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Litmus Test for Leiomyosarcoma?
critical time in development might avert these embryonic losses. Diverse manipulations of the genes encoding these "maternal effect proteins" are currently underway in Drosophila. The possible presence of mutations in man in such fundamental developmental genes dramatized the limitations of our current techniques to investigate early recurrent spontaneous abortion. Defective proteins produced by such genes would also explain why certain women have pure histories of abortion after abortion, even with multiple different partners. The investigation in man of such proteins and the genes encoding them underscores the priority of oocyte research. Thank you, Doctors Douglas, Kim, Batten, and Malpani for your interesting ideas.
to regress that must be used to indicate a potential malignancy.
William R. Meyer, M.D. Allan R. Mayer, M.D. Michael P. Diamond, M.D. Alan H. DeCherney, M.D. Peter E. Schwartz, M.D. Department of Obstetrics and Gynecology Yale School of Medicine New Haven, Connecticut November 6, 1990
REFERENCES
Paul G. McDonough, M.D., Editor, Letters
1. Loong EPL, Wong FWS: Uterine leiomyosarcoma diagnosed
REFERENCES 1. Douglas JW, Kim MH, Batten BE: Electric field mediated
2.
transfer of enzymes into human oocytes. Fertil Steril53:1044, 1990 2. Kohler G, Milstein C: Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495, 1975
3.
4.
Litmus Test for Leiomyosarcoma?
To the Editor: Loong and Wong describe the rapid enlargement of a leiomyosarcoma during luteinizing hormonereleasing hormonal (LH-RH) therapy. 1 This clinical presentation may appear obvious since leiomyosarcomas lack estrogen receptors and are therefore likely to demonstrate continued growth during LHRH treatment. 2 Unfortunately, even benign leiomyomas have been noted to increase in size during LHRH therapy. 3 To further confound this observation, shrinkage of surrounding myometrial tissue may be the sole reason for the observed clinical response to LH-RH therapy in the treatment of a myomatous4 or possibly a leiomyosarcomatous uterus. We have previously described the treatment of an unsuspected leiomyosarcoma with LH-RH therapy .5 In contrast to the case described by Loong and Wong, progressive uterine enlargement did not occur despite stage III sarcomatous disease. As these authors point out, surgical intervention is most likely indicated if rapid uterine enlargement is noted during the induced hypoestrogenic state. 1 Unfortunately, malignant disease may be present despite static uterine size. Perhaps it should be the failure 848
Letters-to-the-editor
5.
during treatment with agonist of luteinizing hormone-releasing hormone for presumed uterine fibroid. Fertil Steril 54:530, 1990 Terenius L, Lindell A, Persson BH: Binding of estradiol-17/3 to human cancer tissue of the female genital tract. Cancer Res 31:1895, 1971 Perl V, Marquez J, Schally AV, Comaru-Schally AM, Leal G, Zacharias S, Gomez-Lira C: Treatment of leiomyomata uteri with D-TRp6 luteinizing hormone releasing hormone. Fertil Steril 48:383, 1987 Schlaff WD, Zerhouni EA, Hutch JA, Chen J, Damewood MD, Rock JA: A placebo-controlled trial of a depot gonadotropin-releasing hormone analogue (Leuprolide) in the treatment of uterine leiomyomata. Obstet Gynecol 74:856, 1989 Meyer WR, Mayer AR, Diamond MP, Carcangiu ML, Schwartz PE, De Cherney AH: Unsuspected leiomyosarcoma: Treatment with a gonadotropin-releasing hormone analogue. Obstet Gynecol 75:529, 1990
Reply of the Authors: We thank Meyer et al. for their interest in our article concerning treatment of unsuspected uterine leiomyosarcoma with agonist of luteinizing hormone-releasing hormone (LH-RH). 1 Their case report2 and that of ours highlighted the potential hazard of medical management of leiomyomata uteri without a definitive histologic diagnosis before initiation of therapy. An enlarging uterine mass, even though considered benign, certainly warrants surgical exploration. Nevertheless, we fully agree with the opinion that the possibility of malignancy needs to be seriously considered if a uterine mass fails to regress during LH-RH agonist therapy. Preoperative tissue biopsy is seldom obtained. Most cases of leiomyosarcoma are diagnosed incidentally during or after hysterectomy/myomectomy. The noninvasive methods commonly used for the assessment of inFertility and Sterility
trauterine masses such as ultrasonography and magnetic resonance imagin~~s have their obvious limitations in that they are incapable of distin~ guishing myomatous from sarcomatous lesions, al~ though reliable quantitative physical measurements may be made. Irrespective of benign or malignant disease being present, the variable response to treatment with a LH-RH agonist with regard to tumor or uterine size, as commented by Meyer et al., emphasizes the difficulty in reaching an accurate clinical diagnosis. Early detection of malignancy may be facilitated by a high index of suspicion and prompt surgical intervention.
Edward P.L. Loong, M.B., Ch.B., M.R.C.O.G. Felix W.S. Wong, M.B., B.S., M.R.C.O.G. The Chinese University of Hong Kong Department of Obstetrics and Gynaecology Prince of Wales Hospital Shatin, Hong Kong January 3, 1991 REFERENCES 1. Loong EPL, Wong FWS: Uterine leiomyosarcoma diagnosed
2.
3.
4.
5.
during treatment with agonist of luteinizing hormone-releasing hormone for presumed uterine fibroid. Fertil Steril 54:530, 1990 Meyer WR, Mayer AR, Diamond MP, Carcangiu ML, Schwartz PE, DeCherney AH: Unsuspected leiomyosarcoma: treatment with a gonadotropin-releasing hormone analogue. Obstet Gynecol 75:529, 1990 Zawin M, McCarthy S, Scoutt L, Lange R, Lavy G, Vulte J, Co mite F: Monitoring therapy with a gonadotropin-releasing hormone analog: utility of MR imaging. Radiology 175:503, 1990 Williams lA, Shaw RW: Effect of nafarelin on uterine fibroids measured by ultrasound and magnetic resonance imaging. Eur J Obstet Gynecol Reprod Biol34:111, 1990 Andreyko JL, Blumenfeld Z, Marshall LA, Monroe SE, Hricak H, Jaffe RB: Use of an agonistic analog of gonadotropinreleasing hormone (nafarelin) to treat leiomyomas: assessment by magnetic resonance imaging. Am J Obstet Gynecol 158:903, 1988
treating clinician. However, it is important to notice that in this study, theE levels were not measured at any time during the cycle. The authors quoted Maxson et al. 2 who reported mean peak serum E levels of 1,254 pg/mL in CC-treated subjects compared with 337 pg/mL in infertile controls. Based on this data, Bateman et al. 1 found it improbable that a relatively small amount of exogenous E should effect the quality of CM. On the other hand, they revealed several high CM scores in each group. These scores were scattered and the pattern did not suggest that a subgroup of patients responded to treatment. Nevertheless, they could not find a satisfactory explanation for this post-treatment high CM scores. Midcycle measurement of E levels done by our group 3 in women treated with CC have shown that although the mean E levels of the treated group was significantly higher than the control, in some of the patients (6 out of 19) the E levels during midcycle were in the nontreated patients level (308 pg/mL mean). In those patients (with both low cervical score and relatively lowE levels), administration of exogenous E improved the CM in 5 out of 6 patients, whereas in patients with E levels above 600 pg/mL the CM did not improve. This data may explain the post-treatment high CM scores found in some patients in Bateman's study, as well as the results obtained by other investigators indicating improved cervical scores after treatment with E. It may be hypothesized that exogenous E treatment in CC-treated women does not improve CM quality in patients with high E levels, whereas patients with low E levels may benefit from this treatment.
Ehud Kokia, M.D. Department of Obstetrics and Gynecology Sheba Medical Center Tel Hashomer, Israel November 26, 1990
REFERENCES Clomid Effect on Cervical Mucus
To the Editor: I read with interest the article by Bateman et al. 1 Their conclusion that "exogenous estrogen (E) treatment in clomiphene citrate (CC) treated women does not improve cervical mucus (CM) quality or quantity," seems to be of great importance to the Vol. 55, No.4, April1991
1. Bateman BG, Nunley WC, Kolp LA: Exogenous estrogen
therapy for treatment of clomiphene citrate induced cervical mucus abnormalities: is it effective? Fertil Steril54:577, 1990 2. Maxson WS, Pittaway DE, Herbert CM, Garner CH, Wentz AC: Antiestrogenic effect of clomiphene citrate: correlation with serum estradiol concentrations. Fertil Steril42:356, 1984 3. Kokia E, Bider D, Lunenfeld B, Blankstein J, Mashiach S, Ben Rafael Z: Addition of exogenous estrogens to improve cervical mucus following clomiphene citrate medication-patient selection. Acta Obstet Gynecol Scand 69:139, 1990
Letters-to-the-editor
849
to regress that must be used to indicate a potential malignancy.
William R. Meyer, M.D. Allan R. Mayer, M.D. Michael P. Diamond, M.D. Alan H. DeCherney, M.D. Peter E. Schwartz, M.D. Department of Obstetrics and Gynecology Yale School of Medicine New Haven, Connecticut November 6, 1990
REFERENCES
Paul G. McDonough, M.D., Editor, Letters
1. Loong EPL, Wong FWS: Uterine leiomyosarcoma diagnosed
REFERENCES 1. Douglas JW, Kim MH, Batten BE: Electric field mediated
2.
transfer of enzymes into human oocytes. Fertil Steril53:1044, 1990 2. Kohler G, Milstein C: Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495, 1975
3.
4.
Litmus Test for Leiomyosarcoma?
To the Editor: Loong and Wong describe the rapid enlargement of a leiomyosarcoma during luteinizing hormonereleasing hormonal (LH-RH) therapy. 1 This clinical presentation may appear obvious since leiomyosarcomas lack estrogen receptors and are therefore likely to demonstrate continued growth during LHRH treatment. 2 Unfortunately, even benign leiomyomas have been noted to increase in size during LHRH therapy. 3 To further confound this observation, shrinkage of surrounding myometrial tissue may be the sole reason for the observed clinical response to LH-RH therapy in the treatment of a myomatous4 or possibly a leiomyosarcomatous uterus. We have previously described the treatment of an unsuspected leiomyosarcoma with LH-RH therapy .5 In contrast to the case described by Loong and Wong, progressive uterine enlargement did not occur despite stage III sarcomatous disease. As these authors point out, surgical intervention is most likely indicated if rapid uterine enlargement is noted during the induced hypoestrogenic state. 1 Unfortunately, malignant disease may be present despite static uterine size. Perhaps it should be the failure 848
Letters-to-the-editor
5.
during treatment with agonist of luteinizing hormone-releasing hormone for presumed uterine fibroid. Fertil Steril 54:530, 1990 Terenius L, Lindell A, Persson BH: Binding of estradiol-17/3 to human cancer tissue of the female genital tract. Cancer Res 31:1895, 1971 Perl V, Marquez J, Schally AV, Comaru-Schally AM, Leal G, Zacharias S, Gomez-Lira C: Treatment of leiomyomata uteri with D-TRp6 luteinizing hormone releasing hormone. Fertil Steril 48:383, 1987 Schlaff WD, Zerhouni EA, Hutch JA, Chen J, Damewood MD, Rock JA: A placebo-controlled trial of a depot gonadotropin-releasing hormone analogue (Leuprolide) in the treatment of uterine leiomyomata. Obstet Gynecol 74:856, 1989 Meyer WR, Mayer AR, Diamond MP, Carcangiu ML, Schwartz PE, De Cherney AH: Unsuspected leiomyosarcoma: Treatment with a gonadotropin-releasing hormone analogue. Obstet Gynecol 75:529, 1990
Reply of the Authors: We thank Meyer et al. for their interest in our article concerning treatment of unsuspected uterine leiomyosarcoma with agonist of luteinizing hormone-releasing hormone (LH-RH). 1 Their case report2 and that of ours highlighted the potential hazard of medical management of leiomyomata uteri without a definitive histologic diagnosis before initiation of therapy. An enlarging uterine mass, even though considered benign, certainly warrants surgical exploration. Nevertheless, we fully agree with the opinion that the possibility of malignancy needs to be seriously considered if a uterine mass fails to regress during LH-RH agonist therapy. Preoperative tissue biopsy is seldom obtained. Most cases of leiomyosarcoma are diagnosed incidentally during or after hysterectomy/myomectomy. The noninvasive methods commonly used for the assessment of inFertility and Sterility
trauterine masses such as ultrasonography and magnetic resonance imagin~~s have their obvious limitations in that they are incapable of distin~ guishing myomatous from sarcomatous lesions, al~ though reliable quantitative physical measurements may be made. Irrespective of benign or malignant disease being present, the variable response to treatment with a LH-RH agonist with regard to tumor or uterine size, as commented by Meyer et al., emphasizes the difficulty in reaching an accurate clinical diagnosis. Early detection of malignancy may be facilitated by a high index of suspicion and prompt surgical intervention.
Edward P.L. Loong, M.B., Ch.B., M.R.C.O.G. Felix W.S. Wong, M.B., B.S., M.R.C.O.G. The Chinese University of Hong Kong Department of Obstetrics and Gynaecology Prince of Wales Hospital Shatin, Hong Kong January 3, 1991 REFERENCES 1. Loong EPL, Wong FWS: Uterine leiomyosarcoma diagnosed
2.
3.
4.
5.
during treatment with agonist of luteinizing hormone-releasing hormone for presumed uterine fibroid. Fertil Steril 54:530, 1990 Meyer WR, Mayer AR, Diamond MP, Carcangiu ML, Schwartz PE, DeCherney AH: Unsuspected leiomyosarcoma: treatment with a gonadotropin-releasing hormone analogue. Obstet Gynecol 75:529, 1990 Zawin M, McCarthy S, Scoutt L, Lange R, Lavy G, Vulte J, Co mite F: Monitoring therapy with a gonadotropin-releasing hormone analog: utility of MR imaging. Radiology 175:503, 1990 Williams lA, Shaw RW: Effect of nafarelin on uterine fibroids measured by ultrasound and magnetic resonance imaging. Eur J Obstet Gynecol Reprod Biol34:111, 1990 Andreyko JL, Blumenfeld Z, Marshall LA, Monroe SE, Hricak H, Jaffe RB: Use of an agonistic analog of gonadotropinreleasing hormone (nafarelin) to treat leiomyomas: assessment by magnetic resonance imaging. Am J Obstet Gynecol 158:903, 1988
treating clinician. However, it is important to notice that in this study, theE levels were not measured at any time during the cycle. The authors quoted Maxson et al. 2 who reported mean peak serum E levels of 1,254 pg/mL in CC-treated subjects compared with 337 pg/mL in infertile controls. Based on this data, Bateman et al. 1 found it improbable that a relatively small amount of exogenous E should effect the quality of CM. On the other hand, they revealed several high CM scores in each group. These scores were scattered and the pattern did not suggest that a subgroup of patients responded to treatment. Nevertheless, they could not find a satisfactory explanation for this post-treatment high CM scores. Midcycle measurement of E levels done by our group 3 in women treated with CC have shown that although the mean E levels of the treated group was significantly higher than the control, in some of the patients (6 out of 19) the E levels during midcycle were in the nontreated patients level (308 pg/mL mean). In those patients (with both low cervical score and relatively lowE levels), administration of exogenous E improved the CM in 5 out of 6 patients, whereas in patients with E levels above 600 pg/mL the CM did not improve. This data may explain the post-treatment high CM scores found in some patients in Bateman's study, as well as the results obtained by other investigators indicating improved cervical scores after treatment with E. It may be hypothesized that exogenous E treatment in CC-treated women does not improve CM quality in patients with high E levels, whereas patients with low E levels may benefit from this treatment.
Ehud Kokia, M.D. Department of Obstetrics and Gynecology Sheba Medical Center Tel Hashomer, Israel November 26, 1990
REFERENCES Clomid Effect on Cervical Mucus
To the Editor: I read with interest the article by Bateman et al. 1 Their conclusion that "exogenous estrogen (E) treatment in clomiphene citrate (CC) treated women does not improve cervical mucus (CM) quality or quantity," seems to be of great importance to the Vol. 55, No.4, April1991
1. Bateman BG, Nunley WC, Kolp LA: Exogenous estrogen
therapy for treatment of clomiphene citrate induced cervical mucus abnormalities: is it effective? Fertil Steril54:577, 1990 2. Maxson WS, Pittaway DE, Herbert CM, Garner CH, Wentz AC: Antiestrogenic effect of clomiphene citrate: correlation with serum estradiol concentrations. Fertil Steril42:356, 1984 3. Kokia E, Bider D, Lunenfeld B, Blankstein J, Mashiach S, Ben Rafael Z: Addition of exogenous estrogens to improve cervical mucus following clomiphene citrate medication-patient selection. Acta Obstet Gynecol Scand 69:139, 1990
Letters-to-the-editor
849