Effect of leuprolide acetate in treatment of abdominal pain and nausea in premenopausal women with functional bowel disease: a double-blind, placebo-controlled, randomized study.

We have previously reported impressive results in using a gonadotropin-releasing hormone analog, leuprolide acetate (Lupron), in the treatment of moderate to severe symptoms (especially abdominal pain and nausea) in patients with functional bowel disease (FBD). Pain is the hallmark of patients with FBD, and there is no consistent therapy for the treatment of these patients. The purpose of the present study was to expand the investigation to study similar patients (menstruating females) in a multicenter, double-blind, placebo-controlled, randomized study using Lupron Depot (which delivers a continuous dose of drug for one month), 3.75 mg (N = 32) or 7.5 mg (N = 33), or placebo (N = 35) given intramuscularly every four weeks for 16 weeks. Symptoms were assessed using daily diary cards to record abdominal pain, nausea, vomiting, early satiety, anorexia, bloating, and altered bowel habits. Additional assessment tools were quality of life questionnaires, psychological profile, oral-to-cecal transit using the hydrogen breath test, antroduodenal manometry, reproductive hormone levels, and global evaluations by both patient and investigator. Patients in both Lupron Depot-treated groups showed consistent improvement in symptoms; however, only the Lupron Depot 7.5 mg group showed a significant improvement for abdominal pain and nausea compared to placebo (P < 0.001). Patient quality of life assessments and global evaluations completed by both patient and investigators were highly significant compared to placebo (P < 0.001). All reproductive hormone levels significantly decreased for both Lupron Depot-treated groups by week 4 and were significantly different compared to placebo at week 16 (P < 0.001). This study shows that leuprolide acetate is effective in controlling the debilitating symptoms of abdominal pain and nausea in patients with FBD.

Relationship of reproductive hormones and neuromuscular disease of the gastrointestinal tract.

Functional disorders of the gastrointestinal tract comprise a common but ill-defined group of diseases; they primarily afflict women. Although predominantly involving nerve and muscle, the cellular and molecular bases of the pathogenesis of these functional disorders are unknown. Clinical studies indicate that some result from neural dysfunction within the enteric nervous system, others may be due to muscular problems, and the causes of still others remain unknown. Laboratory studies have shown that ovarian products such as progesterone, luteinizing hormone, human chorionic gonadotropin, and relaxin (but not estrogen), are neural antagonists of gastrointestinal motility. The production and secretion of these ovarian substances are controlled by gonadotropin-releasing hormone (GnRH) released from the hypothalamus; they probably act on gamma-aminobutyric acid receptors and alter chloride influx into the cell. GnRH analogs are effective drugs that downmodulate the hypothalamic-pituitary-gonadal axis and inhibit the secretion of gonadal products involved in such hormone-dependent diseases as endometriosis and prostate cancer. Acting on the GnRH receptors (seven transmembrane domain receptors) on myenteric neurons, GnRH analogs are also effective neural modulators in such disorders as functional bowel disease. These analogs are a promising new group of compounds that may be used to treat difficult gastrointestinal problems.

Myoelectric activity of the cecum in fed and fasted domestic fowl (Gallus sp.).

To study cecal motility and its relation to the fed and fasted condition in domestic fowl, we sutured 7 miniature electrodes onto the ceca and ileum of 4 roosters. After recovery from the surgery, the birds received recordings of myoelectric activity for a total of 169 h while fasted and for 28 h while in the fed state. We found that single or brief clusters of action potentials (APs) occurred in the cecal smooth muscle at mean frequencies of 10.8 to 25.0/h, with the fewest when the lumen contained little food (after fasting > 24 h). Virtually all APs propagated, whether orad (toward the ileocecocolic junction) or retrograde (toward the cecal tip), with retrograde activity significantly more frequent (P < 0.001). Propagation velocity was rapid, varying from 8 to 750 cm/min (mean = 106 cm/min), being slower when birds were in the fed state. Thus, fasting resulted in fewer and more rapid APs and more that propagated toward the cecal tip. Motor activity was well coordinated between ceca, both organs showing essentially simultaneous spike activity; 72% of APs occurred within 8.1 s of each other. No relationship between ileal and cecal activity was apparent. Prominent slow waves were recorded in the ceca (5 to 5.5/min), the same slow-wave frequency as in the ileum (small intestine). From the results obtained here and from earlier studies, we conclude that the single or brief clusters of APs represent contractions that produce mixing of the luminal contents; occasional periods of protracted APs represent evacuation of cecal contents.

Luteinizing hormone and human chorionic gonadotropin fragment the migrating myoelectric complex in rat small intestine.

We hypothesized that sex hormones may affect motility disorders because these diseases occur more often in women than in men, and symptoms often occur or worsen after ovulation. Luteinizing hormone (LH) is predominantly secreted by the anterior pituitary midway through the menstrual cycle; it results in the development of the corpus luteum. LH levels also increase after bilateral gonadectomy. LH and human chorionic gonadotropin (hCG) bind to the same receptor, but rats lack hCG. To assess how LH and hCG influence myoelectric activity of the small intestine and to test the specificity of the LH receptor, we implanted electrodes on the jejunum of female rats. LH (0.1 or 0.5 NIH units) was administered intraperitoneally to intact and gonadectomized rats and 0.5 NIH units to rats that had been both hypophysectomized and gonadectomized; intact animals were treated with 100 units USP of hCG. Recordings were made with the rats in fasted and in fed states, and their intestinal motility was analysed. The most striking effects of LH, hypophysectomy, and hCG were the same: phase III of the migrating myoelectric complex was markedly fragmented and its duration lengthened (P < 0.0001). Gonadectomy alone and gonadectomy with hypophysectomy also increased fragmentation and phase III duration (P < 0.01 or better). LH receptors respond similarly to LH and hCG, and both hormones alter myoelectric activity of the rat small intestine in comparable ways.

Presence of gonadotropin-releasing hormone (GnRH) receptor mRNA in rat myenteric plexus cells.

Idiopathic neuromuscular disease of the gastrointestinal tract (functional bowel disease) is thought to result from the malfunction of neurons within the enteric nervous system. Gonadotropin-releasing hormone (GnRH) analogs have recently been shown to organize the disordered motility patterns typical in these patients and to produce significant, long-term symptomatic improvement. To determine whether GnRH analogs might bind to an endogenous enteric nervous system GnRH receptor, reverse transcription-polymerase chain reaction (RT-PCR) was performed using cultured neonatal rat enteric neuron RNA and rat GnRH receptor primers. A PCR product of the predicted size was cloned and nucleotide sequence analysis demonstrated that the myenteric plexus PCR product encoded a portion of the GnRH receptor sequence previously identified in rat pituitary. These results suggest that cells in the myenteric plexus express GnRH receptors that may bind exogenously administered GnRH analogs. The expression of GnRH receptors in enteric neurons would provide an explanation for the effectiveness of GnRH analogs in treatment of idiopathic neuromuscular disease of the gastrointestinal tract.

Effect of cloned Salmonella typhimurium enterotoxin on rabbit intestinal motility.

We analysed the small intestine myoelectric responses of anesthetized New Zealand albino rabbits to Escherichia coli lysates containing an entertoxin cloned from Salmonella typhimurium. Migrating action potential complex, which consisted of rapid bursts of actions potentials and secretion of fluid, was observed only in ileal loops, injected with the enterotoxin-containing lysate. Migrating action potential complex produced by Stn usually propagated aborally, which was typical of cholera toxin, but orad or bidirectional propagation occurred from a single point of origin when activity was intense. Cell lysates from an E. coli clone containing vectors alone, as well as proximal control segments injected with phosphate-buffered saline, gave neither a change in motility nor fluid secretion. These results show that Stn caused dramatic changes in intestinal motility and substantial fluid production.

Ampulla of Vater/duodenal wall spasm diagnosed by antroduodenal manometry.

Patients with chronic epigastric to right upper quadrant pain are often considered to have gallbladder of sphincter of Oddi dysfunction, but standard tests are nondiagnostic. In 62 consecutive patients with this compliant undergoing antroduodenal manometry, we correlated a change on duodenal motility with spasm of the ampulla of Vater/duodenal wall. This distinctive motility pattern occurred and was analyzed in 35% of patients. It is characterized by increased duodenal wall tone with phasic contractions of 19-22 or 41-44 contractions/min or by phasic activity alone. The subjects with spasm also underwent cholecystokinin cholescintigraphy, and 50% showed either significantly delayed gallbladder emptying of hilum to small intestine emptying, or both. The disorder appears to be secondary to a loss of neural inhibitory control and a dysfunctional small-bowel pacemaker. Antroduodenal manometry is an essential diagnostic procedure that complements sphincter of Oddi manometry in evaluation of unexplained right upper quadrant pain.

Neuromuscular diseases of the gastrointestinal tract. Specific disorders that often get a nonspecific diagnosis.

Gastrointestinal motor dysfunction, intestinal pseudo-obstruction syndromes, and hollow visceral neuropathy and myopathy were previously considered functional bowel diseases but are now recognized to be organic disorders. They may alter the muscle of the intestinal wall or the nerves of the myenteric plexus, or both. Their symptoms of chronic unexplained abdominal pain, abdominal distention and bloating, early satiety, nausea, vomiting, and alternating diarrhea and constipation are the most common and perhaps the most difficult problems encountered by gastroenterologists. New intestinal recording devices assess motility and allow objective classification of neuromuscular disease, permitting accurate diagnosis and better treatment.

Effect of leuprolide acetate in patients with moderate to severe functional bowel disease. Double-blind, placebo-controlled study.

Moderate to severe functional bowel disease results in debilitating abdominal pain, nausea, intermittent vomiting, early satiety, bloating, abdominal distension, and/or altered bowel habits. Because it occurs approximately 20-30 times more frequently in women than in men and its symptoms often coincide with the menstrual cycle, we hypothesized that reproductive steroids may antagonize diseased nerves of the gastrointestinal tract, enhancing the expression of symptoms. No effective or consistent therapy has existed for these patients. We prospectively investigated the effect of a gonadotropin-releasing hormone analog, leuprolide acetate, in 30 women with symptoms of moderate to severe functional bowel disease. The study was phase II, randomized, double blind, and placebo controlled. Lupron Depot 3.75 mg (which delivers a continuous low dose of drug for one month) or placebo were given intramuscularly monthly for three months. Symptom scores were assessed at each four-week visit. Follicle-stimulating hormone, luteinizing hormone, estradiol, and progesterone levels were assessed before and after therapy. Patients treated with low-dose leuprolide improved progressively and significantly in scores for nausea, vomiting, bloating, abdominal pain, and early satiety, and for overall symptoms (P < 0.01-0.05). All hormone levels decreased significantly (P < 0.05) except luteinizing hormone (P = 0.054).

Effect of leuprolide acetate in patients with functional bowel disease. Long-term follow-up after double-blind, placebo-controlled study.

We initially investigated the effects of a gonadotropin-releasing hormone analog, leuprolide acetate, in 28 patients with moderate to severe functional bowel disease in a phase-II, randomized, double-blind, and placebo-controlled study using Lupron Depot 3.75 mg (which delivers a continuous low dose of drug for one month) or placebo given intramuscularly. After completing that 12-week study period during which their symptoms had improved significantly (P < 0.01-0.5), the 28 patients were allowed to continue receiving leuprolide acetate; they were monitored for an additional 40 weeks. Of those 28, 25 (89%) finished the 52-week treatment. Drug administration was changed from the monthly low-dose form of leuprolide acetate to a daily subcutaneous dose that was gradually increased from 0.5 mg daily to an effective therapeutic dose (1.0-1.5 mg). All subjects received estrogen replacement during this period. Continued use of leuprolide acetate at maximum therapeutic dosage and over longer periods of time produced even more striking and significant changes in the disabling and debilitating symptoms of functional bowel disease. Nausea, abdominal pain, early satiety, anorexia, and abdominal distension decreased markedly (P < 0.0001) and vomiting was also reduced (P < 0.01) more than in the short-term, low-dosage, double-blind study. Combined total symptom scores and overall assessment also changed significantly in the long-term phase (both P < 0.0001).

Clostridium difficile diarrhea in patients with AIDS versus non-AIDS controls. Methods of treatment and clinical response to treatment.

We reviewed the hospital charts of 17 patients with AIDS and Clostridium difficile diarrhea to determine antibiotic use before C. difficile infection, methods of treatment for C. difficile diarrhea, and response of diarrhea to treatment. Left shift and total white blood cell count before and after treatment for C. difficile were also determined. Non-HIV-infected patients with C. difficile diarrhea served as controls. In the patients with AIDS, resolution of diarrhea was noted in 15 (88%) patients. In 25 (76%) control patients, diarrhea resolved with treatment. The patients with AIDS also had a significant decrease (p < 0.05) in left shift in white blood cell count with treatment; the controls did not. Our study therefore suggests that C. difficile diarrhea is at least as likely to resolve with antibiotic therapy in patients with AIDS as it is in those with the non-AIDS-related disorder. We also found that patients with AIDS and C. difficile diarrhea are more likely than patients without AIDS to have a decreased left shift in white blood cell count after antibiotic therapy.

Chronic intestinal pseudoobstruction in a patient with heart-lung transplant. Therapeutic effect of leuprolide acetate.

After orthotopic heart-lung transplantation and immunosuppression, a patient developed intractable nausea and vomiting in association with chronic cytomegalovirus infection. Chronic intestinal pseudoobstruction was documented by antroduodenal manometric study. The patient was treated with leuprolide acetate with resolution of symptoms and improvement of intestinal motility abnormality. This case demonstrates an association of chronic viral infection with acquired intestinal motor disorders. Gastrointestinal complications that are common after organ transplantation might be due to acquired neuromuscular disease. The potential efficacy of leuprolide in such neuromuscular disorders provides a rationale for diagnostic motility studies in patients with "functional" gastrointestinal disorders.

Roux-limb motility after total gastrectomy and Roux-en-Y anastomosis in patients with Zollinger-Ellison syndrome.

The Roux-en-Y syndrome was defined as chronic nausea, intermittent vomiting, and chronic abdominal pain worsened by eating in patients who have undergone a gastrojejunostomy Roux-en-Y reconstruction for peptic ulcer. When these patients fasted, the Roux limb showed striking abnormalities in motor function; when postprandial, they failed to convert to normal fed-state motor activity. In contrast, patients with Zollinger-Ellison syndrome do well after similar surgery; they can eat most foods and maintain their body weight. We studied the motility of the Roux limb and jejunum in six patients with Zollinger-Ellison after an esophagojejunostomy Roux-en-Y anastomosis. Roux-limb motor activity in these patients, as characterized by the migrating motor complex, was more frequent, well organized, and in synchrony with the remaining jejunum; most subjects also converted to the fed state after a liquid meal. We suggest that the enteric nervous system is intact and functions normally in patients who have had a Roux-en-Y reconstruction for ulcer disease secondary to Zollinger-Ellison, but not in patients with idiopathic peptic ulcer disease.

A complex avian intestinal motility response to fasting.

The rhythmic oscillating complex (ROC) is described from a series of experiments that surveyed the myoelectric activity of the avian small intestine as recorded from chronically implanted bipolar electrodes. A highly organized myoelectric event in the fasting avian small intestine, the ROC is demonstrated in detail in chickens (Gallus); it is also found in other gallinaceous birds but not in owls (Strix) or mammals. The ROC comprises rapidly propagating bursts of spike potentials (SPBs) that occur in a regular and predictable pattern: single orad SPBs alternate with groups of aborad SPBs. An average ROC in a chicken contains a mean of 78.9 +/- 2.0 (mean +/- SE) SPBs (37% orad, 63% aborad) that rapidly traverse the full length of the small intestine. The aborad SPBs move at mean velocities of 25.0 +/- 0.5 cm/s and last a mean of 0.9 +/- 0.0 s at an electrode site; the orad SPBs are faster (41.2 +/- 2.3 cm/s) and longer in duration (1.3 +/- 0.0 s). ROC activity continues for a mean of 7.6 +/- 0.2 min. ROCs occur only in a well-fasted gut as often as every 3 h and apparently for as long as the bird remains without food. Because ROCs restimulate fed-state activity in the stomach and small intestine, we hypothesize that they recycle nutritive material for further digestive activity in the distal tract.

Leuprolide acetate affects intestinal motility in female rats before and after ovariectomy.

Leuprolide acetate, a gonadotropin-releasing hormone (GnRH) analogue, is currently being proposed to control debilitating symptoms in women with functional bowel disease. Whether leuprolide alters gastrointestinal motility as part of its actions is unknown. This study was designed to assess, using myoelectric techniques in an animal model, the effects of leuprolide on potential mechanisms of neuromuscular function of small intestine. Female rats with (n = 6) or without (n = 8) bilateral ovariectomy were used to study jejunal motility before and after leuprolide therapy. Throughout the study, daily leuprolide dosages of 0.02, 0.2, or 0.4 micrograms/kg were injected into intact rats and 0.02, 0.2, 0.4, 1.0, or 2.5 micrograms/kg into ovariectomized rats. Recordings were made while the rats were fasted and postprandial and before and after leuprolide administration. Under control conditions, migrating myoelectric complexes (MMCs) were found in intact female rats, whether fasted or postprandial. After ovariectomy, postprandial controls and those treated with low-dose leuprolide (0.02, 0.2, and 0.4 micrograms) had typical fed-state patterns and no MMCs, but at 1.0 and 2.5 micrograms the fed state was inhibited and cycling MMCs occurred at a frequency similar to that of fasted controls. Reproductive hormones thus have a significant effect on gastrointestinal motility.

Intestinal motility changes in rats after enteric serotonergic neuron destruction.

The myenteric plexus consists of several subpopulations of morphologically and chemically distinct neurons known to contain a variety of peptides and amines, one of which is serotonin (5-hydroxytryptamine). These neurons are considered essential for nerve-to-nerve transmission. In the present study, we investigated the effect of 5,6- and 5,7-dihydroxytryptamine (5,6-DHT; 5,7-DHT), indoleamine neurotoxins that selectively and irreversibly injure the serotonergic neurons of the myenteric plexus. Treatment with 5,6-, or 5,7-DHT caused marked disruption of the activity front of the migrating myoelectric complex (MMC), increased its duration, and decreased its propagation velocity. At higher doses, 5,7-DHT also reduced the slow-wave frequency. Immunohistochemical techniques showed that tissue from rats treated with 5,7-DHT was depleted of serotonin-like immunoreactivity within the myenteric plexus neurons. Reserpine also caused motility and immunohistochemical changes similar to those induced by the two neurotoxins. Therefore, destruction of enteric serotonergic neurons disrupts the MMC. These studies support the cellular concepts that serotonergic neurons function as interneurons in the myenteric plexus, modulating and processing the neural stimuli, and that serotonin is an important neurotransmitter in the small intestine.

Debilitating "functional" bowel disease controlled by leuprolide acetate, gonadotropin-releasing hormone (GnRH) analog.

In this informal initial study, four female patients with intractable chronic abdominal pain, daily nausea, intermittent vomiting, and altered stool habits due to "functional" disease were investigated. A gonadotropin-releasing hormone (GnRH) analog agonist, leuprolide acetate (Lupron) [D-leu6, Desgly-NH2(10), Proethylamide9], was administered once daily (0.5 mg subcutaneously) for three months. At the end of the three-month period, three subjects were symptom-free and the fourth experienced only mild and intermittent pain. The leuprolide regimen was continued for an additional three months, and estrogen (0.625 mg orally) and calcium (1000 mg orally) were given daily to prevent osteoporosis. The patients remained symptom-free. A challenge with progesterone then induced recurrence of mild symptoms in each subject. Withdrawing leuprolide induced the baseline symptoms in all patients within three to five days. This regimen has now been continued for up to 15 months, and all four patients have remained generally symptom-free. Progesterone has also been given every three months to induce menses. A fifth patient, with Roux-en-Y syndrome, has also been treated with leuprolide. She is symptom-free after six months and has gained weight. In this initial observation period in patients with severe functional (neuromuscular) bowel disease, the GnRH analog agonist leuprolide controlled pain, nausea, and vomiting.(ABSTRACT TRUNCATED AT 250 WORDS)

Migrating myoelectric complex demonstrated in four avian species.

The migrating myoelectric complex (MMC) is demonstrated in four avian species: three gallinaceous birds (Gallus, Phasianus, Coturnix) and an owl (Strix). The complex in birds is strikingly similar to the MMC that is known in mammalian species. It has the same basic pattern of quiescence, followed by a period of irregular spike activity, then a period of intense regular spike activity, and finally a return to quiescence. The frequency and duration of avian MMCs are similar to those of mammals, but the propagation velocity and slow-wave frequency are slower. Granivorous birds (Gallus, Phasianus) and carnivores (Strix) exhibit the same basic motility patterns whether in the fed or fasted states. Interspecific differences occur, however, in the details of frequency, propagation velocity, duration, and slow-wave frequency. The closely related galliforms (chickens, pheasants) are more similar to each other in MMC characteristics than either is to the more distantly related owls.

Effects of domperidone in patients with chronic unexplained upper gastrointestinal symptoms: a double-blind, placebo-controlled study.

The effects of domperidone, a peripherally acting dopamine antagonist, were compared with those of placebo in a double-blind randomized study in 16 patients with idiopathic gastric stasis, chronic symptoms of "nonulcer dyspepsia" (including nausea, vomiting, and abdominal pain), and altered gastroduodenal motility. Patients received either domperidone or placebo orally (20 mg before meals and at bedtime) for six weeks. Symptoms were assessed by daily diaries kept by the patients for two weeks while receiving no medication for their gastrointestinal complaints (baseline), and throughout the six-week treatment phase. Studies of gastric emptying of a radiolabeled solid-phase meal were performed at baseline and six weeks after treatment. All patients had delayed gastric emptying at baseline, defined as a half-emptying time of more than mean + 1 SD (from studies of normal controls). An 18- to 24-hr recording of gastroduodenal motor function during fasting was also performed at baseline and after six weeks of either domperidone or placebo treatment. After six weeks of treatment, the symptom scores significantly improved in the domperidone group (P less than 0.05), but not in the placebo group. Gastroduodenal motor activity was unchanged from baseline recordings after six weeks. Solid-phase gastric emptying also showed no improvement in either the domperidone or placebo group of patients. Although domperidone therapy had no significant effect on motility, it appears to be an effective drug for the treatment of the symptoms of nonulcer dyspepsia.

Gastric emptying in infants with gastroesophageal reflux. Measurement with a technetium-99m-labeled semisolid meal.

It is well established that liquid emptying occurs in the absence of motor activity of the stomach. In contrast, solid-phase emptying is controlled in part by antral peristalsis and is, therefore, a more precise indicator of gastric motility. We developed a semisolid, radionuclide gastric emptying test using rice cereal and technetium-99m-sulfur colloid to assess antral physiology in infants with vomiting. Computer-programmed mathematical models were used to determine the shape of a line that best fit our emptying data points. Linear, simple exponential [f = 2-(t/t1/2)], and power exponential [f = 2(t/t1/2)beta] patterns of emptying were calculated, where f is the fraction of the meal remaining in the stomach at time t, and t1/2 is the time when 50% of the meal has emptied and is a determinant of the shape of the curve. In infants with simple regurgitation (chalasia) and those with vomiting and failure to gain weight, we made statistical comparisons between gastric emptying patterns after analysis of the mean percentage of retained radionuclide at 120 min, calculated t1/2, and area under the curve. The coefficient of determination, R2, was calculated as an index of whether a curve provided goodness of fit to the data. Differences between groups of patients were statistically significant for all parameters of each mathematical model. However, higher coefficients of determination were noted in the power exponential model. The data suggest that the power exponential mathematical model provides the best analysis of the gastric emptying patterns for infants with chalasia and those with vomiting and failure to gain weight.(ABSTRACT TRUNCATED AT 250 WORDS)