Aberrant adrenal sensitivity to multiple ligands in unilateral incidentaloma with subclinical autonomous cortisol hypersecretion: a prospective clinical study.

BACKGROUND: Incidentally discovered adrenal tumours are frequently associated with subclinical autonomous cortisol hypersecretion of unknown origin. Aberrant hormone receptors have been observed in case reports of overt Cushing's syndrome. The question arises as to whether such receptors may be present in the functioning adrenal incidentaloma, which is common and might be a subclinical stage of Cushing's syndrome. PATIENTS AND METHODS: Twenty-one consecutive patients with a unilateral incidentaloma, the biochemical features of subclinical cortisol hypersecretion and/or the scintigraphic features of an autonomously functioning adrenal adenoma were investigated for plasma cortisol responses to various stimuli: upright posture, meal, combined hypothalamic-hormones, the vasopressin analogue terlipressin, glucagon, angiotensin II, the serotonin 5-HT4 agonist cisapride, and ACTH. Six normal controls were similarly investigated. All subjects were studied during 8 mg per day dexamethasone in order to avoid any ACTH-dependent variation of plasma cortisol. RESULTS: The most constant responses in adrenal incidentalomas were observed after stimulation by terlipressin (18/20 patients, 28-415% cortisol increase) and cisapride (17/21 patients, 25-364% cortisol increase). Eighteen out of 21 patients responded to several stimuli (cortisol increase >or= 25%), and all responded to at least one stimulus other than ACTH, while such responses were absent in the controls. Plasma ACTH remained suppressed in all subjects throughout the study. CONCLUSIONS: Aberrant membrane receptors detected by in vivo stimulation tests appear to be common in autonomously functioning unilateral adrenocortical adenomas. These receptors may be involved in the modulation of cortisol secretion in adrenal incidentaloma, with potential therapeutic consequences for the control of subclinical cortisol hypersecretion.

Prostatic neuroendocrine tumor in multiple endocrine neoplasia Type 2B.

We report the unusual occurrence of a neuroendocrine prostatic tumor in two young males with multiple endocrine neoplasia (MEN) 2B. Immunohistochemistry of the tumor markers may help differentiate a primary neuroendocrine prostate tumor from the metastasis of a medullary thyroid carcinoma of poor prognosis. MEN 2B hallmarks (i.e. plasma thyrocalcitonin and urinary metanephrines) may be systematically investigated in neuroendocrine tumors of the prostate, and conversely prostate examination may be performed in the periodic screening of MEN 2B male patients.

Elevated plasma level of lipotropin revealing an occult carcinoid tumor with normal plasma adrenocorticotropin.

The increases in the level of plasma lipotropin (LPH) and in the LPH/ACTH ratio are considered diagnostic tools in ectopic ACTH syndrome. However, plasma ACTH is also elevated in this syndrome. We report a case of a small carcinoid tumor with an increase in both ACTH and LPH in plasma before surgery. Eight months after the tumoral resection, plasma LPH alone was increased again, whereas plasma ACTH and plasma and urinary cortisol remained normal in this apparently cured patient. This repeated abnormality was the only available feature that allowed successful removal of the occult tumoral residue.

Urinary nandrolone metabolites of endogenous origin in man: a confirmation by output regulation under human chorionic gonadotropin stimulation.

19-Nortestosterone (nandrolone) is an anabolic steroid compound widely used as a doping agent by athletes. The analysis of its urinary metabolites, 19-norandrosterone (NA) and 19-noretiocholanolone (NE) glucuronides, allows the detection of surreptitious administration of nandrolone in sport. A threshold concentration at 2 microgram/L urinary nandrolone metabolites is advocated by the International Olympic Committee for the detection of doping, but some controversy concerning the validity of this threshold arose from the demonstration of endogenous production of nandrolone in mammals, including humans. The regulation of human nandrolone production and its contribution in vivo to the process of aromatization remain unknown. In the present study 10 healthy men were successively submitted to insulinic stress and gonadal stimulation by hCG administration. Urinary NA and NE concentrations were quantified by gas chromatography-mass spectrometry. NA was detected in basal urine samples from all subjects, with a mean urinary excretion rate (UER) of 3.17 +/- 0.35 ng/h, whereas NE was detected in 4 of 10 (UER range, 0.8-4.7 ng/h). Insulinic hypoglycemia did not significantly modify mean NA UER despite random intraindividual variations between timed urine collections. After hCG administration, NA UER increased by 250% (P < 0.01) and estradiol (E(2)) UER by 260% (P < 0.001). The maximum NA concentration obtained after stimulation was 0.43 microgram/L. NA UER, plasma E(2), and E(2)/T ratio peaked on day 1 after hCG administration, whereas plasma T peaked later on day 3. NA UER correlated with plasma E(2) (r = 0.61; P < 0.001) and E(2)/T (r = 0.51; P < 0.001), but not with plasma T. In conclusion, insulinic stress did not significantly alter nandrolone metabolism, whereas the effect of hCG was a stimulation of NA excretion in all subjects, which constitutes strong support for the endogenous origin of low basal NA excretion. The comparative kinetics of NA UER, plasma E(2), and E(2)/T ratio suggest a contribution of the aromatase process to nandrolone biosynthesis in man.

Food-dependent Cushing's syndrome: characterization and functional role of gastric inhibitory polypeptide receptor in the adrenals of three patients.

In the present work, the presence of gastric inhibitory polypeptide (GIP) receptors and their functional role in the adrenal cells of three patients with food-dependent Cushing's syndrome were studied. RT-PCR and in situ hybridization studies demonstrated the presence of GIP receptor in the adrenals of the three patients. The presence of this receptor was also demonstrated in two human fetal adrenals, but not in two normal adult human adrenals or in the adrenals of one patient with nonfood-dependent Cushing's syndrome. Freshly isolated cells from patient adrenals responded in a dose-dependent manner to the steroidogenic action of both ACTH and GIP, whereas cells from normal adrenals responded only to ACTH. Treatment of cultured normal adrenal cells with ACTH, but not with GIP, increased the messenger ribonucleic acid (mRNA) levels of cholesterol side-chain cleavage cytochrome P-450, P450c17, and 3beta-hydroxysteroid dehydrogenase, whereas both hormones enhanced these mRNAs in patients' adrenal cells, although the effects of ACTH were greater than those of GIP. Moreover, pretreatment with ACTH enhanced the steroidogenic responsiveness of both normal and patient adrenal cells, whereas GIP caused homologous desensitization, and this was associated with a marked reduction of GIP receptor mRNA levels, as demonstrated by RT-PCR and in situ hybridization. Finally, both ACTH and GIP inhibited DNA synthesis in one patient's adrenal cells, whereas in normal adrenal cells only ACTH had this effect. In conclusion, the present data demonstrate that ectopic expression of functional GIP receptors is the main cause of food-dependent Cushing's syndrome.

High frequency of IgG antagonizing follicle-stimulating hormone-stimulated steroidogenesis in infertile women with a good response to exogenous gonadotropins.

OBJECTIVE: To investigate the presence of FSH-blocking IgG in infertile women. DESIGN: Retrospective study. Sera from patients and controls were processed for IgG purification, and purified IgG were tested at various concentrations for their ability to inhibit the recombinant human FSH-induced P production in vitro by human granulosa cells. SETTING: Departments of Endocrinology, and Obstetrics and Gynecology, University of Caen. PATIENT(S): Fifty-seven infertile women including 14 women with premature ovarian failure (POF), 29 women with a poor response to IVF-ET, and 14 women with a good response to IVF-ET. Controls consisted of 22 healthy age-matched women. INTERVENTION(S): IVF-ET allowed human granulosa cell pooling and culture for FSH bioassay. MAIN OUTCOME MEASURE(S): Inhibition by purified IgG of the in vitro recombinant human FSH-induced P production by human granulosa cells. RESULT(S): Blocking IgG were identified in only 3 of 14 POF and in 2 of 29 women with a poor response to IVF-ET. In contrast, IgG from women with a good response to IVF-ET inhibited significantly P production, and blocking IgG were detected in 85% women with a good response to IVF-ET. CONCLUSION(S): This study identified FSH-blocking IgG in a high proportion of women with a good response to IVF-ET. The significance of this remains questionable.

Pituitary apoplexy of a gonadotroph adenoma following gonadotrophin releasing hormone agonist therapy for prostatic cancer.

Treatment of prostatic cancer with GnRH agonist is a medical alternative to surgical castration, although hyperstimulation of the tumor can occur. We describe an unusual unwanted effect of such a treatment which unmasked a clinically silent gonadotroph adenoma. A 62-year-old man developed after the first injection of leuprorelin-depot a sudden intracranial hypertension, which was related to apoplexy of an unknown pituitary adenoma. Its gonadotroph origin was recognized after surgery by immunocytochemistry. Retrospectively, the tumor was shown to secrete in vivo both FSH and LH when on therapy with the agonist, demonstrating the lack of desensitization. Testosterone levels were also markedly and sustainly high when on therapy, a particularly unwanted effect in prostatic cancer. As gonadotroph adenomas occur in men in the same age group as prostatic cancer, the question is raised whether hormonal testing and pituitary imaging should be performed before starting a therapy with GnRH agonist in men.

[Topographical diagnosis of insulinoma of the pancreas. Value of the test of intra-arterial calcium infusion]. / Diagnostic topographique d'insulinome du pancréas. Intérêt du test de perfusion calcique intra-artérielle.

OBJECTIVE: The localization of insulinomas is a central problem, because none of the imaging techniques has proved sufficiently reliable for the diagnosis of tumors smaller than 2 cms. PATIENTS AND METHODS: Calcium stimulation test was performed during selective pancreatic angiogram with calcium gluconate injection in the pancreatic arteries, e.g. gastroduodenal, superior mesenteric and splenic. A simultaneous catheterization of hepatic veins through the femoral vein allowed measurement of insulin level increment after calcium stimulation. RESULTS: In our experience, this test allowed a positive location of an insulinoma in three consecutive patients presenting with organic hypoglycemia, and was useful for surgeons while non-invasive imaging techniques failed to locate the tumor in any of the three patients. DISCUSSION: The calcium stimulation test is a reliable preoperative procedure, particularly when other imaging techniques fail to locate the tumor. However it remains invasive, and our data are still too preliminary to clearly define its place within imaging techniques.

Postprandial lipoprotein metabolism in normotriglyceridemic non-insulin-dependent diabetic patients: influence of apolipoprotein E polymorphism.

Non-insulin-dependent diabetes mellitus (NIDDM) is associated with postprandial lipoprotein clearance defects that are correlated with the fasting hypertriglyceridemia widely observed in NIDDM patients. The aim of this study was to determine if such postprandial disturbances are found in NIDDM patients strictly normotriglyceridemic in the fasting state, and if the apolipoprotein E (apo E) polymorphism influences postprandial metabolism of intestinally derived lipoproteins. The vitamin A-fat loading test was used in 18 normotriglyceridemic NIDDM patients and seven normotriglyceridemic obese controls, and postprandial triglyceride (TG) and retinyl palmitate (RP) concentrations were evaluated in total plasma, and in the chylomicron (Sf > 1,000) and nonchylomicron (Sf < 1,000) fractions isolated by ultracentrifugation. NIDDM patients exhibited an amplified response of both TG and RP as compared with obese controls in the three fractions. Incremental TG response to the oral fat load was strongly correlated with fasting TG level (r = .80, P < .0001) in the whole study population. Postprandial lipoprotein profiles were distinguished in NIDDM patients according to apo E phenotype: despite normal fasting TG levels in E3/3 (n = 6), E2/3 (n = 6), and E3/4 (n = 6), postprandial RP response was twofold to threefold higher in E2/3 and E3/4 patients than in the common E3/3 phenotype. Contrasting lower postprandial TG increment and lower fasting and postprandial high-density lipoprotein (HDL) and HDL3 cholesterol levels were observed in E3/4 versus E3/3 patients, possibly reflecting modifications in lipid content of the postprandial lipoproteins driven by a differential lipid transfer activity depending on apo E isoform. These data indicate an enhanced postprandial lipemia in normotriglyceridemic NIDDM patients, and demonstrate the influence of apo E polymorphism on their lipoprotein clearance. Postprandial alterations of lipoprotein remnants may thus accelerate atherogenesis even in normotriglyceridemic NIDDM patients.

Testicular steroidogenesis in adult men with human chorionic gonadotropin-producing tumors.

There are few critical studies on plasma testosterone (T) and 17 beta-estradiol (E2) levels in men with hCG-producing tumors, and the results are contradictory. Plasma E2 levels are most often elevated, whereas plasma T values are high or in the normal range. We studied the plasma levels of such steroids and of delta 4 and delta 5 T precursors in adult men with intact hCG-producing tumors to evaluate the relationship between hCG and steroid hormone levels or steroidogenic enzyme activities. Ten adult men with hCG-producing tumors and 25 normal adult men were investigated. Seven men with testicular tumors were studied before and after hemicastration. The 2 patients with extratesticular tumors were investigated before and during chemotherapy. The remaining patient was studied every 2 months for 1 yr during the spontaneous course of the disease. Plasma progesterone (P), 17 alpha-hydroxyprogesterone (17-OHP), androstenedione (A), 17-hydroxy-delta 5-pregnenolone (17-OH delta 5-P), dehydroepiandrosterone (DHEA), T, E2, and hCG were measured, and ratios of steroid levels were also calculated. In patients with increased hCG values (i.e. > 5 IU/L), the mean plasma P, 17-OHP, A, 17-OH delta 5-P, DHEA, T, and E2 levels were higher (P < 0.01 at least) than those in patients whose hCG values were normalized or in controls. The patterns of these steroids were very different according to plasma hCG levels. Indeed, for hCG levels between more than 5 and 3.5 x 10(3) IU/L, positive correlations (P < 0.05 at least) were found between hCG levels and delta 4 T precursor, delta 5 T precursor, T, or E2 values. Conversely, for hCG values greater than 3.5 x 10(3) IU/L, hCG levels were negatively correlated (P < 0.05 at least) to all steroid values. Furthermore, in patients with increased hCG levels, the mean plasma P to 17-OHP ratio, 17-OHP to A ratio, A to T ratio, 17-OHP to T ratio, and 17-OH delta 5-P to DHEA ratio were similar to those in patients with normalized hCG values or in controls. In contrast, in patients with increased hCG levels, the mean plasma T to E2 ratio value was lower (P < 0.001) than that in patients with normalized hCG levels or in controls.(ABSTRACT TRUNCATED AT 400 WORDS)

[Primary adrenal lymphoma. Report of a case]. / Lymphome primitif surrénalien. Une observation.

The adrenal gland is affected in about 25% of patients with diffuse lymphoma. Conversely, primary lymphoma is a rare cause of non-secreting adrenal tumour. We observed a recent case with exclusive right adrenal localization. An 84-year-old woman was hospitalized for asthenia, anorexia and a 3-kg weight loss. The past history included coronary heart disease. Physical examination was normal and the hemogram revealed pancytopenia. No lymphomatous infiltration was seen on the myelogram or the bone marrow biopsy. Echography of the abdomen showed a well-limited 10 cm mass above the right adrenal gland, distinct from the liver; the left gland had a normal aspect. Hormone assays were within normal limits. The right adrenal gland was removed surgically and histology revealed diffuse proliferation of medium to large sized lymphoid cells invading the entire gland. Immunohistochemistry suggested lymphoid B origin. No curative treatment was begun, but 2 months after surgery local invasion required polychemotherapy. The patient died of septic shock 5 days later. Serum cortisol measured during the septic shock eliminated adrenal gland failure. Malignant primitive non-Hodgkinien lymphomas are extremely rare and usually discovered incidentally. The tumour is always large and sometimes accompanied by adrenal insufficiency when the lesion is bilateral. In spite of suggestive imagery the diagnosis is based on the pathology examination. The lesion is usually a high-grade malignant phenotype B lymphoma. Treatment relies on chemotherapy but is disappointing.

[Hirsutism]. / L'hirsutisme.

Hirsutism is a male pattern of hair distribution in women. It may be caused by hypersecretion of androgens by the adrenal glands or the ovaries and/or by cutaneous sensitivity to circulating androgens due to hyperactivity of 5 alpha-reductase. The degree of hirsutism is evaluated and its cause suspected by physical examination, but the aetiological diagnosis is indicated by plasma testosterone essays: if the testosterone level is above 1.2 ng/mL, investigations must be made to find out whether hirsutism is caused by a virilizing tumour of the ovary or the adrenal gland, or by a congenital adrenal hyperplasia of late presentation. If the testosterone level is below 0.6 ng/mL, hirsutism is idiopathic. Between these two figures the conditions is often idiopathic, but the patient must be investigated for polycystic ovarian dystrophy, adrenal hyperplasia or tumour. Whenever possible, treatment is aetiological, but it is always symptomatic, consisting of electrical depilation of the face and, chiefly, antiandrogens (e.g. Androcur) associated with oestrogens. This treatment usually effective, and it has transformed the outcome of hirsutism, even when the disease is idiopathic.

Luteinizing hormone regulation by sex steroids in men with germinal and Leydig cell tumours.

OBJECTIVE: We examined the gonadotrophin secretion in patients with increased plasma concentrations of testosterone and oestradiol due to hCG-producing tumours. DESIGN: Comparison of plasma gonadotrophin concentrations before and after stimulation by GnRH, in eight men with hCG-producing tumours resulting in increased testosterone and oestradiol plasma levels, and in 29 men with Leydig cell tumours resulting in increased oestradiol and normal to low testosterone plasma levels. PATIENTS: Eight men with hCG-producing tumours (six with testicular tumours, two with extratesticular tumours), 29 men with Leydig cell tumours and 15 normal men. The six men with germinal cell tumours of the testis were studied before and after unilateral orchidectomy. MEASUREMENTS: Plasma concentrations of hCG, testosterone and oestradiol were measured before and after intramuscular injection of hCG. LH and FSH were measured before and after intravenous injection of 100 micrograms GnRH. RESULTS: Plasma LH and FSH concentrations were low in patients with germ cell tumours, who exhibited increased plasma testosterone and oestradiol concentrations, and were normal in patients with Leydig cell tumours, in whom oestradiol only was increased. Plasma LH and FSH were normalized in the five patients with successful (e.g. normal hCG, testosterone and oestradiol) unilateral orchidectomy. Basal plasma testosterone concentrations correlated positively (P < 0.01) with plasma oestradiol concentrations in patients with germ cell tumours and negatively (P < 0.01) in patients with Leydig cell tumours. CONCLUSIONS: In patients with hCG-secreting germ cell tumours complete suppression of plasma LH and FSH with increased plasma concentrations of both testosterone and oestradiol are often discovered. No such gonadotrophin suppression is found in patients with Leydig cell tumours, but the negative correlation observed between plasma testosterone and oestradiol in these patients suggests a weak negative feedback effect of oestradiol on LH secretion, which cannot be demonstrated by basal LH measurements in plasma.

Food-dependent Cushing's syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide.

BACKGROUND: Some patients with Cushing's syndrome have nodular adrenal hyperplasia. In most the disease is corticotropin-dependent, but in others it is corticotropin-independent. The cause of the adrenal hyperplasia in the latter patients is not known. METHODS: We studied a 49-year-old woman with Cushing's syndrome and nodular adrenal hyperplasia in whom food stimulated cortisol secretion. Plasma cortisol concentrations were measured in response to the ingestion of mixed meals, glucose, protein, and fat and after the administration of various gastrointestinal and other types of hormones. We also studied the ability of the long-acting somatostatin analogue octreotide to prevent the food-induced increase in plasma cortisol concentrations and to ameliorate the clinical manifestations of Cushing's syndrome in this patient. RESULTS: The patient's fasting plasma cortisol concentrations were subnormal, ranging from 3.0 to 7.5 micrograms per deciliter (83 to 207 nmol per liter), and they increased to as high as 16.5 micrograms per deciliter (455 nmol per liter) after a mixed meal. Her urinary cortisol excretion ranged from 164 to 250 micrograms per day (453 to 690 nmol per day) and could not be suppressed by a large dose of dexamethasone. Plasma corticotropin concentrations were virtually undetectable at all times. The ingestion of glucose, protein, and fat increased plasma cortisol concentrations to 3.6, 2.2, and 4 times the base-line value, respectively; the meal-induced and glucose-induced increases were inhibited by octreotide. The infusion of gastric inhibitory polypeptide (GIP) increased the patient's plasma cortisol concentration to 3.7 times the base-line value, but had no effect in normal subjects. The patient's fasting plasma GIP concentrations were normal both before and after a meal, and there was a close correlation between her plasma cortisol and GIP concentrations. Treatment with octreotide decreased urinary cortisol excretion and ameliorated the clinical manifestations of Cushing's syndrome. CONCLUSIONS: The development of aberrant adrenal sensitivity to GIP can result in food-dependent adrenal hyperplasia and therefore in Cushing's syndrome.

Polycythemia and steroid overproduction in a gonadotropin-secreting seminoma of the testis.

While investigating the cause of mild polycythemia in a young man, a testicular seminoma was discovered with unusual and tumor-dependent features: an absolute polycythemia with high plasma erythropoietin (EPO) levels, an overproduction of estradiol and testosterone, and a dramatic Leydig cell hyperplasia surrounding the tumor tissue. The authors attempted to gain insight into the relationship between this testicular tumor and the hormonal overproduction, i.e., of EPO, estradiol, and testosterone. Their results favored the conclusion that the high EPO levels and the polycythemia were an indirect effect secondary to the steroid overproduction rather than a direct EPO-producing activity. Moreover, the steroid overproduction by the testis could be caused by a paracrine mechanism through human chorionic gonadotropin activity on the Leydig cells.