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Vol. 54, No.3, September 1990
FERTILITY AND STERILITY
Printed on acid-free paper in U.S.A.
Copyright © 1990 The American Fertility Society
Gonadotropin-Releasing Hormone Therapy Analog and Migraine?
To the Editor: Ashkenazi et aLl describe remarkable neurologic side effects in three patients after gonadotropin-releasing hormone analog (GnRH-a) administration, resembling migraine in its severe form. They hypothesize that the possible mechanism is either a direct effect of GnRH-a or an indirect effect of estrogen (E) withdrawal through serotonin. It is interesting that symptoms in all three patients occurred not immediately after the injection but 8, 10, and 12 days later, when estradiol (E 2) levels were low, and resolved during menotropin stimulation when serum E2 levels rise. The direct effects of E on the central nervous system are well established: from the observation of catamenial epilepsy,2 i.e., that women are more prone to develop epileptic fits during menstruation when E2 is low, to the in vitro finding of immediate and direct effect of E on the firing rate of neurons. 3 Furthermore, Somerville4 demonstrated in 1972 that E withdrawal induces classical migraine attacks. This is probably mediated by its ability to regulate prostacyclin synthesis via specific receptors in vascular smooth-muscle cells. 5 We believe that the neurologic findings described by Ashkenazi et aLl should be attributed to direct effects of E withdrawal on either the central nervous system and/or arterial vascular tone, rather than to a central direct effect of GnRH-a.
Izhar Ben-Shlomo, M.D. David Levran, M.D. Zion Ben-Rafael, M.D. Jhoshua Dor, M.D. Department of Obstetrics and Gynecology Sheba Medical Center Tel Hashomer, Israel June 15, 1990
REFERENCES 1. Ashkenazi J, Goldman JA, Dicker D, Feldberg D, Goldman
GA: Adverse neurological symptoms after gonadotropin-releasing hormone analog therapy for in vitro fertilization cycles. Fertil Steril 53:738, 1990 2. Laidlaw J: Catamenial epilepsy. Lancet 2:1235, 1956 3. Dufy B, Vincent JD: Effects of sex steroids on cell memVol. 54, No.3, September 1990
brane excitability; a new concept for the action of steroids on the brain. IN Hormones and the Brain, Edited by D deWeid, PA van Keep, Baltimore, University Park Press, 1980 pp 29 to 41 4. Somerville BW: The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology 22:355, 1972 5. Chang WC, Nakao S, Orimo H, Murota SI: Stimulation of prostacyclin biosynthetic activity by estradiol in rat aortic smooth muscle cells in culture. Biochim Biophys Acta 619: 107, 1980
Reply of the Authors: We are pleased to note the interest by BenShlomo et al. in our article. I In fact, we agree that there is most likely a relationship between estradiol (E 2) concentrations and classic migraine attacks. 2 Nevertheless, the transient nature of the symptoms described, occurring during the 8th to 12th day of therapy, and subsiding over the next 3 to 7 days, in spite of low E2 levels, weakens the hypothesis that the neurologic findings are directly induced by E2 withdrawal. Moreover, the widerange of the symptoms, as well as the abrupt onset followed by rapid complete resolution, may be attributed to the variations in E2 levels (biphasic effect under gonadotropin-releasing hormone analog [GnRH-a] therapy), resulting in vasospasm of intracerebral blood vessels through serotonin, tryptophan, and pyridoxin metabolism. Furthermore, because the sympathetic ganglia have GnRH receptor sites, 3 a direct effect of potent GnRH -a on the central nervous system, resulting in various neurologic side effects, must be considered. We concur that further study is indicated to more accurately characterize the true nature, prevalence, and causation of this condition.
Jacob Ashkenazi, M.D. Dov Feldberg, M.D. Jack A. Goldman, M.D. Gil A. Goldman, M.D. Dov Dicker, M.D. Sherman Fertility Institute Department of Obstetrics and Gynecology Golda Meir Medical Center (Hasharon Hospital) Petah- Tikva, Israel Tel-Aviv University Medical School Tel-Aviv, Israel May 26,1990 Letters-to-the-editor
541
REFERENCES 1. Ashkenazi J, Goldman JA, Dicker D, Feldberg D, Goldman GA: Adverse neurological symptoms after gonadotropin-releasing hormone analog therapy for in vitro fertilization cycles. Fertil Steril 53:738, 1990 2. Somerville BW: The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology 22:355, 1972 3. Klijn JGM, Foekens JA: Extrapituitary action of GnRH analogues. Gynecol Endocrinoll (Suppl): 16, 1988
Effect of Clomiphene Citrate on Endometrial Receptivity
Lawrence M. Nelson, M.D. Development Endocrinology Branch National Institute of Child Health and Human Development Bethesda, Maryland Robert J. Stillman, M.D. Division of Reproductive Endocrinology and Fertility George Washington University Medical Center Washington, DC
To the Editor:
REFERENCES
I read with interest the paper by Nelson et al. l regarding the effects of clomiphene on implantation in prepubertal mice. They have, however, overlooked one relevant reference by Staples. 2 In this paper Staples also showed that the antiimplantation effects of clomiphene were due not to blastocyst toxicity but to alteration ofthe maternal environment in rats. Blastocysts from untreated females failed to survive in clomiphene-treated recipients, and the decidual reaction in pseudopregnant rats was also inhibited by clomiphene treatment. Thus the results of Nelson et al. l are in good agreement with those of Staples,2 who deserved a citation.
Michael J. K. Harper, Ph.D., Sc.D., F.I.Biol. Chief, Reproductive Biology Division Center for Research in Reproductive Biology The University of Texas Health Science Center at San Antonio Department of Obstetrics and Gynecology San Antonio, Texas April 23, 1990 REFERENCES 1. Nelson LM, Hershlag AV, Kurl RS, Hall JL, Stillman RJ: Clomiphene citrate directly impairs endometrial receptivity in the mouse. Fertil SteriI53:727, 1990 2. Staples RE: Effect of clomiphene on blastocyst nidation in the rat. Endocrinology 78:82, 1966
Reply of the Authors: We thank Dr. Harper for his letter, which gives appropriate citation to Dr. Staples. I Staples provided further evidence that in rodent models clomiphene citrate impairs implantation by altering maternal factors rather than by a direct blastotoxic effect. Our study was designed to define the altered maternal factors more specifically.2 542
Letters-to-the-editor
1. Staples RE: Effects of clomiphene on blastocyst nidation in
the rat. Endocrinology 78:82, 1966 2. Nelson LM, Hershlag AV, Kurl RS, Hall JL, Stillman RJ: Clomiphene citrate directly impairs endometrial receptivity in the mouse. Fertil SteriI53:727, 1990
Management of Interstitial Pregnancy
To the Editor: The hysterotomy procedure for cornual pregnancy described by Confino and Gleicher/ and by Tulandi and Monton,2 enabled the interstitial tube to be conserved intact. But from the authors' descriptions it is doubtful that the abnormal pregnancies were located in the tube. The uterotubal junction is marked embryologically by the point at which the miillerian duct is crossed by the gubernaculum (later the round ligament). A pregnancy that bulges the cornual region of the uterus but pushes the round ligament reflection laterally, as Confino and Gleicher's diagram illustrates, is medial to the uterotubal junction in the lateral uterine angle. This is presumably why the pregnancies were anatomically accessible through an incision in the uterine wall. A tubal interstitial pregnancy, on the other hand, produces a cornual bulge that is lateral to the round ligament reflection. It is hard to envisage a uterine incision allowing easier access to an implantation site that is lateral to the round ligament than an incision over the swelling itself, which in this case would be more laterally placed than Confino and Gleicher show. Angular pregnancies and their differentiation from interstitial tubal pregnancies have been extensively described. 3- 5 They do not ordinarily require laparotomy. If laparoscopy shows the myometrium to be threatened with rupture (an uncommon event, but obviously the case with the authors' first patient), the gestational sac may be accessible to judicious vacuum curettage through the cervix under laparoscopic control, and nothing is lost by Fertility and Sterility
.:r~Ul q~~M~~9no~.g~.JV{.lJ·
Vol. 54, No.3, September 1990
FERTILITY AND STERILITY
Printed on acid-free paper in U.S.A.
Copyright © 1990 The American Fertility Society
Gonadotropin-Releasing Hormone Therapy Analog and Migraine?
To the Editor: Ashkenazi et aLl describe remarkable neurologic side effects in three patients after gonadotropin-releasing hormone analog (GnRH-a) administration, resembling migraine in its severe form. They hypothesize that the possible mechanism is either a direct effect of GnRH-a or an indirect effect of estrogen (E) withdrawal through serotonin. It is interesting that symptoms in all three patients occurred not immediately after the injection but 8, 10, and 12 days later, when estradiol (E 2) levels were low, and resolved during menotropin stimulation when serum E2 levels rise. The direct effects of E on the central nervous system are well established: from the observation of catamenial epilepsy,2 i.e., that women are more prone to develop epileptic fits during menstruation when E2 is low, to the in vitro finding of immediate and direct effect of E on the firing rate of neurons. 3 Furthermore, Somerville4 demonstrated in 1972 that E withdrawal induces classical migraine attacks. This is probably mediated by its ability to regulate prostacyclin synthesis via specific receptors in vascular smooth-muscle cells. 5 We believe that the neurologic findings described by Ashkenazi et aLl should be attributed to direct effects of E withdrawal on either the central nervous system and/or arterial vascular tone, rather than to a central direct effect of GnRH-a.
Izhar Ben-Shlomo, M.D. David Levran, M.D. Zion Ben-Rafael, M.D. Jhoshua Dor, M.D. Department of Obstetrics and Gynecology Sheba Medical Center Tel Hashomer, Israel June 15, 1990
REFERENCES 1. Ashkenazi J, Goldman JA, Dicker D, Feldberg D, Goldman
GA: Adverse neurological symptoms after gonadotropin-releasing hormone analog therapy for in vitro fertilization cycles. Fertil Steril 53:738, 1990 2. Laidlaw J: Catamenial epilepsy. Lancet 2:1235, 1956 3. Dufy B, Vincent JD: Effects of sex steroids on cell memVol. 54, No.3, September 1990
brane excitability; a new concept for the action of steroids on the brain. IN Hormones and the Brain, Edited by D deWeid, PA van Keep, Baltimore, University Park Press, 1980 pp 29 to 41 4. Somerville BW: The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology 22:355, 1972 5. Chang WC, Nakao S, Orimo H, Murota SI: Stimulation of prostacyclin biosynthetic activity by estradiol in rat aortic smooth muscle cells in culture. Biochim Biophys Acta 619: 107, 1980
Reply of the Authors: We are pleased to note the interest by BenShlomo et al. in our article. I In fact, we agree that there is most likely a relationship between estradiol (E 2) concentrations and classic migraine attacks. 2 Nevertheless, the transient nature of the symptoms described, occurring during the 8th to 12th day of therapy, and subsiding over the next 3 to 7 days, in spite of low E2 levels, weakens the hypothesis that the neurologic findings are directly induced by E2 withdrawal. Moreover, the widerange of the symptoms, as well as the abrupt onset followed by rapid complete resolution, may be attributed to the variations in E2 levels (biphasic effect under gonadotropin-releasing hormone analog [GnRH-a] therapy), resulting in vasospasm of intracerebral blood vessels through serotonin, tryptophan, and pyridoxin metabolism. Furthermore, because the sympathetic ganglia have GnRH receptor sites, 3 a direct effect of potent GnRH -a on the central nervous system, resulting in various neurologic side effects, must be considered. We concur that further study is indicated to more accurately characterize the true nature, prevalence, and causation of this condition.
Jacob Ashkenazi, M.D. Dov Feldberg, M.D. Jack A. Goldman, M.D. Gil A. Goldman, M.D. Dov Dicker, M.D. Sherman Fertility Institute Department of Obstetrics and Gynecology Golda Meir Medical Center (Hasharon Hospital) Petah- Tikva, Israel Tel-Aviv University Medical School Tel-Aviv, Israel May 26,1990 Letters-to-the-editor
541
REFERENCES 1. Ashkenazi J, Goldman JA, Dicker D, Feldberg D, Goldman GA: Adverse neurological symptoms after gonadotropin-releasing hormone analog therapy for in vitro fertilization cycles. Fertil Steril 53:738, 1990 2. Somerville BW: The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology 22:355, 1972 3. Klijn JGM, Foekens JA: Extrapituitary action of GnRH analogues. Gynecol Endocrinoll (Suppl): 16, 1988
Effect of Clomiphene Citrate on Endometrial Receptivity
Lawrence M. Nelson, M.D. Development Endocrinology Branch National Institute of Child Health and Human Development Bethesda, Maryland Robert J. Stillman, M.D. Division of Reproductive Endocrinology and Fertility George Washington University Medical Center Washington, DC
To the Editor:
REFERENCES
I read with interest the paper by Nelson et al. l regarding the effects of clomiphene on implantation in prepubertal mice. They have, however, overlooked one relevant reference by Staples. 2 In this paper Staples also showed that the antiimplantation effects of clomiphene were due not to blastocyst toxicity but to alteration ofthe maternal environment in rats. Blastocysts from untreated females failed to survive in clomiphene-treated recipients, and the decidual reaction in pseudopregnant rats was also inhibited by clomiphene treatment. Thus the results of Nelson et al. l are in good agreement with those of Staples,2 who deserved a citation.
Michael J. K. Harper, Ph.D., Sc.D., F.I.Biol. Chief, Reproductive Biology Division Center for Research in Reproductive Biology The University of Texas Health Science Center at San Antonio Department of Obstetrics and Gynecology San Antonio, Texas April 23, 1990 REFERENCES 1. Nelson LM, Hershlag AV, Kurl RS, Hall JL, Stillman RJ: Clomiphene citrate directly impairs endometrial receptivity in the mouse. Fertil SteriI53:727, 1990 2. Staples RE: Effect of clomiphene on blastocyst nidation in the rat. Endocrinology 78:82, 1966
Reply of the Authors: We thank Dr. Harper for his letter, which gives appropriate citation to Dr. Staples. I Staples provided further evidence that in rodent models clomiphene citrate impairs implantation by altering maternal factors rather than by a direct blastotoxic effect. Our study was designed to define the altered maternal factors more specifically.2 542
Letters-to-the-editor
1. Staples RE: Effects of clomiphene on blastocyst nidation in
the rat. Endocrinology 78:82, 1966 2. Nelson LM, Hershlag AV, Kurl RS, Hall JL, Stillman RJ: Clomiphene citrate directly impairs endometrial receptivity in the mouse. Fertil SteriI53:727, 1990
Management of Interstitial Pregnancy
To the Editor: The hysterotomy procedure for cornual pregnancy described by Confino and Gleicher/ and by Tulandi and Monton,2 enabled the interstitial tube to be conserved intact. But from the authors' descriptions it is doubtful that the abnormal pregnancies were located in the tube. The uterotubal junction is marked embryologically by the point at which the miillerian duct is crossed by the gubernaculum (later the round ligament). A pregnancy that bulges the cornual region of the uterus but pushes the round ligament reflection laterally, as Confino and Gleicher's diagram illustrates, is medial to the uterotubal junction in the lateral uterine angle. This is presumably why the pregnancies were anatomically accessible through an incision in the uterine wall. A tubal interstitial pregnancy, on the other hand, produces a cornual bulge that is lateral to the round ligament reflection. It is hard to envisage a uterine incision allowing easier access to an implantation site that is lateral to the round ligament than an incision over the swelling itself, which in this case would be more laterally placed than Confino and Gleicher show. Angular pregnancies and their differentiation from interstitial tubal pregnancies have been extensively described. 3- 5 They do not ordinarily require laparotomy. If laparoscopy shows the myometrium to be threatened with rupture (an uncommon event, but obviously the case with the authors' first patient), the gestational sac may be accessible to judicious vacuum curettage through the cervix under laparoscopic control, and nothing is lost by Fertility and Sterility
