CO, P = 0.001). Although phylloquinone was highest in the EPM women, %ucOC was also higher when compared with all cycling women (21.9 ± 1.7% vs 17.4 ± 0.9%, n = 40; P = 0.02). Conclusions: Premenopausal women show reduced BMD despite normal estrogen profiles. %ucOC may be a specific bone marker of the early postmenopause in healthy women.

Midlife Women's Responses to a Hospital Sleep Challenge: Aging and Menopause Effects on Sleep Architecture

OBJECTIVE To distinguish aging from menopause effects on sleep architecture, we studied an episode of disturbed hospital sleep in asymptomatic midlife women during the follicular phase of an ovulatory cycle and three control groups differing by age or menopause status. METHODS Fifty-one studies were conducted in four groups of volunteers: young cycling (YC, 20-30 years, n = 14), older cycling (OC, 40-50 years, n = 15), ovariectomized receiving estrogen therapy (OVX, 40-50 years, n = 12), and spontaneously postmenopausal (PM, 40-50 years, n = 10). Subjects were admitted to the University Hospital General Clinical Research Center (GCRC) for a first-night sleep study conducted during a 24-hour, frequent blood sampling protocol. RESULTS Despite similar estrogen concentrations in the YC (28 +/- 4 pg/ml) and OC (34 +/- 6 pg/ml) groups, OC women had reduced sleep efficiency (79% +/- 2%) vs. YC (87% +/- 3%; p = 0.009). In the OVX and PM groups where estrogen concentrations were markedly different, sleep efficiency was also reduced vs. the YC group (OVX vs. YC, 79% +/- 3% vs. 87% +/- 3%, p = 0.05; PM vs. YC, 75% +/- 3% vs. 87% +/- 3%, p = 0.007). Wake time was longer in the three older groups (103 +/- 10 minutes, 101 +/- 12 minutes, 123 +/- 12 minutes for OC, OVX, PM, respectively) vs. YC (63 +/- 13 minutes, p < 0.05). The number of stage shifts was positively associated with advancing age (rho = 0.3, p < 0.03) but not with estrogen concentration. CONCLUSIONS Aging-related sleep deficits in response to an experimental stressor occur in midlife women prior to menopause.

Adipokine concentrations in nonobese women: a study of reproductive aging, body mass index, and menstrual cycle effects.

Objective: To explore the influence of reproductive aging, body mass index (BMI), and the menstrual cycle on adiponectin (AD) and leptin concentrations. Design: Cross-sectional comparison in age- and BMI-matched nonobese volunteers with regular cycles (CO, n = 19) or in early postmenopause (EPM, n = 19), aged 40—52 years, and a young cycling group (CY, n = 21), aged 20—30 years. Measures: Sex steroids, fasting AD, leptin, insulin, glucose, AD/leptin (A/L) ratio, and insulin resistance (IR) by homeostasis model assessment (HOMA-IR). In ovulatory women, AD, estradiol (E2), and progesterone were assessed weekly across the same menstrual cycle. Results: Insulin, glucose, HOMA-IR, A/L ratio, and leptin values were similar across the three study groups. AD differed, with the highest concentrations in the EPM group (CY: 13.0 ± 0.9 μg/ml vs. CO: 14.0 ± 1.1 μg/ml vs. EPM: 17.7 ± 1.5 μg/ml; p = .05). Values among cycling women were similar. When the cycling groups were combined into a premenopausal (PRE) group and compared to EPM women by BMI (> or ≤25 kg/m2), leptin concentrations were higher and A/L ratios lower in PRE and EPM overweight (OW) subgroups versus normal-weight (NW) subgroups. AD was lower in OW, cycling women and higher in the NW EPM subgroup compared to NW PRE women. In cycling women, AD did not vary across the menstrual cycle. Conclusion: Nonobese, midlife women experience minimal adverse effects from reproductive aging on insulin sensitivity and adipokine secretion. The menstrual cycle is not a key mediator of AD. Early menopause has differential, BMI-dependent effects on adipokine secretion.

Concentrations of Follicle-Stimulating Hormone Correlate with Alkaline Phosphatase and a Marker for Vitamin K Status in the Perimenopause

Serum alkaline phosphatase (ALP), a gross marker of bone turnover, has been reported to be elevated after menopause, a period characterized by hallmark increases in follicle-stimulating hormone (FSH). Whether the ALP rise coincides with the perimenopausal transition when changes in FSH, estrogen levels, and menstrual cycles are first apparent is not known. The purpose of this cross-sectional study was twofold: (1) to characterize the influence of the perimenopausal transition on ALP activity and (2) to correlate ALP activity with more precise markers for bone, osteocalcin (OC), and vitamin K status assessed with undercarboxylated osteocalcin (ucOC). Thirty-eight studies of hourly FSH were conducted on cycle day 6 of the follicular phase in perimenopausal women volunteers, aged 40-54 years (mean body mass index [BMI] = 24.2 +/- 0.5). Mean FSH was used to define the perimenopausal stage (early perimenopausal, mean FSH </= 15 IU/L, n = 27; late perimenopausal, mean FSH > 15 IU/L, n = 11). As expected, late perimenopausal women had irregular and longer menstrual cycles, lower estradiol (E(2)) and estrone (E(1)) levels, and a lower frequency of ovulations vs. the early group. ALP was higher (76.5 +/- 8.3 vs. 58.3 +/- 2.7 IU/L, p = 0.045) compared with the early perimenopausal group. In a subsample (n = 10), OC was associated with ALP (r = 0.69, p < 0.03), FSH was positively related to ucOC concentrations (r = 0.7, p < 0.03), and women with E(1) concentrations <40 pg/ml had double the percentage of ucOC compared with those where E(1) was >40 pg/ml (46.3% +/- 6.6% vs. 22.0% +/- 3. 1%, p < 0.006). Clinical markers of the perimenopause are associated with a nonspecific but inexpensive marker of enhanced bone turnover (i.e., higher ALP) and correlate well with more precise markers of bone activity. These findings suggest that health-promotion strategies for preserving bone should be instituted well before the last menstrual period.