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Cyclic Cushing’s disease associated with primary empty sella
European Journal of Internal Medicine 11 (2000) 168–170 www.elsevier.com / locate / ejim
Brief report
Cyclic Cushing’s disease associated with primary empty sella ´ Calvo-Romero a , *, Francisco Morales-Perez ´ b , Jose´ Dıaz-Perez ´ ´ b Jose´ Marıa a
Internal Medicine Service, Infanta Cristina Universitary Hospital, Badajoz, Spain b Endocrinology Section, Infanta Cristina Universitary Hospital, Badajoz, Spain
Received 11 October 1999; received in revised form 3 February 2000; accepted 23 March 2000
Abstract A small number of cases of Cushing’s disease (CD) associated with primary empty sella (ES) have been described in the literature. Pituitary microsurgery is the recommended treatment. An alternative is chronic treatment with ketoconazole, an inhibitor of adrenal cortisol synthesis. Cyclic Cushing’s syndrome is characterized by episodic cortisol hypersecretion. CD is the most frequent etiology of cyclic Cushing’s syndrome. To our knowledge, cyclic CD has not previously been reported in association with primary ES. We describe a patient with cyclic CD associated with primary ES who was initially treated with ketoconazole and subsequently cured by transsphenoidal surgery. 2000 Elsevier Science B.V. All rights reserved. Keywords: Cushing’s disease; Cyclic Cushing’s disease; Primary empty sella
1. Introduction
2. Case report
In 1976, Ganguly et al. described the first case of Cushing’s disease (CD) and empty sella (ES) with a microadenoma of the adenohypophysis [1]. It is important to differentiate a primary ES from the enlarged, partial ES caused by a degenerated pituitary adenoma. The association of CD with primary ES is exceptional [2,3]. Cyclic Cushing’s syndrome is characterized by episodic cortisol hypersecretion [4,5]. CD is the most common cause of cyclic Cushing’s syndrome [5]. To our knowledge, cyclic CD has not previously been reported in association with primary ES. We reviewed the medical literature in Medline, Index Medicus, and Excerpta Medica up until June 1999 (key words: Cushing’s syndrome, Cushing’s disease, cyclic, empty sella, empty sella turcica, primary empty sella). We report a patient with a cyclic CD associated with primary ES.
A 51-year-old female had a 3-year history of recurrent episodes of weakness, weight gain, facial acne, severe hypertension, and the tendency to bruise easily. Hypertension had been diagnosed 12 years earlier. There was no history of diabetes mellitus, headache, visual defects, or galactorrhea. Physical examination revealed central obesity, facial acne, and ecchymoses. There were no other signs of Cushing’s syndrome. The blood chemical and hematological values were normal. The patient’s 24-h urinary free cortisol (UFC) exceeded 1200 nmol (normal value 55–250 nmol) during symptomatic periods and was normal during asymptomatic periods. There were four symptomatic, irregular cycles of hypercortisolism with intercurrent, asymptomatic periods of normocortisolism (Fig. 1). Cycles of hypercortisolism varied in length from 2 to 3 months. During symptomatic periods, the circadian plasma cortisol rhythm was 632, 1347, 588, and 605 nmol / l and the circadian plasma corticotropin rhythm was 18.2, 14.8, 13.1, and 7.2 pmol / l at 08, 12, 18, and 24 h, respectively. The plasma cortisol after 1 mg and 8 mg overnight dexamethasone suppression was 506 and 748 nmol / l,
´ *Corresponding author. Heroes de Cascorro 9, 38A. 06004 Badajoz, Spain.
0953-6205 / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0953-6205( 00 )00079-0
J.M. Calvo-Romero et al. / European Journal of Internal Medicine 11 (2000) 168 – 170
169
Fig. 1. 24-h urinary free cortisol (UFC) before ketoconazole therapy. The horizontal line denotes the upper normal limit.
respectively. The plasma DHEAS level was 7.4 mmol / l (normal range: 1.3–6.8 mmol / l). The plasma free thyroxine, thyrotropin, IGF-1, FSH, LH, and prolactin were normal. A 24-h GH profile was also normal. Magnetic resonance imaging (MRI) of the pituitary (Fig. 2) showed a ballooning of the sella with an arachnoid
hernia and a flattened pituitary without evidence of adenoma. The results of MRI were similar in posterior studies. Inferior-petrosal-sinus sampling before and after the administration of 100 mg of corticotropin-releasing hormone (CRH) was performed during the symptomatic period. The sinus-to-peripheral-vein plasma corticotropin
Fig. 2. MRI of pituitary (T1-weighted sagital image) revealing an empty sella without evidence of adenoma.
170
J.M. Calvo-Romero et al. / European Journal of Internal Medicine 11 (2000) 168 – 170
ratio was 2.2 and 3.6 before and after CRH, respectively. The left–right gradient could not be determined. During the fourth cycle of hypercortisolism, after 3 years, the patient initiated treatment with ketoconazole. The ketoconazole was prescribed during symptomatic periods of hypercortisolism and doses were titrated in order to normalize the 24-h urinary cortisol excretion (from 400 to 600 mg ketoconazole daily). There was no hepatotoxicity or other adverse effects. Twenty-eight months later, the patient underwent transsphenoidal surgery. The neurosurgeon was not able to identify a microadenoma and a subtotal hypophysectomy was carried out. Anatomopathological examination revealed no abnormalities. Seven days after surgery, the patient’s 24-h UFC was 11.5 nmol and plasma corticotropin was undetectable. She was treated with replacement doses of hydrocortisone (100 mg / day intravenously for 5 days and subsequently 20 mg p.o. in the morning and 10 mg p.o. in the late afternoon). Thirty-eight months later, she is asymptomatic and continues receiving hydrocortisone to achieve normal 24-h UFC levels. The clinical manifestations of Cushing’s syndrome have not reappeared.
3. Discussion Our patient had a CD (pituitary-dependent Cushing’s syndrome), presenting with hypercortisolism with high plasma corticotropin levels and a sinus-to-peripheral-vein plasma corticotropin ratio before and after the administration of CRH $2 and $3, respectively [6]. Subtotal hypophysectomy seems to have cured the syndrome after a follow-up period of 38 months. Our case presented four irregular, symptomatic cycles of hypercortisolism before ketoconazole therapy (Fig. 1). The manifestations of cyclic Cushing’s syndrome may vary from daily to yearly regular or irregular intervals, with or without corresponding clinical changes [5]. Primary ES is a neuroanatomical condition that is most common in middle-aged, obese, multiparous females with long-standing hypertension. Usually, there are no symptoms, but nonspecific headache and visual disturbances may be present [7]. Most patients have a normal pituitary function. Nevertheless, hyperprolactinemia, hypogonadism, hypopituitarism, and diabetes insipidus occur on occasion [7,8]. CD is present in about 2% of cases of primary ES [7,8]. It has been suggested that the infarction of a pituitary adenoma may be a frequent cause of ES [9]. Pituitary apoplexy is able to cause a remission of CD [10]. In our case, neither repeated MRI studies nor neurosurgery exploration nor anatomopathological examination revealed
a pituitary adenoma, and there was no clinical history of pituitary apoplexy. Thus, the association between cyclic CD and primary ES in our patient may have been due to chance. The treatment of choice for patients with CD is transsphenoidal adenomectomy when a clearly circumscribed pituitary adenoma can be identified and resected. Otherwise, patients should undergo 85–90% resection of the anterior pituitary gland [6]. Pituitary irradiation, bilateral adrenalectomy, and ketoconazole administration are alternative therapies [6]. Ketoconazole is a potent adrenal cortisol synthesis inhibitor that is indicated to lower cortisol secretion under specific circumstances, such as in preparation for surgery, in those not cured by surgery, while waiting for radiotherapy to be effective or when there are severe consequences of hypercortisolism [11]. Our case was successfully treated with ketoconazole and subsequently cured by subtotal hypophysectomy.
References [1] Ganguly A, Stanchfield JB, Roberts TS, West CD, Tyler FH. Cushing’s syndrome in a patient with an empty sella turcica and a microadenoma of the adenohypophysis. Am J Med 1976;60:306–9. [2] Yamamoto N, Negoro M, Yokoe T, Ichihara K, Nakane T, Kuyawama et al. ACTH dependent Cushing’s syndrome with an empty sella turcica: report of three cases with emphasis on diagnostic value of selective venous sampling. No Shinkei Geka 1985;13:1323–8. [3] Mancini A, Calabro F, Lagonigro G, Saporosi A, Colosimo Jr. C, Anile C et al. Cushing’s syndrome: new variants and association with empty sella syndrome. J Nucl Med Allied Sci 1990;2:59–66. [4] Jordan RM, Ramos-Gabatin A, Kendall JW, Gaudette D, Walls RC. Dynamics of adrenocorticotropin (ACTH) secretion in cyclic Cushing’s syndrome: evidence for more than one abnormal ACTH biorhythm. J Clin Endocrinol Metab 1982;55:531–7. [5] Saphiro MS, Shenkman L. Variable hormonogenesis in Cushing’s syndrome. Q J Med 1991;79:351–63. [6] Orth DN. Cushing’s syndrome. N Engl J Med 1995;332:791–803. [7] Gallardo E, Schachter D, Caberes E, Becker P, Colin E, Martinez C et al. The empty sella: results of treatment in 76 successive cases and high frequency of endocrine and neurological disturbances. Clin Endocrinol (Oxf) 1992;37:529–33. [8] Bragagni G, Biaconcini G, Mazzali F, Baldini A, Brogna R, Iori I et al. 43 cases of primary empty sella syndrome: a case series. Ann Ital Med Int 1995;10:138–42. [9] Wakai S, Fukushima T, Teramoto A, Sano K. Pituitary apoplexy: its incidence and clinical significance. J Neurosurg 1981;55:187–93. [10] Dickstein G, Spindel A, Schechner C, Adawi F, Gutman H. Spontaneous remission in Cushing’s disease. Arch Intern Med 1991;151:185–9. [11] Sonino N, Boscaro M, Paoletta A, Mantero F, Ziliotto D. Ketoconazole treatment in Cushing’s syndrome: experience in 34 patients. Clin Endocrinol (Oxf) 1991;35:347–52.
Brief report
Cyclic Cushing’s disease associated with primary empty sella ´ Calvo-Romero a , *, Francisco Morales-Perez ´ b , Jose´ Dıaz-Perez ´ ´ b Jose´ Marıa a
Internal Medicine Service, Infanta Cristina Universitary Hospital, Badajoz, Spain b Endocrinology Section, Infanta Cristina Universitary Hospital, Badajoz, Spain
Received 11 October 1999; received in revised form 3 February 2000; accepted 23 March 2000
Abstract A small number of cases of Cushing’s disease (CD) associated with primary empty sella (ES) have been described in the literature. Pituitary microsurgery is the recommended treatment. An alternative is chronic treatment with ketoconazole, an inhibitor of adrenal cortisol synthesis. Cyclic Cushing’s syndrome is characterized by episodic cortisol hypersecretion. CD is the most frequent etiology of cyclic Cushing’s syndrome. To our knowledge, cyclic CD has not previously been reported in association with primary ES. We describe a patient with cyclic CD associated with primary ES who was initially treated with ketoconazole and subsequently cured by transsphenoidal surgery. 2000 Elsevier Science B.V. All rights reserved. Keywords: Cushing’s disease; Cyclic Cushing’s disease; Primary empty sella
1. Introduction
2. Case report
In 1976, Ganguly et al. described the first case of Cushing’s disease (CD) and empty sella (ES) with a microadenoma of the adenohypophysis [1]. It is important to differentiate a primary ES from the enlarged, partial ES caused by a degenerated pituitary adenoma. The association of CD with primary ES is exceptional [2,3]. Cyclic Cushing’s syndrome is characterized by episodic cortisol hypersecretion [4,5]. CD is the most common cause of cyclic Cushing’s syndrome [5]. To our knowledge, cyclic CD has not previously been reported in association with primary ES. We reviewed the medical literature in Medline, Index Medicus, and Excerpta Medica up until June 1999 (key words: Cushing’s syndrome, Cushing’s disease, cyclic, empty sella, empty sella turcica, primary empty sella). We report a patient with a cyclic CD associated with primary ES.
A 51-year-old female had a 3-year history of recurrent episodes of weakness, weight gain, facial acne, severe hypertension, and the tendency to bruise easily. Hypertension had been diagnosed 12 years earlier. There was no history of diabetes mellitus, headache, visual defects, or galactorrhea. Physical examination revealed central obesity, facial acne, and ecchymoses. There were no other signs of Cushing’s syndrome. The blood chemical and hematological values were normal. The patient’s 24-h urinary free cortisol (UFC) exceeded 1200 nmol (normal value 55–250 nmol) during symptomatic periods and was normal during asymptomatic periods. There were four symptomatic, irregular cycles of hypercortisolism with intercurrent, asymptomatic periods of normocortisolism (Fig. 1). Cycles of hypercortisolism varied in length from 2 to 3 months. During symptomatic periods, the circadian plasma cortisol rhythm was 632, 1347, 588, and 605 nmol / l and the circadian plasma corticotropin rhythm was 18.2, 14.8, 13.1, and 7.2 pmol / l at 08, 12, 18, and 24 h, respectively. The plasma cortisol after 1 mg and 8 mg overnight dexamethasone suppression was 506 and 748 nmol / l,
´ *Corresponding author. Heroes de Cascorro 9, 38A. 06004 Badajoz, Spain.
0953-6205 / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0953-6205( 00 )00079-0
J.M. Calvo-Romero et al. / European Journal of Internal Medicine 11 (2000) 168 – 170
169
Fig. 1. 24-h urinary free cortisol (UFC) before ketoconazole therapy. The horizontal line denotes the upper normal limit.
respectively. The plasma DHEAS level was 7.4 mmol / l (normal range: 1.3–6.8 mmol / l). The plasma free thyroxine, thyrotropin, IGF-1, FSH, LH, and prolactin were normal. A 24-h GH profile was also normal. Magnetic resonance imaging (MRI) of the pituitary (Fig. 2) showed a ballooning of the sella with an arachnoid
hernia and a flattened pituitary without evidence of adenoma. The results of MRI were similar in posterior studies. Inferior-petrosal-sinus sampling before and after the administration of 100 mg of corticotropin-releasing hormone (CRH) was performed during the symptomatic period. The sinus-to-peripheral-vein plasma corticotropin
Fig. 2. MRI of pituitary (T1-weighted sagital image) revealing an empty sella without evidence of adenoma.
170
J.M. Calvo-Romero et al. / European Journal of Internal Medicine 11 (2000) 168 – 170
ratio was 2.2 and 3.6 before and after CRH, respectively. The left–right gradient could not be determined. During the fourth cycle of hypercortisolism, after 3 years, the patient initiated treatment with ketoconazole. The ketoconazole was prescribed during symptomatic periods of hypercortisolism and doses were titrated in order to normalize the 24-h urinary cortisol excretion (from 400 to 600 mg ketoconazole daily). There was no hepatotoxicity or other adverse effects. Twenty-eight months later, the patient underwent transsphenoidal surgery. The neurosurgeon was not able to identify a microadenoma and a subtotal hypophysectomy was carried out. Anatomopathological examination revealed no abnormalities. Seven days after surgery, the patient’s 24-h UFC was 11.5 nmol and plasma corticotropin was undetectable. She was treated with replacement doses of hydrocortisone (100 mg / day intravenously for 5 days and subsequently 20 mg p.o. in the morning and 10 mg p.o. in the late afternoon). Thirty-eight months later, she is asymptomatic and continues receiving hydrocortisone to achieve normal 24-h UFC levels. The clinical manifestations of Cushing’s syndrome have not reappeared.
3. Discussion Our patient had a CD (pituitary-dependent Cushing’s syndrome), presenting with hypercortisolism with high plasma corticotropin levels and a sinus-to-peripheral-vein plasma corticotropin ratio before and after the administration of CRH $2 and $3, respectively [6]. Subtotal hypophysectomy seems to have cured the syndrome after a follow-up period of 38 months. Our case presented four irregular, symptomatic cycles of hypercortisolism before ketoconazole therapy (Fig. 1). The manifestations of cyclic Cushing’s syndrome may vary from daily to yearly regular or irregular intervals, with or without corresponding clinical changes [5]. Primary ES is a neuroanatomical condition that is most common in middle-aged, obese, multiparous females with long-standing hypertension. Usually, there are no symptoms, but nonspecific headache and visual disturbances may be present [7]. Most patients have a normal pituitary function. Nevertheless, hyperprolactinemia, hypogonadism, hypopituitarism, and diabetes insipidus occur on occasion [7,8]. CD is present in about 2% of cases of primary ES [7,8]. It has been suggested that the infarction of a pituitary adenoma may be a frequent cause of ES [9]. Pituitary apoplexy is able to cause a remission of CD [10]. In our case, neither repeated MRI studies nor neurosurgery exploration nor anatomopathological examination revealed
a pituitary adenoma, and there was no clinical history of pituitary apoplexy. Thus, the association between cyclic CD and primary ES in our patient may have been due to chance. The treatment of choice for patients with CD is transsphenoidal adenomectomy when a clearly circumscribed pituitary adenoma can be identified and resected. Otherwise, patients should undergo 85–90% resection of the anterior pituitary gland [6]. Pituitary irradiation, bilateral adrenalectomy, and ketoconazole administration are alternative therapies [6]. Ketoconazole is a potent adrenal cortisol synthesis inhibitor that is indicated to lower cortisol secretion under specific circumstances, such as in preparation for surgery, in those not cured by surgery, while waiting for radiotherapy to be effective or when there are severe consequences of hypercortisolism [11]. Our case was successfully treated with ketoconazole and subsequently cured by subtotal hypophysectomy.
References [1] Ganguly A, Stanchfield JB, Roberts TS, West CD, Tyler FH. Cushing’s syndrome in a patient with an empty sella turcica and a microadenoma of the adenohypophysis. Am J Med 1976;60:306–9. [2] Yamamoto N, Negoro M, Yokoe T, Ichihara K, Nakane T, Kuyawama et al. ACTH dependent Cushing’s syndrome with an empty sella turcica: report of three cases with emphasis on diagnostic value of selective venous sampling. No Shinkei Geka 1985;13:1323–8. [3] Mancini A, Calabro F, Lagonigro G, Saporosi A, Colosimo Jr. C, Anile C et al. Cushing’s syndrome: new variants and association with empty sella syndrome. J Nucl Med Allied Sci 1990;2:59–66. [4] Jordan RM, Ramos-Gabatin A, Kendall JW, Gaudette D, Walls RC. Dynamics of adrenocorticotropin (ACTH) secretion in cyclic Cushing’s syndrome: evidence for more than one abnormal ACTH biorhythm. J Clin Endocrinol Metab 1982;55:531–7. [5] Saphiro MS, Shenkman L. Variable hormonogenesis in Cushing’s syndrome. Q J Med 1991;79:351–63. [6] Orth DN. Cushing’s syndrome. N Engl J Med 1995;332:791–803. [7] Gallardo E, Schachter D, Caberes E, Becker P, Colin E, Martinez C et al. The empty sella: results of treatment in 76 successive cases and high frequency of endocrine and neurological disturbances. Clin Endocrinol (Oxf) 1992;37:529–33. [8] Bragagni G, Biaconcini G, Mazzali F, Baldini A, Brogna R, Iori I et al. 43 cases of primary empty sella syndrome: a case series. Ann Ital Med Int 1995;10:138–42. [9] Wakai S, Fukushima T, Teramoto A, Sano K. Pituitary apoplexy: its incidence and clinical significance. J Neurosurg 1981;55:187–93. [10] Dickstein G, Spindel A, Schechner C, Adawi F, Gutman H. Spontaneous remission in Cushing’s disease. Arch Intern Med 1991;151:185–9. [11] Sonino N, Boscaro M, Paoletta A, Mantero F, Ziliotto D. Ketoconazole treatment in Cushing’s syndrome: experience in 34 patients. Clin Endocrinol (Oxf) 1991;35:347–52.