Effect of severe gastroesophageal reflux on sleep stage in patients with aperistaltic esophagus

Polysomnography and esophageal pH studies were conducted in 13 patients with an aperistaltic esophagus; seven of these had scleroderma and six were patients treated for achalasia. The percentage total time of pH <4.0 when recumbent exceeded 30% for both groups. There was a total of 51 reflux events for both groups. There were 22 reflux events recorded for both groups that were less than 5 min in length and 29 events greater than 5 min. In 26 of 32 (81%) instances, patients either began awake and went to sleep during a reflux event or did not awake during a reflux event. Only six of 32 (19%) reflux events caused sleep disruption. We conclude that even the severe reflux demonstrated in this subset of patients does not always disrupt sleep. Patients may have severe prolonged reflux and not arouse.This paper was presented in part at the AGA meeting, San Diego, California, 1995.     

Laparoscopic fundoplication for gastroesophageal reflux disease

Gastroesophageal reflux disease(GERD) is a condition that develops when the reflux of gastric contents into the esophagus leads to troublesome symptoms and/or complications. Heartburn is the cardinal symptom, often associated with regurgitation. In patients with endoscopy-negative heartburn refractory to proton pump inhibitor(PPI) therapy and when the diagnosis of GERD is in question, direct reflux testing by impedance-pH monitoring is warranted. Laparoscopic fundoplication is the standard surgical treatment for GERD. It is highly effective in curing GERD with a 80% success rate at 20-year follow-up. The Nissen fundoplication, consisting of a total(360°) wrap, is the most commonly performed antireflux operation. To reduce postoperative dysphagia and gas bloating, partial fundoplications are also used, including the posterior(Toupet) fundoplication, and the anterior(Dor) fundoplication. Currently, there is consensus to advise laparoscopic fundoplication in PPI-responsive GERD only for those patients who develop untoward side-effects or complications from PPI therapy. PPI resistance is the real challenge in GERD. There is consensus that carefully selected GERD patients refractory to PPI therapy are eligible for laparoscopic fundoplication, provided that objective evidence of reflux as the cause of ongoing symptoms has been obtained. For this purpose, impedance-pH monitoring is regarded as the diagnostic gold standard.     

Double lumen esophagus: A rare complication of gastroesophageal reflux disease

Double lumen esophagus or esophagogastric fistula is a very rare endoscopic finding. Approximately 11 cases have been reported in the past. Formation of an esophagogastric fistula is predisposed by previous esophagogastric surgery, persistent gastroesophageal reflux, esophageal ulcer or esophageal carcinoma. Dysphagia and odynophagia are common symptoms. Endoscopy is the procedure of choice for diagnosis. Symptomatic management is the mainstay of treatment. Early diagnosis andmanagement of gastroesophageal reflux is essential to prevent reflux‐related fistulas. We report the case of a 48‐year‐old man with a history of dysphagia who was found to have esophagogastric fistula on endoscopy. He was treated conservatively with proton pump inhibitors leading to symptomatic improvement.     

Esophageal striated muscle contractions in patients with gastroesophageal reflux symptoms

Although there are studies showing that the amplitude of contraction in the distal esophageal body may be lower in gastroesophageal reflux (GER) disease than in asymptomatic subjects, there are no data about proximal striated muscle contraction in this disease. We studied the esophageal contraction 2 or 3 cm below the upper esophageal sphincter in response to swallowing a 5-ml bolus of water in 122 consecutive patients submitted to esophageal manometry who complained of heartburn and acid regurgitation. Sixty-nine had esophagitis seen at endoscopy. Thirty-three also complained of dysphagia. No patients had esophageal stenosis, esophageal motility abnormalities in distal esophagus, chest pain, or extraesophageal manifestations of GER. We also studied 20 patients with systemic sclerosis (SSc), a disease with no involvement of striated muscle. When we measured the amplitude, duration, and area under the curve (AUC) of the proximal esophageal contraction, we did not find any differences (P > 0.05) between patients with esophagitis (N = 69) or without esophagitis (N = 53), with dysphagia (N = 33) or without dysphagia (N = 89), with mild (N = 55) or severe (N = 14) esophagitis, or younger than 40 years (N = 45) or older than 60 years (N = 19). There was also no difference between patients with GER symptoms and patients with SSc (P > 0.05). We conclude that patients with GER symptoms with or without esophagitis and with or without dysphagia have similar esophageal striated muscle contractions.     

The lower esophageal sphincter strength in patients with gastroesophageal reflux before and after laparoscopic Nissen fundoplication

Lower esophageal sphincter pressure (LESP) and sphincter strength (LESS) were measured before and after short and floppy laparoscopic Nissen fundoplication (LNF) in 38 patients with severe gastro-esophageal reflux disease (GERD). These patients were compared with a control group of 23 healthy volunteers. GERD was assessed by stationary manometry, 24-h pH recordings and endoscopy. LESS was verified by motorized pull-back of an air-filled balloon catheter from the stomach into the esophagus. The catheter assembly was well tolerated by all study participants. LESP increased significantly after operation from 8 mmHg to 14 mmHg (75% of normal values; P < 0.0001), but compared to the control group, LESP (22 mmHg) decreased significantly (P < 0.002). In the control group and in patients with GERD, LESP and LESS showed excellent correlation (r = 0.97, r = 0.94, respectively). After LNF, LESS increased significantly from 0.6 to 1.6 N (P < 0.0001), about 166%. We conclude that the measurement of LESS is able to explain the discrepancy between satisfactory NF operation and the distinct increase of postoperative LESP. The evaluation of LESS is a helpful tool in assessing functional understanding of laparoscopic Nissen fundoplication with a short and floppy wrap.     

Use of multiple channel pH monitoring for evaluation of ultra‐distal reflux in patients after fundoplication for treatment of Barrett's esophagus

Dysplasia and esophageal adenocarcinoma may arise in patients with Barrett's esophagus after fundoplication esophageal pH monitoring showing no acid in esophagus. This suggests the need to develop methodology to evaluate the occurrence of ultra‐distal reflux (1 cm above the LES). The objective of the study was to compare acid exposition in three different levels: 5 cm above the upper border of the LES, 1 cm above the LES and in the intrasphincteric region. Eleven patients with Barrett's esophagus after Nissen fundoplication with no clinical, endoscopic and radiologic evidence of reflux were selected. Four‐channel pH monitoring took place: channel A, 5 cm above the upper border of the LES; channel B, 1 cm above the LES; channel C, intrasphincteric; channel D, intragastric. The results of channels A, B and C were compared. There was significant increase in number of reflux episodes and a higher fraction of time with pH <4.0 in channel B compared to channel A. There was significant decrease in fraction of time with pH <4.0 in channel B compared to channel C. Two cases of esophageal adenocarcinoma were diagnosed in the studied patients. The region 1 cm above the upper border of the LES is more exposed to acid than the region 5 cm above the upper border of the LES, although this exposure occurred in reduced levels. The region 1 cm above the upper border of the LES is less exposed to acid than the intrasphincteric region.     

Systematic review:Laparoscopic fundoplication for gastroesophageal reflux disease in partial responders to proton pump inhibitors

AIM:To assess laparoscopic fundoplication(LF)in partial responders to proton pump inhibitors(PPIs)for gastroesophageal reflux disease(GERD).METHODS:We systematically searched PubMed and Embase(1966-Dec 2011)for articles reporting data on LF efficacy in partial responders.Due to a lack of randomized controlled trials,observational studies were included.Of 558 articles screened,17 were eligible for inclusion.Prevalence data for individual symptoms were collated across studies according to mutually compatible time points(before and/or after LF).Where suitable,prevalence data were presented as percentage of patients reporting symptoms of any frequency or severity.RESULTS:Due to a lack of standardized reporting of symptoms,the proportion of patients experiencing symptoms was recorded across studies where possible.After LF,the proportion of partial responders with heartburn was reduced from 93.1%(5 studies)to 3.8%(5 studies),with similar results observed for regurgitation[from 78.4%(4 studies)to 1.9%(4 studies)].However,10 years after LF,35.8%(2 studies)of partial responders reported heartburn and 29.1%(1 study)reported regurgitation.The proportion using acidsuppressive medication also increased,from 8.8%(4studies)in the year after LF to 18.2%(2 studies)at 10years.In the only study comparing partial responders to PPI therapy with complete responders,higher symptom scores and more frequent acid-suppressive medication use were seen in partial responders after LF.CONCLUSION:GERD symptoms improve after LF,but subsequently recur,and acid-suppressive medication use increases.LF may be less effective in partial responders than in complete responders.     

New diagnostic criteria for nutcracker esophagus using conventional water‐perfused manometry: A comparison between nutcracker esophagus with and without gastroesophageal reflux disease

Background and Aim: Controversy continues as to whether nutcracker esophagus (NE) is a ‘real’ manometric disease due to its poor correlation with clinical symptoms such as chest pain or dysphagia. While new NE criteria were proposed in a recent study, that study included NE patients both with and without gastroesophageal reflux disease (GERD). We aimed to analyze both general NE (with or without GERD) and pure NE (without GERD) patients in terms of distal esophageal amplitude (DEA) and its correlation with symptoms. Methods: Using previously known normal DEA values (mean and SD), patients were stratified into three different groups: group A (DEA 180 to 220 mmHg, 2 to 3 SD), B (DEA 220 to 260 mmHg, 3 to 4 SD), and C (DEA > 260 mmHg, > 4 SD). Results: A total of 72 patients who simultaneously underwent esophageal manometry and 24‐h pH monitoring were diagnosed with NE. They were separated into groups A (n = 43), B (n = 18), and C (n = 11). Although the proportion of general NE patients with symptoms appeared to be greater in group A (65.6%) than in group C (90.9%), statistical analysis showed that this was not a significant correlation (P = 0.07). Pure NE patients were defined as those returning negative findings after 24‐h pH monitoring. These patients were separated into three groups based on the same DEA criteria as above: group A‐1 (n = 33), B‐1 (n = 11), C‐1 (n = 8). The proportion of patients with symptoms increased from 54.5% in group A‐1 to 87.5% in group C‐1, and this correlation was found to be significant (P < 0.05). Conclusions: There exists in the general NE population a subset with pure NE. DEA values correlated with symptoms in this subset.     

Laparoscopic fundoplication in mentally normal children with gastroesophageal reflux disease

Laparoscopic antireflux surgery has been performed in neurologically impaired and scoliotic children. We aimed to assess the effectiveness of laparoscopic fundoplication in mentally normal children with gastroesophageal reflux disease that failed to respond to medical therapy. Data were prospectively collected (symptoms, medical therapy, endoscopies' findings) on 12 children (nine boys, three girls) aged 9-15 years with gastroesophageal reflux disease. Pre- and postoperative ambulatory 24-h pH and DeMeester and Johnson scores were also recorded. Effectiveness of surgery was assessed by comparison of pre- and postoperative total acid exposure time, Visick grade, need for antireflux medication and symptom scores. In total, 11 children underwent a laparoscopic Nissen fundoplication and one underwent a Toupet procedure. Median length of stay was 2 (2-3) nights. The median preoperative pH acid exposure time (AET) was 4.7 (0.8-16.4) percent compared with postoperative AET of 0.4 (0-3) percent. Early postoperative dysphagia occurred in four out of 12 patients, requiring a total of six dilatations. Postoperative Visick scores were: grade I=7 and grade II=5. Laparoscopic fundoplication can be safely performed and is effective in children with GERD who have failed to respond to medical therapy.     

Provocation of transient lower esophageal sphincter relaxations by meals in patients with symptomatic gastroesophageal reflux

The effect of a meal on the rate of transient lower esophageal sphinter (LES) relaxations and patterns of gastroesophageal reflux was investigated in 49 patients referred for evaluation of gastroesophageal reflux. Esophageal motility and pH were recorded concurrently before and after a standard meal. In the patients with symptomatic reflux, the meal induced a four-to sevenfold increase in the gastroesophageal reflux through two mechanisms: a four-to fivefold increase in the rate of transient LES relaxations and an increase in the proportion of transient LES relaxations accompanied by reflux from 47% to 68^. Overall the rate of reflux episodes that occurred by mechanisms other than transient LES relaxation did not increase significantly. An exception to these findings were those in six patients with chronically absent basal LES pressure in whom transient LES relaxations could not be scored. In these patients, reflux increased postprandially through mechanisms other than transient LES relaxation. These findings confirm the pivotal importance of transient LES relaxations in the pathogenesis of gastroesophageal reflux.     

Laparoscopic fundoplication for patients with symptoms but no objective evidence of gastroesophageal reflux

In general terms, all patients who undergo a laparoscopic fundoplication procedure should have objective evidence of gastroesophageal reflux. However, occasionally patients without objective evidence of reflux disease are referred for surgery. This study assessed the outcome of a highly selected group of patients who underwent laparoscopic fundoplication without objective evidence of reflux at either preoperative endoscopy or pH monitoring. Data from all patients undergoing laparoscopic fundoplication in our department over a 9-year period from December 1991 to January 2001 were collected prospectively. From a total of 1,003 patients, a subgroup of 15 patients was identified who had no evidence of ulcerative oesophagitis at endoscopy or abnormal reflux on 24-h pH monitoring. Eight of these patients had typical symptoms of reflux (four had predominantly heartburn, four had predominantly volume regurgitation) and seven patients had atypical symptoms such as cough, bloating, chest pain, or sore throat. All patients had tried medication for acid suppression before surgery, with five gaining little or no benefit. The mean acid exposure time was 2% (range 0.1-3.6%). A correlation between typical symptoms and reflux events of over 50% was noted in three patients. All patients underwent laparoscopic fundoplication, with one conversion to an open procedure. Mean patient satisfaction score (0-10 linear score) was 8.7 at 3 months and 1 year postoperatively. Three patients failed to improve following surgery. These three all had atypical symptoms, a symptom correlation of less than 50% with acid reflux on pH monitoring, and two of the three had a poor response to medication. All other patients benefited symptomatically from surgery. We concluded that the absence of objective evidence of reflux should not always preclude patients from a laparoscopic fundoplication. Carefully selected patients with typical reflux symptoms can have a good outcome. However, patients who do not have typical symptoms and who respond poorly to acid suppression are not likely to benefit from surgery.     

胃底折叠术治疗胃食管反流病对高血压的影响

[目的]观察胃底折叠术治疗胃食管反流病对高血压的影响。[方法]回顾性分析2011-06—2012-08期间20例行腹腔镜胃底折叠术的胃食管反流病合并高血压患者的临床资料,依照反流病诊断问卷在手术前和手术后进行反流症状评分。[结果]20例均成功实施腹腔镜手术并于术后第12个月随访。反流总积分(Sc)由术前20.0±9.5降至术后0.5±0.9(P0.05),术后收缩压下降了(11.0±12.0)mm Hg(1mmHg=0.133kPa),舒张压下降了(9.0±11.5)mm Hg(均P0.05)。术后随访12个月11例血压恢复正常,停药时间均在9个月以上;2例减少2种降压药,1例减少1种降压药;6例无效,仍用术前降压药物。[结论]胃食管反流病与部分高血压密切相关,腹腔镜胃底折叠术治疗胃食管反流病合并高血压安全、有效。     

Risk factors for Barrett's esophagus in Indian patients with gastroesophageal reflux disease

Background and Aims: Barrett's esophagus (BE) is reported to be infrequent in Asians, with no data from India regarding its prevalence and risk factors. We investigated the frequency and risk factors of columnar mucosa with or without specialized intestinal metaplasia (SIM) in Indian patients with gastroesophageal reflux disease (GERD). Methods: A total of 278 GERD patients over 2 years underwent gastroscopy and completed a questionnaire for possible BE risk factors. Patients with columnar mucosa on endoscopy underwent four‐quadrant biopsy; BE was histologically defined as columnar mucosa with or without SIM. Patients without columnar mucosa at endoscopy were considered as controls and compared to patients with BE and those with SIM. Results: Forty‐six patients with GERD had columnar mucosa on histology (16.54%); 25 (8.99%) of these had SIM. The risk factors for BE were the presence of hiatus hernia (odds ratio [OR]: 3.14; 95% confidence interval [CI]: 1.2–8.17) and a history of eructation (OR: 2.28; CI: 1.11–4.66). The risk factors for SIM were age ≥ 45 years (OR: 2.63; CI: 1.03–6.71), hiatus hernia (OR: 3.95; CI: 1.24–12.56), and a history of eructation (OR: 3.41; CI: 1.19–9.78). Sex, severity of symptoms, dietary factors, tobacco or alcohol use, and body mass index were not associated with BE. The median circumferential segment length was 2 (1–10) cm, and the maximal length was 3 (2–11) cm in both groups. Conclusion: BE is not an uncommon finding among Indian GERD patients. Age ≥ 45 years, history of eructation, and the presence of hiatus hernia are associated with SIM.     

Laparoscopic fundoplication versus lansoprazole for gastro-oesophageal reflux disease. A pH-metric comparison

BACKGROUND: Treatment strategies that abolish abnormal reflux could prevent long-term complications of gastro-oesophageal reflux disease. AIMS: To compare the efficacy of laparoscopic fundoplication and lansoprazole in abolishing abnormal reflux in patients with gastro-oesophageal reflux disease. PATIENTS: Study population comprised 130 patients referred for possible antireflux surgery and with heartburn as the dominant symptom. METHODS: After oesophageal manometric and pH-metric evaluation and detailed information 55 patients asked to undergo laparoscopic antireflux surgery while 75 chose a medical treatment regimen based on lansoprazole. Treatment efficacy was assessed by ambulatory oesophageal pH-monitoring. RESULTS: All 55 patients who underwent fundoplication became free of heartburn: oesophageal pH-monitoring gave normal results in 85%. In patients treated with lansoprazole, at individualized daily dosages titrated to abolish both heartburn and abnormal acid reflux, normal pH-metric results were obtained in 96% of cases (p<0.05 vs surgically treated patients). CONCLUSIONS: Lansoprazole at individualized dosages was significantly more effective than laparoscopic fundoplication, in the short-term, in abolishing abnormal reflux in gastro-oesophageal reflux disease patients.     

Duodenogastric reflux in patients with Barrett's esophagus

The role of duodenogastric reflux in the pathogenesis of gastroesophageal reflux disease is not clear. Using hepatobiliary scanning techniques, we found evidence of duodenogastric reflux in six of 13 patients with Barrett's esophagus. This compares with only two positive studies in 19 control subjects. This difference is statistically significant P=0.038, two-tailed Fisher's exact test). Three of nine patients who had gastroesophageal reflux without Barrett's esophagus had evidence of duodenogastric reflux, a frequency not significantly different from either of the other groups. Gastroesophageal reflux of bile and pancreatic enzymes, in addition to gastric acid may contribute to the greater esophageal damage often seen in Barrett's esophagus. The presence of duodenogastric reflux in these patients may have important pathophysiologic and therapeutic implications.     

Relevance of sleep disturbance to the integrity and characteristics of secondary peristalsis in patients with gastroesophageal reflux disease

Objective: Sleep disturbance is common in patients with gastroesophageal reflux disease (GERD). Secondary peristalsis is important for clearance of the refluxate from the esophagus. We aimed to test the hypothesis whether secondary peristalsis is impaired in GERD patients with sleep disturbance.

Methods: Secondary peristalsis was stimulated with slow and rapid air injections into mid-esophagus in 8 age-matched health controls and 41 patients with GERD. Sleep disturbance was assessed by the Pittsburg Sleep Quality Index (PSQI). Objective sleep measures were assessed by ambulatory actigraphy.

Results: The threshold volume for inducing secondary peristalsis during slow air injection was significantly higher in GERD patients with sleep disturbance than healthy controls (14.3?±?1.2 vs. 8.9?±?0.5?mL, p?<?.05). GERD patients with sleep disturbance had higher threshold volume of secondary peristalsis during rapid air injection than GERD patients without sleep disturbance (5.1?±?0.4 vs. 3.9?±?0.2?mL, p?<?.05) and healthy controls (5.1?±?0.4 vs. 3.6?±?0.2?mL, p?<?.05). There was a negative correlation between PSQI score and peristaltic frequency during rapid air injection (r?=??.39, p?=?.01). Secondary peristaltic amplitude during rapid air injection was negatively correlated with wake after sleep onset (r?=??.34, p?=?.04).

Conclusions: Sleep disturbance is associated with secondary peristaltic response to distension-induced esophageal stimulation in patients with GERD. Our study suggests that sleep disturbance per se may adversely influence the effectiveness of esophageal peristalsis and bolus clearance during sleep in patients with GERD.     

Effect of graded exercise on esophageal motility and gastroesophageal reflux in nontrained subjects

The effects of graded exercise on esophageal motility and gastroesophageal reflux were evaluated in nine nontrained subjects, using a catheter with three strain-gauge transducers connected to a solid-state datalogger and an ambulatory intraesophageal pH monitor. Subjects exercised on a stationary bike at 45%, 60%, 75%, and 90% of peak O₂ uptake ( O₂ max). Durations of exercise sessions and rest periods varied among subjects. Studies were performed after an overnight fast and subjects received only intravenous infusion of 5% glucose solution during the study. Plasma concentrations of gastrin, motilin, glucagon, pancreatic polypeptide (PP), and vasoactive intestinal peptide (VIP) were determined at rest and before and after each exercise session. The duration, amplitude, and frequency of esophageal contractions declined with increasing exercise intensity, and the differences were significant (P0.05) for all three variables at 90% O₂ max. The number of gastroesophageal reflux episodes and the duration of esophageal acid exposure were significantly (P0.05) increased during exercise at 90% O₂ max. Plasma regulatory peptide concentrations showed no significant changes between rest and the various exercise sessions. Thus, exercise has profound effects on esophageal contractions and gastroesophageal reflux, which are intensity dependent. These effects were not mediated by the hormones measured. The results were similar to those observed in highly trained athletes, suggesting that the effects of exercise on esophageal function are similar in trained and nontrained subjects performing at similar percentages of O₂ max, even though the absolute levels of exercise achieved in each group are different.A preliminary report of this work was given at the annual meeting of the American Gastroenterological Association, May 1992, and was published as an abstract in Gastroenterology (102:517, 1992).     

Gastroesophageal reflux disease in children: efficacy of Nissen fundoplication in treating digestive and respiratory symptoms. Experience of a single center

Fundoplication has been commonly performed in neurologically impaired and normal children with complicated gastroesophageal reflux disease. The relationship between gastroesophageal reflux disease and respiratory diseases is still unclear. We aimed to compare results of open and laparoscopic procedures, as well as the impact of fundoplication over digestive and respiratory symptoms. From January 2000 to June 2007, 151 children underwent Nissen fundoplication. Data were prospectively collected regarding age at surgery, presence of neurologic handicap, symptoms related to reflux (digestive or respiratory, including recurrent lung infections and reactive airways disease), surgical approach, concomitant procedures, complications, and results. Mean age was 6 years and 9 months. Eighty‐two children (54.3%) had neurological handicaps. The surgical approach was laparoscopy in 118 cases and laparotomy in 33. Dysphagia occurred in 23 patients submitted to laparoscopic and none to open procedure (P = 0.01). A total of 86.6% of patients with digestive symptoms had complete resolution or significant improvement of the problems after the surgery. A total of 62.2% of children with recurrent lung infections showed any reduction in the frequency of pneumonias. Only 45.2% of patients with reactive airway disease had any relief from bronchospasm episodes after fundoplication. The comparisons demonstrated that Nissen fundoplication was more effective for the resolution of digestive symptoms than to respiratory manifestations (P = 0.04). Open or laparoscopic fundoplication are safe procedures with acceptable complication indices and the results of the surgery are better for digestive than for respiratory symptoms.     

Effect of graded exercise on esophageal motility and gastroesophageal reflux in trained athletes

We evaluated the effect of graded exercise on esophageal motility and gastroesophageal reflux. We studied eight trained cyclists using a catheter with three strain-gauge transducers connected to a solid-state datalogger and an ambulatory intraesophageal pH monitor. Each study lasted 4 hr during which subjects exercised on a stationary bike for 1 hr at 60% of peak O₂ uptake (O₂ max), 45 min at 75% of O₂ max, and for 10 min at 90% of O₂ max. Subjects rested 1 hr before exercise (control period) and for 30 min between exercise sessions. Studies were performed after an overnight fast and subjects received only intravenous infusion of 5% glucose solution during the study. Plasma concentrations of gastrin, motilin, glucagon, pancreatic polypeptide (PP), and vasoactive intestinal peptide (VIP) were determined at rest and before and after each exercise session. The duration, amplitude, and frequency of esophageal contractions declined with increasing exercise intensity, and the differences were significant (P0.05) for all three variables at 90% O₂ max. The number of gastroesophageal reflux episodes and the duration of esophageal acid exposure were significantly (P0.05) increased during exercise at 90% O₂ max. Plasma hormone concentrations showed no significant changes between rest and the various exercise sessions. Thus, exercise has profound effects on esophageal contractions and gastroesophageal reflux which are intensity dependent. These effects are not mediated by the hormones measured.