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Temporolimbic Epilepsy and Polycystic Ovary Syndrome
cycles, which are typically associated with lower E2 levels at the time of LH surge (4), they observed lower IVF rates. A review ofthe stimulated IVF cycle parameters (5) indicates comparable fertilization rates in endometriosis and "no endometriosis" groups in all studies published, except for the two reports by the Bristol group. Could this be the result of a different stimulation protocol?
W. Paul Dmowski, M.D., Ph.D. Nasir Rana, M.D., M.P.H. Janina Michalowska, Ph.D. Jan Friberg, M.D. Cynthia Papierniak, M.S. Endometriosis Institute at Grant Hospital Chicago, Illinois Albert El-Roeiy, M.D. Reproductive Endocrinology and Fertility Center Crozer Chester Medical Center Upland, Pennsylvania August 9, 1995 REFERENCES 1. Dmowski WP, Rana N, Michalowska J, Friberg J, Papierniak C, El-Roeiy A. The Effect of endometriosis, its stage and activity, and of autoantibodies on in vitro fertilization and embryo transfer success rates. Fertil Steril 1995;63:555-562. 2. Gleicher N, El-Roeiy A, Confino E, Friberg J. Autoantibodies in reproductive failure: is endometriosis an autoimmune disease? Obstet Gyneco11987;70:115-22. 3. Gleicher N. The role of humoral immunity in endometriosis. Acta Obstet Gynecol Scand 1994; 73(Supp1)159:15-7. 4. Tummon I, Maclin V, Radwanska E, Binor Z, Dmowski WP. Occult ovulatory dysfunction in women with minimal endometriosis or unexplained infertility. Fertil Steril 1988;50: 716-20. 5. Dmowski WP. Endometriosis and in vitro fertilization. Assisted Reproduction Rev 1995;5:74-81.
Temporolimbic Epilepsy and Polycystic Ovary Syndrome
To the Editor: Lanzone et al. (1) implicate altered hypothalamopituitary regulation of adrenal steroid secretion in the pathogenesis of polycystic ovary syndrome (PCOS) and note a similarity of this process to the mechanism proposed for stress-related reproductive dysfunction such as hypothalamic amenorrhea. Polycystic ovary syndrome and hypothalamic amenorrhea also have been related to altered hypothalamopituitary regulation of ovarian steroidogenesis (1). Despite the evidence for hypothalamopituitary dysfunction in PCOS and hypothalamic amenorrhea, primary structural lesions in the hypothala210
Letters-to-the-editor
mus are rare, raising the possibility that the hypothalamopituitary dysfunction may be secondary. Primary processes have been sought in the ovary, adrenal gland, adipose tissue, endocrine pancreas, and elsewhere. We propose consideration of another candidate structure: the limbic system of the brain (cf. 2). Medial temporal lobe limbic structures, most notably the amygdala, have massive direct connections to the ventromedial hypothalamus. They exert modulatory influences on reproductive function and hypothalamopituitary secretion. Reproductive dysfunction and reproductive endocrine disorders, specifically PCOS and hypothalamic amenorrhea, are unusually common in women with temporolimbic epilepsy. They are more common in temporolimbic epilepsy than in other forms of epilepsy. Temporolimbic epilepsy is associated with abnormal LH response to LH-releasing hormone stimulation and altered pulsatile secretion of LH (3). Although antiseizure medications may playa role, endocrine abnormalities are more common in untreated individuals (2, 3). Moreover, PCOS is statistically significantly related to left-sided temporolimbic epilepsy, whereas hypothalamic amenorrhea is related to right-sided temporolimbic epilepsy (4), a finding that would be difficult to explain on a medication basis. The temporolimbic system plays a major role in the cerebral representation of emotion. It is also densely populated with cortisol receptors and appears to play an important role in stress response. Activation of this system, therefore, could be responsible for stress-related changes in hypothalamopituitary secretion and reproductive function. Indeed, temporolimbic epilepsy is associated with altered patterns of ACTH and adrenal steroid secretion (5). The possible contribution of temporolimbic dysfunction to altered hypothalamopituitary secretion and the pathogenesis of peos and hypothalamic amenorrhea may warrant further consideration.
Andrew G. Herzog, M.D., M.Sc. Harvard Neuroendocrine Unit Beth Israel Hospital Boston, Massachusetts June 28, 1995 REFERENCES 1. Lanzone A, Ciampelli M, Petraglia F, Caruso A, Fulghesu AM, Mancuso S. Corticotropin-releasing hormone induces an exaggerated response of adrenocorticotropic hormone and cortisol in polycystic ovary syndrome. Fertil Steril 1995;63:1195-9. 2. Herzog AG, Seibel MM, Schomer DL, Vaitukaitis JL, Geschwind N. Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. Arch Neurol 1986;43:341-6.
Fertility and Sterility
3. Drislane FW, Coleman AE, Schomer DL, Ives J, Levesque LA, Seibel MM, et al. Altered pulsatile secretion ofluteinizing hormone in women with epilepsy. Neurology 1994;44:30610. 4. Herzog AG. A relationship between particular reproductive endocrine disorders and the laterality of epileptiform discharges in women with epilepsy. Neurology 1993;43:190710. 5. Gallagher BB, Murvin A, Flnigin HF, King DW, Luney D. Pituitary and adrenal function in epileptic patients. Epilepsia 1984;25:683-9.
Reply of the Authors: We are grateful for Dr. Herzog's comments on our paper 0), which shows the response to an acute N CRH (corticotropin-releasing hormone) injection in patients with polycystic ovary syndrome (PC OS) and in control patients. We observed markedly higher ACTH and cortisol responses to CRH in the PCOS population compared with controls; this finding is consistent with the hypothesis that in such subjects a hyperfunction of the hypothalamic-pituitary-adrenal (HPA) axis may be involved in the physiopathological events of the syndrome. The letter of Dr. Herzog raises other considerations on this crucial point. On the basis of the relationships between epilepsy, altered gonadotropin secretion, and PCOS (2, 3), he proposes the involvement of temporolymbic brain dysfunction in the pathogenesis of PCOS. The hypothesis is suggestive and needs full attention to stimulate further studies. In our paper we did not investigate gonadotropin secretion after CRH bolus. Furthermore conflicting reports exist about the presence of adrenal abnormalities in women suffering from PCOS. Adrenocorticotropic hormone is one but not the only regulator of adrenal function. Taken together, these data indicate an heterogeneity of the syndrome in terms of adrenal hyperfunction. Moreover, the hypothesis of hypothalamic-pituitary disfunction does not exclude the possibility that brain structures may take part in or modulate the imbalance of HPA function.
Antonio Lanzone, M.D. Anna Maria Fulhesu, M.D. Department of Obstetrics and Gynecology Universita Cattolica del Sacro Cuore Rome, Italy July 26, 1995 REFERENCES 1. Lanzone A, Petraglia F, Ciampelli M, Fulghesu AM, Caruso A, Mancuso S. Corticotropin-releasing hormone induces an exaggerated response of adrenocorticotropic hormone and cortisol in polycystic ovary syndrome. Fertil Steril 1995;63:1195-9.
Vol. 65, No.1, January 1996
2. Herzog AG, Seibel MM, Shomer DL, Vaitukaitis JL, Geschwind N. Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. Arch Neurol 1986;43:341-6. 3. Herzog AG. A relationship between particular reproductive endocrine disorders and the laterality of epileptiform discharges in women with epilepsy. Neurology 1993;43: 1907-10.
Commentary-Regulations on Assisted Reproductive Technology
Readers of Mr. John Robertson's thoughtful editorial should know that in mid November 1995, the leadership of the American Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technology (SART) released a statement on the regulation of the treatment of infertility by the assisted reproductive technologies (ART). A portion of that statement is as follows: ". . . now is the time to consider establishing an independent licensing authority. Such an authority might oversee and validate the clinic and laboratory practice of the ART and function independently of and be funded separately from ASRM and SART. We are willing to assist in the development of this body. Ultimately, we must protect the health and safety of infertile couples and their offspring and preserve the patients' rights to access medically appropriate care. The welfare, safety, and effectiveness of care for infertile couples is ofparamount important to ASRM and SART." The Editor-R.D.K.
Retraction
To the Editor: Re: Friedman AJ, Hornstein MD: Gonadotropin-releasing hormone agonist plus estrogen-progestin "add-back" therapy for endometriosis-related pelvic pain. Fertil Steril1993;60:236-41 I am retracting the above article as it contains invalid data. Readers should be advised not to base clinical decisions on conclusions made in this paper. I accept full and sole responsibility for the invalid data.
Andrew J. Friedman, M.D. Wellesley, Massachusetts September 20, 1995 Letters-to-the-editor
211
W. Paul Dmowski, M.D., Ph.D. Nasir Rana, M.D., M.P.H. Janina Michalowska, Ph.D. Jan Friberg, M.D. Cynthia Papierniak, M.S. Endometriosis Institute at Grant Hospital Chicago, Illinois Albert El-Roeiy, M.D. Reproductive Endocrinology and Fertility Center Crozer Chester Medical Center Upland, Pennsylvania August 9, 1995 REFERENCES 1. Dmowski WP, Rana N, Michalowska J, Friberg J, Papierniak C, El-Roeiy A. The Effect of endometriosis, its stage and activity, and of autoantibodies on in vitro fertilization and embryo transfer success rates. Fertil Steril 1995;63:555-562. 2. Gleicher N, El-Roeiy A, Confino E, Friberg J. Autoantibodies in reproductive failure: is endometriosis an autoimmune disease? Obstet Gyneco11987;70:115-22. 3. Gleicher N. The role of humoral immunity in endometriosis. Acta Obstet Gynecol Scand 1994; 73(Supp1)159:15-7. 4. Tummon I, Maclin V, Radwanska E, Binor Z, Dmowski WP. Occult ovulatory dysfunction in women with minimal endometriosis or unexplained infertility. Fertil Steril 1988;50: 716-20. 5. Dmowski WP. Endometriosis and in vitro fertilization. Assisted Reproduction Rev 1995;5:74-81.
Temporolimbic Epilepsy and Polycystic Ovary Syndrome
To the Editor: Lanzone et al. (1) implicate altered hypothalamopituitary regulation of adrenal steroid secretion in the pathogenesis of polycystic ovary syndrome (PCOS) and note a similarity of this process to the mechanism proposed for stress-related reproductive dysfunction such as hypothalamic amenorrhea. Polycystic ovary syndrome and hypothalamic amenorrhea also have been related to altered hypothalamopituitary regulation of ovarian steroidogenesis (1). Despite the evidence for hypothalamopituitary dysfunction in PCOS and hypothalamic amenorrhea, primary structural lesions in the hypothala210
Letters-to-the-editor
mus are rare, raising the possibility that the hypothalamopituitary dysfunction may be secondary. Primary processes have been sought in the ovary, adrenal gland, adipose tissue, endocrine pancreas, and elsewhere. We propose consideration of another candidate structure: the limbic system of the brain (cf. 2). Medial temporal lobe limbic structures, most notably the amygdala, have massive direct connections to the ventromedial hypothalamus. They exert modulatory influences on reproductive function and hypothalamopituitary secretion. Reproductive dysfunction and reproductive endocrine disorders, specifically PCOS and hypothalamic amenorrhea, are unusually common in women with temporolimbic epilepsy. They are more common in temporolimbic epilepsy than in other forms of epilepsy. Temporolimbic epilepsy is associated with abnormal LH response to LH-releasing hormone stimulation and altered pulsatile secretion of LH (3). Although antiseizure medications may playa role, endocrine abnormalities are more common in untreated individuals (2, 3). Moreover, PCOS is statistically significantly related to left-sided temporolimbic epilepsy, whereas hypothalamic amenorrhea is related to right-sided temporolimbic epilepsy (4), a finding that would be difficult to explain on a medication basis. The temporolimbic system plays a major role in the cerebral representation of emotion. It is also densely populated with cortisol receptors and appears to play an important role in stress response. Activation of this system, therefore, could be responsible for stress-related changes in hypothalamopituitary secretion and reproductive function. Indeed, temporolimbic epilepsy is associated with altered patterns of ACTH and adrenal steroid secretion (5). The possible contribution of temporolimbic dysfunction to altered hypothalamopituitary secretion and the pathogenesis of peos and hypothalamic amenorrhea may warrant further consideration.
Andrew G. Herzog, M.D., M.Sc. Harvard Neuroendocrine Unit Beth Israel Hospital Boston, Massachusetts June 28, 1995 REFERENCES 1. Lanzone A, Ciampelli M, Petraglia F, Caruso A, Fulghesu AM, Mancuso S. Corticotropin-releasing hormone induces an exaggerated response of adrenocorticotropic hormone and cortisol in polycystic ovary syndrome. Fertil Steril 1995;63:1195-9. 2. Herzog AG, Seibel MM, Schomer DL, Vaitukaitis JL, Geschwind N. Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. Arch Neurol 1986;43:341-6.
Fertility and Sterility
3. Drislane FW, Coleman AE, Schomer DL, Ives J, Levesque LA, Seibel MM, et al. Altered pulsatile secretion ofluteinizing hormone in women with epilepsy. Neurology 1994;44:30610. 4. Herzog AG. A relationship between particular reproductive endocrine disorders and the laterality of epileptiform discharges in women with epilepsy. Neurology 1993;43:190710. 5. Gallagher BB, Murvin A, Flnigin HF, King DW, Luney D. Pituitary and adrenal function in epileptic patients. Epilepsia 1984;25:683-9.
Reply of the Authors: We are grateful for Dr. Herzog's comments on our paper 0), which shows the response to an acute N CRH (corticotropin-releasing hormone) injection in patients with polycystic ovary syndrome (PC OS) and in control patients. We observed markedly higher ACTH and cortisol responses to CRH in the PCOS population compared with controls; this finding is consistent with the hypothesis that in such subjects a hyperfunction of the hypothalamic-pituitary-adrenal (HPA) axis may be involved in the physiopathological events of the syndrome. The letter of Dr. Herzog raises other considerations on this crucial point. On the basis of the relationships between epilepsy, altered gonadotropin secretion, and PCOS (2, 3), he proposes the involvement of temporolymbic brain dysfunction in the pathogenesis of PCOS. The hypothesis is suggestive and needs full attention to stimulate further studies. In our paper we did not investigate gonadotropin secretion after CRH bolus. Furthermore conflicting reports exist about the presence of adrenal abnormalities in women suffering from PCOS. Adrenocorticotropic hormone is one but not the only regulator of adrenal function. Taken together, these data indicate an heterogeneity of the syndrome in terms of adrenal hyperfunction. Moreover, the hypothesis of hypothalamic-pituitary disfunction does not exclude the possibility that brain structures may take part in or modulate the imbalance of HPA function.
Antonio Lanzone, M.D. Anna Maria Fulhesu, M.D. Department of Obstetrics and Gynecology Universita Cattolica del Sacro Cuore Rome, Italy July 26, 1995 REFERENCES 1. Lanzone A, Petraglia F, Ciampelli M, Fulghesu AM, Caruso A, Mancuso S. Corticotropin-releasing hormone induces an exaggerated response of adrenocorticotropic hormone and cortisol in polycystic ovary syndrome. Fertil Steril 1995;63:1195-9.
Vol. 65, No.1, January 1996
2. Herzog AG, Seibel MM, Shomer DL, Vaitukaitis JL, Geschwind N. Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. Arch Neurol 1986;43:341-6. 3. Herzog AG. A relationship between particular reproductive endocrine disorders and the laterality of epileptiform discharges in women with epilepsy. Neurology 1993;43: 1907-10.
Commentary-Regulations on Assisted Reproductive Technology
Readers of Mr. John Robertson's thoughtful editorial should know that in mid November 1995, the leadership of the American Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technology (SART) released a statement on the regulation of the treatment of infertility by the assisted reproductive technologies (ART). A portion of that statement is as follows: ". . . now is the time to consider establishing an independent licensing authority. Such an authority might oversee and validate the clinic and laboratory practice of the ART and function independently of and be funded separately from ASRM and SART. We are willing to assist in the development of this body. Ultimately, we must protect the health and safety of infertile couples and their offspring and preserve the patients' rights to access medically appropriate care. The welfare, safety, and effectiveness of care for infertile couples is ofparamount important to ASRM and SART." The Editor-R.D.K.
Retraction
To the Editor: Re: Friedman AJ, Hornstein MD: Gonadotropin-releasing hormone agonist plus estrogen-progestin "add-back" therapy for endometriosis-related pelvic pain. Fertil Steril1993;60:236-41 I am retracting the above article as it contains invalid data. Readers should be advised not to base clinical decisions on conclusions made in this paper. I accept full and sole responsibility for the invalid data.
Andrew J. Friedman, M.D. Wellesley, Massachusetts September 20, 1995 Letters-to-the-editor
211