correspondence the Centers for Disease Control and Prevention. Since publication of their article, the authors report no further potential conflict of interest. 1. Kissin DM, Kulkarni AD, Kushnir VA, Jamieson DJ, National
ART Surveillance System Group. Number of embryos transferred after in vitro fertilization and good perinatal outcome. Obstet Gynecol 2014;123:239-47.
2. Sunderam S, Kissin DM, Crawford S, et al. Assisted repro-
ductive technology surveillance — United States, 2010. MMWR Surveill Summ 2013;62(SS-9):1-24. 3. Centers for Disease Control and Prevention, National Center for Health Statistics, Division of Vital Statistics. CDC WONDER online database. November 2013 (http://wonder.cdc.gov). DOI: 10.1056/NEJMc1400242
Intraadrenal Corticotropin in Bilateral Macronodular Adrenal Hyperplasia To the Editor: Louiset et al. (Nov. 28 issue)1 report that bilateral macronodular adrenal hyperplasia (also called corticotropin-independent macronodular adrenal hyperplasia) appears to induce hypercortisolism through intraadrenal corticotropin production. We previously reported the same effect with corticotropin-independent macronodular adrenal hyperplasia and found that the patient had ectopic corticotropin production.2 We completely agree with the mechanism the authors suggest for this disease, since corticotropinindependent macronodular adrenal hyperplastic cells could synthesize cortisol autonomously by means of intraadrenal corticotropin production.2 In vitro incubation studies with gastric inhibitory polypeptide, serotonin, and gonadotropin could increase corticotropin secretion and thereby cortisol response, but vasopressin was not shown to have an effect.1 The responsiveness of cortisol levels to vasopressin has often been reported in patients with corticotropin-independent macronodular adrenal hyperplasia.3 Moreover, pitressin has been reported to induce an increase in cortisol levels by a factor of 3. The vasopressin- induced cortisol secretion is reasonably postulated to result from the eutopic overexpression of the vasopressin V1 receptor.2 However, the question of whether vasopressin can directly or indirectly activate cortisol synthesis has not been fully addressed. Therefore, the authors should clarify these aspects of vasopressin-induced cortisol synthesis in unique corticotropin-producing adrenocortical lesions. Tetsuo Nishikawa, M.D., Ph.D. Yokohama Rosai Hospital Yokohama, Japan [email protected]
Minoru Iwata, M.D., Ph.D. University of Toyama Toyama, Japan
Hironobu Sasano, M.D., Ph.D. Tohoku University School of Medicine Sendai, Japan No potential conflict of interest relevant to this letter was reported. 1. Louiset E, Duparc C, Young J, et al. Intraadrenal corticotro-
pin in bilateral macronodular adrenal hyperplasia. N Engl J Med 2013;369:2115-25. 2. Iwata M, Oki Y, Okazawa T, et al. A rare case of adrenocorticotropic hormone (ACTH)-independent macroadrenal hyperplasia showing ectopic production of ACTH. Intern Med 2012; 51:2181-7. 3. Tatsuno I, Uchida D, Tanaka T, et al. Vasopressin responsiveness of subclinical Cushing’s syndrome due to ACTH-independent macronodular adrenocortical hyperplasia. Clin Endocrinol (Oxf) 2004;60:192-200. DOI: 10.1056/NEJMc1316140
The Authors Reply: Among our 30 patients with bilateral macronodular adrenal hyperplasia and hypercortisolism, there were 9 with an exaggerated plasma cortisol response to vasopressin. We did not evaluate the action of vasopressin on adrenal specimens from these patients. However, similar findings have been previously reported and were ascribed to the abnormal expression of messenger RNA (mRNA), which encoded the vasopressin receptors in the hyperplastic adrenals.1,2 Nevertheless, vasopressin-receptor mRNAs are not always translated into functional receptors in these tissues,3 and the molecular mechanisms actually involved in the increased sensitivity of cortisol secretion to vasopressin have not been fully elucidated.2 It is conceivable, as suggested by Nishikawa et al., that vasopressin may indirectly activate corticosteroidogenesis by stimulating adrenal corticotropin secretion, given the fact that vasopressin is known to stimulate corticotropin production at the pituitary level.4 Secretion of adrenal corticotropin may be triggered by circulating vasopressin or intraadrenal vasopressin, which is abnormally expressed in bilateral macronodular
n engl j med 370;11 nejm.org march 13, 2014
The New England Journal of Medicine Downloaded from nejm.org on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1071
The
n e w e ng l a n d j o u r na l
hyperplasias.5 Therefore, we agree that in future experiments it would be relevant to investigate the action of vasopressin on corticotropin release in samples of adrenal hyperplastic tissue. Estelle Louiset, Ph.D. Hervé Lefebvre, M.D., Ph.D. INSERM Unité 982 Rouen, France [email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. Mune T, Murase H, Yamakita N, et al. Eutopic overexpres-
sion of vasopressin v1a receptor in adrenocorticotropin-independent macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2002;87:5706-13. 2. Lacroix A, Bourdeau I, Lampron A, Mazzuco TL, Tremblay J,
of
m e dic i n e
Hamet P. Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction. Clin Endocrinol (Oxf) 2010;73:1-15. 3. Louiset E, Contesse V, Groussin L, et al. Expression of vasopressin receptors in ACTH-independent macronodular bilateral adrenal hyperplasia causing Cushing’s syndrome: molecular, immunohistochemical and pharmacological correlates. J Endocrinol 2008;196:1-9. 4. Papadimitriou A, Priftis KN. Regulation of the hypothalamic-pituitary-adrenal axis. Neuroimmunomodulation 2009; 16:265-71. 5. Bertherat J, Contesse V, Louiset E, et al. In vivo and in vitro screening for illegitimate receptors in adrenocorticotropin- independent macronodular adrenal hyperplasia causing Cushing’s syndrome: identification of two cases of gonadotropin/gastric inhibitory polypeptide-dependent hypercortisolism. J Clin Endocrinol Metab 2005;90:1302-10. DOI: 10.1056/NEJMc1316140
Global Maternal, Newborn, and Child Health To the Editor: In their article on the health of mothers and their children worldwide, Bhutta and Black (Dec. 5 issue)1 say very little about mental health. According to the World Health Organization (WHO), mental health disorders are the leading cause of disability around the world,2 and women of childbearing age shoulder a disproportionate burden of disease. Clinical depression develops after childbirth in as many as one in five women in Africa and South Asia.3 Depression is accompanied by sadness, fatigue, disinterest, and withdrawal — symptoms that interfere with a mother’s ability to adhere to medication regimens, keep appointments, raise resources for family essentials, breast-feed, and meet other needs of their children.4 Although policymakers and host governments have rightly charged ahead with the implementation of new interventions for mothers and children, mental health services have been left frustratingly behind. As we look beyond 2015 to the next iteration of development goals, it would be shortsighted to ignore the centrality of mental health to maternal and child health and development. Samantha Meltzer-Brody, M.D., M.P.H. Elizabeth M. Stringer, M.D. University of North Carolina at Chapel Hill Chapel Hill, NC [email protected] No potential conflict of interest relevant to this letter was reported.
1072
1. Bhutta ZA, Black RE. Global maternal, newborn, and child
health — so near and yet so far. N Engl J Med 2013;369:2226-35.
2. Depression: fact sheet no. 369. Geneva: World Health Orga-
nization, 2012. 3. Halbreich U, Karkun S. Cross-cultural and social diversity of prevalence of postpartum depression and depressive symptoms. J Affect Disord 2006;91:97-111. 4. Adewuya AO, Ola BO, Aloba OO, Mapayi BM, Okeniyi JA. Impact of postnatal depression on infants’ growth in Nigeria. J Affect Disord 2008;108:191-3. DOI: 10.1056/NEJMc1316332
To the Editor: Bhutta and Black highlight the causes of insufficient progress toward Millennium Development Goals (MDGs) 4 and 5. However, they seriously underplay two widespread, persistent causes of maternal death: unintended pregnancy and unsafe abortion. Worldwide, 41% of all pregnancies are unintended,1 with approximately half of such pregnancies resulting in abortion. Of these procedures, half are unsafe and occur in the developing world.2 Approximately 70,000 women die from unsafe abortions every year,3 and millions more have short-term and long-term abortion-related disorders. Enabling women to control their fertility through access to family planning and safe abortion services will directly reduce preventable, pregnancy-related deaths in every setting, including armed conflict, in which the risks of maternal death and complications from unsafe abortion are high because of widespread rape and social disruption.4 Providing such services will also re-
n engl j med 370;11 nejm.org march 13, 2014
The New England Journal of Medicine Downloaded from nejm.org on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
ART Surveillance System Group. Number of embryos transferred after in vitro fertilization and good perinatal outcome. Obstet Gynecol 2014;123:239-47.
2. Sunderam S, Kissin DM, Crawford S, et al. Assisted repro-
ductive technology surveillance — United States, 2010. MMWR Surveill Summ 2013;62(SS-9):1-24. 3. Centers for Disease Control and Prevention, National Center for Health Statistics, Division of Vital Statistics. CDC WONDER online database. November 2013 (http://wonder.cdc.gov). DOI: 10.1056/NEJMc1400242
Intraadrenal Corticotropin in Bilateral Macronodular Adrenal Hyperplasia To the Editor: Louiset et al. (Nov. 28 issue)1 report that bilateral macronodular adrenal hyperplasia (also called corticotropin-independent macronodular adrenal hyperplasia) appears to induce hypercortisolism through intraadrenal corticotropin production. We previously reported the same effect with corticotropin-independent macronodular adrenal hyperplasia and found that the patient had ectopic corticotropin production.2 We completely agree with the mechanism the authors suggest for this disease, since corticotropinindependent macronodular adrenal hyperplastic cells could synthesize cortisol autonomously by means of intraadrenal corticotropin production.2 In vitro incubation studies with gastric inhibitory polypeptide, serotonin, and gonadotropin could increase corticotropin secretion and thereby cortisol response, but vasopressin was not shown to have an effect.1 The responsiveness of cortisol levels to vasopressin has often been reported in patients with corticotropin-independent macronodular adrenal hyperplasia.3 Moreover, pitressin has been reported to induce an increase in cortisol levels by a factor of 3. The vasopressin- induced cortisol secretion is reasonably postulated to result from the eutopic overexpression of the vasopressin V1 receptor.2 However, the question of whether vasopressin can directly or indirectly activate cortisol synthesis has not been fully addressed. Therefore, the authors should clarify these aspects of vasopressin-induced cortisol synthesis in unique corticotropin-producing adrenocortical lesions. Tetsuo Nishikawa, M.D., Ph.D. Yokohama Rosai Hospital Yokohama, Japan [email protected]
Minoru Iwata, M.D., Ph.D. University of Toyama Toyama, Japan
Hironobu Sasano, M.D., Ph.D. Tohoku University School of Medicine Sendai, Japan No potential conflict of interest relevant to this letter was reported. 1. Louiset E, Duparc C, Young J, et al. Intraadrenal corticotro-
pin in bilateral macronodular adrenal hyperplasia. N Engl J Med 2013;369:2115-25. 2. Iwata M, Oki Y, Okazawa T, et al. A rare case of adrenocorticotropic hormone (ACTH)-independent macroadrenal hyperplasia showing ectopic production of ACTH. Intern Med 2012; 51:2181-7. 3. Tatsuno I, Uchida D, Tanaka T, et al. Vasopressin responsiveness of subclinical Cushing’s syndrome due to ACTH-independent macronodular adrenocortical hyperplasia. Clin Endocrinol (Oxf) 2004;60:192-200. DOI: 10.1056/NEJMc1316140
The Authors Reply: Among our 30 patients with bilateral macronodular adrenal hyperplasia and hypercortisolism, there were 9 with an exaggerated plasma cortisol response to vasopressin. We did not evaluate the action of vasopressin on adrenal specimens from these patients. However, similar findings have been previously reported and were ascribed to the abnormal expression of messenger RNA (mRNA), which encoded the vasopressin receptors in the hyperplastic adrenals.1,2 Nevertheless, vasopressin-receptor mRNAs are not always translated into functional receptors in these tissues,3 and the molecular mechanisms actually involved in the increased sensitivity of cortisol secretion to vasopressin have not been fully elucidated.2 It is conceivable, as suggested by Nishikawa et al., that vasopressin may indirectly activate corticosteroidogenesis by stimulating adrenal corticotropin secretion, given the fact that vasopressin is known to stimulate corticotropin production at the pituitary level.4 Secretion of adrenal corticotropin may be triggered by circulating vasopressin or intraadrenal vasopressin, which is abnormally expressed in bilateral macronodular
n engl j med 370;11 nejm.org march 13, 2014
The New England Journal of Medicine Downloaded from nejm.org on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1071
The
n e w e ng l a n d j o u r na l
hyperplasias.5 Therefore, we agree that in future experiments it would be relevant to investigate the action of vasopressin on corticotropin release in samples of adrenal hyperplastic tissue. Estelle Louiset, Ph.D. Hervé Lefebvre, M.D., Ph.D. INSERM Unité 982 Rouen, France [email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. Mune T, Murase H, Yamakita N, et al. Eutopic overexpres-
sion of vasopressin v1a receptor in adrenocorticotropin-independent macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2002;87:5706-13. 2. Lacroix A, Bourdeau I, Lampron A, Mazzuco TL, Tremblay J,
of
m e dic i n e
Hamet P. Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction. Clin Endocrinol (Oxf) 2010;73:1-15. 3. Louiset E, Contesse V, Groussin L, et al. Expression of vasopressin receptors in ACTH-independent macronodular bilateral adrenal hyperplasia causing Cushing’s syndrome: molecular, immunohistochemical and pharmacological correlates. J Endocrinol 2008;196:1-9. 4. Papadimitriou A, Priftis KN. Regulation of the hypothalamic-pituitary-adrenal axis. Neuroimmunomodulation 2009; 16:265-71. 5. Bertherat J, Contesse V, Louiset E, et al. In vivo and in vitro screening for illegitimate receptors in adrenocorticotropin- independent macronodular adrenal hyperplasia causing Cushing’s syndrome: identification of two cases of gonadotropin/gastric inhibitory polypeptide-dependent hypercortisolism. J Clin Endocrinol Metab 2005;90:1302-10. DOI: 10.1056/NEJMc1316140
Global Maternal, Newborn, and Child Health To the Editor: In their article on the health of mothers and their children worldwide, Bhutta and Black (Dec. 5 issue)1 say very little about mental health. According to the World Health Organization (WHO), mental health disorders are the leading cause of disability around the world,2 and women of childbearing age shoulder a disproportionate burden of disease. Clinical depression develops after childbirth in as many as one in five women in Africa and South Asia.3 Depression is accompanied by sadness, fatigue, disinterest, and withdrawal — symptoms that interfere with a mother’s ability to adhere to medication regimens, keep appointments, raise resources for family essentials, breast-feed, and meet other needs of their children.4 Although policymakers and host governments have rightly charged ahead with the implementation of new interventions for mothers and children, mental health services have been left frustratingly behind. As we look beyond 2015 to the next iteration of development goals, it would be shortsighted to ignore the centrality of mental health to maternal and child health and development. Samantha Meltzer-Brody, M.D., M.P.H. Elizabeth M. Stringer, M.D. University of North Carolina at Chapel Hill Chapel Hill, NC [email protected] No potential conflict of interest relevant to this letter was reported.
1072
1. Bhutta ZA, Black RE. Global maternal, newborn, and child
health — so near and yet so far. N Engl J Med 2013;369:2226-35.
2. Depression: fact sheet no. 369. Geneva: World Health Orga-
nization, 2012. 3. Halbreich U, Karkun S. Cross-cultural and social diversity of prevalence of postpartum depression and depressive symptoms. J Affect Disord 2006;91:97-111. 4. Adewuya AO, Ola BO, Aloba OO, Mapayi BM, Okeniyi JA. Impact of postnatal depression on infants’ growth in Nigeria. J Affect Disord 2008;108:191-3. DOI: 10.1056/NEJMc1316332
To the Editor: Bhutta and Black highlight the causes of insufficient progress toward Millennium Development Goals (MDGs) 4 and 5. However, they seriously underplay two widespread, persistent causes of maternal death: unintended pregnancy and unsafe abortion. Worldwide, 41% of all pregnancies are unintended,1 with approximately half of such pregnancies resulting in abortion. Of these procedures, half are unsafe and occur in the developing world.2 Approximately 70,000 women die from unsafe abortions every year,3 and millions more have short-term and long-term abortion-related disorders. Enabling women to control their fertility through access to family planning and safe abortion services will directly reduce preventable, pregnancy-related deaths in every setting, including armed conflict, in which the risks of maternal death and complications from unsafe abortion are high because of widespread rape and social disruption.4 Providing such services will also re-
n engl j med 370;11 nejm.org march 13, 2014
The New England Journal of Medicine Downloaded from nejm.org on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
