Literature Review and Commentary

by Alan R. Gaby, M.D.

DHEA for Dyspareunia Associated with Menopause

Two hundred fifty-three women with dyspareunia associated with menopause were randomly assigned to receive, in double-blind fashion, placebo, 3.25 mg of dehydroepiandrosterone (DHEA), or 6.5 mg of DHEA, administered intravaginally once a day before bedtime for 12 weeks. Compared with placebo, the higher dose of DHEA decreased dyspareunia by 46% (p < 0.02) and decreased moderate-to-severe vaginal dryness by 42% (p < 0.02). The higher dose of DHEA also produced histological improvements (a 45.8% decrease in the mean percentage of parabasal cells [p < 0.0001] and a 4.7% increase in the percentage of superficial cells [p < 0.0001]) and decreased mean vaginal pH by 0.83 units (p < 0.0001). The effect of the lower dose of DHEA was less pronounced, and the reduction in dyspareunia compared with placebo was not statistically significant. No significant adverse effects were reported.

Comment

: These results indicate that daily intravaginal administration of 6.5 mg of DHEA (but not 3.25 mg of DHEA) resulted in clinical and histological improvement in women with dyspareunia associated with menopause. DHEA is metabolized in part to estrogen and testosterone, which may account for its beneficial effect on dyspareunia. However, DHEA may also have physiological actions unrelated to its function as a precursor to estrogen and testosterone, since DHEA receptors have been identified on some human cells. In previous research, intravaginal administration of DHEA did not cause endometrial proliferation and produced little or no change in serum concentrations of estrogen and testosterone. Because it appears to be effective at low doses, intravaginal administration of DHEA may be preferable to oral or transdermal administration when treating symptoms related to vaginal atrophy.

Archer DF et al. Treatment of pain at sexual activity (dyspareunia) with intravaginal dehydroepiandrosterone (prasterone). Menopause. 2015;22:950–963

Vitamin D and Bone: Racial Differences

The association between serum 25-hydroxyvitamin D (25[OH]D) levels and lumbar bone mineral density (BMD) was examined in a cross-sectional study of 1773 adult participants in the Multi-Ethnic Study of Atherosclerosis (714 white, 353 black, 249 Chinese, and 457 Hispanic). Serum 25(OH)D was highest among whites and lowest among blacks, but BMD was highest among blacks. Higher serum 25(OH)D was significantly associated with higher BMD only among white and Chinese participants. Among Hispanics, higher serum 25(OH)D was nonsignificantly associated with higher BMD. Among blacks, BMD was significantly higher in those with a serum 25(OH)D level less than 20 ng/ml than in those with a serum 25(OH)D of 30 ng/ml or greater.

Comment

: This is one of several studies to show that the association between 25(OH)D levels and BMD differs among different racial and ethnic groups. Whereas higher 25(OH)D was associated with greater BMD in white and Chinese participants, the opposite association was seen in blacks. Previous research has found that the concentration of vitamin D-binding protein is lower in blacks than in whites, and that this difference is largely genetically determined. Although blacks have lower 25(OH)D levels than whites do, a higher proportion of their circulating 25(OH)D is bioavailable, because less is bound to vitamin D-binding protein. The net effect is that the serum concentration of bioavailable 25(OH)D is very similar between whites and blacks (Powe CE et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med. 2013;369:1991–2000). Based on the available evidence, a case can be made that blacks who have normal BMD and moderately low serum 25(OH)D levels should not be given vitamin D supplements.

Van Ballegooijen AJ et al. Vitamin D metabolites and bone mineral density: The multi-ethnic study of atherosclerosis. Bone. 2015;78:186–193.

Vitamin D and Bone: Higher Doses Not More Effective Than Lower Doses

Two hundred thirty postmenopausal women (mean age, 61 years) who had a serum 25-hydroxyvitamin D level of 14 to 27 ng/ml were randomly assigned to receive, in double-blind fashion, placebo, low-dose vitamin D3 (800 IU per day) or high-dose vitamin D3 (800 IU per day plus twice monthly 50,000 IU; equivalent to a total of about 4,000 IU per day) for 1 year. After 1 year, fractional calcium absorption (measured using 2 stable isotopes) increased by 1% (equivalent to about 10 mg per day of additional calcium absorbed) in the high-dose group, decreased by 2% in the low-dose group (p = 0.005 vs. high dose), and decreased by 1.3% in the placebo group (p = 0.03 vs. high dose). Mean changes in bone mineral density of the spine, total hip, femoral neck, and total body did not differ significantly between groups, and there was no clear trend favoring high-dose over low-dose vitamin D.

Comment

: In this study of postmenopausal women with low or borderline-low serum 25-hydroxyvitamin D levels, supplementation with 4,000 IU per day of vitamin D, as compared with 800 IU per day, resulted in a small increase in calcium absorption, but this increase did not translate into beneficial effects on bone mineral density. The results of this study are consistent with those of a previous study in which postmenopausal women received daily either 800 IU or 6500 IU of vitamin D3 for 1 year. While bone mineral density increased in both groups, the mean increase was nonsignificantly greater with the lower dose of vitamin D than with the higher dose. (Grimnes G et al. The effect of high-dose vitamin D on bone mineral density and bone turnover markers in postmenopausal women with low bone mass – a randomized controlled 1-year trial. Osteoporos Int. 2012;23:201–211). The results of these studies indicate that high-dose vitamin D is not more effective than 800 IU per day for preventing osteoporosis in postmenopausal women.

Hansen KE et al. Treatment of vitamin D insufficiency in postmenopausal women: a randomized clinical trial. JAMA Intern Med. 2015;175:1612–1621.

Can Inositol Prevent Gestational Diabetes?

Two hundred twenty obese pregnant women were randomly assigned to receive, in open-label fashion, 2 g of myo-inositol plus 200 µg of folic acid twice a day or placebo (200 µg of folic acid twice a day), starting in week 12-13 of gestation. Oral glucose tolerance tests were conducted at 24 to 28 weeks of gestation. The incidence of gestational diabetes was significantly lower by 58% in the myo-inositol group than in the placebo group (14.0% vs. 33.6%; p = 0.001). Insulin resistance improved slightly in the myo-inositol group and worsened slightly in the placebo group (p < 0.05 for the difference in the change between groups).

Comment

: Myo-inositol (commonly referred to simply as inositol) is a compound that occurs naturally in food and is synthesized in the body. A typical daily diet contains about 1300 mg of myo-inositol with beans being among the best sources. Myo-inositol and one of its naturally occurring stereoisomers, D-chiro-inositol, are each thought to play a role in regulating glucose levels. In the present study, supplementation with 4 g per day of myo-inositol significantly reduced the incidence of gestational diabetes and improved insulin resistance in obese pregnant women. The mechanism by which myo-inositol improves glycemic control is not known. Additional studies are needed to determine whether it is safe to supplement with this relatively large dose of myo-inositol during pregnancy.

DʼAnna R et al. Myo-inositol supplementation for prevention of gestational diabetes in obese pregnant women: a randomized controlled trial. Obstet Gynecol. 2015;126:310–315.

Cranberry Prevents Post-Surgery Urinary Tract Infections

One hundred sixty women undergoing elective gynecological surgery involving urinary catheterization were randomly assigned to receive, in double-blind fashion, 2 cranberry capsules twice a day (equivalent to 8 ounces of cranberry juice twice a day) or placebo, beginning at the time of hospital discharge and continuing for 6 weeks. The proportion of women who developed a urinary tract infection (UTI) was significantly lower by 50% in the cranberry group than in the placebo group (19% vs. 38%; p < 0.01).

Comment

: The incidence of UTI is 10-64% among women undergoing elective gynecological surgery during which a catheter is placed. Cranberry juice has been used for many years to prevent and treat UTIs. There are several different mechanisms by which cranberry juice could be beneficial. First, the proanthocyanidins in cranberry extracts have been shown to prevent the adherence of uropathogenic strains of E. coli to human uroepithelial cells. Second, ingestion of cranberry juice may acidify the urine, and thereby inhibit the growth of some uropathogenic bacteria. Third, cranberries contain hippuric acid, which has antibiotic activity. The results of the present study demonstrate that, among women undergoing elective gynecological surgery involving urinary catheterization, the use of cranberry extract capsules during the postoperative period reduced the incidence of urinary tract infections by 50%.

Foxman B et al. Cranberry juice capsules and urinary tract infection after surgery: results of a randomized trial. Am J Obstet Gynecol. 2015;213:194.e1–194.e8.

Fish Oil for Rheumatoid Arthritis

One hundred thirty-nine patients with rheumatoid arthritis for less than 12 months who had not previously received disease-modifying anti-rheumatic drugs (DMARDs) were randomly assigned to receive, in double-blind fashion, in a 2:1 ratio, a high dose (5.5 g per day) or a low dose (0.4 g per day) of omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) from fish oil. All patients also began a regimen of DMARDs (methotrexate, sulfasalazine, and hydroxychloroquine). After 12 months, the proportion of patients who had commenced leflunomide (an indicator of failure of medical therapy) was significantly lower in the high-dose group than in the low-dose group (10.5% vs. 32.1%; p = 0.002). The remission rate was significantly higher in the high-dose group than in the low-dose group (approximations from figure 3: 41% vs. 23%; p = 0.03).

Comment

: EPA and DHA, the major omega-3 fatty acids present in fish oil, have anti-inflammatory activity. Numerous double-blind trials have found that supplementation with fish oil improves symptoms in patients with rheumatoid arthritis. The results of the present study demonstrate that supplementation with a high dose of fish oil (about 18 g per day) can provide additional benefits to those achieved with DMARDs. Specifically, high-dose fish oil increased the remission rate and also decreased the number of patients for whom DMARDs were ineffective.

Proudman SM et al. Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug use. Ann Rheum Dis. 2015;74:89–95.

Can Cherry Juice

Ameliorate

Dementia?

Forty-nine elderly individuals (mean age, 79.8 years) with mild-to-moderate dementia were randomly assigned to consume 200 ml per day of cherry juice or a control juice (apple juice) for 12 weeks. The cherry juice was produced by a novel method designed to retain the anthocyanins. Compared with baseline, cherry juice significantly improved measures of verbal fluency (p < 0.02), short-term memory (p < 0.02), and long-term memory (p = 0.001). No significant changes were seen in the control group, but it was not stated whether the difference in the change between groups was significant.

Comment

: Basic-science research suggests that anthocyanins (which are present in large amounts in cherry juice) may have neuroprotective effects. The results of the present study suggest that cherry juice may improve cognitive function in elderly people with mild-to-moderate dementia. However, the study had some weaknesses. First, it was not stated whether the improvement with cherry juice relative to apple juice was statistically significant. Second, the cherry juice provided 103 kcal per day more energy and 2.8 g per day more protein than the apple juice. In elderly people, some of whom might be malnourished, a small amount of additional calories and protein could be nutritionally significant. Cognitive function depends in part on the availability of neurotransmitters, many of which are synthesized from amino acids. An increase in dietary protein, when combined with the potential protein-sparing effect of a higher caloric intake, may increase neurotransmitter synthesis. That effect, as opposed to any effect specific to cherry juice, could have contributed to the improvements observed in this study.

Kent K et al. Consumption of anthocyanin-rich cherry juice for 12 weeks improves memory and cognition in older adults with mild-to-moderate dementia. Eur J Nutr. Epub 2015 Oct 19.

Fish Oil Improves Muscle Mass in Elderly People

Sixty healthy elderly men and women (aged 60-85 years) were randomly assigned to receive, in double-blind fashion, in a 2:1 ratio, omega-3 fatty acid esters (Lovaza; 1.9 g per day of eicosapentaenoic acid and 1.5 g per day of docosahexaenoic acid) or placebo (corn oil) for 6 months. Compared with placebo, omega-3 fatty acids significantly increased mean thigh muscle volume by 3.6%, handgrip strength by 2.3 kg, and one-repetition maximum lower- and upper-body strength by 4.0% (all p < 0.05).

Comment

: In this study, supplementation with omega-3 fatty acids slowed the decline in muscle mass and muscle function that typically occurs with advancing age. Increasing omega-3 fatty acid intake may therefore help maintain physical independence in elderly people. While the mechanism of action of omega-3 fatty acids is not known, it is thought to involve alterations in both anabolic and catabolic pathways.

Smith GI et al. Fish oil-derived n-3 PUFA therapy increases muscle mass and function in healthy older adults. Am J Clin Nutr. 2015;102:115–122.