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A premature and potentially harmful conclusion
- Lian S G Ulrich (27 February 2006)
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Lian S G Ulrich, consultant Copenhagen University Hospital - Dpt. of Gynecology - Blegdamsvej 9 - 2100 Copenhagen Ø - Denmark
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The headline and conclusion of the Kendall paper that vaginal estradiol should be contraindicated in women with a history of breast cancer treated by aromatase inhibitors seems premature and potentially harmful to many breast cancer patients suffering from symptoms of vaginal atrophy. Based upon seven patients of whom only two had estradiol levels exceeding 20 pmol/l after the fourth week of treatment, it does not seem justified to frighten thousands of women with breast cancer around the world from using vaginal estradiol to relieve dyspareunia, itching, discharge, urinary tract infections and other annoying symptoms of urogenital atrophy. Aromatase inhibitors work by blocking the conversion of androgens produced in the suprarenal glands and the postmenopausal ovary to estrogens in the peripheral tissues and possibly more important by blocking conversion to estradiol in the breast tumour itself (1). Thus the levels of endogenously produced estrogens or estrogens given as treatment are not affected by aromatase inhibitors. If a considerable absorption of vaginal estradiol takes place, this is of course potentially harmful to the patient especially if the level of estradiol in tumour cells is elevated. However it is only potentially harmful and not so proven. On the contrary clinical and epidemiological trials have not shown risk of breast cancer to be increased in naive patients on vaginal estrogen treatment or indeed an increased risk of breast cancer recurrence with systemic estrogen treatment in breast cancer patients although not treated with aromatase inhibitors ( 2,3 ). In previous publications with 24 subjects or more on vaginal low dose estradiol even steady state maximal absorption estradiol levels in postmenopausal women have not exceeded 200 pmol/ml and generally have been much lower (4-6). Previously absorption has been shown to occur with Vagifem during the first two weeks when estradiol is given daily, but levels have never been shown to rise again when daily administration is changed to bi-weekly. Consequently it looks strange that two of the women in the Kendall paper having experienced estradiol levels of 40 and 16 pmol/l respectively at week 4 suddenly show levels of 219 and 137 week 7- 10. Postmenopausal status is generally ascertained retrospectively when more than a year has passed without menstrual bleeding in the untreated woman. FSH and estradiol are poor determinators of menopausal status especially if measured only once, as values fluctuate during the menstrual cycle and during menopausal transition. FSH start to increase about 5 years before menopause and culminates 2-3 years post menopause whereas estradiol levels show decline and only reach steady state low levels around three years post menopause (7). The women in the Kendall paper were quite young with a median age of 52 years. As menopause occurs on average by age 51, one may speculate whether patient 1 and 5 were indeed truly postmenopausal or possibly perimenopausals experiencing an ovulation, which could explain the estradiol levels rising on twice weekly administration of vaginal estradiol as compared to daily use. The information given in the paper does not tell the reader the age of the individual women and whether these women have been on Aromatase inhibitors prior to study start or whether they changed from other treatment e.g. Tamoxifen blocking the effect of estradiol. Women who have been on Tamoxifen in my experience may regain ovarian function when switched to aromatase inhibitors, which do not affect ovarian production of estradiol. Another possible explanation could be the assay used – reference is not given to the ability of this assay to avoid co-measurement of other steroids than estradiol after precipitation. If absorption occurs to the degree indicated in patient 1 and 5 during week 7-10 it is puzzling that FSH levels are not affected. Whatever the explanation of the unexpected increase in estradiol after more than four weeks of treatment is, the issue needs further investigation before a conclusion preventing women treated for breast cancer to get relief for symptoms of vaginal atrophy is justified. References: 1) Miller W R. Biology of aromatase inhibitors: pharmacology/endocrinology within the breast Endocrine-Related Cancer 1999; 6: 187-195 2) Weiderpass E, Baron JA, Adami H-O et al. Low-potency oestrogen and risk of endometrial cancer: a case-control study. Lancet 1999; 353: 1824–28 3) Eden JA, Bush T, Nand S, Wren BG. A case-control study of combined continuous estrogen-progestin replacement therapy among women with a personal history of breast cancer. Menopause 1995; 2 ( suppl 2): 67-72 4)Notelovitz M, Funk S, Nanavati N and Mazzeo M. Estradiol Absorption From Vaginal Tablets in Postmenopausal Women Obstet Gynecol 2002; 99: 556–62. 5)Nilsson K, Heimer G. Low-dose estradiol in the treatment of urogenital estrogen deficiency—a pharmacokinetic and pharmacodynamic study. Maturitas 1992; 15: 121–127. 6)Bachmann G. The estradiol vaginal ring – a study of existing clinical data. Maturitas 22 Suppl. 1995; S21-S29 7)Rannevik G, Jeppsson S, Johnell O et al. A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas 1995; 21: 103-13. Conflict of Interest:Have received honoraria for speaking at meetings organised by the pharmaceutical industry. |
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