doses; [3] the tissue concentrations at the site of action differ because of different sites of administration. The local intracellular MTX concentration, which is related to efficacy of the therapy, is not measured in peripheral bloodsamples; and, [4] possibly, the time-span from injection time to peaklevel time reflects a delayed delivery of MTX from the application site. Because of good local vascularization, this time-span is not delayed after intraamniotic MTX injection. We did analyze the results of a locallaparoscopicguided MTX injection of 100 mg and the peripheral MTX levels during the first hours thereafter. Timeto-peak levels were two to three hours after injection, suggesting the localizing effect of adrenaline.
Sjarlot Kooi Hans C. L. V. Koch Maria Hospital Tilburg, The Netherlands June 17, 1992 REFERENCES 1. Schiff E, Shalev E, Bustan M, Tsabouri A, Mashiach S, Wei-
ner E. Pharmacokinetics of methotrexate after local tubal injection for conservative treatment of ectopic pregnancy. Fertil Steril 1992;57:688-90. 2. Leme PR, Creaven PJ, Allen LM, Bergman M. Kinetic model for the disposition and metabolism of moderate and high dose methotrexate in man. Cancer Chemother Rep 1975;59:811-
icant difference. This conclusion is probably correct even though the data presented by Dr. Kooi indicate a complicated MTX pharmacokinetic mechanism. We agree that the local intracellular MTX concentration is not measured in peripheral blood samples. However, we do not know whether the local intracellular MTX concentration is related to efficacy of therapy. We also do not know for sure whether this concentration in the trophoblastic target tissue is really higher after the local intratubal injection compared with after the systemic injection. Because we reported the measurements on a very limited number of patients in our brief communication and because our results could not address the question of whether the increased local disclosure of drug to the trophoblastic tissue is an advantage in terms of treatment efficacy, we suggested a prospective controlled trial comparing the clinical success of these two modes of treatment.
Eyal Schiff, M.D. Department of Obstetrics and Gynecology University of Tennessee College of Medicine Memphis, Tennessee Eliezer Shalev, M.D. Department of Obstetrics and Gynecology Haemek Medical Center Afula, Israel August 3, 1992
6.
3. Myers CE, Young RC, Chabner BA. Biochemical determinants of 5-fluorouracil response in vivo. J Clin Invest 1975;56: 1231-6. 4. Curt GA, Allegra CJ, Fine RL, et al. Antimetabolites. Cancer Chemother Annual 1984;6:1-12.
Reply of the Authors: We thank Dr. Kooi for his letter and appreciate the important points raised by him regarding the issues of methotrexate (MTX) distribution, metabolism, and excretion. However, these points are not in contflict with our comments. Lower systemic exposure to MTX was considered a possible advantage of the local intratubal injection over systemic injection. We have reported similar average plasma MTX levels during the 24 hours after injection for patients treated by local or systemic injection of the same dose of MTX, and these levels were significantly lower than those plasma concentrations, which are generally considered at risk for toxicity. We therefore assumed that in terms of systemic risk for toxicity, the site of injection should not make a signif1270
Letters-to-the-editor
Oral Contraceptives and Breast Cancer
To the Editor (Letter 1 of 2): In the excellent epidemiologic review on progestins and breast cancer by Staffa et al. (1), we appreciated the suggestion to differentiate the progestins according to their androgenic potency. In fact, as outlined by the authors, some 19-nortestosterone derivatives, such as norethindrone and norgestrel, oppose an estrogen hepatocellular effect potentially protective to the breast: the sex hormone-binding globulin (SHBG) increase. As recently reviewed by us (2), oral estrogens can have other hepatocellular effects potentially protective to the breast. Several studies show that in postmenopausal women, oral ethinyl estradiol (EE), 10 to 20 /-lg daily, causes a reduction in serum insulinlike growth factor I (IGF-I) and an even more pronounced increase in serum growth hormone (GH) levels (3). Because circulating IGF-I is mainly of hepatic derivation, its suppression is probably a heFertility and Sterility
patocellular effect of oral (EE), whereas the GH increase seems to be a consequence of the IGF-I reduction (3). In fact, trans dermal administration of estradiol does not produce significant modifications of GH levels; it results instead in a slight increase of serum IGF-I (3). Conjugated estrogens modify the circulating levels of IGF-I. For example, after 6 months of cyclic treatment with oral conjugated estrogens 0.625 mg/ day in 13 postmenopausal women, we observed a significant decrease of IGF-I levels (9% to 67%, mean 34.5%; P < 0.002; Wilcoxon matched pair test) as compared with the pretreatment levels (unpublished observations of authors). IGF-I is a potent mitogen, potentially involved in the growth of breast cancer cells, particularly of the "estrogen-receptor positive" ones (4). If, as possible, the progestins with high androgenic potency oppose, together with other estrogen hepatocellular effects, the IGF-I level reduction, such an interference could be even more dangerous to the breast than the mere interference on SHBG levels. Undoubtedly, this topic deserves further study.
Carlo Campagnoli, M.D. Maria Gina Lanza, M.D. Clementina Peris, M.D. Servizio di Ginecologia Endocrinologica Ospedale Ginecologico Sant'Anna Torino, Italy Nicoletta Biglia, M.D. Piero Sismondi, M.D. Istituto di Ginecologia e Ostetricia Cattedra di Ginecologica Oncologica Universita di Torino Torino, Italy June 19, 1992
REFERENCES 1. Staffa JA, Newschaffer CJ, Jones JK, Miller V. Progestins and breast cancer: an epidemiologic review. Fertil Steril 1992;57:473-91. • 2. Campagnoli C, Biglia N, Belforte P, Botta D, Pedrini E, Sismondi P. Post-menopausal breast cancer risk: oral estrogen treatment and abdominal obesity induce opposite changes in possibly important biological variables. Eur J Gynaecol Oncol 1992;13:139-54. 3. Weissberger AJ, Ho KKY, Lazarus L. Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women. J Clin Endocrinol Metab 1991;72:374-81. Vol. 58, No.6, December 1992
4. Rosen N, Yee D, Lippman ME, Paik S, Cullen KJ. Insulinlike growth factors in human breast cancer. Breast Cancer Res Treat 1991;18:S55-S62. '
To the Editor (Letter 2 of 2): Several points in the excellent review of this subject by Staffa and associates (1) and the editorial comments of Grimes (2) warrant comment. Staffa et al. continue the now discredited concept that ethynodiol diacetate, the progestagen in Demulen, is a high potency progestagen. I, and later Sturtevant (3), detailed reasons for this erroneous evaluation, which were confirmed in a study mounted by Swyer (4) specifically to resolve the issue. Furthermore, Swyer also demonstrated that norethindrone acetate was a weak progestagen when compared with norethindrone itself in the-delay-of-menses test. This is not surprising because both norethindrone acetate and ethynodiol diacetate are hydrolyzed in the body to produce norethindrone, the active principle. Staffa et al. confuse the pharmacologic concept of potency with amount and attempt to deal with single numbers for potency of oral contraceptive (OC) preparations that are combinations of progestagens and estrogens. Some years ago, Sturtevant and I discussed the impossibility of reaching meaningful interpretations by such methods (5). Grimes' editorial comments, also much to the point, segregate OCs on the basis of microgram content of estrogen, i.e., 50 jlg. Although common practice, this is erroneous because all OCs that contained >50 jlg of estrogen were formulated with mestranol and those with
Sjarlot Kooi Hans C. L. V. Koch Maria Hospital Tilburg, The Netherlands June 17, 1992 REFERENCES 1. Schiff E, Shalev E, Bustan M, Tsabouri A, Mashiach S, Wei-
ner E. Pharmacokinetics of methotrexate after local tubal injection for conservative treatment of ectopic pregnancy. Fertil Steril 1992;57:688-90. 2. Leme PR, Creaven PJ, Allen LM, Bergman M. Kinetic model for the disposition and metabolism of moderate and high dose methotrexate in man. Cancer Chemother Rep 1975;59:811-
icant difference. This conclusion is probably correct even though the data presented by Dr. Kooi indicate a complicated MTX pharmacokinetic mechanism. We agree that the local intracellular MTX concentration is not measured in peripheral blood samples. However, we do not know whether the local intracellular MTX concentration is related to efficacy of therapy. We also do not know for sure whether this concentration in the trophoblastic target tissue is really higher after the local intratubal injection compared with after the systemic injection. Because we reported the measurements on a very limited number of patients in our brief communication and because our results could not address the question of whether the increased local disclosure of drug to the trophoblastic tissue is an advantage in terms of treatment efficacy, we suggested a prospective controlled trial comparing the clinical success of these two modes of treatment.
Eyal Schiff, M.D. Department of Obstetrics and Gynecology University of Tennessee College of Medicine Memphis, Tennessee Eliezer Shalev, M.D. Department of Obstetrics and Gynecology Haemek Medical Center Afula, Israel August 3, 1992
6.
3. Myers CE, Young RC, Chabner BA. Biochemical determinants of 5-fluorouracil response in vivo. J Clin Invest 1975;56: 1231-6. 4. Curt GA, Allegra CJ, Fine RL, et al. Antimetabolites. Cancer Chemother Annual 1984;6:1-12.
Reply of the Authors: We thank Dr. Kooi for his letter and appreciate the important points raised by him regarding the issues of methotrexate (MTX) distribution, metabolism, and excretion. However, these points are not in contflict with our comments. Lower systemic exposure to MTX was considered a possible advantage of the local intratubal injection over systemic injection. We have reported similar average plasma MTX levels during the 24 hours after injection for patients treated by local or systemic injection of the same dose of MTX, and these levels were significantly lower than those plasma concentrations, which are generally considered at risk for toxicity. We therefore assumed that in terms of systemic risk for toxicity, the site of injection should not make a signif1270
Letters-to-the-editor
Oral Contraceptives and Breast Cancer
To the Editor (Letter 1 of 2): In the excellent epidemiologic review on progestins and breast cancer by Staffa et al. (1), we appreciated the suggestion to differentiate the progestins according to their androgenic potency. In fact, as outlined by the authors, some 19-nortestosterone derivatives, such as norethindrone and norgestrel, oppose an estrogen hepatocellular effect potentially protective to the breast: the sex hormone-binding globulin (SHBG) increase. As recently reviewed by us (2), oral estrogens can have other hepatocellular effects potentially protective to the breast. Several studies show that in postmenopausal women, oral ethinyl estradiol (EE), 10 to 20 /-lg daily, causes a reduction in serum insulinlike growth factor I (IGF-I) and an even more pronounced increase in serum growth hormone (GH) levels (3). Because circulating IGF-I is mainly of hepatic derivation, its suppression is probably a heFertility and Sterility
patocellular effect of oral (EE), whereas the GH increase seems to be a consequence of the IGF-I reduction (3). In fact, trans dermal administration of estradiol does not produce significant modifications of GH levels; it results instead in a slight increase of serum IGF-I (3). Conjugated estrogens modify the circulating levels of IGF-I. For example, after 6 months of cyclic treatment with oral conjugated estrogens 0.625 mg/ day in 13 postmenopausal women, we observed a significant decrease of IGF-I levels (9% to 67%, mean 34.5%; P < 0.002; Wilcoxon matched pair test) as compared with the pretreatment levels (unpublished observations of authors). IGF-I is a potent mitogen, potentially involved in the growth of breast cancer cells, particularly of the "estrogen-receptor positive" ones (4). If, as possible, the progestins with high androgenic potency oppose, together with other estrogen hepatocellular effects, the IGF-I level reduction, such an interference could be even more dangerous to the breast than the mere interference on SHBG levels. Undoubtedly, this topic deserves further study.
Carlo Campagnoli, M.D. Maria Gina Lanza, M.D. Clementina Peris, M.D. Servizio di Ginecologia Endocrinologica Ospedale Ginecologico Sant'Anna Torino, Italy Nicoletta Biglia, M.D. Piero Sismondi, M.D. Istituto di Ginecologia e Ostetricia Cattedra di Ginecologica Oncologica Universita di Torino Torino, Italy June 19, 1992
REFERENCES 1. Staffa JA, Newschaffer CJ, Jones JK, Miller V. Progestins and breast cancer: an epidemiologic review. Fertil Steril 1992;57:473-91. • 2. Campagnoli C, Biglia N, Belforte P, Botta D, Pedrini E, Sismondi P. Post-menopausal breast cancer risk: oral estrogen treatment and abdominal obesity induce opposite changes in possibly important biological variables. Eur J Gynaecol Oncol 1992;13:139-54. 3. Weissberger AJ, Ho KKY, Lazarus L. Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women. J Clin Endocrinol Metab 1991;72:374-81. Vol. 58, No.6, December 1992
4. Rosen N, Yee D, Lippman ME, Paik S, Cullen KJ. Insulinlike growth factors in human breast cancer. Breast Cancer Res Treat 1991;18:S55-S62. '
To the Editor (Letter 2 of 2): Several points in the excellent review of this subject by Staffa and associates (1) and the editorial comments of Grimes (2) warrant comment. Staffa et al. continue the now discredited concept that ethynodiol diacetate, the progestagen in Demulen, is a high potency progestagen. I, and later Sturtevant (3), detailed reasons for this erroneous evaluation, which were confirmed in a study mounted by Swyer (4) specifically to resolve the issue. Furthermore, Swyer also demonstrated that norethindrone acetate was a weak progestagen when compared with norethindrone itself in the-delay-of-menses test. This is not surprising because both norethindrone acetate and ethynodiol diacetate are hydrolyzed in the body to produce norethindrone, the active principle. Staffa et al. confuse the pharmacologic concept of potency with amount and attempt to deal with single numbers for potency of oral contraceptive (OC) preparations that are combinations of progestagens and estrogens. Some years ago, Sturtevant and I discussed the impossibility of reaching meaningful interpretations by such methods (5). Grimes' editorial comments, also much to the point, segregate OCs on the basis of microgram content of estrogen, i.e., 50 jlg. Although common practice, this is erroneous because all OCs that contained >50 jlg of estrogen were formulated with mestranol and those with
