Pathology and genetics of tumours of the urinary system and male genital organs

Objective: The objective of the study was to develop clinical practice guidelines for the diagnosis of Cushing's syndrome. Participants: The Task Force included a chair, selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, five additional experts, a methodologist, and a medical writer. The Task Force received no corporate funding or remuneration. Consensus Process: Consensus was guided by systematic reviews of evidence and discussions. The guidelines were reviewed and approved sequentially by The Endocrine Society's CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage the Task Force incorporated needed changes in response to written comments. Conclusions: After excluding exogenous glucocorticoid use, we recommend testing for Cushing's syndrome in patients with multiple and progressive features compatible with the syndrome, particularly those with a high discriminatory value, and patients with adrenal inci...

The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline.

Advanced Statistical Methods in Biometric Research.

During the last decade, the GH axis has become the compelling focus of remarkably active and broad-ranging basic and clinical research. Molecular and genetic models, the discovery of human GHRH and its receptor, the cloning of the GHRP receptor, and the clinical availability of recombinant GH and IGF-I have allowed surprisingly rapid advances in our knowledge of the neuroregulation of the GH-IGF-I axis in many pathophysiological contexts. The complexity of the GHRH/somatostatin-GH-IGF-I axis thus commends itself to more formalized modeling (154, 155), since the multivalent feedback-control activities are difficult to assimilate fully on an intuitive scale. Understanding the dynamic neuroendocrine mechanisms that direct the pulsatile secretion of this fundamental growth-promoting and metabolic hormone remains a critical goal, the realization of which is challenged by the exponentially accumulating matrix of experimental and clinical data in this arena. To the above end, we review here the pathophysiology of the GHRH somatostatin-GH-IGF-I feedback axis consisting of corresponding key neurotransmitters, neuromodulators, and metabolic effectors, and their cloned receptors and signaling pathways. We propose that this system is best viewed as a multivalent feedback network that is exquisitely sensitive to an array of neuroregulators and environmental stressors and genetic restraints. Feedback and feedforward mechanisms acting within the intact somatotropic axis mediate homeostatic control throughout the human lifetime and are disrupted in disease. Novel effectors of the GH axis, such as GHRPs, also offer promise as investigative probes and possible therapeutic agents. Further understanding of the mechanisms of GH neuroregulation will likely allow development of progressively more specific molecular and clinical tools for the diagnosis and treatment of various conditions in which GH secretion is regulated abnormally. Thus, we predict that unexpected and enriching insights in the domain of the neuroendocrine pathophysiology of the GH axis are likely be achieved in the succeeding decades of basic and clinical research.

Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human

THIS REVIEW will deal with the biosynthesis of many of the members of the ACTH/lipotropin (LPH) family of peptides (Fig. 1). Peptides in this family fall into two groups: peptides related to ACTH include α-melanotropin (αMSH) and corticotropin-like intermediate lobe peptide (CLIP); peptides related to βLPH include γLPH, βMSH, and β-endorphin. In several species ACTH and βLPH each contain an identical heptapeptide segment located in the region of the molecule that is responsible for melanotropic bioactivity (1, 2). In this review we have taken a somewhat historical approach, and will therefore begin with a discussion of the biosynthesis of ACTH and the characterization of biosynthetic precursors to ACTH. When this work began, βLPH, γLPH, and βMSH were well-characterized pituitary peptides, but the opioid peptides (and β-endorphin in particular) had not yet been identified (3–5). Studies on the biosynthesis of ACTH were heavily influenced by prior work defining the biosynthetic pathways for insulin and para...

Structure and Biosynthesis of Pro-Adrenocorticotropin/Endorphin and Related Peptides*

The present studies had 2 objectives: I. To delineate more precisely the time course of adrenal secretory activity in the normal human and patients with Cushing's syndrome, by measurement of plasma corticosteroid and ACTH levels half-hourly throughout the 24 hr cycle. II. To describe hitherto lacking clinically optimal and suitable conditions for determination and definition of the normal circadian pattern of plasma corticosteroid levels (CPOHCS). 1. I. Four control subjects with normal activity sleep and meal time patterns were studied: 3 were restudied during “constant feeding,” 1 was restudied during constant glucose administration and again under different dexamethasone regimens. CPOHCS consisted of 5–10 peaks in a given subject. Fifty to 75% of peaks occurred in a 9 hr period (midnight to 9:00 am) describing a gradual upward course with maximum plasma corticosteroid levels occurring 1/2–2 hr following awakening. A downward trend followed with other peaking activity occurring between 11:30 am...

Characterization of the normal temporal pattern of plasma corticosteroid levels.

α-Endorphin, β-endorphin, γ-endorphin, and N-terminal ACTH immunoreactivity were detectable in acid extracts of rat testes with concentrations of 0.07 ± 0.01, 0.18 ± 0.03, 0.06 ± 0.01, and 0.33 ± 0.08 (±SD) pmol/g wet wt, respectively. The forms of these immunoreactive peptides were characterized by reverse phase high performance liquid chromatography. Immunoreactive β-endorphin was also analyzed by gelfiltration and sodium dodecyl sulfate-polyacrylamide gel electro-phoresis. The results indicated that the major form of immuno-reactive β-endorphin present appears to be β-endorphin-(l–31).No α-N-acetylated forms of β-endorphin or β-lipotropin-sized material were detected. Immunoreactive α- and γ-endorphin appear to be present as a-endorphin and des-Tyr1-γ-endorphin, respectively. Immunoreactive αMSH was presentas its desace-tylated form. No immunoreactive ACTH fractionating with ACTH-(l-39) or its glycosylated forms was detected. This peptide profile is most similar to that seen for proopiomelanocortin-der...

Characterization of Immunoreactive Proopiomelanocortin-Related Peptides in Rat Testes

Nocturnal sleep EEG stages and concomitant plasma growth hormone (GH) and cortisol concentrations were examined in subjects with endogenous or exogenous elevation of plasma corticosteroid or ACTH concentrations, and in patients with hypothalamic tumors. These studies were designed to determine whether central nervous system (CNS) function was uniquely altered in Cushing's disease, independent of the effects of hypercortisolemia per se. Marked reductions of sleep EEG stages III-IV and of the nocturnal GH rise were present in 4 treated (remission 5 months to 2 yr) and 6 untreated patients with Cushing's disease (clinically active 2 months to 10 yr duration) as well as in 4 “eu-corticoid” patients with hypothalamic tumors. In contrast, similar EEG and hormonal changes, present in a patient with Cushing's syndrome secondary to an adrenal adenoma, returned to normal 16 months following removal of the adenoma. These findings suggest that altered CNS function may be involved in the pathophysiology of Cu...

Sleep EEG stages and plasma growth hormone concentration in states of endogenous and exogenous hypercortisolemia or ACTH elevation.

Enzymatically dispersed hypothalamic cells derived from 15-day-old female rats were maintained in tissue culture for 4 days and then incubated for 2 hr in the presence of [35S]methionine. After such incubation, cell extracts contained multiple forms of 35S-labeled products that were specifically bound by immobilized affinity-purified antisera to corticotropin and beta-endorphin. Sequential use of these immobilized antisera revealed two molecular species (apparent Mr of 33,000 and 36,500) that contained both corticotropin and beta-endorphin antigenic determinants within the same molecule. Substances containing only one of these determinants were also present and co-eluted with corticotropin, alpha-melanotropin, beta-lipotropin, or beta-endorphin upon Sephadex G-50 gel filtration. Extracts of similarly labeled rat anterior and intermediate pituitary lobe cells contained two forms of the common precursor molecule corresponding to the same molecular weights estimated for the hypothalamic material and similar to it with respect to other physicochemical parameters. These data suggest that rat hypothalamus synthesizes corticotropin-related and beta-endorphin-related products via sequential cleavage of a larger common precursor molecule in a manner similar to the processing pathway demonstrated for the intermediate lobe of the pituitary.

Biosynthesis of precursor corticotropin/endorphin-, corticotropin-, alpha-melanotropin-, beta-lipotropin-, and beta-endorphin-like material by cultured neonatal rat hypothalamic neurons

Enzymatically dispersed bovine hypothalamic or cortical tissue was maintained in culture in the presence of 3H-labeled amino acids. After such incubation, extracts of cells and of media contained 3H-labeled products that were specifically bound by immobilized affinity-purified antisera to corticotropin (ACTH) and β-endorphin. The majority of these products eluted in the void volume (V0) upon Sephadex G-50 gel filtration; minor 3H-labeled products eluted in the regions of the ovine β-lipotropin marker and in fractions having apparent molecular weights of approximately 12,000 and 3800. Sequential use of these immobilized antisera revealed that most of the V0 material contained both ACTH and β-endorphin antigenic determinants within the same molecule(s), whereas retarded material contained only one of the determinants. When this V0 material was rerun on a Sephadex G-75 column, it coeluted with the 31-kilodalton precursor of both ACTH and β-endorphin obtained from a bovine anterior pituitary extract. Thus, the high molecular weight immunoreactive ACTH/β-endorphin-like 3H-labeled product(s) derived from the hypothalamic culture is similar to the pituitary-derived precursor in containing the dual antigenic determinants and in its gel filtration characteristics. In contrast, the cortex-derived cell preparation was devoid of 3H-labeled products specifically reactive with the antisera employed.

https://www.pnas.org/content/pnas/76/3/1448.full.pdf

Dorothy T. Krieger

Papers

Characterization of the normal temporal pattern of plasma corticosteroid levels.

Characterization of Immunoreactive Proopiomelanocortin-Related Peptides in Rat Testes

Sleep EEG stages and plasma growth hormone concentration in states of endogenous and exogenous hypercortisolemia or ACTH elevation.

Biosynthesis of precursor corticotropin/endorphin-, corticotropin-, alpha-melanotropin-, beta-lipotropin-, and beta-endorphin-like material by cultured neonatal rat hypothalamic neurons

Biosynthesis in vitro of immunoreactive 31,000-dalton corticotropin/β-endorphin-like material by bovine hypothalamus