Clincal Abstracts
Progesterone’s Effect on Endometrium
January 2000; Volume 2: 6-7
Source: Wren BG, et al. Micronized transdermal progesterone and endometrial response. Lancet 1999;354:1447-1448.
Design and Setting: Twelve-week randomized clinical trial at the Sydney Menopause Centre, Randwick, Australia.
Subjects: Twenty-seven postmenopausal women aged 50-65 years, with intact uteri.
Treatment/Dose/Route/Duration: All women were treated with a once-weekly transdermal estrogen patch (Climara® 100, Schering, Berlin) that contains 17 b-estradiol and one of three different doses (16 mg, 32 mg, or 64 mg daily) of a micronized progesterone topical cream (ProFemme, Lawley Pharmaceuticals) for the latter two weeks of each four-week treatment cycle.
Outcome Measures: Blood and endometrial biopsy samples were obtained on day 14 of the first cycle of transdermal estrogen (prior to progesterone treatment), and then on day 27 or 28 of the third cycle of progesterone treatment.
Results: Pretreatment progesterone levels ranged from 0.1-1.1 nmol/L; during the third cycle of progesterone treatment, progesterone levels rose only to 0.6-3.2 nmol/L, and none of the endometrial biopsies indicated a secretory endometrium (evidence of a progesterone response). Four women did not complete the study, and in two cases endometrial samples were not obtained. The authors concluded that transdermal progesterone cream in daily doses up to 64 mg administered for 14 days to postmenopausal women on estrogen is insufficient to induce a biological response in the endometrium.
Funding: Not noted.
Comments by Adriane Fugh-Berman, MD: A previous study of Pro-Gest® cream in surgically menopausal women (see Alternative Therapies in Women’s Health, April 1999, pp. 33-36) found that topical application of two to four times the recommended daily dose resulted in plasma levels of only 2.9 nmol/L progesterone. This level is very similar to that noted in this more recent study and is considered inadequate to protect the uterus. The major proponent of progesterone cream in this country, John Lee M.D, has argued that plasma progesterone levels do not accurately reflect bioavailable levels. This recent study, however, by examining endometrial biopsy samples in postmenopausal women on estrogen, has provided the most relevant endpoint in the most relevant population. The two studies of two different products should provide ample evidence for the inability of progesterone creams to protect the uterus from estrogen-induced endometrial stimulation.
Publication Bias in Medical Literature
January 2000; Volume 2: 7
Source: Vickers A, et al. Do certain countries produce only positive results? A systematic review of controlled trials. Controlled Clin Trials 1998;19:159-166.
Design and Setting: Blinded literature reviews using MEDLINE, from the Research Council for Complementary Medicine in London.
Methods: The authors performed two separate MEDLINE literature searches. They analyzed the abstracts of clinical trials that were published in different countries, and determined the outcome of clinical efficacy (favorable or unfavorable) for the treatments or therapies studied. Only articles with English abstracts were included in the analysis. The reviewers were blinded as much as possible to the study’s country of origin.
The first search included all studies investigating the use of acupuncture published from 1966 to 1995. Of 1,085 studies initially located, 252 abstracts were eligible for analysis.
The second search retrieved all other controlled clinical trials (i.e., other than acupuncture) published from 1991 to 1995 from four specific countries: China, Taiwan, Japan, and Russia/USSR. Of 1,100 abstracts initially located, 414 were eligible for analysis, and these were compared to the 330 most recent controlled trials published in England.
Results: For the major countries analyzed, the ratio of positive outcomes to total number of studies is as follows: China (36/36), Russia/USSR (10/11), Taiwan (6/6), and Japan (5/5). A much lower proportion of favorable outcomes (roughly 50-60%) were published in most Western countries: US (27/45), Sweden (16/27), UK (12/20), Denmark (8/16), and Germany (10/16). A few Western countries also published high proportions of favorable acupuncture studies: Austria (8/9), Italy (8/9), and France (5/6); however, like some of the Eastern countries in this study, the denominator numbers were small.
The second review of controlled clinical trials was able to analyze larger numbers of studies per country, and concentrated on four specific countries found to have high proportions of positive results from the previous review. These were compared to a control group of studies from England. The percent of positive studies were as follows: China 99% (108/109), Russia/USSR 97% (28/29), Taiwan 95% (38/40), Japan, 89% (107/120) compared to England 75% (80/107). In the two trials from China and Russia/USSR that did not favor the test treatment, both treatments were reported to be as effective as standard therapies used as controls.
Funding: Not stated.
Comments by Michael D. Rotblatt, MD, PharmD: Can we rely on the clinical literature from Asian and Eastern European countries with confidence? Apparently not. This article provides good evidence for what has been informally noticed by readers of Asian and Eastern European literature: Almost all studies seem to report favorable outcomes. China and Russia/USSR appear to be the most flagrant. Of 121 and 29 trials reviewed from these countries respectively, not one published study found the test treatment ineffective. One can argue that acupuncture studies from Asian countries might be more favorable, because Asians are more experienced with this therapy. The same argument cannot be made for the other therapies analyzed in the second literature review.
Publication bias (a tendency not to publish negative outcomes) is a likely explanation for these findings, which may be country specific. However, a lack of objective or unbiased study methodologies, thus favoring the treatment groups, may also permeate the scientific climates of many countries. Whatever the reason, readers and reviewers of clinical trials from China, Russia/USSR, and other Asian and Eastern European countries, must interpret positive outcomes with caution, and take extra care to search for potential bias.
January 2000; Volume 2: 6-7
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