Cushing's syndrome: problems in management.

CS comprises a group of disorders characterized by hypercortisolism. The variety of causes--pituitary-dependent CS (CD), adrenal tumor, and the ectopic ACTH syndrome--necessitates a variety of therapies--surgical, radiotherapeutic, and medical. Once a specific diagnosis is made, specific therapy can be instituted. Although some controversy persists regarding treatment, particularly that of CD, for most patients it is straightforward. However, in our experience with more than 60 patients, therapeutic dilemmas can arise in a number of circumstances, e.g. the patient with the radiologically normal sella or recurrent CD after adrenalectomy. In addition, the treatment of such conditions as the large ACTH-producing pituitary tumor, Nelson's syndrome, the malignant ectopic ACTH syndrome, and adrenal carcinoma is not entirely satisfactory. Our approach to these problems is illustrated by seven cases, and we emphasize that the proper management of CS requires both correct diagnosis and the logical application of all available therapies.

Opportunistic infections in acquired immune deficiency syndrome result from synergistic defects of both the natural and adaptive components of cellular immunity.

We evaluated the cellular immunity of 408 clinically stratified subjects at risk for acquired immune deficiency syndrome (AIDS), to define the role of interferon-alpha production deficits in the pathogenesis of opportunistic infections (OI). We followed 115 prospectively for up to 45 mo. Onset of OI was associated with, and predicted by, deficiency both of interferon-alpha generation in vitro, and of circulating Leu-3a+ cells. Interferon-alpha production is an index of the function of certain non-T, non-B, large granular lymphocytes (LGL) that are independent of T cell help. Leu-3a+ cell counts are a marker of T cell function. OI did not usually develop until both of these mutually independent immune functions were simultaneously critically depressed, leading to a synergistic interaction. These data suggest that the AIDS virus affects a subset of LGL, and that cytokine production by these cells is an important component of the host defense against intracellular pathogens that becomes crucial in the presence of severe T cell immunodeficiency.

Human pituitary tumors secrete chromogranin-A.

Chromogranin-A (CgA) has emerged as a serum and tissue marker for a number of endocrine tumors. We studied 15 patients with pituitary tumors to evaluate the clinical value of CgA as a serum and tissue marker for such tumors. One third of the patients had elevated serum CgA levels; 2 of these patients had nonsecreting pituitary tumors, and the other 3 had corticotroph adenomas. CgA-positive cells were detected in 9 of the 11 anterior pituitary tumors that were immunostained; in these 9 tumors at least half of the cells were CgA positive. We conclude that CgA production is common in pituitary tumors and that immunohistochemical studies for CgA may aid in their classification. In addition, serum CgA measurements may help to identify patients with pituitary tumors, especially those that do not secrete a known pituitary peptide.

Silent pituitary apoplexy: subclinical infarction of an adrenocorticotropin-producing pituitary adenoma.

A young woman developed intermittent headaches and progressive hyperpigmentation after bilateral adrenalectomy for Cushing's disease. Results of sellar polytomography were abnormal. Her plasma ACTH levels increased to 4750-7340 pg/ml and did not rise with insulin-induced hypoglycemia. Although she experienced no clinical features associated with spontaneous infarction of a pituitary tumor, plasma ACTH levels fell to 474-575 pg/ml, and hemorrhagic necrosis was found in a 5-mm chromophobe adenoma at transsphenoidal surgery. Postoperatively, ACTH levels returned to normal (51-88 pg/ml), with the rest of her anterior pituitary function remaining intact 4 yr later. Spontaneous infarction of pituitary microadenomas may be subclinical, resulting in improvement of pituitary hormone hypersecretion without impairment of other anterior pituitary hormone secretion.

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.

Cushing's syndrome: problems in diagnosis.

Cushing's syndrome, an unusual group of disorders characterized by hypercortisolism, must be considered in the differential diagnosis of such common clinical problems as hirsutism, menstrual irregularity, hypertension, diabetes mellitus, and obesity. Its distinct forms--pituitary-dependent Cushing's syndrome (Cushing's disease), adrenal tumor and ectopic ACTH syndrome--must be identified correctly so that specific therapy can be administered. In the majority of cases, use of a relatively simple diagnostic sequence will provide accurate and rapid diagnosis. However, in our experience with more than 60 patients, diagnostic difficulties may arise from a variety of conditions (e.g., drug interference, alcohol ingestion, and depression). In addition, unusual circumstances, such as unexpected responses to dexamethasone, may complicate the diagnosis. Our approach to these problems is illustrated through a report of seven cases, and we emphasize that the proper management of Cushing's syndrome mandates a thorough marshalling of all the available data.

Pituitary ACTH dependency of nodular adrenal hyperplasia in Cushing's syndrome. Report of two cases and review of the literature.

Cushing's syndrome due to nodular adrenal hyperplasia comprises a clinically and biochemically heterogeneous group of disorders whose pathogenesis is unclear. We describe two patients with atypical steroid dynamics and large unilateral adrenal nodules who had pituitary ACTH-dependent disease. In the differential diagnosis of Cushing's syndrome, we recommend repeated ACTH measurement and selective venous sampling-particularly in those patients with impaired dexamethasone suppressibility and abnormal findings on computerized tomography.

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.

Deficiency of interferon-alpha generating capacity is associated with susceptibility to opportunistic infections in patients with AIDS.

Acquired immune deficiency syndrome (AIDS) is a newly described syndrome in which patients are susceptible to certain malignancies and opportunistic infections (OI) usually found only in immunosuppressed individuals. Patients with AIDS have been found to have deficiencies of virtually all of their host defense systems. In this report, the natural resistance systems have been discussed. Although a deficiency of NK-cell function has been found in many patients with AIDS, this deficiency failed to distinguish patients susceptible to OI or malignancy from male homosexual controls. A deficiency of interferon-alpha generation by mononuclear cells upon exposure to HSV-1 infected fibroblasts was the best correlate with susceptibility to OI in AIDS patients. This deficiency failed to correlate with serum levels of acid-labile interferon-alpha in these patients. Although the interferon generating deficiency may be caused by the infections in these patients, it is more likely that the deficiency lays the groundwork for the establishment of the opportunistic infections.

Iatrogenic pheochromocytomatosis: a previously unreported result of laparoscopic adrenalectomy.

BACKGROUND: Laparoscopic adrenalectomy is now regarded as the procedure of choice for treatment of small or benign adrenal tumors, including pheochromocytoma. However, long-term outcomes have not been critically assessed. We report here 3 cases of pheochromocytomatosis recurring 3 to 4 years after laparoscopic adrenalectomy. We postulate laparoscopic-induced seeding of tumor as the mechanism of recurrence. METHODS: We retrospectively reviewed the cases of 3 patients with documented biochemical and radiolabeled metaiodobenzylguanidine evidence of recurrent pheochromocytoma after prior presumed curative laparoscopic adrenalectomy. RESULTS: Original pheochromocytomas were 5.5 to 6.5 cm in diameter. At the time of laparoscopic adrenalectomy, tumors were not believed to be malignant, based on clinical or histopathologic data. However, on 3- to 4-year follow-up, each patient developed symptoms, elevated urinary catecholamine levels, and metaiodobenzylguanidine imaging consistent with recurrence. At reoperation, multiple small tumor nodules were found in the adrenal bed near the site of the initial laparoscopic resection. The original operative notes suggested some possible method of local seeding: tumor fragmentation and spillage or excessive tumor manipulation. CONCLUSIONS: Pheochromocytoma recurrence may occur as a result of local spillage of tumor during laparoscopic adrenalectomy. The relative risk of recurrence between open and laparoscopic resection needs to be assessed. Long-term follow-up will continue to be important, regardless of operative approach.

Cerebral salt wasting after pituitary exploration and biopsy: case report.

We report a case of hyponatremia associated with volume depletion after pituitary exploration and biopsy. The presence of clinical dehydration precluded diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone. The absence of a hypoadrenal state and the patient's response to volume reexpansion were consistent with a diagnosis of primary cerebral salt wasting.

Occult virilizing ovarian tumours in postmenopausal women: problems in evaluation with reference to a case.

A 53-year-old postmenopausal presented with hirsutism, acne, receding hairline, male-pattern baldness, and deepening of voice developing over the last five years. Her left ovary had been removed at the age of 38 years old for a benign cyst and vaginal hysterectomy was performed one year later for cervical carcinoma. She had taken premarin 0.625 mg daily since her surgeries. Initial hormonal studies revealed elevated serum concentrations of total testosterone 524 ng/dL (N: 6-86 ng/dL), free testosterone 20.9 pg/mL (N: 0.3-2.7 pg/mL), and 17-hydroxyprogesterone 270 ng/dL (N: < 70 ng/dL); but normal baseline concentrations of dehydroepiandrosterone-sulfate, androstenedione, and cortisol. Computed tomographic (CT) scans of the adrenals and ultrasonography of the pelvis were negative. Magnetic resonance imaging (MRI) of the abdomen and pelvis similarly were non-revealing. She was given glucocorticoids without effect. Subsequently, retrograde selective venous sampling showed a marked testosterone gradient in the right ovarian vein. A laparoscopic right oophorectomy was performed and a 11 mm Leydig cell tumour of hilus cell type was detected on histologic examination. Postoperative testosterone levels returned to normal and she had slow regression of hirsutism. Our case illustrates that a virilizing ovarian neoplasm can be small and elude imaging studies. We suggest bilateral oophorectomy for postmenopausal women with severe recent-onset virilization and without Cushing's syndrome and with normal adrenal imaging. This approach avoids unnecessary investigations and delays in definitive management.

Aging of natural and acquired immunity of mice. I. Decreased natural killer cell function and hybrid resistance.

Two "natural resistance" functions, natural killer (NK) cell activity against YAC-1 lymphoma cells and rejection by irradiated mice of parental-strain or H-2 allogeneic bone marrow cell grafts (hybrid or allogeneic resistance) were compared in mice at ages between 10 weeks and 26 months. NK cell numbers, as assessed by target-binding cells, decreased to one-half that of young mouse spleen cells, whereas NK lytic function was much more depressed. Hybrid, but not allogeneic, resistance to marrow grafts was weakened by 17 months of age. The immunogenicity of marrow stem cells of old Fl hybrid mice had not changed. The interferon inducer polyinosinic:polycytidylic acid (pI:pC) restored hybrid resistance to marrow grafts but only weakly boosted NK cell function in old mice. Incubation of spleen cells of old mice with beta interferon resulted in a weak boosting of NK cell activity. No cells capable of inhibiting NK cell function were detected in the spleens of old mice. These findings in old mice were similar to findings in young mice treated with 89Sr, with the exceptions that both hybrid and allogeneic resistance to marrow grafts are defective in 89Sr-treated mice and pI:pC failed to restore hybrid resistance in mice treated with 89Sr. This loss of "natural resistance" by aged mice, perhaps mediated by marrow-dependent effector cells, can partially explain the increased incidence of tumors in aging populations.

Aging of natural and acquired immunity of mice. II. Decreased T cell responses to syngeneic tumor cells and parental-strain spleen cells.

Cytolytic T lymphocyte (CTL) functions were compared in mice between the ages of 2 and 30 months. The stimulator cells were H-2 allogeneic spleen or tumor cells, parental-strain spleen cells, or syngeneic tumor cells. Effector cells capable of lysing syngeneic tumor cells were shown to be T cells and not NK cells. The cell-mediated lympholysis (CML) responses by spleen cells of aged mice were near normal against H-2 allogeneic spleen or tumor cells but were defective against syngeneic tumor cells or parental-strain spleen cells. The defective syngeneic tumor CML response was observed at various responder:stimulator ratios and at various days of incubation. The defect was in the nonadherent, and not in the adherent, fraction of spleen cells. Suppressor cells were detected in spleens of 30 month, but not of 18 month old mice. Aged mice were more susceptible than young mice to small inocula of syngeneic C57BL EL-4 lymphoma cells. The immunogenicity of irradiated spleen cells of old mice had not changed for the F1 antiparent CML response. Splenic CML responses of young mice treated with 89Sr demonstrated a similar pattern, i.e., good responses to H-2 allogeneic stimulator cells but poor responses to syngeneic tumor cells or to parental-strain spleen cells. This loss of certain CTL functions influenced by marrow dependent cells can partially explain the increased susceptibility of old animals to tumors.

Genetically modified foods--safety and regulatory issues.

Gene technology is a new form of biotechnology with much greater potential applications.