AUTHOR(S): Coyne, Terry J., F.R.A.C.S.; Atkinson, R. Leigh, F.R.A.C.S.; Prins, John B., M.B.B.S. Departments of Neurosurgery (TJC, RLA) and Endocrinology (JBP), Princess Alexandra Hospital, Brisbane, Australia Neurosurgery 31; 953-955, 1992 ABSTRACT: A PATIENT WITH an adrenocorticotropic hormone-secreting pituitary adenoma diagnosed at the same time as pregnancy is reported. Treatment was by transsphenoidal tumor resection, which has only been described once previously in such a case. Treatment rationale is discussed, and transsphenoidal tumor resection is recommended as the therapy of choice. KEY WORDS: Cushing's syndrome; Pituitary adenoma; Pregnancy Although much knowledge and experience of Cushing's syndrome have been gathered since its original description in 1932 (6), it has only rarely been reported in association with pregnancy. This report describes such an association successfully managed by transsphenoidal tumor resection. CASE REPORT A previously well 22-year-old woman gave a 3year history of episodic facial and lower limb swelling, for which no cause had been found. More recently, she had complained of 9 months of persistent moonlike facial swelling, which had aroused suspicions of Cushing's syndrome, and she had been referred to our institution for further investigation. At the same time, she complained of an 8-week history of amenorrhea, morning nausea, and vomiting; a serum pregnancy test was positive. Examination revealed a nondistressed, normotensive patient with plethoric moonlike facies and a mild proximal myopathy. Other classical clinical features of Cushing's syndrome were absent. A high-dose dexamethasone suppression test demonstrated failure of suppression of the serum cortisol level, along with marked variability of 24hour urinary free cortisol measurements (Table 1). The results indicated Cushing's syndrome of pituitary origin, with episodic hormone production. Ultrasound imaging of the adrenal glands was normal. A magnetic resonance imaging (MRI) scan demonstrated a pituitary mass causing expansion and ballooning of the pituitary fossa (Figure 1). There was extension of the mass to the lateral wall of the left cavernous sinus with encasement of the left internal carotid artery, and on the right, the mass
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extended to the medial margin of the right internal carotid artery. The mass extended superiorly to the suprasellar cistern. A uterine ultrasound revealed a normal, 11-week pregnancy, consistent with the patient's dates. It was thought that transsphenoidal resection of the lesion was the most appropriate form of treatment, and this was performed when the patient was 14 weeks pregnant. Although it was felt that radical tumor clearance was obtained at the time of surgery, with preservation of some normal pituitary gland, total extirpation was understandably not achieved. Postoperatively, the patient developed diabetes insipidus, which has persisted and for which she requires supplementation with desmopressin acetate (Minerin; Ferring A.B., Malmo, Sweden). Otherwise, the postoperative course was uneventful and she was discharged 7 days after surgery. Perioperative steroid cover had been given, and subsequently, steroids were continued in a tapered fashion for 1 month. A uterine ultrasound before she was discharged continued to demonstrate a healthy pregnancy. A histological examination of the resected tissue demonstrated a pituitary adenoma of unremarkable morphology. Immunoperoxidase stains were positive for adrenocorticotropic hormone (ACTH) and negative for prolactin and growth hormone. Immediately postoperatively, the 24-hour urinary free cortisol measurements fell to the upper limits of normal, consistent with either some continued tumor ACTH production or placental cortisol production. Five months postoperatively, all 24-hour urinary free cortisol measurements were less than 300 mmol/d (within normal limits). In view of the inability to achieve total tumor removal, a course of radiotherapy was planned. The patient has remained well, and the pregnancy was otherwise uneventful. DISCUSSION Pregnancy associated with Cushing's syndrome is uncommon, because the syndrome is associated with reduced fertility and is thought to be caused by corticosteroid-mediated suppression of gonadotropin release (3). The association is well described, and including this patient, 59 patients with Cushing's syndrome and pregnancy have been reported (12). Cushing's disease has been reported as the cause in approximately 45% of these cases, adrenal adenoma or carcinoma was the cause in 50%, and in several cases, no cause of the Cushing's syndrome was identified (11,12). In contrast, in the general population with Cushing's syndrome, more than 60% of cases are caused by pituitary disease (14). Within this group, 80% or more have a pituitary adenoma (8), of which 20% are macroadenomas (4). This is the first report of a patient with an ACTHsecreting adenoma and pregnancy in which the tumor has been demonstrated with MRI. Adenomas of the size harbored by this patient are more commonly associated with Nelson's syndrome than with Cushing's disease (4). Although in this instance, the patient may have developed a macroadenoma anyway, an increase in size with pregnancy has been
Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
Neurosurgery 1992-98 November 1992, Volume 31, Number 5 953 Adrenocorticotropic Hormone-Secreting Pituitary Tumor Associated with Pregnancy: Case Report Case Report
4.
5.
6.
7.
8.
9.
10.
11. 12.
13. Received, November 18, 1991. Accepted, March 12, 1992. Reprint requests: Dr. R. L. Atkinson, Department of Neurosurgery, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland 4102, Australia. REFERENCES: (1-14) 1. 2.
3.
Anderson KJ, Walters WAW: Cushing's syndrome and pregnancy. Aust NZ Obstet Gynaecol 16:225-230, 1976. Bergmann P, Ekman H, Hakansson B, Sjogren B: Adrenalectomy during pregnancy with the appearance of pre-eclampsia at term in a case of Cushing's syndrome. Acta Endocrinol 35:293- 298, 1960. Bocuzzi G, Angel A, Bistrocci D, Fonzo D, Gaifano GP, Ceresa F: Effect of synthetic luteinizing releasing hormone (LHRH) on the release of gonadotrophin in Cushing's disease.
Downloaded from https://academic.oup.com/neurosurgery/article-abstract/31/5/953/2281000 by UB Frankfurt/Main user on 04 March 2018
14.
J Clin Endocrinol Metab 40:892-895, 1975. Boggan JE, Wilson CB: Cushing's disease and Nelson's syndrome, in Wilkins RM, Sengachary SS (eds): Neurosurgery. New York, McGraw-Hill, 1985, pp 859-863. Casson IF, Davis JC, Jeffreys RV, Silas JH, Williams J, Belchetz PE: Successful management of Cushing's disease during pregnancy by transsphenoidal adenectomy. Clin Endocrinol 27:423-428, 1987. Cushing H: The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism) Bull Johns Hopkins Hosp 50:137-195, 1932. Kasperlick-Zaluska A, Migdalska B, Hartwig W, Wilczynska J, Marionowski L, StopinsjaGluszak U, Losinska D: Two pregnancies in a woman with Cushing's syndrome treated with cyproheptadine. Br J Obstet Gynaecol 87:1171-1173, 1980. Krieger DT: Pharmacological therapy of Cushing's disease and Nelson's syndrome, in Linfoot JA (ed): Recent Advances in the Diagnosis and Treatment of Pituitary Tumors. New York, Raven Press, 1979, pp 337-340. Lunardi P, Rizzo A, Missori P, Fraioli B: Pituitary apoplexy in an acromegalic woman operated on during pregnancy by transsphenoidal approach. Int J Gynaecol Obstet 34:71-74, 1990. Mampalam TJ, Tyrrell JB, Wilson CB: Transsphenoidal microsurgery for Cushing's disease. A report of the 216 cases. Ann Intern Med 109:487- 493, 1988. Pickard J, Jochen AL, Sadur CN, Hofeldt FB: Cushing's syndrome in pregnancy. Obstet Gynaecol Survey 45:87-93, 1990. Pricolo VE, Monchik JM, Prinz RA, DeJong S, Chadwick DA, Lamberton RP: Management of Cushing's syndrome secondary to adrenal adenoma during pregnancy. Surgery 108:1072-1077, 1990. Toffle RC, Webb SM, Togatz GE, Taylor S, Nagel TC, Campbell B, Phipps W, Okagaki T: Pregnancy induced changes in prolactinomas as assessed with computed tomography. J Reproductive Med 33:821-826, 1988. Tyrrell JB: Cushing's syndrome, in Wyngaarden JB, Smith LM (eds): Cecil Textbook of Medicine. Philadelphia, WB Saunders, 1988, ed 18, pp 1353-1360.
COMMENTS Neurosurgical indications in a pregnant patient are always challenging and require a great deal of thoughtful consideration. Cushing's disease can affect the fetus, be it in terms of protracted hypercortisolism effects or in terms of repeat miscarriages, as was the case in one of our patients with Cushing's disease, who had previous miscarriages and a premature delivery with infant mortality. The decision reached in our case was similar to that of the authors', namely, to proceed with transsphenoidal removal of the
Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
reported for prolactin- (13) and growth hormonesecreting adenomas (9) and it is likely that pregnancy similarly contributed to the uncommonly large size of this ACTH-secreting tumor. It has been well-established that Cushing's syndrome in pregnancy is associated with an increased incidence of premature labor, fetal loss, and maternal morbidity. It has been noted that only 40% of these pregnancies reach term, with a 35% incidence of prematurity and a 20% abortion rate (11). Although adrenal tumors have generally been treated by surgical removal (12), treatment of Cushing's disease in pregnancy has varied. Historically, the condition has generally been managed by observation only (11). Therapies that have been used are bilateral adrenalectomy (2), pituitary irradiation during the pregnancy (1), and cyproheptadine (7); there has been one case report of transsphenoidal resection of a pituitary adenoma, which brought control of the Cushing's disease, although cesarean section was required for eclampsia at 28 weeks' gestation (5). It has generally become accepted that transsphenoidal removal is the treatment of choice for an ACTH-secreting pituitary tumor (10). This second report of successful surgery during pregnancy confirms that the procedure can be performed during pregnancy with safety for both mother and fetus. In conclusion, we have described the second patient with an ACTH-secreting pituitary adenoma associated with pregnancy who was managed by transsphenoidal surgery. It was demonstrated that, in pregnancy, an ACTH-secreting adenoma may be a macroadenoma, but may none the less be successfully treated surgically. We have also demonstrated the use of modern imaging techniques (ultrasound and MRI) to establish the cause of the Cushing's syndrome in our patient without recourse to diagnostic x-rays and their theoretical risk in pregnancy. In view of the potential complications of an ACTH-secreting pituitary tumor in pregnancy, we recommend transsphenoidal tumor excision as the initial treatment of choice for these patients.
adrenocorticotropic hormone-secreting microadenoma in the second trimester. The procedure resulted in a cure, and the patient delivered a healthy baby after a normal pregnancy. The number of similar cases in the literature is rather limited to make any recommendations on the basis of statistical data. Our inclination would be to recommend surgery in the second trimester of pregnancy in a patient with Cushing's disease.
Dr. Coyne and colleagues report the history of a woman suffering from Cushing's disease who became pregnant in spite of the fact that menstrual disorders are present in 77% of the patients at the onset of the disease. The disorders are probably caused by the increased androgens and their suppressive effect on pituitary gonadotropin secretion (2). Pregnancy could be maintained by transsphenoidal pituitary surgery and terminated by a normal delivery. The authors were able to save this pregnancy in spite of an elevated abortion rate. They avoided a premature termination of the pregnancy as well. This shows that pituitary surgery can be performed safely during the 14th week of pregnancy. There remains the question of whether consistently elevated serum cortisol levels (about double of the upper normal limit) may be dangerous to the fetus. The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 34 of which had first-trimester exposure to cortisone. No evidence of a relationship to congenital malformations was found. In another group of 35 first-trimester exposures, however, congenital defects (cataracts, cyclopia, intraventricular septal defect, gastroschisis, hydrocephalus, cleft lip, coarctation of the aorta, clubfoot, and undescended testicles) were observed in 9 infants (1). No evidence of increased fetal abnormalities was observed by Krieger (2), who reviewed the literature of pregnancies of patients with Cushing's syndrome. The problem of possible danger to the fetus therefore remains open (the referee thanks Prof. G. Duc, Zürich, for his help). Alex M. Landolt Zürich, Switzerland REFERENCES: (1,2) 1. 2.
Briggs GG, Freeman RK, Yaffe SJ: Drugs in Pregnancy and Lactation. Baltimore, Williams & Wilkins, 1990, ed 3, p 157/c. Krieger DT: Cushing's Syndrome. Monographs on Endocrinology. Berlin, Springer-Verlag, 1982, vol 22, pp 47-53.
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Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
Ivan Ciric Evanston, Illinois
Table 1. Preoperative High-Dose Dexamethasone Test
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Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
Figure 1. Coronal MRI scan through the pituitary fossa, demonstrating a pituitary mass.
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extended to the medial margin of the right internal carotid artery. The mass extended superiorly to the suprasellar cistern. A uterine ultrasound revealed a normal, 11-week pregnancy, consistent with the patient's dates. It was thought that transsphenoidal resection of the lesion was the most appropriate form of treatment, and this was performed when the patient was 14 weeks pregnant. Although it was felt that radical tumor clearance was obtained at the time of surgery, with preservation of some normal pituitary gland, total extirpation was understandably not achieved. Postoperatively, the patient developed diabetes insipidus, which has persisted and for which she requires supplementation with desmopressin acetate (Minerin; Ferring A.B., Malmo, Sweden). Otherwise, the postoperative course was uneventful and she was discharged 7 days after surgery. Perioperative steroid cover had been given, and subsequently, steroids were continued in a tapered fashion for 1 month. A uterine ultrasound before she was discharged continued to demonstrate a healthy pregnancy. A histological examination of the resected tissue demonstrated a pituitary adenoma of unremarkable morphology. Immunoperoxidase stains were positive for adrenocorticotropic hormone (ACTH) and negative for prolactin and growth hormone. Immediately postoperatively, the 24-hour urinary free cortisol measurements fell to the upper limits of normal, consistent with either some continued tumor ACTH production or placental cortisol production. Five months postoperatively, all 24-hour urinary free cortisol measurements were less than 300 mmol/d (within normal limits). In view of the inability to achieve total tumor removal, a course of radiotherapy was planned. The patient has remained well, and the pregnancy was otherwise uneventful. DISCUSSION Pregnancy associated with Cushing's syndrome is uncommon, because the syndrome is associated with reduced fertility and is thought to be caused by corticosteroid-mediated suppression of gonadotropin release (3). The association is well described, and including this patient, 59 patients with Cushing's syndrome and pregnancy have been reported (12). Cushing's disease has been reported as the cause in approximately 45% of these cases, adrenal adenoma or carcinoma was the cause in 50%, and in several cases, no cause of the Cushing's syndrome was identified (11,12). In contrast, in the general population with Cushing's syndrome, more than 60% of cases are caused by pituitary disease (14). Within this group, 80% or more have a pituitary adenoma (8), of which 20% are macroadenomas (4). This is the first report of a patient with an ACTHsecreting adenoma and pregnancy in which the tumor has been demonstrated with MRI. Adenomas of the size harbored by this patient are more commonly associated with Nelson's syndrome than with Cushing's disease (4). Although in this instance, the patient may have developed a macroadenoma anyway, an increase in size with pregnancy has been
Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
Neurosurgery 1992-98 November 1992, Volume 31, Number 5 953 Adrenocorticotropic Hormone-Secreting Pituitary Tumor Associated with Pregnancy: Case Report Case Report
4.
5.
6.
7.
8.
9.
10.
11. 12.
13. Received, November 18, 1991. Accepted, March 12, 1992. Reprint requests: Dr. R. L. Atkinson, Department of Neurosurgery, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland 4102, Australia. REFERENCES: (1-14) 1. 2.
3.
Anderson KJ, Walters WAW: Cushing's syndrome and pregnancy. Aust NZ Obstet Gynaecol 16:225-230, 1976. Bergmann P, Ekman H, Hakansson B, Sjogren B: Adrenalectomy during pregnancy with the appearance of pre-eclampsia at term in a case of Cushing's syndrome. Acta Endocrinol 35:293- 298, 1960. Bocuzzi G, Angel A, Bistrocci D, Fonzo D, Gaifano GP, Ceresa F: Effect of synthetic luteinizing releasing hormone (LHRH) on the release of gonadotrophin in Cushing's disease.
Downloaded from https://academic.oup.com/neurosurgery/article-abstract/31/5/953/2281000 by UB Frankfurt/Main user on 04 March 2018
14.
J Clin Endocrinol Metab 40:892-895, 1975. Boggan JE, Wilson CB: Cushing's disease and Nelson's syndrome, in Wilkins RM, Sengachary SS (eds): Neurosurgery. New York, McGraw-Hill, 1985, pp 859-863. Casson IF, Davis JC, Jeffreys RV, Silas JH, Williams J, Belchetz PE: Successful management of Cushing's disease during pregnancy by transsphenoidal adenectomy. Clin Endocrinol 27:423-428, 1987. Cushing H: The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism) Bull Johns Hopkins Hosp 50:137-195, 1932. Kasperlick-Zaluska A, Migdalska B, Hartwig W, Wilczynska J, Marionowski L, StopinsjaGluszak U, Losinska D: Two pregnancies in a woman with Cushing's syndrome treated with cyproheptadine. Br J Obstet Gynaecol 87:1171-1173, 1980. Krieger DT: Pharmacological therapy of Cushing's disease and Nelson's syndrome, in Linfoot JA (ed): Recent Advances in the Diagnosis and Treatment of Pituitary Tumors. New York, Raven Press, 1979, pp 337-340. Lunardi P, Rizzo A, Missori P, Fraioli B: Pituitary apoplexy in an acromegalic woman operated on during pregnancy by transsphenoidal approach. Int J Gynaecol Obstet 34:71-74, 1990. Mampalam TJ, Tyrrell JB, Wilson CB: Transsphenoidal microsurgery for Cushing's disease. A report of the 216 cases. Ann Intern Med 109:487- 493, 1988. Pickard J, Jochen AL, Sadur CN, Hofeldt FB: Cushing's syndrome in pregnancy. Obstet Gynaecol Survey 45:87-93, 1990. Pricolo VE, Monchik JM, Prinz RA, DeJong S, Chadwick DA, Lamberton RP: Management of Cushing's syndrome secondary to adrenal adenoma during pregnancy. Surgery 108:1072-1077, 1990. Toffle RC, Webb SM, Togatz GE, Taylor S, Nagel TC, Campbell B, Phipps W, Okagaki T: Pregnancy induced changes in prolactinomas as assessed with computed tomography. J Reproductive Med 33:821-826, 1988. Tyrrell JB: Cushing's syndrome, in Wyngaarden JB, Smith LM (eds): Cecil Textbook of Medicine. Philadelphia, WB Saunders, 1988, ed 18, pp 1353-1360.
COMMENTS Neurosurgical indications in a pregnant patient are always challenging and require a great deal of thoughtful consideration. Cushing's disease can affect the fetus, be it in terms of protracted hypercortisolism effects or in terms of repeat miscarriages, as was the case in one of our patients with Cushing's disease, who had previous miscarriages and a premature delivery with infant mortality. The decision reached in our case was similar to that of the authors', namely, to proceed with transsphenoidal removal of the
Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
reported for prolactin- (13) and growth hormonesecreting adenomas (9) and it is likely that pregnancy similarly contributed to the uncommonly large size of this ACTH-secreting tumor. It has been well-established that Cushing's syndrome in pregnancy is associated with an increased incidence of premature labor, fetal loss, and maternal morbidity. It has been noted that only 40% of these pregnancies reach term, with a 35% incidence of prematurity and a 20% abortion rate (11). Although adrenal tumors have generally been treated by surgical removal (12), treatment of Cushing's disease in pregnancy has varied. Historically, the condition has generally been managed by observation only (11). Therapies that have been used are bilateral adrenalectomy (2), pituitary irradiation during the pregnancy (1), and cyproheptadine (7); there has been one case report of transsphenoidal resection of a pituitary adenoma, which brought control of the Cushing's disease, although cesarean section was required for eclampsia at 28 weeks' gestation (5). It has generally become accepted that transsphenoidal removal is the treatment of choice for an ACTH-secreting pituitary tumor (10). This second report of successful surgery during pregnancy confirms that the procedure can be performed during pregnancy with safety for both mother and fetus. In conclusion, we have described the second patient with an ACTH-secreting pituitary adenoma associated with pregnancy who was managed by transsphenoidal surgery. It was demonstrated that, in pregnancy, an ACTH-secreting adenoma may be a macroadenoma, but may none the less be successfully treated surgically. We have also demonstrated the use of modern imaging techniques (ultrasound and MRI) to establish the cause of the Cushing's syndrome in our patient without recourse to diagnostic x-rays and their theoretical risk in pregnancy. In view of the potential complications of an ACTH-secreting pituitary tumor in pregnancy, we recommend transsphenoidal tumor excision as the initial treatment of choice for these patients.
adrenocorticotropic hormone-secreting microadenoma in the second trimester. The procedure resulted in a cure, and the patient delivered a healthy baby after a normal pregnancy. The number of similar cases in the literature is rather limited to make any recommendations on the basis of statistical data. Our inclination would be to recommend surgery in the second trimester of pregnancy in a patient with Cushing's disease.
Dr. Coyne and colleagues report the history of a woman suffering from Cushing's disease who became pregnant in spite of the fact that menstrual disorders are present in 77% of the patients at the onset of the disease. The disorders are probably caused by the increased androgens and their suppressive effect on pituitary gonadotropin secretion (2). Pregnancy could be maintained by transsphenoidal pituitary surgery and terminated by a normal delivery. The authors were able to save this pregnancy in spite of an elevated abortion rate. They avoided a premature termination of the pregnancy as well. This shows that pituitary surgery can be performed safely during the 14th week of pregnancy. There remains the question of whether consistently elevated serum cortisol levels (about double of the upper normal limit) may be dangerous to the fetus. The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 34 of which had first-trimester exposure to cortisone. No evidence of a relationship to congenital malformations was found. In another group of 35 first-trimester exposures, however, congenital defects (cataracts, cyclopia, intraventricular septal defect, gastroschisis, hydrocephalus, cleft lip, coarctation of the aorta, clubfoot, and undescended testicles) were observed in 9 infants (1). No evidence of increased fetal abnormalities was observed by Krieger (2), who reviewed the literature of pregnancies of patients with Cushing's syndrome. The problem of possible danger to the fetus therefore remains open (the referee thanks Prof. G. Duc, Zürich, for his help). Alex M. Landolt Zürich, Switzerland REFERENCES: (1,2) 1. 2.
Briggs GG, Freeman RK, Yaffe SJ: Drugs in Pregnancy and Lactation. Baltimore, Williams & Wilkins, 1990, ed 3, p 157/c. Krieger DT: Cushing's Syndrome. Monographs on Endocrinology. Berlin, Springer-Verlag, 1982, vol 22, pp 47-53.
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Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
Ivan Ciric Evanston, Illinois
Table 1. Preoperative High-Dose Dexamethasone Test
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Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
Figure 1. Coronal MRI scan through the pituitary fossa, demonstrating a pituitary mass.
