Oral DHEA Increases Bone Mass in Women
Fifty-five men and 58 women (aged 65–75 years) were randomly assigned to receive, in double-blind fashion, 50 mg per day of dehydroepiandrosterone (DHEA) or placebo for one year. Thereafter, all participants received 50 mg per day of DHEA for an additional year. All participants received daily 640 IU of vitamin D and 700 mg of calcium. In women, mean lumbar spine bone mineral density (BMD) increased during the first year by 1.9% (p = 0.0003 compared with baseline) in the DHEA group and by 0.8% in the placebo group (p = 0.03 for the difference in the change between groups). After two years, mean spine BMD increased by a total of 3.6% in the DHEA group. Hip BMD did not change. In men, there were no differences in BMD between DHEA and placebo.
Comment: DHEA is an androgen produced in women primarily by the adrenal glands and to a lesser extent by the ovaries. It is metabolized in part to estrogen and testosterone. In addition, DHEA appears to have physiological actions that are unrelated to its function as a precursor hormone, including stimulation of osteoblasts. The results of the present study indicate that DHEA can increase bone mass in elderly women, although it was not effective in men.
Weiss EP et al. Dehydroepiandrosterone replacement therapy in older adults: 1- and 2-y effects on bone. Am J Clin Nutr. 2009;89:1459–1467.
Intravaginal DHEA for Menopausal Symptoms
Two hundred sixteen postmenopausal women (median age, 58 years) with symptomatic vaginal atrophy were randomly assigned to daily intravaginal administration of a suppository containing 3.25, 6.5, or 13 mg of DHEA or placebo at bedtime for 12 weeks. After 2 weeks, all 3 doses of DHEA induced a decrease in the percentage of parabasal cells (indicating histologic improvement in vaginal atrophy), a significant reduction in vaginal pH, and a significant improvement in the most bothersome vaginal symptom (e.g., dryness, irritation/itching, or pain during sexual activity). After 12 weeks, the 6.25 mg dose produced a 46% decrease in the percentage of parabasal cells (p < 0.0001 vs. placebo), a 1.3-unit decrease in vaginal pH (p < 0.0001 vs. placebo), and a 1.5-point decrease (on a 3-point scale) in the severity of the most bothersome vaginal symptom (p = 0.0001 vs. placebo). Comparable improvements were seen with the other DHEA dosages. No endometrial proliferation was observed after 3 months of DHEA treatment.
Comment: The results of this study indicate that intravaginal administration of DHEA improved signs and symptoms of vaginal atrophy in postmenopausal women, without causing endometrial proliferation. Intravaginal DHEA therefore compares favorably with estrogen therapy, which is known to cause endometrial proliferation, a possible precursor to endometrial cancer. Previous studies by this same group of investigators found that intravaginal administration of DHEA caused little or no change in serum concentrations of estrogen and testosterone. In contrast, serum levels of these hormones often increase after oral administration of DHEA, although oral DHEA does not appear to cause endometrial proliferation. Oral DHEA has been found to be an effective alternative to estrogen-replacement therapy in women suffering from vasomotor and psychological symptoms of menopause. The results of the present study suggest that intravaginal DHEA may be the preferred treatment for women whose postmenopausal symptoms are related mainly to vaginal atrophy.
Labrie F et al. Intravaginal dehydroepiandrosterone (Prasterone), a physiological and highly efficient treatment of vaginal atrophy. Menopause. 2009;16:907–922.
Progesterone and Osteoporosis: Uncertain Efficacy
One hundred and two healthy women (mean age, 53 years) within five years of menopause were randomly assigned to receive, in double-blind fashion, transdermal progesterone cream or placebo for one year. The women were instructed to apply one-quarter teaspoon of cream (containing 20 mg of progesterone) to the skin daily, rotating the application site between the upper arms, thighs, and breasts. All women also received a daily multivitamin plus 1,200 mg per day of calcium. After one year, mean bone mineral density at the hip and lumbar spine did not differ significantly between groups, and there was no trend in favor of progesterone.
Comment: Progesterone has been found to promote bone formation by stimulating osteoblastic activity. In an uncontrolled trial, Lee reported that application of transdermal progesterone cream markedly increased bone mineral density and prevented fractures in postmenopausal women. However, the study by Leonetti summarized above found that progesterone was of no benefit in preventing bone loss in postmenopausal women. It is difficult to compare the dosages of progesterone in the two studies, because the product used by Lee was, according to verbal reports, 3% progesterone by volume rather than by weight. However, it appears that the amount of progesterone applied per month was less in the Lee study than in the Leonetti study. One might speculate that the higher dosage used by Leonetti exceeded a hypothetical "therapeutic window." However, at a conference I attended, Lee stated that higher doses of progesterone than those used in his study were more effective for treating osteoporosis. Another difference between the two studies was that the patients treated by Lee were somewhat older (mean age, 65 years; range, 38–83 years) than those treated by Leonetti. It is possible that the effect of progesterone differs during the early postmenopausal period (when bone loss is very rapid) than during the later postmenopausal years (when bone loss is slower). However, Lee reported that the beneficial effect of progesterone was not affected by age or by time since onset of menopause. Because of these conflicting results, the effect of progesterone on postmenopausal bone loss remains uncertain.
Leonetti HB et al. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol. 1999;94:225–228.
Lee JR. Is natural progesterone the missing link in osteoporosis prevention and treatment? Med Hypotheses. 1991;35:316–318.
Flaxseed for Cyclical Breast Pain
One hundred-sixteen premenopausal women with severe cyclical mastalgia for at least six months were randomly assigned to receive, in double-blind fashion, a daily muffin containing 25 g of flaxseed or a placebo wheat-based muffin for three months. Breast pain, as measured on a visual analogue scale, improved in both groups, but the median improvement was significantly greater in the flaxseed group than in the control group after two and three months. No significant side effects were reported.
Comment: Cyclical mastalgia is believed to be caused by hormonal fluctuations. Flaxseed is a rich source of mammalian lignan precursors, which are structurally similar to tamoxifen, and may therefore antagonize the effects of endogenous estrogen. Flaxseed oil contains only minimal amounts of lignans, so it would not be expected to have the same effect as that of whole ground flaxseeds.
Goss PE et al. Effects of dietary flaxseed in women with cyclical mastalgia. Breast Cancer Res Treat. 2000;64:49.
Iodine for Fibrocystic Breast Changes
Two hundred thirty-three women with fibrocystic breast changes received Lugol's iodine (consisting of 95% iodide and 5% iodine) orally for two years. The dosage was 510 drops per day, based on body weight. Five hundred eighty-eight other women received protein-bound iodide (iodized casein) at a dose of 10 mg per day for an unspecified period of time. Seventy percent of the women receiving Lugol's iodine and 40% of those receiving iodized casein had clinical improvement. One hundred forty-five women who had only partial improvement with iodized casein were switched to a preparation containing diatomic elemental iodine, and an additional 108 women received this preparation as their initial treatment. Details about this product were not provided. The dosage of elemental iodine was 0.08 mg per kg of body weight (presumably per day, although this was not stated), and treatment was continued for 9 to 10 months. Of the 145 women who switched to iodine from iodized casein, 75% had a resolution of breast pain. Of the 108 women who received elemental iodine initially, 98% were pain free after nine months and 72% showed objective improvement. Sixty-five percent of the women had a reduction in breast size coincident with the clinical improvement. Adverse effects were seen in about 10% of patients, and consisted mainly of acne, nausea, diarrhea, hair thinning, skin rash, headache, and a transient increase in breast pain. Hypothyroidism and hyperthyroidism occurred in 0.3% and 0.1% of patients, respectively.
Comment: In rats, iodine deficiency caused histologic lesions in breast tissue that resembled fibrocystic changes in humans. Once these breast lesions developed, chronic iodine therapy was necessary to keep them under control. The results of the present study indicate that iodine supplementation is beneficial for a majority of women with fibrocystic breast changes. The dosage of iodine used in this study was more than 30 times the Recommended Dietary Allowance. Large doses of iodine have the potential to cause thyroid dysfunction and other adverse effects. For that reason, it has been my practice to reserve high-dose iodine therapy for women who do not respond to more conservative measures such as methylxanthine avoidance and supplementation with vitamin E.
Ghent WR et al. Iodine replacement in fibrocystic disease of the breast. Can J Surg. 1993;36:453–460.
Iodine supplements relieve painful, swollen breasts. Fam Pract News. December 1, 1986;16(23):9.
Vitamin D Improves Muscle Strength in the Elderly
Fifty-six elderly institutionalized Brazilians (mean age, 78 years) were randomly assigned to receive, in double-blind fashion, vitamin D3 or placebo for 6 months (from December to May). The dosage was 150,000 IU once a month for two months, followed by 90,000 IU once a month for four months. All subjects received 1,000 mg per day of supplemental calcium. At baseline, the median serum 25-hydroxyvitamin D level was 43 nmol/L, indicating moderate vitamin D deficiency. In the vitamin D group, compared with baseline, median strength of the hip flexor muscles increased by 16.4% (p = 0.0001) and median strength of the knee extensor muscles increased by 24.6% (p = 0.0007). Muscle strength did not improve in the placebo group. No patient receiving vitamin D developed hypercalcemia.
Comment: Muscle weakness is one of the known manifestations of vitamin D deficiency. Vitamin D deficiency is common in elderly people, particularly those who live in nursing homes and spend little time outdoors. The results of the present study indicate that vitamin D supplementation can improve muscle strength in elderly institutionalized individuals, even in the absence of any regular physical exercise practice. Improvement in muscle strength may explain in part why vitamin D supplementation has been found to decrease the incidence of falls in elderly people.
Moreira-Pfrimer LD et al. Treatment of vitamin D deficiency increases lower limb muscle strength in institutionalized older people independently of regular physical activity: a randomized double-blind controlled trial. Ann Nutr Metab. 2009;54:291–300.
Ginkgo Biloba Extract and Cognitive Function in the Elderly.
A six-year double-blind study published in 2008 found that treatment with Ginkgo biloba extract (ginkgo) did not prevent dementia or Alzheimer's disease in elderly volunteers who had normal cognitive function or mild cognitive impairment at baseline. The data from that study have now been analyzed further, to determine whether ginkgo produced any subtle benefits that were not identified in the original report. No such benefits were found, and the new analysis concluded that ginkgo did not slow the rate of cognitive decline in elderly individuals with normal cognitive function or mild cognitive impairment.
Comment: Ginkgo has been reported to increase cerebral blood flow and to increase cellular metabolism in the brain, irrespective of changes in blood flow. Numerous studies have found that ginkgo is beneficial in the treatment of Alzheimer's disease and other types of dementia. A review of nine double-blind trials (each lasting between 2 and 12 months) concluded that ginkgo is more effective than placebo in patients with dementia.
An important weakness of the new study was the high dropout rate. Only 60% of the participants were still taking their assigned tablets at the end of the trial. However, all subjects who entered the trial were included in the analysis, even those for whom final data were not available. Adherence to the study protocol may actually have been lower than that reported by the investigators. Previous research has shown that participants in clinical trials frequently engage in deceptive behavior in order to hide the fact that they have not been taking their assigned medication. In the new ginkgo trial, adherence to the protocol was monitored by counting the number of unused pills each time the participant attended the clinic. It would have been easy for noncompliant subjects to avoid embarrassment by surreptitiously discarding most or all of their unused tablets.
Considering that the subjects only had to take 50% of the assigned tablets to be categorized as compliant, it would not be surprising if the lack of benefit observed in this study was due largely to poor adherence to the protocol.
Notwithstanding this limitation of the new study, there is no convincing evidence that ginkgo is effective for preventing dementia, even though it appears to be beneficial for treating dementia. Based on the available evidence, people with normal cognitive function or mild age-related cognitive impairment should not take ginkgo for the sole purpose of preventing dementia. However, treatment with ginkgo seems appropriate for individuals with clinically significant cognitive impairment. Most of the studies in which ginkgo was effective used 120 mg per day of an extract standardized to contain 24% ginkgo heterosides or 24% ginkgoflavone glycosides and 6% terpenes.
Snitz BE et al. Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial. JAMA. 2009;302:2663–2670.
How to Fix the Doctor Shortage
In an opinion piece in the Wall Street Journal, the president and CEO of the Association of American Medical Colleges pointed out that the current shortage of physicians will grow substantially worse as the population ages and the new health-care bill expands coverage to 30 million more Americans. He argued that one solution to this impending crisis is for medical schools to increase their class sizes and for the US government to increase funding to support new residency training programs.
Comment: Reading this article reminded me of an 11-year-old boy I worked with who was being treated by a rheumatologist for rheumatoid arthritis, a gastroenterologist for severe abdominal pain, and a neurologist for daily migraines. Since each of these conditions can be caused by food allergy, he was advised to undergo an elimination diet followed by individual food challenges. He was found to be allergic to corn, and when all corn products were removed from his diet he became symptom free and had no further need for the three -ologists. I have worked with countless other patients who were seeing multiple doctors for multiple symptoms. In many cases, the symptoms were treated effectively with various "natural medicine" approaches (such as dietary modifications, nutritional supplements, or low doses of thyroid hormone), and these interventions greatly reduced the patients' need for ongoing medical care. One might reasonably argue (with no disrespect intended) that we do not have a doctor shortage, but, rather a shortage of doctors who know how to get people well.
Kirch DG. How to fix the doctor shortage. Wall Street Journal January 5, 2010:A17.
Alan R. Gaby, MD