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Corpus luteum dysfunction—is the treatment reallyineffective?
958
Letters Am
minisatellite probes to identify parental contributions to the genome. In these studies we demonstrated that both choriocarcinoma'- ' and placental site trophoblastic tumors' may arise from a hydatidiform mole or a normal conception. Postmole tumors were found to be androgenetic in origin, whereas tumors originating from term pregnancies had both a maternal and paternal contribution to the genome. We have confirmed these results by using the polymerase chain reaction to examine DNA polymorphisms. The use of the polymerase chain reaction has enabled us to examine very small pieces of tumor tissue and to extend our studies to sections of tumor dissected from paraffin-embedded pathologic blocks, thereby minimizing contamination of tumor samples by host DNA. In all caseswhere we have used the polymerase chain reaction to examine tissue taken at hysterectomy, we have identified paternal DNA polymorphisms in the tumor, confirming a gestational origin. However, we have identified three cases of metastatic tumor that had characteristic trophoblast morphologic characteristics and produced human chorionic gonadotrophin, as evidenced by immunostaining and elevated serum levels in the patient, but in which there were no paternally derived DNA polymorphisms. As in the two cases described by Azuma et al. (1990) all DNA polymorphisms found in the tumor were consistent with those found in the host. That the DNA examined was from tumor cells, and not infiltrating host cells, was confirmed by the demonstration of allelic loss at some loci in the tumor sample' (unpublished observations). Our interpretation of these cases is that they are nongestational tumors showing inappropriate morphologic characteristics and human chorionic gonadotropin production. The nongestational tumors that can differentiate toward trophoblast morphologic characteristics and behavior include carcinoma of the bronchus, bladder, stomach, and colon and ovarian germ cell tumors. In view of their differing response to chemotherapy we feel that, for appropriate management of patients with trophoblastic tumors, it is important to distinguish between gestational and nongestational tumors and that genetic studies should be carried out where possible.
RosemmyA. Fisher,PhD, and EdwardS. Newlands,MD, PhD CancerResearchCampaignLaboratories,Departmentsof Medical Oncologyand Btochemtstr)ý CharingCrossand Westminster Medical School,St. Dunstan'sRoad, HamnierTmah, London, United Kingdom W6 8RP REFERENCES 1. Fisher RA, Lawler SD, Povey S, Bagshawe KD. Genetically homozygous choriocarcinoma following pregnancy with hydaticliform mole. Br J Cancer 1988; 58: 788-92. 2. Fisher RA, Newlands ES, Jeffreys A], et al. Gestational and non-gestational trophoblastic tumours distinguished by DNA analysis. Cancer 1992; 69.839-45. 3. Fisher RA, Paradinas Fj, Newlands ES, Boxer GM. Genetic evidence that placental site trophoblastic tumours can originate from a hydatidiform mole or a normal conceptus. Brj Cancer 1992;65: 355-8.
March 1994 Obstet Gynecol .1
Corpus luteum dysfunction -Is the treatment really Ineffective? To the Milors: We read with interest the article by Karamardian and Grimes (Karamardian LM, Grimes DA. Luteal phase deficiency: effect of treatment on pregnancy rates. Am J OBMT GYNECOL1992; 167: 1391-8) because of our previous interest and experience' in luteal dysfunction. Although the authors declared that they attempted to thoroughly "review the English literature and examine the effect of treatment on pregnancy rates, " we felt that their review was incomplete. As felt by many and also cited by the authors, "Pregnancy is the ultimate outcome of interest and also the only one of concern to the couple" and "changes in endometrial histologic type or hormone levels are only indirect measurement of treatment efficacy."' For a study power of 80%, as requested by the authors, assuming a spontaneous cycle fecundity of 5% to 10%, one would need to include 312 cycles, and for a study power of a 90% one would need 414 cycles in the study. " Therefore we felt the authors' work was incomplete because they included in their review studies consisting of six to 82 subjects and failed to include our study, ' which was based on > 600 cycles. The main reason we think the review article is deficient is because the conclusion reached by our study' is completely different from the conclusion reached by Karamardian and Grimes, on the basis of only part of the study dealing with the practical question of "to treat or not treat. " As elaborated in our study, alternating luteal support with repetitive human chorionic gonadotropin injections in ovulation induction cycles, prone to luteal dysfunction, in the same group of patients brought about the conclusion that repetitive supplementation of the luteal phase with human chorionic gonadotropin significantly improved the pregnancy rates. We felt the readers may be misled by a conclusion biased by failure to include studies of different conclusions.
ZeevBlumenfeld,MD, and Shai Linn, MD, DPh Reproductive Endocrinology and Infertility Section,Department of Obstetricsand Gynecolooand the Epidemiology Unit, Rambam MedicalCenter,BruceRappaportFacultyof Medwine, Technion-Israel Instituteof Technology, Haifa,31096,Israel REFERENCES 1. Blumenfeld Z, Nahhas F. Luteal dysfunction in ovulation induction: the role of repetitive human chorionic gonadotropin supplementation during the luteal phase. Fertil Steril 1988; 50: 403-7. 2. Batista MC, Cartledge RP, Merino Mj, et al. Midluteal phase endometrial biopsy does not accurately predict luteal function. Fertil Steril 1993; 59: 294-300. 3. Dean AG, Dean JA. Epidemiology for microcomputers. Version 5. Atlanta: Centers for Disease Control, and Geneva: World Health Organization, 1990: 133-9.
Reply To the Editors:Although we were aware of the study of Blumenfeld and Nahhas, we excluded it from our review becauseit did not meet our stated inclusion criteria. As specified in our Material and methods, a report
Letters Am
minisatellite probes to identify parental contributions to the genome. In these studies we demonstrated that both choriocarcinoma'- ' and placental site trophoblastic tumors' may arise from a hydatidiform mole or a normal conception. Postmole tumors were found to be androgenetic in origin, whereas tumors originating from term pregnancies had both a maternal and paternal contribution to the genome. We have confirmed these results by using the polymerase chain reaction to examine DNA polymorphisms. The use of the polymerase chain reaction has enabled us to examine very small pieces of tumor tissue and to extend our studies to sections of tumor dissected from paraffin-embedded pathologic blocks, thereby minimizing contamination of tumor samples by host DNA. In all caseswhere we have used the polymerase chain reaction to examine tissue taken at hysterectomy, we have identified paternal DNA polymorphisms in the tumor, confirming a gestational origin. However, we have identified three cases of metastatic tumor that had characteristic trophoblast morphologic characteristics and produced human chorionic gonadotrophin, as evidenced by immunostaining and elevated serum levels in the patient, but in which there were no paternally derived DNA polymorphisms. As in the two cases described by Azuma et al. (1990) all DNA polymorphisms found in the tumor were consistent with those found in the host. That the DNA examined was from tumor cells, and not infiltrating host cells, was confirmed by the demonstration of allelic loss at some loci in the tumor sample' (unpublished observations). Our interpretation of these cases is that they are nongestational tumors showing inappropriate morphologic characteristics and human chorionic gonadotropin production. The nongestational tumors that can differentiate toward trophoblast morphologic characteristics and behavior include carcinoma of the bronchus, bladder, stomach, and colon and ovarian germ cell tumors. In view of their differing response to chemotherapy we feel that, for appropriate management of patients with trophoblastic tumors, it is important to distinguish between gestational and nongestational tumors and that genetic studies should be carried out where possible.
RosemmyA. Fisher,PhD, and EdwardS. Newlands,MD, PhD CancerResearchCampaignLaboratories,Departmentsof Medical Oncologyand Btochemtstr)ý CharingCrossand Westminster Medical School,St. Dunstan'sRoad, HamnierTmah, London, United Kingdom W6 8RP REFERENCES 1. Fisher RA, Lawler SD, Povey S, Bagshawe KD. Genetically homozygous choriocarcinoma following pregnancy with hydaticliform mole. Br J Cancer 1988; 58: 788-92. 2. Fisher RA, Newlands ES, Jeffreys A], et al. Gestational and non-gestational trophoblastic tumours distinguished by DNA analysis. Cancer 1992; 69.839-45. 3. Fisher RA, Paradinas Fj, Newlands ES, Boxer GM. Genetic evidence that placental site trophoblastic tumours can originate from a hydatidiform mole or a normal conceptus. Brj Cancer 1992;65: 355-8.
March 1994 Obstet Gynecol .1
Corpus luteum dysfunction -Is the treatment really Ineffective? To the Milors: We read with interest the article by Karamardian and Grimes (Karamardian LM, Grimes DA. Luteal phase deficiency: effect of treatment on pregnancy rates. Am J OBMT GYNECOL1992; 167: 1391-8) because of our previous interest and experience' in luteal dysfunction. Although the authors declared that they attempted to thoroughly "review the English literature and examine the effect of treatment on pregnancy rates, " we felt that their review was incomplete. As felt by many and also cited by the authors, "Pregnancy is the ultimate outcome of interest and also the only one of concern to the couple" and "changes in endometrial histologic type or hormone levels are only indirect measurement of treatment efficacy."' For a study power of 80%, as requested by the authors, assuming a spontaneous cycle fecundity of 5% to 10%, one would need to include 312 cycles, and for a study power of a 90% one would need 414 cycles in the study. " Therefore we felt the authors' work was incomplete because they included in their review studies consisting of six to 82 subjects and failed to include our study, ' which was based on > 600 cycles. The main reason we think the review article is deficient is because the conclusion reached by our study' is completely different from the conclusion reached by Karamardian and Grimes, on the basis of only part of the study dealing with the practical question of "to treat or not treat. " As elaborated in our study, alternating luteal support with repetitive human chorionic gonadotropin injections in ovulation induction cycles, prone to luteal dysfunction, in the same group of patients brought about the conclusion that repetitive supplementation of the luteal phase with human chorionic gonadotropin significantly improved the pregnancy rates. We felt the readers may be misled by a conclusion biased by failure to include studies of different conclusions.
ZeevBlumenfeld,MD, and Shai Linn, MD, DPh Reproductive Endocrinology and Infertility Section,Department of Obstetricsand Gynecolooand the Epidemiology Unit, Rambam MedicalCenter,BruceRappaportFacultyof Medwine, Technion-Israel Instituteof Technology, Haifa,31096,Israel REFERENCES 1. Blumenfeld Z, Nahhas F. Luteal dysfunction in ovulation induction: the role of repetitive human chorionic gonadotropin supplementation during the luteal phase. Fertil Steril 1988; 50: 403-7. 2. Batista MC, Cartledge RP, Merino Mj, et al. Midluteal phase endometrial biopsy does not accurately predict luteal function. Fertil Steril 1993; 59: 294-300. 3. Dean AG, Dean JA. Epidemiology for microcomputers. Version 5. Atlanta: Centers for Disease Control, and Geneva: World Health Organization, 1990: 133-9.
Reply To the Editors:Although we were aware of the study of Blumenfeld and Nahhas, we excluded it from our review becauseit did not meet our stated inclusion criteria. As specified in our Material and methods, a report