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Estrogens (Combined)

Also indexed as: Cenestin, Conjugated Estrogens, Esterified Estrogens, Estratab, Menest, Premarin

Combination drugs: Estratest/Estratest HS, Prempro

Illustration

Conjugated estrogens and esterified estrogens are both combinations of estrogenic hormones used to treat menopausal symptoms, to prevent osteoporosis in postmenopausal women, and as replacement therapy in other conditions of inadequate estrogen production. They are also used to treat some people with advanced breast and prostate cancers. Conjugated estrogens are extracted and purified from the urine of pregnant horses. A synthetic conjugated estrogen product (Cenestin®) is also available, as are combination products.

Combinations of estrogens with other hormones are also available. For example, Estratest® is a combination of methyltestosterone and esterified estrogens. Premarin is a combination of estrogens and progestins.

The information in this article pertains to combined estrogens in general. The interactions reported here may not apply to all the Also Indexed As terms. Talk to your doctor or pharmacist if you are taking any of these drugs.

Summary of Interactions with Vitamins, Herbs, and Foods
In some cases, an herb or supplement may appear in more than one category, which may seem contradictory. For clarification, read the full article for details about the summarized interactions.

Beneficial May Be Beneficial: Depletion or interference—The medication may deplete or interfere with the absorption or function of the nutrient. Taking these nutrients may help replenish them.

Vitamin B6*

Beneficial May Be Beneficial: Supportive interaction—Taking these supplements may support or otherwise help your medication work better.

Calcium

Ipriflavone*

Vitamin D* (increased bone density)

Avoid Avoid: Reduced drug absorption/bioavailability—Avoid these supplements when taking this medication since the supplement may decrease the absorption and/or activity of the medication in the body.

Herbal sources of isoflavone supplements (red clover*, soy*)

Avoid Avoid: Adverse interaction—Avoid these supplements when taking this medication because taking them together may cause undesirable or dangerous results.

Tobacco

Vitamin D*

Check Check: Other—Before taking any of these supplements or eating any of these foods with your medication, read this article in full for details.

Magnesium

Zinc

Side effect reduction/prevention

None known

An asterisk (*) next to an item in the summary indicates that the interaction is supported only by weak, fragmentary, and/or contradictory scientific evidence.

Interactions with Dietary Supplements

Calcium
Two months of conjugated estrogen therapy in women with surgically induced menopause decreased urinary calcium loss and increased serum vitamin D levels.1 In a six-month placebo-controlled study of 21 women with postmenopausal osteoporosis, conjugated estrogens increased both calcium absorption and vitamin D blood levels.2

While estrogen may improve calcium absorption, it remains important for women taking estrogen to maintain adequate calcium intake through diet and supplementation. Many doctors recommend 800–1,200 mg of supplemental calcium in addition to the several hundred milligrams found in a typical daily diet.

Ipriflavone
Ipriflavone, a synthetic variation of isoflavones found in soy, is available as a supplement. In a controlled trial, ipriflavone (400 mg per day) plus conjugated estrogens increased vertebral bone density, while calcium (500 mg per day) plus conjugated estrogens could not prevent a decrease in bone density in postmenopausal women.3 Similarly, a double-blind trial found ipriflavone (600 mg per day) plus conjugated estrogens and calcium (1 gram per day) increased bone density, while calcium with or without conjugated estrogens could not prevent bone loss.4 While low doses of estrogens can counteract some menopausal symptoms, higher doses are required to prevent bone loss in postmenopausal women. However, the addition of ipriflavone to low-dose estrogen therapy has been shown in a controlled trial to preserve bone mass in postmenopausal women.5

Minerals
A preliminary trial found that osteoporotic postmenopausal women with elevated urinary zinc and magnesium excretion experienced reduced losses of these minerals after being treated with conjugated estrogens and medroxyprogesterone.6 More research is needed to determine the significance of this finding.

Vitamin B6
A small preliminary trial found most women taking conjugated estrogens therapy without a progestin to have lower levels or a deficiency of vitamin B6.7 Numerous studies have found negative effects of oral contraceptives (OCs) on vitamin B6 status,8 9 10 although some studies suggest that vitamin B6 deficiency does not occur when low-dose OCs are used.11 While OCs contain different forms of estrogen than conjugated estrogens, there is a possibility of a similar problem when any form of estrogen is supplemented, but more research is needed.

Vitamin D
A controlled trial found two months of conjugated estrogens therapy in women with surgically induced menopause increased blood levels of vitamin D and decreased urinary calcium loss.12 In a controlled study of women with postmenopausal osteoporosis, conjugated estrogens therapy was associated with increased blood levels of vitamin D and increased calcium absorption.13 While conjugated estrogens appear to improve vitamin D metabolism, it remains important for women taking such hormones to consume adequate levels of vitamin D through diet and supplements.

One controlled study showed that taking 300 IU of vitamin D per day with estradiol, an estrogen related to conjugated estrogens, plus a progestin led to greater improvement in bone density compared with estradiol/progestin alone.14 Further controlled studies are needed to determine whether taking conjugated estrogens and vitamin D together might also increase bone strength and prevent fractures. In contrast to the beneficial effects on bone, the study also revealed that supplementing vitamin D together with estradiol/progestin tended to reduce beneficial HDL cholesterol levels, unlike estradiol/progestin alone. These undesirable results were confirmed by two additional studies.15 16

Additional research is needed to determine the degree to which supplemental vitamin D might exert a supportive or adverse effect on the actions of conjugated estrogens. Until more information is available, women taking hormone replacement therapy are advised to talk with a physician before combining vitamin D with conjugated estrogens.

Interactions with Herbs

Isoflavones
Herbal sources of isoflavones, such as red clover, may interfere with or even have an additive effect with conjugated estrogens.17 Further studies are needed to establish the potential interaction of isoflavone supplements from red clover and soy with conjugated estrogens. Consult with your healthcare professional if you are currently taking estrogen replacement therapy and wish to take a supplement high in isoflavones.

Interactions with Foods and Other Compounds

Tobacco
Conjugated estrogens therapy in postmenopausal women has been reported to decrease LDL (“bad”) cholesterol levels and to increase HDL (“good”) cholesterol levels. However, despite the positive changes in blood levels of LDL and HDL cholesterol, there is evidence that conjugated estrogens do not reduce the risk of heart disease.18 Nonetheless, smoking offsets the cholesterol changes induced by taking conjugated estrogens,19 and this interference is likely to be detrimental. Women taking conjugated estrogens who do not smoke should avoid starting, and those who do smoke should talk with their doctor about quitting.

References:

1. Lobo RA, Roy S, Shoupe D, et al. Estrogen and progestin effects on urinary calcium and calciotropic hormones in surgically-induced postmenopausal women. Horm Metab Res 1985;17:370–3.

2. Gallagher JC, Riggs BL, DeLuca HF. Effect of estrogen on calcium absorption and serum vitamin D metabolites in postmenopausal osteoporosis. J Clin Endocrinol Metab 1980;51:1359–64.

3. Gambacciani M, Ciaponi M, Cappagli B, et al. Effects of combined low dose of the isoflavone derivative ipriflavone and estrogen replacement on bone mineral density and metabolism in postmenopausal women. Maturitas 1997;28:75–81.

4. Melis GB, Paoletti AM, Bartolini R, et al. Ipriflavone and low doses of estrogens in the prevention of bone mineral loss in climacterium. Bone Miner Oct 1992;19 suppl 1:S49–56.

5. Agnusdei D, Gennari C, Bufalino L. Prevention of early postmenopausal bone loss using low doses of conjugated estrogens and the non-hormonal, bone-active drug ipriflavone. Osteoporos Int 1995;5:462–6.

6. Herzberg M, Lusky A, Blonder J, et al. The effect of estrogen replacement therapy on zinc in serum and urine. Obstet Gynecol 1996;87:1035–40.

7. Haspels AA, Bennink HJ, Schreurs WH. Disturbance of tryptophan metabolism and its correction during oestrogen treatment in postmenopausal women. Maturitas 1978;1:15–20.

8. Lubby AL, Brin M, Gordon M, et al. Vitamin B6 metabolism in users of oral contraceptive agents. I. Abnormal urinary xanthurenic acid excretion and its correction by pyridoxine. Am J Clin Nutr 1971;24:684–93.

9. Adams PW, Rose DP, Folkard J, et al. Effect of pyridoxine hydrochloride (vitamin B6) upon depression associated with oral contraception. Lancet 1973;1:897–904.

10. Larsson-Cohn U. Oral contraceptives and vitamins: a review. Am J Obstet Gynecol 1975;121:84–90 [review].

11. Massé PG, van den Berg H, Duguay C, et al. Early effect of a low dose (30 mcg) ethinyl estradiol-containing Triphasil® on vitamin B6 status. Int J Vit Nutr Res 1996;66:46–54.

12. Lobo RA, Roy S, Shoupe D, et al. Estrogen and progestin effects on urinary calcium and calciotropic hormones in surgically-induced postmenopausal women. Horm Metab Res 1985;17:370–3.

13. Gallagher JC, Riggs BL, DeLuca HF. Effect of estrogen on calcium absorption and serum vitamin D metabolites in postmenopausal osteoporosis. J Clin Endocrinol Metab 1980;51:1359–64.

14. Tuppurainen MT, Komulainen M, Kröger H, et al. Does vitamin D strengthen the increase in femoral neck BMD in osteoporotic women treated with estrogen? Osteoporosis Int 1998;7:32–8.

15. Myrup B, Hensen GF, McNair P. Cardiovascular risk factors during estrogen-norethindrone and cholecalciferol treatment. Arch Intern Med 1992;152:2265–8.

16. Heikkinen A-M, Tuppurainen MT, Niskanen L, et al. Long-term vitamin D3 supplementation may have adverse effects on serum lipids during postmenopausal hormone replacement therapy. Eur J Endocrinol 1997;137:495–502.

17. Collins BM, McLachlan JA, Arnold SF. The estrogenic and antiestrogenic activities of phytochemicals with the human estrogen receptor expressed in yeast. Steroids 1997;62:365–72.

18. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605–13.

19. Krauss RM, Perlman JA, Ray R, Petitti D. Effects of estrogen dose and smoking on lipid and lipoprotein levels in postmenopausal women. Am J Obstet Gynecol 1988;158:1606–11.

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