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Biomedical subjects

G B Cutler

Publications and source records attributed to G B Cutler.

At least 91 records · Page 5Linked to original sources
PubMed1995

Selective venous sampling from the cavernous sinuses is not a more reliable technique than sampling from the inferior petrosal sinuses in Cushing's syndrome.

The purpose of this study was to compare ACTH levels in unstimulated samples obtained from the cavernous sinuses (CS) to unstimulated and CRH-stimulated samples obtained from the inferior petrosal sinuses (IPS) in 15 patients with surgically proven Cushing's disease. After unstimulated samples were obtained through 5-French catheters placed in both IPS, tracker catheters were introduced into both cavernous sinuses, and unstimulated samples were obtained within 5 min of the initial set. The Tracker catheters were removed, CRH was administered, and CRH-stimulated samples were obtained from the IPS. We compared the central to peripheral ACTH ratios in unstimulated samples from the cavernous sinuses to unstimulated and CRH-stimulated samples from the IPS as a basis for distinguishing pituitary from ectopic ACTH production. In addition, we compared the ability of the intercavernous and interpetrosal ACTH ratios to correctly predict the site of the microadenoma. Unstimulated levels of ACTH in the cavernous sinuses were generally higher than unstimulated levels of ACTH in the petrosal sinuses. However, 3 of 15 patients failed to show central to peripheral ACTH ratios greater than 2 in unstimulated samples from the cavernous sinuses and were thus falsely negative for the diagnosis of Cushing's disease (test sensitivity, 80%). By comparison, the test sensitivity for the petrosal sinus samples was 87% for the unstimulated samples and 100% for the CRH-stimulated samples. Lateralization was correct in 6 of 15 patients based on CS samples and in 9 of 15 patients based on IPS samples. Because of the 20% false negative rate, CS sampling without CRH stimulation is not recommended for the differential diagnosis of ACTH-dependent hypercortisolism.

Adenoma↗
PubMed1995

Use of ultrasensitive recombinant cell bioassay to measure estrogen levels in women with breast cancer receiving the aromatase inhibitor, letrozole.

The development of well tolerated, potent, specific, and nontoxic aromatase inhibitors for the treatment of postmenopausal women with estrogen-dependent breast cancer has been a major goal of recent studies. The third generation inhibitors now under investigation are nearly 10,000-fold more potent than first generation compounds. Currently available RIAs for plasma estradiol lack sufficient sensitivity to measure levels during aromatase inhibition and, thus, to assess drug potency precisely. The availability of an ultrasensitive bioassay for estradiol provided the opportunity to accurately assess the potency of a new third generation triazole aromatase inhibitor, letrozole (CGS 20267). We used this assay to measure estradiol levels in 14 women with metastatic breast cancer given letrozole at doses of 100 micrograms to 5.0 mg/day over a 12-week period. The lack of differences between doses and sampling times allowed pooling of data. Basal estradiol levels of 7.2 +/- 1.9 pmol/L (mean +/- SEM, 1.95 +/- 0.52 pg/mL) fell to 0.26 +/- 0.11 pmol/L (0.07 +/- 0.03 pg/mL) during the first 6 weeks of therapy and to 0.48 +/- 0.18 pmol/L (0.13 +/- 0.05 pg/mL) during the second 6 weeks of therapy. Although plasma estradiol levels measured by RIA were significantly correlated with levels measured by bioassay (r = 0.79; P < 0.01), the degree of suppression assessed by the bioassay (95 +/- 2% after 6 weeks) was greater than that determined by the RIA (81 +/- 4%), presumably due to improved ability to measure very low estradiol levels. We conclude that plasma estradiol is suppressed by letrozole to lower levels than previously observed, with equivalent suppression at all doses studied. A slight, although not statistically significant, rebound in estradiol levels occurs during the second 6 weeks of therapy compared to the first 6 weeks. Maximum inhibition of aromatase is achieved at letrozole doses as low as 100 micrograms.

Aromatase Inhibitors↗
PubMed1994

Cushing's syndrome in children and adolescents. Presentation, diagnosis, and therapy.

BACKGROUND AND METHODS: Cushing's syndrome is rare in children and adolescents. We analyzed the clinical presentation, diagnostic evaluation, and treatment of 59 patients with Cushing's syndrome between the ages of 4 and 20 years who were admitted to the National Institutes of Health during the period from 1982 to 1992. The cause of hypercortisolism was identified by low- and high-dose dexamethasone suppression tests, the ovine corticotropin-releasing hormone (CRH) stimulation test, imaging studies, and bilateral sampling of the inferior petrosal sinuses combined with administration of CRH. RESULTS: Fifty patients had Cushing's disease, six had primary adrenal disease, and three had ectopic corticotropin secretion. The initial signs were excessive weight gain in 90 percent of the patients and growth retardation in 83 percent. Most patients (81 percent) had normal bone age at the time of diagnosis. Forty-seven percent had hypertension, whereas only 19 percent had mental or behavioral problems. The high-dose dexamethasone suppression test and the CRH stimulation test identified 68 and 80 percent, respectively, of the patients with Cushing's disease. Magnetic resonance imaging of the pituitary indicated the presence of tumor in 52 percent of the patients with pituitary adenomas. The maximal central-to-peripheral ratio of plasma corticotropin during sampling of the interior petrosal sinuses was > or = 2.5 in all the patients with Cushing's disease and < 2.5 in those with ectopic corticotropin secretion. Remission of hypercortisolism was achieved in 48 of the 49 patients who underwent transsphenoidal surgery for Cushing's disease, in all 6 of the patients who underwent adrenalectomy for primary adrenal disease, and in the 2 patients in whom the ectopic source of corticotropin could be identified. CONCLUSIONS: Weight gain and growth retardation are common clinical characteristics of Cushing's syndrome in children and adolescents. Diagnostic evaluation of such patients with CRH stimulation alone and combined with inferior petrosal sinus sampling and imaging studies is accurate, and therapy is usually successful.

Adenoma↗
PubMed1994

The metyrapone and dexamethasone suppression tests for the differential diagnosis of the adrenocorticotropin-dependent Cushing syndrome: a comparison.

OBJECTIVE: To develop criteria for interpreting results of the metyrapone test for the differential diagnosis of the adrenocorticotropin (ACTH)-dependent Cushing syndrome and to compare its diagnostic accuracy with that of the high-dose dexamethasone suppression test. DESIGN: Retrospective cohort study. SETTING: Inpatient research ward. PATIENTS: 186 patients believed to have the ACTH-dependent Cushing syndrome who had the metyrapone test, the dexamethasone test, and a surgical procedure to remove the source of excessive ACTH. MEASUREMENTS: The sensitivity, specificity, and diagnostic accuracy were determined for the metyrapone test using urine excretion of hydroxysteroid and plasma levels of 11-deoxycortisol. For the dexamethasone suppression test, urine excretions of 17-hydroxysteroid (17-OHS) and free cortisol were used. MAIN RESULTS: 156 patients had pituitary disease, 15 had ectopic ACTH secretion, and 15 had no diagnosis after pituitary surgery. Of those 15 patients, 14 were ultimately classified as having pituitary disease on the basis of follow-up, and 1 was found to have ACTH-independent Cushing syndrome. After administration of metyrapone, stimulation of 17-OHS excretion greater than 70% or of a plasma 11-deoxycortisol level greater than 400-fold did not result in the misclassification of any of the patients with surgically confirmed cases of ectopic ACTH secretion. When these criteria were combined, the percentage of correct predictions (122 of 186 [71%; 95% CI, 62% to 79%]) was higher than that for either steroid alone (116 of 186 [62%; CI, 52% to 71%]) for excretion of 17-OHS and that for plasma 11-deoxycortisol (82 of 186 [44%; CI, 34% to 54%]). When the criteria for both the metyrapone test and the dexamethasone test were combined, the percentage of correct predictions (153 of 186 [82%; CI, 75% to 87%]) was higher than that obtained when the criteria for either test alone were used (P = 0.001). Similar results were found when the 15 patients with indeterminate surgery were assigned to the appropriate group on the basis of follow-up. When the criteria for both the metyrapone and dexamethasone tests were combined to identify patients with the pituitary Cushing syndrome, the sensitivity and diagnostic accuracy improved to 88% and 89%, respectively. CONCLUSIONS: The metyrapone test, which can be done in 48 hours, has a sensitivity and specificity for the diagnosis of the Cushing syndrome identical to that of the standard 6-day high-dose dexamethasone suppression test. Combining both tests results in greater accuracy than that obtained with either test alone.

Adrenocorticotropic Hormone↗
PubMed1994

Spontaneous vulvar necrotizing fasciitis in Cushing's syndrome.

Necrotizing fasciitis is a potentially fatal condition, and the prognosis is worsened by immunosuppression. We describe what appears to be the first reported case of spontaneous vulvar necrotizing fasciitis occurring in a woman with uncontrolled hypercortisolism due to an ACTH-secreting thymic carcinoid tumor.

ACTH Syndrome, Ectopic↗
PubMed1994

Adrenocorticotropic hormone--secreting islet cell tumors: are they always malignant?

PURPOSE: To evaluate the frequency with which benign occult islet cell tumors cause ectopic adrenocorticotropic hormone (ACTH) syndrome. MATERIALS AND METHODS: Ten patients with Cushing syndrome due to the production of ACTH by a pancreatic islet cell tumor were studied. In addition, 53 cases of ACTH-secreting islet cell tumors in the English-language literature were reviewed. RESULTS: All 10 of the authors' patients had malignant islet cell tumors. Liver metastases were present in all 10 patients at presentation. Five patients are dead, four patients are alive with liver metastases, and one patient is alive without gross evidence of residual tumor after distal pancreatectomy and right hepatectomy. Eight of the 10 islet cell carcinomas produced gastrin in addition to ACTH. In the 53 reported cases of ectopic ACTH production, there was only one benign adenoma with a prolonged follow-up. CONCLUSION: When ectopic ACTH production is caused by an islet cell tumor, the tumor is large and malignant and has usually metastasized to the liver by the time Cushing syndrome is diagnosed. No occult ACTH-producing islet cell tumor was encountered in the authors' experience or in a review of the literature.

ACTH Syndrome, Ectopic↗
PubMed1994

Estrogen levels in childhood determined by an ultrasensitive recombinant cell bioassay.

We hypothesized that estradiol levels are higher in prepubertal girls than in prepubertal boys and that this greater secretion of estradiol might drive the more rapid epiphyseal development and earlier puberty in girls. Since previous estradiol assays have lacked adequate sensitivity to test the hypothesis of higher estradiol levels in girls, we developed a new ultrasensitive assay to measure estrogen levels. The assay uses a strain of Saccharomyces cerevisiae genetically engineered for extreme sensitivity to estrogen. Yeast were transformed with plasmids encoding the human estrogen receptor and an estrogen-responsive promoter fused to the structural gene for beta-galactosidase. Ether extracts of 0.8 ml of serum were incubated with yeast for 8 h and the beta-galactosidase response was used to determine estrogen bioactivity relative to estradiol standards prepared in charcoal-stripped plasma. The assay was highly specific for estradiol with < 3% cross-reactivity with estrone, estriol, or estradiol metabolites. The detection limit was < 0.02 pg/ml estradiol equivalents (100-fold lower than existing assays). Using this assay, we measured estrogen levels in 23 prepubertal boys (9.4 +/- 2.0 yr) and 21 prepubertal girls (7.7 +/- 1.9 [SD] yr). The estrogen level in girls, 0.6 +/- 0.6 pg/ml estradiol equivalents, was significantly greater than the level in boys, 0.08 +/- 0.2 pg/ml estradiol equivalents (P < 0.05). We conclude that the ultrasensitive recombinant cell bioassay for estrogen is approximately 100-fold more sensitive than previous estradiol assays, that estrogen levels are much lower prepubertally, in both sexes, than reported previously, and that prepubertal girls have 8-fold higher estrogen levels than prepubertal boys.

Adolescent↗
PubMed1994

Linear growth in the rabbit is continuous, not saltatory.

A recent report in Science suggests that human growth occurs in brief bursts, up to 1.65 cm in a single day, separated by extended periods of stasis, lasting up to 63 days. Thus, the organism is proposed to alternate between two states, one with a growth velocity of zero, the other with a mean annualized growth velocity greater than 350 cm/yr. These observations, if correct, suggest the existence of a previously unsuspected hormonal mechanism capable of abruptly switching growth plate cell division on and off and of synchronizing cellular growth not only throughout the growth plate, but presumably throughout all the growth plates in the organism. However, the experimental assessment of short-term growth velocity in the human faces the formidable obstacle of a technical error of measurement that exceeds the mean daily growth rate. Accordingly, we tested the saltatory growth hypothesis by measuring proximal tibial growth in the rabbit, a model in which daily growth rate could be measured more than 15 times more accurately than in the human. The model of saltation and stasis predicts a majority of daily growth velocities clustered around zero, and a minority of high growth velocities, that is, a bimodal distribution. The frequency distribution of observed daily growth velocities instead approximated a single Gaussian distribution, indicating continuous growth. We conclude that linear growth, in the most accurate mammalian system yet studied, is continuous, not saltatory.

Animals↗
PubMed1994

Dexamethasone increases growth hormone receptor messenger ribonucleic acid levels in liver and growth plate.

Glucocorticoid inhibits linear growth and renders target tissues, particularly liver and growth plate, insensitive to GH. We hypothesized that glucocorticoid-induced GH insensitivity is due to decreased gene expression of the GH receptor at the messenger RNA (mRNA) level. To test this hypothesis, we treated 4.5-wk-old male rabbits (n = 6-9 per group) with ip dexamethasone or vehicle and measured GH receptor mRNA levels (by RNase protection assay) and serum GH-binding protein levels (by radioimmunoprecipitation assay). Contrary to our hypothesis, dexamethasone administered in growth-suppressing doses did not decrease GH receptor mRNA levels in liver or growth plate. Instead a tissue-specific stimulation of GH receptor mRNA levels was observed. The dose-response relationship of this effect was biphasic, since the lower growth-suppressing dose of dexamethasone (0.1 mg/kg.day) caused the greater increase in GH receptor mRNA levels, whereas the higher growth-suppressing dose (4 mg/kg.day) had less effect. The dexamethasone-induced increase in GH receptor mRNA was observed in growth plate and liver, target tissues important for linear growth, but not in kidney. Serum GH-binding protein levels also showed a stimulatory response to dexamethasone treatment, with a biphasic dose-response relationship. These data suggest that glucocorticoid-induced GH insensitivity cannot be explained by decreased GH receptor mRNA levels. To the contrary, dexamethasone causes a tissue-specific stimulation in GH receptor mRNA levels with a biphasic dose-response relationship.

Animals↗
PubMed1994

Catch-up growth after glucocorticoid excess: a mechanism intrinsic to the growth plate.

In humans and other mammals, the release from growth-inhibiting conditions, such as glucocorticoid excess, leads to supranormal linear growth. The prevailing explanation for this catch-up growth involves a central nervous system mechanism that compares actual body size to an age-appropriate set-point and adjusts growth rate accordingly via a circulating factor. Although such a neuroendocrine "sizostat" was hypothesized more than 30 yr ago, its existence has never been confirmed experimentally. Here we show that suppression of growth within a single growth plate by locally administered glucocorticoid is followed by local catch-up growth that is restricted to the affected growth plate. Thus, the catch-up growth cannot be explained by neuroendocrine mechanism but, rather, must arise from a mechanism intrinsic to the growth plate. To explain this finding, we propose that the normal senescent decline in growth plate function depends not on age per se, but on the cumulative number of stem cell divisions, and that glucocorticoid administration, by suppressing stem cell proliferation, delays senescence, resulting in catch-up growth after the growth-inhibiting agent is removed.

Aging↗
PubMed1994

Induction of growth plate cartilage ossification by basic fibroblast growth factor.

In mammals, longitudinal bone growth results from the precise coupling of chondrogenesis and osteogenesis within the epiphyseal growth plate, a process termed endochondral ossification. The mechanisms coupling chondrogenesis and osteogenesis are unknown. Previous studies have shown that both basic fibroblast growth factor (bFGF) and acidic FGF are expressed by growth plate chondrocytes. Here we show that bFGF, infused directly into the rabbit proximal tibial growth plate, accelerates vascular invasion and ossification of growth plate cartilage. Our results suggest the possibility that bFGF (or a related member of the FGF family) couples osteogenesis to chondrogenesis by attracting vascular and bone cell invasion from the adjacent metaphyseal bone.

Animals↗
PubMed1994

A comparison of the standard high dose dexamethasone suppression test and the overnight 8-mg dexamethasone suppression test for the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome.

To improve the overnight 8-mg dexamethasone (DEX) suppression test (DST) for differential diagnosis of Cushing's syndrome and to develop optimal criteria for its interpretation, we increased the number of blood samples and measured the suppression of both plasma ACTH and cortisol. Forty-one patients who were subsequently proven at surgery to have Cushing's syndrome were studied (34 Cushing's disease and 7 ectopic ACTH secretion). DEX (8 mg, orally) was administered at 2300 h. Blood samples for ACTH and cortisol measurements were obtained at 0800, 0830, and 0900 h on the day before and at 0700, 0800, 0900, and 1000 h on the morning after DEX treatment. The conventional 6-day DST was also performed, with measurement of both urinary free cortisol and urinary 17-hydroxysteroids as indices of suppression. Optimal criteria for the diagnosis of Cushing's disease were developed for both the overnight 8-mg and the 6-day tests using receiver operating characteristic curves. The results were compared with those using the previously published criteria for diagnosis of Cushing's disease by the overnight 8-mg test (> 50% suppression of plasma cortisol at 0700-0800 h). In our patients, the previously published criterion for the overnight 8-mg test yielded high sensitivity (88%), but low specificity (57%), in making the diagnosis of Cushing's disease. When the time of cortisol measurement and the diagnostic criteria for Cushing's disease were revised to achieve 100% specificity, the sensitivity of the overnight 8-mg test was 71%, which was not significantly different from that of the 6-day test (79%; P = NS). Addition of plasma ACTH levels to the test did not improve diagnostic accuracy compared to that with measurement of plasma cortisol levels alone. When the revised 8-mg overnight dexamethasone suppression test was combined with the 6-day dexamethasone suppression test, sensitivity increased to 91%, with a specificity of 100%, which was significantly better than that of the overnight 8-mg test alone (P < 0.002). We conclude that the overnight 8-mg DST has low specificity for the diagnosis of Cushing's disease when performed as originally described. However, with revised sampling times and diagnostic criteria, the overnight test has sensitivity and specificity similar to those of the conventional 6-day DST. The diagnostic performance of a criterion that combines the results of both tests is better than the diagnostic performance of either test alone.

Administration, Oral↗
PubMed1994

The effects of estrogen priming and puberty on the growth hormone response to standardized treadmill exercise and arginine-insulin in normal girls and boys.

To determine the effects of puberty and estrogen priming on the GH response to standardized treadmill exercise and arginine-insulin in normal boys and girls, we performed tests in 84 normal children (41 girls and 43 boys) representing all stages of puberty. A subset of the prepubertal children received the tests twice, with or without the administration of ethinyl estradiol (40 micrograms/m2 daily) for 2 days before the tests. The peak GH response to the three tests increased significantly with pubertal stage (r = 0.57; P < 0.0001), but did not differ between boys and girls at the same stage. With advancing puberty, the percentage of normal children who failed to attain a GH level greater than 7 micrograms/L during any of the three tests declined from 61% at pubertal stage 1 to 44% at stage 2, 11% at stage 3, and 0% at stages 4 and 5. Administration of estrogen to the prepubertal subjects raised the normal range for the peak GH response to the three tests from 1.9-20.3 to 7.2-40.5 micrograms/L. We conclude that both puberty and estrogen administration significantly increase the peak GH response to exercise, arginine, or insulin in normal subjects. Moreover, the conventional criterion that the peak GH response to three stimulation tests should exceed 7 micrograms/L was applicable in our study only to subjects who had attained pubertal stage 4 or 5 or who had received estrogen administration.

Adolescent↗
PubMed1994

A sporadic case of male-limited precocious puberty has the same constitutively activating point mutation in luteinizing hormone/choriogonadotropin receptor gene as familial cases.

Familial male-limited precocious puberty (FMPP) is an autosomal dominant disorder characterized by marked elevation of serum testosterone despite low levels of gonadotropin. Recently, a single point mutation in the LH/hCG receptor (LH/CGR) gene was found in FMPP families that constitutively activates the LH/CGR, causing Leydig cell activation and precocious puberty. Among the Japanese population, only four sporadic cases of male-limited precocious puberty have been reported. In the current study, we examined one of the four reported Japanese patients with sporadic male-limited precocious puberty and found the same mutation as that in the FMPP families. Genomic DNA was isolated, and the polymerase chain reaction (PCR) was performed to amplify a fragment of LH/CGR DNA encoding amino acid residues that include transmembrane helixes 5 and 6. Sequencing of the PCR products revealed a heterozygous adenosine-guanine transition at nucleotide 1733 in codon 578. The mutation encodes an aspartic acid578-glycine substitution in transmembrane helix 6. The mutant LH/CGR, created by site-directed mutagenesis in vitro, exhibited constitutively higher cAMP levels in transfected COS-7 cells than the wild-type LH/CGR, as described previously; however, basal inositol phosphate levels were not increased by transfection with complementary DNA for the mutant receptor. The concentration and affinity of [125I]hCG-binding sites were similar in cells transfected with the mutant and wild-type LH/CGR complementary DNAs, indicating that the mutant did not alter the production of receptor or its ability to bind human LH/CG. The sporadic occurrence of this case was confirmed by further studies. The mutation creates a recognition site for the restriction endonuclease MspI. Restriction digestion was positive for the mutant not digested by MspI, indicating that the patient's mutant allele was not inherited from his parents. DNA analysis of the patient and the parents, using microsatellite repeat markers, was compatible with biological paternity and maternity. We conclude that the aspartic acid578-->glycine mutation in the LH/CGR has arisen in the Japanese population and is the cause of a sporadic case of male-limited precocious puberty.

Aspartic Acid↗
PubMed1994

Early repeat surgery for persistent Cushing's disease.

The potential efficacy of early repeat transsphenoidal surgery for persistent Cushing's disease has not previously been examined. On 222 patients with no prior pituitary treatment and a preoperative diagnosis of Cushing's disease, 29 (13%) remained hypercortisolemic after an initial transsphenoidal pituitary exploration. Seventeen of these 29 patients underwent further surgery 7 to 46 days after the initial transsphenoidal approach in order to completely excise suspected residual tumor. Patients were followed for 4 to 84 months (mean +/- standard deviation, 34 +/- 25 months) to document sustained remission or recurrence of Cushing's disease (a urine free cortisol level > 90 micrograms/day was considered evidence of recurrence). Of the 17 patients with repeat surgery, 12 (71%) had resolution of hypercortisolism (morning plasma cortisol level < 5 micrograms/dl); however, in three of these 12, hypercortisolism recurred 5, 12, and 24 months later. In 14 patients a lesion that appeared to be a tumor was identified during the initial procedure or on histological examination. Of these, 12 had immediate resolution of hypercortisolism and nine are still in remission. Three patients, in whom no adenoma could be identified during the initial surgery or an examination of the partial hypophysectomy specimen from the initial surgery, had persistent Cushing's syndrome after the second operation. Seven (41%) of the 17 patients developed hypopituitarism requiring treatment with thyroid hormone, gonadal steroid, or vasopressin replacement. The low incidence of identification of an adenoma on computerized tomography or magnetic resonance images (three of 17 patients), the failure to find a corticotrophic adenoma during the initial surgery (10 of 17 patients), and the failure of these 17 patients to respond to the initial transsphenoidal surgery suggest that they may comprise a subset of patients who are more difficult to treat successfully with surgery than most patients with Cushing's disease. Despite that, early reoperation induced immediate remission of hypercortisolism in 71% of cases, but did so at the expense of a high risk of hypopituitarism. However, since the alternative treatments (such as radiation therapy, long-term drug therapy, or bilateral adrenalectomy) also have potential adverse effects, early reoperation deserves consideration for the management of persistent Cushing's disease, especially when an adrenocorticotrophic hormone-secreting adenoma was partially excised during the first surgery.

Adult↗
PubMed1994

Glucocorticoid action and the clinical features of Cushing's syndrome.

Glucocorticoids mainly act through binding to cytosolic receptors that translocate to the nucleus after ligand binding, and dimerize to affect gene transcription in multiple fashions. The liganded receptors may interact with DNA at specific glucocorticoid responsive-elements, may physically hinder the ability of other transcription-regulating proteins to interact with their own DNA response-elements, and may form intranuclear complexes with the transcription factor c-jun, thus changing the number of c-jun/c-fos heterodimers that bind at AP-1 sites. By these, and perhaps other, mechanisms, physiologic concentrations of glucocorticoids regulate normal tissue metabolism, and supraphysiologic concentrations cause Cushing's syndrome. Cushing's syndrome leaves virtually no body tissue untouched. Left untreated, it results in progressive adiposity, myopathy, dermopathy (atrophy, stria, purpura, and hirsutism), psychopathy, glucose intolerance, hypercholesterolemia, hypertension, atherosclerosis, immunosuppression, and, ultimately, death. The physiology underlying each of these effects of hypercortisolism has been reviewed. The differences in the presentation of Cushing's syndrome in children and adults have also been discussed. The goal of the clinician must be to identify individuals with Cushing's syndrome as early in the course of the disease as possible so as to avoid the devastating complications that result from prolonged hypercortisolism. In patients for whom screening tests are equivocal, or only intermittently elevated, it may be necessary to re-evaluate the patient over time to establish that the patient has hypercortisolism. Some clinical guidelines for which patients to screen for hypercortisolism have been presented. Once hypercortisolism is established, patients with mild hypercortisolism (urine free cortisol less than four-fold above the upper limit of normal) should undergo tests to differentiate true Cushing's syndrome from a pseudo-Cushing state.

Cushing Syndrome↗
PubMed1993

A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty.

Familial male precocious puberty (FMPP) is a gonadotropin-independent disorder that is inherited in an autosomal dominant, male-limited pattern. Affected males generally exhibit signs of puberty by age 4. Testosterone production and Leydig cell hyperplasia occur in the context of prepubertal levels of luteinizing hormone (LH). The LH receptor is a member of the family of G-protein-coupled receptors, and we hypothesized that FMPP might be due to a mutant receptor that is activated in the presence of little or no agonist. A single A-->G base change that results in substitution of glycine for aspartate at position 578 in the sixth transmembrane helix of the LH receptor was found in affected individuals from eight different families. Linkage of the mutation to FMPP was supported by restriction-digest analysis. COS-7 cells expressing the mutant LH receptor exhibited markedly increased cyclic AMP production in the absence of agonist, suggesting that autonomous Leydig cell activity in FMPP is caused by a constitutively activated LH receptor.

Adenine↗