Primary Pancreatic Secretinoma: Further Evidence Supporting Secretin as a Diarrheogenic Hormone.

OBJECTIVES: To document the existence of primary pancreatic secretinoma in patients with watery diarrhea syndrome (WDS) and achlorhydria and establish secretin as a diarrheogenic hormone. BACKGROUND: Vasoactive intestinal peptide (VIP) has been widely accepted as the main mediator of WDS. However, in 1968, Zollinger et al reported 2 female patients with pancreatic neuroendocrine tumors, WDS, and achlorhydria. During surgery on the first, a 24-year-old patient, they noticed distended duodenum filled with fluid and a dilated gallbladder containing dilute bile with high bicarbonate concentration. After excision of the tumor, WDS ceased and gastric acid secretion returned. The second, a 47-year-old, patient's metastatic tumor extract given intravenously in dogs, produced significantly increased pancreatic and biliary fluid rich in bicarbonate. They suggested a secretin-like hormone of islet cell origin explains WDS and achlorhydria. These observations, however, predated radioimmunoassay, immunohistochemical staining, and other molecular studies. METHODS: The first patient's tumor tissue was investigated for secretin and VIP. Using both immunohistochemistry and laser microdissection and pressure catapulting technique for RNA isolation and subsequent reverse transcription polymerase chain reaction, the expression levels of secretin, and VIP were measured. RESULTS: Immunoreactive secretin and its mRNA were predominantly found in the tumor tissue whereas VIP and its mRNA were scarce. CONCLUSIONS: The findings strongly support that the WDS and achlorhydria in this patient may have been caused by secretin as originally proposed in 1968 and that secretin may act as a diarrheogenic hormone.

Mega-Cecum: An Unrecognized Cause of Symptoms in Some Female Patients with Uro-Gynecological Symptoms and Severe Slow Transit Constipation.

BACKGROUND: A subset of female patients with severe constipation report overlapping uro-gynecological symptoms which have been attributed to visceral hypersensitivity. AIMS: To study colon morphology and motor function in female patients with medically refractory chronic constipation with or without uro-gynecological symptoms and to assess clinical outcomes following laparoscopic ileo-proctostomy. METHODS: Colon anatomy and cecal emptying time were assessed with plain films and fluoroscopy following a standardized test meal mixed with barium. Transit time was determined with radiopaque markers. IBS-QOL and urinary incontinence questionnaires were employed to assess post-colectomy clinical response. RESULTS: In 21 consecutive patients, mean colon transit time (h) was 211.1 ± 11.3, which was significantly greater than 58.9 ± 5.1 of 10 normal subjects (P < 0.001). Mega-cecum was found in 15 (Group 1) with mean cecal volume of 587 ± 27.9 cm3, significantly greater (P < 0.001) than 169.5 ± 10.4 cm3 of six without mega-cecum (Group 2). Mean cecal empting time (days) of barium-mixed feces in Group 1, 4.0 ± 0.6 was significantly greater than 1.33 ± 0.21 in Group 2 (P < 0.001). Eighteen patients (Groups 1 and 2) who had laparoscopic ileo-proctostomy experienced significantly improved quality of life (P < 0.001). In particular, Group 1 patients benefited significantly from improved uro-gynecological symptoms. CONCLUSIONS: Hitherto an unrecognized mega-cecum with markedly impaired emptying function was found in patients with severe slow transit constipation and uro-gynecological symptoms. Subtotal colectomy relieved constipation and improved significantly uro-gynecological symptoms, suggesting strongly that mega-cecum is causally related to these symptoms.

Androgen receptor (AR) physiological roles in male and female reproductive systems: lessons learned from AR-knockout mice lacking AR in selective cells.

Androgens/androgen receptor (AR) signaling is involved primarily in the development of male-specific phenotypes during embryogenesis, spermatogenesis, sexual behavior, and fertility during adult life. However, this signaling has also been shown to play an important role in development of female reproductive organs and their functions, such as ovarian folliculogenesis, embryonic implantation, and uterine and breast development. The establishment of the testicular feminization (Tfm) mouse model exploiting the X-linked Tfm mutation in mice has been a good in vivo tool for studying the human complete androgen insensitivity syndrome, but this mouse may not be the perfect in vivo model. Mouse models with various cell-specific AR knockout (ARKO) might allow us to study AR roles in individual types of cells in these male and female reproductive systems, although discrepancies are found in results between labs, probably due to using various Cre mice and/or knocking out AR in different AR domains. Nevertheless, no doubt exists that the continuous development of these ARKO mouse models and careful studies will provide information useful for understanding AR roles in reproductive systems of humans and may help us to develop more effective and more specific therapeutic approaches for reproductive system-related diseases.

Evidence on the presence of secretin cells in the gastric antral and oxyntic mucosa.

Secretin is released from upper small intestinal mucosa to drive pancreatic secretion of fluid and bicarbonate and inhibit gastric acid secretion. Recently, we found that, in isolated, vascularly perfused rat stomach model, the inhibition of acid secretion by pituitary adenylate cyclase activating polypeptide (PACAP) was mediated in part via local release of secretin. However, the presence of secretin-producing cells and mRNA in gastric mucosa, particularly in oxyntic mucosa, has not been established. The present study was carried out to establish the presence of secretin cells by immunohistochemical and mRNA by biochemical methods in gastric mucosa. Secretin cells were identified in antral mucosa (27.8 +/- 2.0 cells/mm(2)) and corpus (4.7 +/- 0.5 cells/mm(2)). They were distinguishable, through double immunostaining, from gastrin and somatostatin cells in the antrum and from somatostatin cells in the corpus. The results of reverse transcription (RT)-PCR and Southern blot indicated that a secretin gene transcript of 454 bp was present in the mRNA extracts of both antral and corpus mucosae. The results indicated that secretin mRNA is present in gastric mucosa. In conclusion, secretin-producing cells and mRNA are present in gastric mucosa and the locally released secretin may exert a paracrine effect to inhibit acid secretion.

Secretin, 100 years later.

One hundred years have elapsed since the discovery of secretin by Bayliss and Starling in 1902. In the past century, the research of secretin has gone by many milestones including isolation, purification and structural determination, chemical synthesis, establishment of its hormonal status by radioimmunoassay and immunoneutralization, identification of the specific receptor, cloning of secretin and its receptor, and identification of a secretin-releasing peptide. It has become clear that secretin is a hormone-regulating pancreatic exocrine secretion of fluid and bicarbonate, gastric acid secretion, and gastric motility. The release and actions of secretin is regulated by hormone-hormonal and neurohormonal interactions. The vagus nerve, particularly its afferent pathway, plays an essential role in the physiological actions of secretin. Substantial information about the property of the secretin receptor has been accumulated, but a potent secretin receptor-specific antagonist remains to be formulated. The neural regulatory mechanisms of the release and action of secretin await further elucidation. The physiological role of secretin in intestinal secretions and motility and extragastrointestinal organs remains to be defined. The presence of secretin and its receptor in the central nervous system is well documented, but its function as a neuropeptide has been recognized gradually and requires extensive study in the future.

Secretin: historical perspective and current status.

This review describes the history of secretin discovery, identification, purification, and structural determination; cloning of secretin and its receptor; synthetic secretin; and highly specific and sensitive radioimmunoassay to define the characteristic physiological role on postprandial pancreatic fluid and bicarbonate secretion, which requires robust potentiation by cholecystokinin. Secretin plays a key role in the negative and positive regulatory mechanisms of exocrine pancreatic secretion. Secretin-releasing peptides were discovered in duodenal acid perfusates of both rat and dog and in canine pancreatic juice. The release and action of secretin and secretin-releasing peptides are in part mediated via vagovagal reflex mechanism involving afferent sensory neurons in proximal intestine and efferent cholinergic neurons in the pancreas. Besides acetylcholine, many neurotransmitters or neuromodulators influence release and action of secretin. The action of secretin in the pancreas depends on insulin, which also suppresses local release of somatostatin and pancreatic polypeptide. Thus, release and action of secretin are mediated via neurohormonal interaction. Clinical conditions with hypersecretinemia and hyposecretinemia are discussed. Synthetic human secretin is used for studies of exocrine pancreatic secretion, secretin-enhanced magnetic resonance cholangiopancreatography combined with exocrine pancreatic function test and diagnosis of gastrinoma syndrome. Therapeutic use of secretin is considered for the relief of severe pain in chronic pancreatitis.

Androgen receptor (AR) pathophysiological roles in androgen-related diseases in skin, bone/muscle, metabolic syndrome and neuron/immune systems: lessons learned from mice lacking AR in specific cells.

The androgen receptor (AR) is expressed ubiquitously and plays a variety of roles in a vast number of physiological and pathophysiological processes. Recent studies of AR knockout (ARKO) mouse models, particularly the cell type- or tissue-specific ARKO models, have uncovered many AR cell type- or tissue-specific pathophysiological roles in mice, which otherwise would not be delineated from conventional castration and androgen insensitivity syndrome studies. Thus, the AR in various specific cell types plays pivotal roles in production and maturation of immune cells, bone mineralization, and muscle growth. In metabolism, the ARs in brain, particularly in the hypothalamus, and the liver appear to participate in regulation of insulin sensitivity and glucose homeostasis. The AR also plays key roles in cutaneous wound healing and cardiovascular diseases, including atherosclerosis and abdominal aortic aneurysm. This article will discuss the results obtained from the total, cell type-, or tissue-specific ARKO models. The understanding of AR cell type- or tissue-specific physiological and pathophysiological roles using these in vivo mouse models will provide useful information in uncovering AR roles in humans and eventually help us to develop better therapies via targeting the AR or its downstream signaling molecules to combat androgen/AR-related diseases.