Clincal Briefs

With Comments from John La Puma, MD, FACP

Licorice and Serum Testosterone Levels

January 2000; Volume 3: 11

Source: Armanini D, et al. Reduction of serum testosterone in men by licorice. N Engl J Med 1999;341:1158.

We evaluated the effect of licorice on gonadal function in seven normal men, 22 to 24 years of age. The men were given 7 g/d of a commercial preparation of licorice in the form of tablets (Saila, Bologna, Italy) containing 0.5 g of glycyrrhizic acid, as determined by gas chromatography-mass spectrometry; the effect on the metabolism of mineralocorticoids in these men was reported previously.

Serum testosterone, androstenedione, and 17-hydroxyprogesterone were measured by radioimmunoassay before and after four and seven days of administration of licorice and four days after it was discontinued. During the period of licorice administration, the men’s serum testosterone concentrations decreased and their serum 17-hydroxyprogesterone concentrations increased.

These results demonstrate that licorice inhibits both 17-ß hydroxy-steroid dehydrogenase and 17,20-lyase, which catalyzes the conversion of 17-hydroxyprogesterone to androstenedione. Men with decreased libido or other sexual dysfunction, as well as those with hypertension, should be questioned about licorice ingestion.

Comment

Real licorice is hard to come by, but those seeking the distinct wet leaves, dark tobacco, thickly bitter flavors that the root offers will be disappointed by these results. These Italian investigators studied the effects of licorice, extracted from real licorice root, on hormone levels. The effects of testosterone, andro-stenedione, and 17-hydroxyprogesterone are of real interest to men. The investigators demonstrated a progressive drop in testosterone level (which rebounded 4 days after licorice discontinuation); a progressive rise in 17-hydroxyprogesterone (which dropped 4 days after licorice discontinuation); and an uncertain effect on androstenedione, which is normally converted to testosterone (see Alternative Medicine Alert, September 1999, pp. 97-100).

The mineralocorticoid-like, blood pressure-raising effect of licorice is well known: Licorice is known to inhibit 11-ß hydroxysteroid dehydrogenase, which catalyzes the conversion of cortisol to cortisone. Less well established are the inhibitory effects proposed above. Nevertheless, the fall in testosterone level and rise in 17-hydroxyprogesterone level were significant at the P < 0.001 level.

The fact that there were only seven men; that they were all young; that the commercial preparation likely cannot be found in the United States; and that red licorice Twizzlers (with lots more sugar than licorice) are far more popular than glycyrrhizic acid will ever be make this study an interesting hors d’oeurve instead of a main course.

Recommendation

Sustained licorice use has its downside for men. Though the connection to libido and sexual performance is still modest, a question about supplements (and candies) of all kinds is much cheaper than Viagra.


"Alternatives" for Fibromyalgia

January 2000; Volume 3: 11-12

Source: Rossy LA, et al. A meta-analysis of fibromyalgia treatment interventions. Ann Behav Med 1999;21:180-191.

To evaluate and compare the efficacy of pharmacological and non-pharmacological treatments of fibro-myalgia syndrome (FMS), we performed a meta-analysis of 49 fibromyalgia treatment outcome studies assessing efficacy across four types of outcome measures—physical status, self-report of FMS symptoms, psychological status, and daily functioning.

After controlling for study design, antidepressants resulted in improvements on physical status measures (e.g., tender point index and myalgic score), and self-reported FMS symptoms (e.g., fatigue, morning stiffness, and pain). All non-pharmacological treatments were associated with significant improvements in all four categories of outcome measures with the exception of physically-based treatment (primarily exercise), which improved three of four outcome measures.

When compared, non-pharmacological treatment appears to be more efficacious in improving self-report of FMS symptoms than pharmacological treatment alone. A similar trend was suggested for functional measures. The optimal intervention for FMS would include non-pharmacological treatments, specifically exercise and cognitive-behavioral therapy, in addition to appropriate medication management as needed for sleep and pain symptoms.

Comment

Sleep disturbances, fatigue, pain, slowed daily function, and emotional distress trouble many patients with FMS, constantly. Many physicians feel as helpless with these patients as the patients do, not knowing what to try next.

These investigators, nearly all from the Department of Psychology at the University of Missouri, received NIH and NIDDR support to search MEDLINE, CINAHL, PsycINFO, and Dissertation Abstracts and to create a quantitative review of FMS treatment outcomes. Their review is rigorous, carefully performed, and extensively referenced. Unfortunately, no pharmacological treatment alone resulted in improved daily functioning, and antidepressants and muscle relaxants did not improve psychological outcomes.

Significant improvements were observed in the use of antidepressants for FMS symptoms, and muscle relaxants for FMS symptoms and physical status measures. Many "alternative" measures positively influenced physical status, FMS symptoms, and psychological status. Fewer data were available about the use of NSAIDS alone, but as such, they had no significant impact on any outcome measure. "Alternative" pharmacological treatments reviewed include S-adensyl-L-methionine (SAMe) and 5-hydroxytryptophan; other alternatives included ibuprofen combined with cyclobenzaprine, and then again with alprazolam, and amitryptiline with naproxen. Non-pharmacological treatments include biofeedback, acupuncture, aerobic exercise, education, and hypnotherapy.

Although it may seem paradoxical (or worse, impossible) to recommend exercise to patients who cannot find the energy to get out of bed, cycling, treadmill, walking, and stretching were all found in different studies to have significant effects on physical status and on symptoms, and in one study on psychological effects of illness. In fact, physically based and psychologically based non-pharmacological treatments positively influenced outcomes more than did pharmacological treatments.

The authors are well aware of potential recruitment, retention, and selection biases in their methods. The effect size (ranging from 0.29-0.89 for pharmacological treatments and 0.38-0.71 for non-pharmacological treatments), however, is substantial and appears adequate to draw conclusions. The experience of more than 2,000 patients is analyzed.

Recommendation

Non-pharmacological treatments—specifically cognitive-behavioral therapy and exercise, preferably aerobic—should be prescribed to help manage FMS symptoms and daily function. Medication, including antidepressants and muscle relaxants, should be used for sleep and pain symptoms. NSAIDS should not be used alone.


Progesterone Cream and Menopause

January 2000; Volume 3: 12

Source: Leonetti HB, et al. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol 1999;94:225-228.

To determine the effectiveness of transdermal progesterone cream for controlling vasomotor symptoms and preventing postmenopausal bone loss, we randomly assigned 102 healthy women within five years of menopause to transdermal progesterone cream or placebo.

Study subjects and investigators were masked until data analysis was completed. An initial evaluation included complete history, physical examination, bone mineral density determination, and serum studies (TSH, FSH, lipid profile, and chemistry profile). The subjects were instructed to apply a quarter teaspoon of cream (containing 20 mg progesterone or placebo) to the skin daily. Each woman received daily multivitamins and 1,200 mg calcium and was seen every four months for review of symptoms. Bone scans and serum chemistries were repeated after one year.

Thirty of the 43 (69%) in the treatment group and 26 of the 47 (55%) in the placebo group complained initially of vasomotor symptoms. Improvement or resolution of vasomotor symptoms, as determined by review of weekly symptom diaries, was noted in 25 of 30 (83%) treatment subjects and five of 26 (19%) placebo subjects (P < 0.001). The number of women who gained bone density of 1.2% or more did not differ (a = 0.05, power of 80%). Two women developed rashes (one placebo and one control), and lipid profiles were not significantly changed. Eight of 43 treated subjects reported vaginal spotting lasting 1-2 days. Although we found no protective effect on bone density after one year, we saw a significant improvement in vasomotor symptoms in the treated group.

Comment

These Pennsylvania investigators recruited women for a randomized, double-masked, placebo-controlled trial to answer the question: "Does natural progesterone’ control menopausal symptoms and prevent bone loss?"

Many women are reluctant to take hormone replacement therapy; discovering that Premarin® is drawn from the urine of mares, and that cardiovascular disease is a bigger threat than breast or uterine cancer is not reassuring to most women. Can topical progesterone from diosgenin, extracted from Mexican yams, reportedly identical to the progesterone of the human ovary and placenta, have the beneficial effects of oral medroxy-progesterone acetate without side effects?

These investigators say yes to symptom control, no to bone density. Flushing is common and bothersome to many menopausal women, and this once daily cream seemed effective in controlling it within four months: Most reported maximal relief within a month. The presence of spotting in the treated women suggests a systemic effect. Insignificant declines in bone mineral density, performed using a Hologic Quantitative Digital Machine, were observed.

Weaknesses of this study include the absence of published tabular data at four, eight, and 12 months, including remeasurement of initial baseline values, and the absence of control of other measures known to influence bone density, e.g., weight-bearing exercise and Vitamin D intake.

Recommendation

Transdermal progesterone derived from Mexican yams appears effective in controlling hot flushes, and can be offered to women with the same provisos as oral progesterone. To protect the heart and the bone, however, other tools are needed. Aerobic, weight-bearing exercise and a plant-based, high complex carbohydrate, whole foods diet should be part of every menopausal woman’s repertoire.