Successful treatment of a large macroprolactinoma with cabergoline during pregnancy.

We report a pregnant woman with a large macroprolactinoma successfully treated with cabergoline after a suboptimal response to bromocriptine. A 7 week pregnant woman with a history of a prolactinoma presented to the endocrine clinic with the complaints of headaches and nausea. She had a prolactin level of 65 microg/L 1 1/2 weeks following her last menstrual period. Bromocriptine was discontinued at 6 weeks gestation when pregnancy was confirmed. A PRL concentration was 1899 microg/L (non-pregnant normal range 1.39-24.20 microg/L, the mean peak levels during pregnancy reported from the literature are 200-210 microg/L) at 7 weeks gestation, and a repeat was 2197 microg/L. An MRI showed a 3 x 2.2 x 2.5 cm seller mass abutting the optic chiasm and displacing the optic nerves superiorly; the visual field testing was normal. Bromocriptine was reinitiated and the patient responded initially with decreasing headaches and declining PRL concentrations to 1488 microg/L at 15 weeks gestation. However, PRL increased to 1836 microg/L at 16 weeks and remained elevated despite bromocriptine 2.5 mg three times a day; in addition, she complained of severe nausea, vomiting, and persistent headaches. Cabergoline was added at 18 weeks gestation. PRL decreased dramatically from 1710 to 859 microg/L in 1 week, and to 488 microg/L within 4 weeks. A repeat MRI showed more than 30% reduction in tumor size. Bromocriptine was discontinued at 24 weeks gestation; she was maintained on cabergoline 0.5 mg twice a week without complaints. PRL levels ranged from 190 to 278 microg/L during the last 10 weeks of pregnancy. She had a C-section electively at 37 weeks gestation and delivered a healthy baby. Management options in this patient and during pregnancy are discussed.

Normal female infants born of mothers with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, especially those patients with the salt-losing form, have decreased fertility rates. Pregnancy experience in this population is limited. We report the pregnancy outcomes and serial measurements of maternal serum steroid levels in four women with classic 21-hydroxylase deficiency, three of whom were female pseudohermaphrodites with the salt-losing form. These glucocorticoid-treated women gave birth to four healthy female newborns with normal female external genitalia, none of whom were affected with 21-hydroxylase deficiency. In three women, circulating androgen levels increased during gestation, but remained within the normal range for pregnancy during glucocorticoid therapy. In the fourth patient, androgen levels were strikingly elevated during gestation despite increasing the dose of oral prednisone from 5 to 15 mg/day (two divided doses). Notwithstanding the high maternal serum concentration of androgens, however, placental aromatase activity was sufficient to prevent masculinization of the external genitalia of the female fetus and quite likely the fetal brain, consistent with the idea that placental aromatization of androgens to estrogens is the principal mechanism that protects the female fetus from the masculinizing effects of maternal hyperandrogenism. These four patients highlight key issues in the management of pregnancy in women with 21-hydroxylase deficiency, particularly the use of endocrine monitoring to assess adrenal androgen suppression in the mother, especially when the fetus is female. Recommendations for the management of pregnancy and delivery in these patients are discussed.

Transsphenoidal microsurgical therapy of prolactinomas: initial outcomes and long-term results.

OBJECTIVE: Prolactinomas are frequently treated primarily with dopamine agonists; however, these agents have disadvantages and require life-long therapy. We therefore reassessed transsphenoidal microsurgery as an alternative therapy. METHODS: We reviewed the data for 121 female patients treated surgically for prolactinomas between 1976 and 1979 (Group 1) and 98 patients treated between 1988 and 1992 (Group 2). RESULTS: Of 219 women, 92% with preoperative prolactin (PRL) values of < or = 100 ng/ml and 91% with intrasellar microadenomas experienced initial remission; 80 to 88% of patients with intrasellar macroadenomas or macroadenomas showing moderate suprasellar extension or focal sphenoid sinus invasion experienced remission. Women with PRL values of > 200 ng/ml and those with larger and more invasive adenomas experienced poorer outcomes (37-41% remission). Lower preoperative PRL values and adenoma stage were the best predictors of initial surgical outcomes. At the most recent evaluations, 89% of women who experienced initial remission continued to experience clinical remission; 85% exhibited normal PRL values, and 5% demonstrated mild, asymptomatic, recurrent hyperprolactinemia (PRL values of < 34 ng/ml). In Group 1, 84% of patients continued to experience remission (82% with normal PRL values) after a median follow-up period of 15.6 years. In Group 2, 97% of patients continued to experience remission (88% with normal PRL values) after a median follow-up period of 3.2 years. Lower postoperative PRL values were the best predictors of long-term remission. CONCLUSION: Transsphenoidal microsurgery is an effective alternative to long-term medical therapy for selected patients with prolactinomas. Successful outcomes and long-term remission were achieved in patients with microadenomas and noninvasive macroadenomas.

Transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas: initial outcome and long-term results.

Treatment of acromegaly has long been recognized as necessary to relieve symptoms, halt progression of deformities, and decompress the sella turcica. More recently, treatment strategies have focused on decreasing GH levels to a point at which mortality rates normalize, thereby redefining previous concepts of a cure. No surgical series to date has investigated the long-term effect of treatment on mortality rates. We retrospectively reviewed 254 consecutive patients with acromegaly who underwent transsphenoidal microsurgery of GH-secreting adenomas between 1974-1992. Seventy-six percent of these patients had basal GH levels <5 ng/mL within 30 days of surgery, and 24% had persistent disease. Multivariate analysis revealed that higher stage, grade, and preoperative GH levels were all predictive of persistence (P < 0.01). Long-term follow-up was obtained on 129 of the patients in initial remission. Of these, 9 (7%) had disease recurrence and 120 remained in remission. The incidence of major postoperative complications was 8% (2% permanent diabetes insipidus, 2% cerebrospinal fluid leaks requiring surgery, 2% meningitis, and 2% hypopituitarism), with no mortality. In contrast to the 2.4- to 4.8-fold increased mortality among untreated acromegalics, the mortality rate among patients with posttherapy GH levels <5 ng/mL was equivalent to that of age- and sex-matched controls. Aggressive therapy to normalize GH levels should therefore be instituted at diagnosis.

Diabetes insipidus from sarcoidosis confined to the posterior pituitary.

A young white man with new-onset central diabetes insipidus was discovered to have a posterior pituitary mass on magnetic resonance imaging. No other radiological abnormalities were noted in the anterior pituitary, infundibulum or hypothalamus. No other endocrinopathies were present: laboratory investigations showed normal basal concentrations of anterior pituitary hormones, including prolactin. The patient was suspected to have sarcoidosis affecting the posterior pituitary, because of the discovery of pulmonary sarcoidosis during his diagnostic evaluation. His symptoms of polydipsia and polyuria responded promptly to intranasal administration of 1-desamino-8-D-arginine vasopressin (DDAVP). The patient demonstrated complete regression of the posterior pituitary mass after a course of corticosteroid therapy. However, his diabetes insipidus persisted and he continues to need DDAVP treatment, currently at 12 months of follow-up. The resolution of the neurohypophysial mass was compatible with the diagnosis of pituitary sarcoidosis and this precluded the need for a transsphenoidal biopsy or surgery.

Venous angiography is needed to interpret inferior petrosal sinus and cavernous sinus sampling data for lateralizing adrenocorticotropin-secreting adenomas.

Bilateral simultaneous venous sampling of ACTH from the inferior petrosal sinus is a reliable test for diagnosing Cushing's disease, but is not reliable for lateralizing ACTH-secreting pituitary adenomas. We reviewed 23 consecutive patients with Cushing's disease who underwent venous angiography of the cavernous and inferior petrosal sinuses followed by bilateral simultaneous venous sampling of ACTH in the inferior petrosal and cavernous sinuses. Venous drainage was bilaterally symmetric in 14 patients (61%) and asymmetric in 9 (39%). The most common asymmetric pattern (6 patients) was for blood from both cavernous sinuses to drain into the right inferior petrosal sinus, with no significant drainage into the left. Cavernous sinus sampling in 21 patients correctly lateralized the tumor in 12 cases of symmetric venous drainage, but in only 3 cases of asymmetric drainage. Inferior petrosal sinus sampling in all 23 patients correctly lateralized the tumor in 12 cases of symmetric drainage, but in only four cases of asymmetric drainage. Overall, venous sampling correctly lateralized 70% of the tumors. Incorrect lateralization in cases of asymmetric venous drainage is probably attributable to shunting of blood toward the side of dominant venous drainage. Our findings illustrate the need for venography in all patients undergoing venous sampling of ACTH because an understanding of the venous drainage patterns is essential to correctly interpret venous sampling data and warn physicians that the lateralization data may be incorrect or unreliable.

Delayed onset of hyponatremia after transsphenoidal surgery for pituitary adenomas.

Hyponatremia is rarely reported as a delayed complication of transsphenoidal resection of pituitary adenoma. Usually attributed to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), hyponatremia causes nonspecific symptoms, often after hospital discharge. To clarify the frequency, presentation, and outcome of this poorly understood complication, we reviewed our database of 2297 patients who underwent transsphenoidal pituitary surgery between February 1971 and June 1993. Of 53 patients (2.3%) treated for symptomatic hyponatremia, 11 were excluded (2 received arginine vasopressin within 24 hours, 1 had untreated hypothyroidism, 4 had untreated adrenal insufficiency, and 4 had incomplete records). The remaining 42 patients (1.8%), 11 men and 31 women aged 21 to 79 years, presented 4 to 13 days (mean, 8 d) postoperatively with nausea and vomiting (20 patients), headache (18 patients), malaise (12 patients), dizziness (4 patients), anorexia (2 patients), and seizures (1 patient). Hyponatremia was unrelated to sex, age, adenoma type, tumor size, or glucocorticoid tapering. Although the clinical picture in our patients is consistent with SIADH, this was not supported by the antidiuretic hormone levels, which were normal or low-normal in the two patients in whom they were measured, suggesting the possibility that low serum sodium may not reflect SIADH. In all patients, hyponatremia resolved within 6 days (mean, 2 d); treatment consisted of salt replacement and mild fluid restriction in 37 patients and fluid restriction only in 4 (treatment unknown in 1). Delayed hyponatremia after transsphenoidal resection of pituitary adenoma is not as rare as previously thought, nor is it necessarily associated with SIADH or with hypoadrenalism during glucocorticoid tapering.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracardiac pheochromocytoma with dual coronary blood supply: case report and literature review.

An intracardiac pheochromocytoma is extremely rare. This patient first presented postpartum at age 28 with clinical signs, symptoms and biochemical evidence suspicious for the diagnosis of pheochromocytoma. Multiple radiologic studies and laparotomy failed to confirm the diagnosis. Some 20 years later the patient presented with complaints of chest pain, palpitations, and flushing. Cardiac catheterization demonstrated a 'tumor blush' superior to the left atrium with a blood supply derived from the coronary arteries. Open-heart surgery was performed and the tumor successfully removed.

Extrasellar, intracavernous sinus adrenocorticotropin-releasing adenoma causing Cushing's disease.

This report describes a patient with pituitary-dependent Cushing's disease who had a preoperative ACTH gradient to the left at the level of the cavernous sinus. Intraoperatively, an adenoma was found entirely within the left cavernous sinus, with no direct connection to the pituitary gland. To our knowledge, such a tumor has not been reported previously. This case has implications for the diagnosis, treatment, and follow-up of patients with pituitary-dependent Cushing's disease. The presence of an entirely extrasellar ACTH-releasing adenoma in the cavernous sinus could explain why pituitary-dependent Cushing's disease may persist postoperatively, even after total hypophysectomy. The diagnosis of an intracavernous tumor can be established by cavernous sinus venography. An extrasellar intracavernous adenoma can be diagnosed intraoperatively after careful negative exploration of the sellar contents followed by incision of the cavernous sinus on the side of the ACTH gradient established by venous sampling.

Pituitary tumors. Current concepts in diagnosis and management.

Diagnostic advances have resulted in earlier and more frequent recognition of pituitary tumors. Pituitary tumors cause problems owing to the hormones they secrete or the effects of an expanding sellar mass--hypopituitarism, visual field abnormalities, and neurologic deficits. Prolactin-secreting tumors (prolactinomas), which cause amenorrhea, galactorrhea, and hypogonadism, constitute the most common type of primary pituitary tumors, followed by growth hormone-secreting tumors, which cause acromegaly, and corticotropin-secreting tumors, which cause Cushing's syndrome. Hypersecretion of thyroid-stimulating hormone, the gonadotrophins, or alpha-subunits is unusual. Nonfunctional tumors currently represent only 10% of all clinically diagnosed pituitary adenomas, and some of these are alpha-subunit-secreting adenomas. Insights into the pathogenesis and biologic behavior of these usually benign tumors have been gained from genetic studies. We review some of the recent advances and salient features of the diagnosis and management of pituitary tumors, including biochemical and radiologic diagnosis, transsphenoidal surgery, radiation therapy, and medical therapy. Each type of lesion requires a comprehensive but individualized treatment approach, and regardless of the mode of therapy, careful follow-up is essential.

Cushing's disease. Therapy of pituitary adenomas.

Treatment of Cushing's disease has evolved over the past 20 years from the era of bilateral adrenalectomy to the current era of pituitary microsurgery. Therapy directed to the pituitary gland is currently the first approach in Cushing's disease and transphenoidal exploration of the sellar contents is the procedure of choice. Tumor localization and pituitary surgery are reviewed. Pituitary radiotherapy, pharmacologic inhibition of ACTH secretion, and Nelson's syndrome are also discussed.

Transsphenoidal microsurgery for Cushing disease. A report of 216 cases.

We report cumulative results of the transsphenoidal microsurgical treatment of Cushing disease in 221 patients: 173 patients had selective adenomectomy, 25 had total hypophysectomy, 6 had partial hypophysectomy, and 12 had exploration only. Five patients were excluded from analysis because intraoperative technical difficulties precluded exposure of the pituitary gland. The selection of candidates for transsphenoidal exploration was based on endocrinologic criteria. Magnetic resonance imaging was the preferred radiologic test. Selective venous sampling of adrenocorticotropic hormone further refined the diagnosis when endocrinologic and radiologic procedures were not definitive. Remission of disease was achieved in 164 of 216 (76%) patients analyzed (95% CI, 69 to 81). Among patients with histologic confirmation of adenomas, the percentage having remission was significantly higher (P less than 0.001) in patients with microadenomas than in patients with macroadenomas and in patients with intrasellar adenomas than in patients with extrasellar extension of their adenoma or perforation of the sellar floor by adenoma (P less than 0.001). Five patients had an ectopic source of adrenocorticotropic hormone secretion. Two patients had diffuse pituitary hyperplasia. Complications occurred in 9.3% of the patients, including two deaths that were apparently unrelated to surgery (CI, 5.4 to 13). The results indicate that transsphenoidal surgery is the preferred treatment for most patients with Cushing disease.

Cushing's disease.

Cushing's disease is a form of Cushing's syndrome, persistent inappropriate hypercortisolism, that results from pituitary ACTH hypersecretion. It currently accounts for 70 per cent of adult cases of Cushing's syndrome and affects mainly women of childbearing age. The pathology, cause, and clinical and laboratory features of the disease are discussed. The initial step in diagnosis is documentation of endogenous hypercortisolism, which is followed by identification of the cause. Selective transsphenoidal resection of ACTH-producing pituitary adenomas is the initial treatment of choice. The roles of radiotherapy and medical therapy are discussed.

Chronic administration of corticotropin-releasing factor increases pituitary corticotroph number.

The effect of chronic administration of CRF on rat pituitary morphology was studied. Experimental animals received CRF (10 micrograms/day) over a period of 52 days by means of sc osmotic pumps changed at 10- to 14-day intervals. The average 0800 h plasma corticosterone levels in the treated animals were significantly greater than control values [7.52 +/- 0.99 (+/- SE) vs. 1.14 +/- 0.5 micrograms/dl; P less than 0.001]. The CRF-treated animals also had a significantly greater adrenal weight (16.44 +/- 1.38 vs. 12.24 +/- 0.85 mg; P less than 0.05) and lower thymus weight (164 +/- 12 vs. 248 +/- 27 mg; P less than 0.005). There was a marked increase in the number of ACTH-producing cells in the anterior pituitaries of the rats that received CRF (13.3 +/- 0.8% vs. 4.5 +/- 0.3% ACTH-producing cells; P less than 0.001), as determined by immunocytochemical methods. Corticotrophs of rats treated with CRF manifested a significant increase in nuclear area (24.0 +/- 0.7 vs. 21.4 +/- 0.4 micron 2; P less than 0.001) and an increased diameter of forming and storage granules (191.1 +/- 1.1 vs. 158.6 +/- 3.5 nm and 196.1 +/- 1.2 vs. 170.1 +/- 3.7 nm, respectively; P less than 0.001). There was no demonstrable increase in ACTH cell area. These data indicate that long term administration of CRF is capable of increasing the number of pituitary corticotrophs. It also supports the view that the corticotroph hyperplasia occurring after adrenalectomy, in unusual cases of ectopic CRF production, and in rare instances of Cushing's disease is a proliferative response to CRF.

Urinary cortisol in the assessment of pituitary-adrenal function: utility of 24-hour and spot determinations.

To more conveniently assess dynamic changes in the biologically active fraction of cortisol, we measured cortisol in 1-h urine samples obtained from 0700-0800 and from 2200-2300 h. In 20 normal subjects, morning 1-h urinary cortisol levels were 78 +/- 36 ng/mg creatinine (mean +/- SD), whereas levels from 2200-2300 h were 22 +/- 12 ng/mg creatinine, demonstrating diurnal variability. In 14 patients with Cushing's syndrome, mean morning urinary cortisol was elevated (207 +/- 176 ng/mg creatinine), but there was overlap with values in normal subjects. In contrast, evening values in Cushing's syndrome (248 +/- 208 ng/mg creatinine) were elevated in each patient; there was no diurnal variation and no overlap with normal subjects. Similarly, the morning urinary cortisol response to dexamethasone (1 mg, orally, at 2300 h) clearly separated normal subjects from those with Cushing's syndrome (5 +/- 6 vs. 169 +/- 149 ng/mg creatinine, respectively). In 10 patients with secondary hypoadrenalism, urinary cortisol levels were less than 2 ng/mg creatinine in both morning and evening 1-h samples. Thus, the determination of cortisol in 1-h samples is a practical and simple method of assessing cortisol secretion and allows multiple sampling without hospitalization. It is effective in assessing dynamic cortisol responses, such as diurnal variation and responsiveness to suppression, and it is an effective screening test for Cushing's syndrome and hypoadrenalism.

Occult ectopic secretion of corticotropin.

The clinical, biochemical, radiographic, and morphologic features of ectopic corticotropin (ACTH)-dependent Cushing's syndrome are often indistinguishable from those of Cushing's disease (pituitary-dependent Cushing's syndrome). We encountered ten patients whose ectopic ACTH-secreting neoplasms were not clinically apparent for two months to 12 years after the diagnosis of hypercortisolism or in whom the site remains unknown. Five of these patients underwent unnecessary pituitary microsurgery, and a sixth was referred for surgery. The occult ectopic ACTH syndrome occurs with equal frequency in men and women and hypokalemia is present in 60%, in contrast to the female predominance and rarity of hypokalemia in Cushing's disease. We emphasize the importance of selective venous sampling for ACTH to establish the correct diagnosis. Thirty-nine similar cases from the literature help characterize this syndrome further.

An overnight high-dose dexamethasone suppression test for rapid differential diagnosis of Cushing's syndrome.

We have developed a high-dose dexamethasone suppression test that can be administered overnight with a single 8-mg dose and used the new procedure in the differential diagnosis of 83 patients with Cushing's syndrome. In 76 patients with surgically or pathologically proven cause--60 with Cushing's disease, 7 with the ectopic adrenocorticotrophic hormone syndrome, and 9 with adrenal tumors--suppression of plasma cortisol levels to less than 50% of baseline indicated a diagnosis of Cushing's disease. The test had a sensitivity of 92%, a specificity of 100%, and a diagnostic accuracy of 93%. These values equal or exceed those of the standard 2-day test whether based on suppression of urinary 17-hydroxycorticosteroids or plasma cortisol. We conclude that this overnight, high-dose dexamethasone suppression test is practical and reliable in the differential diagnosis of Cushing's syndrome.