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Placebo Effect—How Powerful?
understanding whether the HIV infection that has been documented in prostate is the route of entry of the virus into seminal fluid or a consequence of the appearance of infectious virus in the male reproductive tract. Taken together, these two letters emphasize the importance of fully understanding the route of entry of HIV into semen.
Ann A. Kiessling, Ph.D. Faulkner Centre For Reproductive Medicine Boston, Massachusetts January 20, 1993 REFERENCE 1. Kiessling AA. Semen transmission of human immunodefi-
ciency virus. Fertil Steril 1992;58:667-9.
Placebo Effect-How Powerful?
To the Editor: Case reports by Ashkenazi et al. (1) and Penzias et al. (2) described the occurrence of neurological symptoms, including prominent peripheral paresthesias, during GnRH-agonist administration. The neurological symptoms reported arose during the uncontrolled clinical use of this medication and cannot with certainty, therefore, be related causally to the GnRH -a. We recently have observed the development of similar symptoms in one woman participating in a double-blind placebo-controlled trial of depot leuprolide acetate in the treatment of premenstrual syndrome. Three weeks after the first injection of medication, she complained of numbness over her left lower leg, right foot, and left arm lasting for 3 days. No other neurological symptoms were present, and a neurological exam was within normal limits. Although all of these symptoms were time limited, the two reports cited above prompted our concern, and we broke the medication blind. The patient was on placebo and had not received depot leuprolide acetate. We do not intend in any way to de-emphasize the importance of careful clinical monitoring of patients undergoing treatment with any medication. However, our experience emphasized what is commonly observed in placebo-controlled trials-that side effects may accompany medication ingestion without being caused by the medication.
Peter J. Schmidt, M.D. Unit on Reproductive Endocrine Studies Section on Behavioral Endocrinology National Institute of Mental Health Bethesda, Maryland 1144
Letters-to-the-editor
David R. Rubinow, M.D. National Institute of Mental Health Bethesda, Maryland July 23, 1992 REFERENCES 1. Ashkenazi J, Feldberg D, Goldman JA, Goldman GA, Dicker
D. Adverse neurological symptoms after gonadotropin-releasing hormone analog therapy for in vitro fertilization cycles. Fertil Steril 1990;53:738-40. 2. Penzias AS, Gutmann JN, Seifer DB, DeCherney AH. Facial and neck paresthesia associated with nafarelin administration. Fertil Steril1991;56:357-8.
Reply of the Author: Thank you for the comments of Schmidt and Rubinow concerning our report, describing the occurrence of neurological symptoms during GnRHagonist administration. We felt that it was important to report any side effects during therapy of any medication even if they were not a result of that therapy. Because we have since encountered two further cases with mild neurological symptoms, (headaches and paraesthesias) during GnRH-a (DTRP6) therapy, we assume that these signs may have been caused by the medication, although we cannot be absolutely certain they did. Further reports of controlled double-blind clinical studies may confirm or deny such association. We must not forget, though, that GnRH-a results in a postmenopausal syndrome. Jack A. Goldman, M.D. Golda Meir Medical Center Petah Tikua, Israel January 24, 1993
Reply of the Authors: We read with interest the case encountered by Drs. Schmidt and Rubinow. Their letter raises several important issues. First, we are in agreement that the symptoms observed in our case report (1) occurred in a clinical setting and that they cannot be attributed with certainty exclusively to the GnRH -agonist. We questioned the mechanism of the observed symptoms when we wrote ". . . nafarelin acetate or its carriers, which enter the cerebral circulation through the nasal mucus membrane, may be exerting an idiopathic effect on blood vessels in the hypoestrogenic milieu that had been established after three weeks of its use." Second, we believe that case reports serve a valuable purpose. They raise awareness of interesting or unusual phenomena. These findings may be encountered by many physicians but go unclassified Fertility and Sterility
until a larger collective experience is gathered. At that point, a hypothesis can be generated and tested in a more controlled way. We look forward to seeing the results of Drs. Schmidt and Rubin_ow's study.
Alan S. Penzias, M.D. Alan H. DeCherney, M.D. Tufts University School of Medicine Boston, Massachusetts Jacqueline N. Gutmann, M.D. Yale University School of Medicine New Haven, Connecticut David B. Seifer, M.D. Brown University School of Medicine Providence, Rhode Island August 14, 1992 REFERENCE 1. Penzias AS, Gutmann JN, Seifer DB, DeCherney AH. Facial and neck paresthesia associated with nafarelin administration. 1991;56:357-8.
Vol. 59, No.5, May 1993
Erratum
To the Editor: Re: Balasch J, Jove IC, Moreno V, Civico S, Puerto B, Vanrell JA. The comparison of two gonadotropin-releasing hormone agonists in an in vitro fertilization program. Fertil Steril 1992;58: 991-4. There is an error in our article referenced above. The dose of buserelin acetate is incompletely detailed; on page 992, under Materials and Methods, the text should have read 300 J.Lg two times per day.
Juan Balasch, M.D. Departamento de Obstetricid u Ginecologia Hospital Clinico y Provincial Universidad de Barcelona Barcelona, Spain Received January 15, 1993
Letters-to-the-editor
1145
Ann A. Kiessling, Ph.D. Faulkner Centre For Reproductive Medicine Boston, Massachusetts January 20, 1993 REFERENCE 1. Kiessling AA. Semen transmission of human immunodefi-
ciency virus. Fertil Steril 1992;58:667-9.
Placebo Effect-How Powerful?
To the Editor: Case reports by Ashkenazi et al. (1) and Penzias et al. (2) described the occurrence of neurological symptoms, including prominent peripheral paresthesias, during GnRH-agonist administration. The neurological symptoms reported arose during the uncontrolled clinical use of this medication and cannot with certainty, therefore, be related causally to the GnRH -a. We recently have observed the development of similar symptoms in one woman participating in a double-blind placebo-controlled trial of depot leuprolide acetate in the treatment of premenstrual syndrome. Three weeks after the first injection of medication, she complained of numbness over her left lower leg, right foot, and left arm lasting for 3 days. No other neurological symptoms were present, and a neurological exam was within normal limits. Although all of these symptoms were time limited, the two reports cited above prompted our concern, and we broke the medication blind. The patient was on placebo and had not received depot leuprolide acetate. We do not intend in any way to de-emphasize the importance of careful clinical monitoring of patients undergoing treatment with any medication. However, our experience emphasized what is commonly observed in placebo-controlled trials-that side effects may accompany medication ingestion without being caused by the medication.
Peter J. Schmidt, M.D. Unit on Reproductive Endocrine Studies Section on Behavioral Endocrinology National Institute of Mental Health Bethesda, Maryland 1144
Letters-to-the-editor
David R. Rubinow, M.D. National Institute of Mental Health Bethesda, Maryland July 23, 1992 REFERENCES 1. Ashkenazi J, Feldberg D, Goldman JA, Goldman GA, Dicker
D. Adverse neurological symptoms after gonadotropin-releasing hormone analog therapy for in vitro fertilization cycles. Fertil Steril 1990;53:738-40. 2. Penzias AS, Gutmann JN, Seifer DB, DeCherney AH. Facial and neck paresthesia associated with nafarelin administration. Fertil Steril1991;56:357-8.
Reply of the Author: Thank you for the comments of Schmidt and Rubinow concerning our report, describing the occurrence of neurological symptoms during GnRHagonist administration. We felt that it was important to report any side effects during therapy of any medication even if they were not a result of that therapy. Because we have since encountered two further cases with mild neurological symptoms, (headaches and paraesthesias) during GnRH-a (DTRP6) therapy, we assume that these signs may have been caused by the medication, although we cannot be absolutely certain they did. Further reports of controlled double-blind clinical studies may confirm or deny such association. We must not forget, though, that GnRH-a results in a postmenopausal syndrome. Jack A. Goldman, M.D. Golda Meir Medical Center Petah Tikua, Israel January 24, 1993
Reply of the Authors: We read with interest the case encountered by Drs. Schmidt and Rubinow. Their letter raises several important issues. First, we are in agreement that the symptoms observed in our case report (1) occurred in a clinical setting and that they cannot be attributed with certainty exclusively to the GnRH -agonist. We questioned the mechanism of the observed symptoms when we wrote ". . . nafarelin acetate or its carriers, which enter the cerebral circulation through the nasal mucus membrane, may be exerting an idiopathic effect on blood vessels in the hypoestrogenic milieu that had been established after three weeks of its use." Second, we believe that case reports serve a valuable purpose. They raise awareness of interesting or unusual phenomena. These findings may be encountered by many physicians but go unclassified Fertility and Sterility
until a larger collective experience is gathered. At that point, a hypothesis can be generated and tested in a more controlled way. We look forward to seeing the results of Drs. Schmidt and Rubin_ow's study.
Alan S. Penzias, M.D. Alan H. DeCherney, M.D. Tufts University School of Medicine Boston, Massachusetts Jacqueline N. Gutmann, M.D. Yale University School of Medicine New Haven, Connecticut David B. Seifer, M.D. Brown University School of Medicine Providence, Rhode Island August 14, 1992 REFERENCE 1. Penzias AS, Gutmann JN, Seifer DB, DeCherney AH. Facial and neck paresthesia associated with nafarelin administration. 1991;56:357-8.
Vol. 59, No.5, May 1993
Erratum
To the Editor: Re: Balasch J, Jove IC, Moreno V, Civico S, Puerto B, Vanrell JA. The comparison of two gonadotropin-releasing hormone agonists in an in vitro fertilization program. Fertil Steril 1992;58: 991-4. There is an error in our article referenced above. The dose of buserelin acetate is incompletely detailed; on page 992, under Materials and Methods, the text should have read 300 J.Lg two times per day.
Juan Balasch, M.D. Departamento de Obstetricid u Ginecologia Hospital Clinico y Provincial Universidad de Barcelona Barcelona, Spain Received January 15, 1993
Letters-to-the-editor
1145