Important New Monkey Study from Tom Clarkson
Important New Monkey Study from Tom Clarkson
Abstract & Commentary
Synopsis: Tibolone treatment does not increase coronary artery atherosclerosis, and an equal reduction in atherosclerosis is seen with unopposed conjugated equine estrogen treatment and with conjugated equine estrogen combined with medroxyprogesterone acetate.
Source: Clarkson TB, et al. J Clin Endocrinol Metab. 2001;86:5396-5404.
Tom Clarkson and Associates at the Wake Forest University School of Medicine report an important new study using their monkey model for the study of atherosclerosis. In this 2-year-long randomized trial, a total of 151 monkeys with surgical menopause were fed an atherogenic diet and divided into groups comparing the placebo response to high and low doses of tibolone, unopposed conjugated equine estrogens, and combined conjugated estrogens and medroxyprogesterone acetate. The daily doses of tibolone were equivalent to women’s doses of 3.0 mg and 0.75 mg (human studies with tibolone have used 1.25 mg and 2.5 mg daily). The Premarin dose was equivalent to a little lower than 0.625 mg (Premarin) daily in women, and the combined estrogen and medroxyprogesterone acetate dose was equivalent to the daily regimen of PremPro (0.625/2.5). The observed changes in circulating lipids were similar to those reported in humans. Estrogen and combined estrogen-medroxyprogesterone acetate raised triglycerides and HDL-cholesterol, and lowered LDL-cholesterol. Tibolone lowered HDL-cholesterol, and in the high dose, increased LDL-cholesterol (this has not been observed with the doses used in women). Despite the "adverse" effect on lipids, the extent of coronary artery atherosclerosis was no different comparing the tibolone group with the placebo group. In fact, the tibolone animals even had slightly less atherosclerosis than the control animals. As expected, unopposed estrogen treatment reduced plaque size and intimal area in the coronary arteries with atherosclerosis, and there was no significant difference comparing the unopposed estrogen group with the estrogen-medroxyprogesterone acetate combination. Tibolone treatment increased bone mineral density a little more than estrogen treatment. Thus Clarkson et al concluded that tibolone treatment did not have an adverse effect on coronary artery atherosclerosis.
Comment by Leon Speroff, MD
This is an important research report for 2 reasons. First, there has been concern that tibolone would have a negative effect on atherosclerosis because it lowers HDL-cholesterol. Second, concern has been raised that the daily presence of medroxyprogesterone acetate attenuates estrogen’s beneficial actions on the vascular system.
Tibolone is metabolized into 3 steroid isomers with varying estrogenic, progestogenic, and androgenic properties. The metabolites differ in their activities and dominance according to the target tissue. Thus, tibolone provides estrogenic effects on bone and hot flushing, but it induces atrophy of the endometrium.1 In the endometrium, tibolone is converted locally (by endometrial 3 beta-hydroxysteroid dehydrogenase/isomerase) to its D4-progestational isomer, explaining its nonproliferative effect on the endometrium.2 The 3a-hydroxy and 3b-hydroxy metabolites bind only to the estrogen receptor, but the D4-isomer binds to the progesterone and androgen receptors. The decrease in HDL-cholesterol also indicates D4-isomer activity. Blood levels of the 3 metabolites in the monkeys were comparable to those measured in women receiving the standard doses of 1.25-2.50 mg/d.
Its beneficial impact on bone (2.5 mg dose) is comparable to or even better than standard hormonal therapy.3 In a randomized trial, tibolone increased bone density over 3 years in contrast to 0.625 mg conjugated estrogens and 10 mg medroxyprogesterone acetate in a sequential regimen, in which bone density was maintained after an increase limited to the first 6 months.4 Tibolone has an estrogenic effect on the vagina, and women report improvements in the symptoms of vaginal dryness and dyspareunia, and an increase in sexual enjoyment and libido.5,6 A major advantage of tibolone (2.5 mg daily) is its low (10-20%) incidence of bleeding.1 In a randomized trial comparing tibolone and continuous combined estrogen-progestin therapy, there was less breast tenderness and 50% less bleeding and spotting with tibolone.7 Because tibolone inhibits breast cell proliferation in vitro and decreases breast density on mammography, it is possible that future studies will indicate that tibolone offers some protection against breast cancer. In this monkey trial, tibolone did not stimulate endometrial or mammary gland proliferation.
Clarkson et al suggest that the neutral effect of tibolone on atherosclerosis does not preclude some beneficial effect in women from the 3a-hydroxy and 3b-hydroxy metabolites, in that the decrease in HDL-cholesterol was greater than that observed in women and the increase in LDL-cholesterol observed in this monkey trial is not seen in women. In treadmill experiments, tibolone reduces the signs of ischemia and prolongs the time to angina in a fashion similar to estrogen.8 Tibolone also has a beneficial effect in short-term studies on insulin resistance in normal women and in women with noninsulin-dependent diabetes mellitus.9,10 Tibolone has no effect on blood pressure.11
The results in the unopposed estrogen and the combined estrogen-medroxyprogesterone acetate groups are especially noteworthy, because this laboratory previously reported (in a frequently cited report) that the daily presence of medroxyprogesterone acetate attenuates the ability of conjugated equine estrogens to inhibit the development of atherosclerosis. (Adams MR, et al, Arterioscler Thromb Vasc Biol. 1997;17:217-221). Clarkson et al suggest the difference in the 2 reports may be due to daily treatment (the 1997 report) and twice-daily treatment (the current report) with a lesser progestin effect. However, I personally asked Tom Clarkson regarding this important clinical issue. He replied that his new study was bigger and better, and he does not believe that the daily presence of medroxyprogesterone acetate blocks estrogenic action on the coronary arteries.
The reason this is an important clinical issue is because some have attributed the early increase in clinical cardiac events in the HERS trial to the presence of medroxyprogesterone acetate. This new monkey report plus the failure to detect a difference between the unopposed estrogen arm and the combined estrogen-medroxyprogesterone acetate arm in the ERA trial are strong arguments that medroxyprogesterone acetate need not be feared. Avoidance of its use because of a concern over its effect on the coronary arteries is not justified.
References
1. Ginsburg J, et al. Maturitas. 1995;21:71-76.
2. Tang B, et al. J Steroid Biochem Mol Biol. 1993;45: 345-351.
3. Lippuner K, et al. J Bone Miner Res. 1997;12:806-812.
4. Thiébaud D, et al. Climacteric. 1998;1:202-210.
5. Rymer J, et al. Maturitas. 1994;18:127-133.
6. Nathorst-Böös J, Hammar M. Maturitas. 1997;26: 15-20.
7. Hammar M, et al. Br J Obstet Gynaecol. 1998;105: 904-911.
8. Lloyd GWL, et al. Int J Clin Pract. 1998;52:155-157.
9. Cagnacci A, et al. J Clin Endocrinol Metab. 1997;82: 251-253.
10. Prelevic GM, et al. Maturitas. 1998;28:271-276.
11. Feher MD, et al. Br J Obstet Gynaecol. 1996;103: 281-283.
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.