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Keywords:

  • colon;
  • oestradiol;
  • gastrointestinal;
  • menopause;
  • progesterone;
  • transit;
  • women

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Abstract  Females are disproportionately affected by constipation, which is often aggravated during pregnancy. Bowel function also changes during the luteal phase of the menstrual cycle. The aim was to compare the effects of acute administration of female sex steroids on gastric emptying, small bowel transit and colonic transit in healthy postmenopausal subjects. A second aim was to determine whether withdrawal of the hormones was associated with a change in transit. Forty-nine postmenopausal females were randomized to receive for 7 days 400 mg day−1 micronized progesterone, 0.2 mg day−1 oestradiol, combination of the two, or placebo. Treatment groups were balanced on age. Participants underwent whole gut transit measurement by scintigraphy using a 99m-labeled technetium-egg meal and 111-labeled indium-charcoal via a delayed-release capsule. Transit measurement was repeated after withdrawal of the study medications. The primary endpoints were ascending colon (AC) emptying half-life time (t1/2) and colonic geometric centre (GC) at 24 h. Secondary analysis variables were GC at 4 and 48 h, gastric emptying t1/2 and colonic filling at 6 h. There was a significant overall effect of progesterone on colonic transit with shorter AC emptying t1/2 and significantly greater colonic GC at 48 h. No transit endpoints were altered by oestradiol or combined hormonal treatment relative to placebo. Oestradiol and progesterone resulted in looser stool consistency. Withdrawal of the hormone supplement was not associated with significant alteration in transit. Micronized progesterone does not retard colonic transit in postmenopausal females.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Women develop lower gastrointestinal (GI) symptoms associated with menses and hysterectomy,1 and there may be disparities in the delivery of health care for GI problems in women.2

Constipation is a very common clinical problem3 which affects up to 20% of people in a US community4 and may be associated with slow colonic transit in tertiary referral patients.5

Women, particularly premenopausal women, experience constipation more often than men,6,7 with significant prolongation of mean colonic transit in women.8,9 The physiologic explanation for this remains unclear. Some investigations in the past have focused on female sex hormones as a potential cause for this gender difference. The rationale for examining the effect of female sex hormones is that symptoms of constipation often begin at menarche,7,10 and a large number of women experience a change in bowel habits (looser consistency) with onset of menses11 when progesterone and oestradiol levels dramatically fall, thus leading to menstruation.10 Pregnancy is commonly complicated by constipation, a time when progesterone and oestradiol levels are significantly elevated.12 However, there are several other changes associated with pregnancy including the presence of an enlarging uterus. Female sex hormones also induce changes in the soft tissues of the pelvic floor and uterine support in rats,13 apart from changes in function that might occur in the colon.

At the tissue level, sex hormones inhibit muscle contractility in a variety of sites, including uterus, gall bladder,14 lower oesophageal sphincter,15 and colon.16 Progesterone and oestradiol receptors have been found in normal colonic tissue.17

Multiple studies failed to show a clear or consistent effect of female sex hormones on gastric emptying, small bowel transit and colonic transit with either longer orocecal transit time in the luteal phases compared with the follicular phases9,11,12 or no significant variation with the phase of the menstrual cycle in whole gut,18,19 orocecal,19 or colonic transit.8

Our aim was to clarify the effects on colonic transit of doses of progesterone and oestradiol that intended to mimic the levels occurring in the luteal phase of the menstrual cycle and the withdrawal of sex hormones, as occurs immediately prior to menstruation. The (null) hypothesis for our study was that progesterone, oestradiol, and the combination of oestradiol and progesterone have no effect on GI and colonic transit and bowel function. Study of a postmenopausal, healthy group of women obviates one of the pitfalls in prior studies as they are relatively free of endogenous female sex hormones.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Study design

This was a randomized, double blind, double-dummy, placebo-controlled, single-centre, parallel-group study with concealed allocation. This had the structure of a two by two analysis of variance (anova) design, which would provide an assessment of overall main effects of oestradiol and, separately, progesterone on gastric emptying, small bowel transit and colonic transit as the primary aim.

Subjects were allocated to the treatment groups (or sequences) in the chronological order of their entry into the study with respect to a pre-established randomization schedule provided by the study statistician and communicated to the research pharmacist. Subjects and investigators were blinded to treatment assignment, and the randomization schedule was balanced on age, as age was considered as a surrogate for time from menopause and, thus, balancing on age provided treatment groups that were balanced on ‘time from menopause’.

After initial screening, there was a treatment period lasting 7 days, with the final 48 h used to measure effects of treatment on GI and colonic transit on days 5–7. Study medications were withdrawn and repeat GI transit studies were conducted on days 11–13. Participants attended the General Clinical Research Center on screen visit day, day 1 and day 4 to have the transdermal patches applied, and on days 5–7 and days 11–13 for transit testing, as above. The total duration of the study, from screening to completion, was 2–4 weeks, depending on the time lag between screening exam and start of treatment, which was never more than 2 weeks.

Study participants

Forty-nine healthy postmenopausal female subjects with no history of GI symptoms, particularly no evidence of diarrhoea or constipation or irritable bowel syndrome (absence of >3 GI symptoms on the bowel disease questionnaire20) were recruited to participate in the study. Healthy females who were naturally or surgically postmenopausal, age 40–65 years old, were recruited. All had either no menstrual period for 12 months or serum follicle stimulating hormone >50 IU mL−1 and a negative serum pregnancy test, which are standard criteria defining menopause in clinical practice. Subjects had a negative cervical pap smear documented in the medical records within the past year or they had a documented total abdominal hysterectomy or a negative pap smear in the past 3 years after having previously had three or more consecutive normal cytology results. Subjects also had a documented normal mammogram within the past year. Standard exclusion criteria were used, which included use of drugs or agents within the past 7 days or planned use of agents that alter GI transit, antidepressants, analgesics and hormone replacement pills in the subsequent 7 days during the study period. In addition, the following criteria were used for exclusion from participation: body mass index (BMI) >33 kg m−2, history of breast or ovarian cancer, history of thrombo-embolic disorders such as deep vein thrombosis or pulmonary embolus, and significant hot flashes in the previous 3 months.

All participants signed informed consent and the study was approved by the Mayo Clinic Institutional Review Board.

Medications

Participants were randomized to one of four treatment groups with 12 subjects per group:

  • 1
    Oestradiol patch (0.2 mg), and placebo pill
  • 2
    Micronized progesterone (200 mg) b.i.d. and placebo patch
  • 3
    Micronized progesterone (200 mg) b.i.d. and the 0.2 mg oestradiol patch
  • 4
    Placebo pill and patch matching micronized progesterone and oestradiol

When given transdermally as an oestradiol patch of 29.0 cm2 (Vivelle®, Noven Pharmaceuticals, Miami, FL, USA), oestradiol can provide 0.1 mg over a 24-h period with consistent pharmacokinetics. In the past, oestradiol has been given in doses up to 0.2 mg per 24 h without significant adverse effects.21,22 The Vivelle® system provides systemic oestradiol replacement therapy by releasing 17β oestradiol, the major oestradiolic hormone secreted by the human ovary. Transdermal administration of Vivelle® produces mean serum concentrations of oestradiol comparable to those produced by premenopausal women in the early follicular phase of the ovulatory cycle. There is a mean half-life of 4.4 h and, after removal of the transdermal patch, oestradiol levels return to baseline within 24 h. A Cmax of 133 pg mL−1 is reached by 12 h with consistent pharmacokinetics.

The progesterone micronized powder (Product no. PR112 CAS 57-83-0; Spectrum Pharmaceuticals, Tucson, AZ, USA) used in our study has enhanced bioavailability compared with other progesterone formulations.23,24 After oral administration of progesterone as a micronized soft gelatin capsule formulation, maximum serum concentrations are attained within 3 h. Serum progesterone concentrations are linear and dose proportional following multiple dose administration of micronized progesterone capsules. The half-life for micronized progesterone is about 16–17 h. At 300 mg day−1, plasma levels of progesterone remain significantly elevated for up to 36 h. The dose of 400 mg day−1 is similar to high-dose hormone replacement therapy. Higher doses may cause side effects typical of premenstrual syndrome.

Co-administration of conjugated oestradiols and micronized progesterone capsules over a 12-day period results in increases in total oestrone and equilin concentrations and a decrease in circulating 17β oestradiol concentrations.21 The half-life of the conjugated oestradiols was similar with co-administration of micronized progesterone capsules.

Compliance

The study drug was self-administered by the subjects on days 1–5, and morning doses were administered in the General Clinical Research Center by nurses on days 5–7. The nurses also applied the study transdermal patch and participants came to the General Clinical Research Center to exchange the patch on day 4. Every effort was made to assure compliance of study drug dosing. For all doses administered at home, subjects were instructed to use a diary to record the timing of study medication administration. Subjects were instructed to return empty containers of study medication to the General Clinical Research Center, at which time pill counts were performed. For the duration of the study, subjects were ambulatory and were advised to go about their usual activity.

Scintigraphic transit: gastric emptying, small bowel and colonic transit

Transit measurement was conducted using a standard and validated method.25,26 99m-labeled technetium (99mTc)–sulphur colloid was used to label two scrambled eggs, which were ingested with one slice of whole wheat bread and one glass of skim milk (300 kcal) to facilitate measurement of gastric and small bowel transit using scintigraphic imaging.25,26 111-labeled indiumCl3 (0.10 mCi) was mixed with a slurry of 5 mg activated charcoal in order to measure colonic transit.26 The slurry was evaporated to dryness on a hot plate at 90 °C, and the dried charcoal was placed into a size one gelatin capsule (Eli Lilly, Indianapolis, IN, USA) and coated with methacrylate (Eudragit S100, Degussa AG, Darmstadt, Germany), as in previous studies. A marker, to be used to map the location of the capsule in the colon, was placed on the patient's anterior superior iliac spine. The capsule was administered with a 3 ounce glass of water.

We obtained abdominal images every hour for the first 6 h and at 10, 24, and 48 h. A variable region of interest programme was used to measure transit as in previous studies. The proportion of 99mTc reaching the colon at 6 h was used as a surrogate marker for small bowel transit. The primary summaries for comparison of transit profiles were: gastric emptying half-life time (t1/2); colonic filling at 6 h; colonic geometric centre (GC) at 8, 24 and 48 h; and ascending colon (AC) emptying t1/2 measurements based on geometric mean of counts in anterior and posterior AC regions of interest.

Data were analysed as in previous studies.25,26 The GC is the weighted average of counts in the different colonic regions [ascending (AC), transverse (TC), descending (DC), rectosigmoid (RS)] and stool, respectively one to five. Thus, at any time, the proportion of colonic counts in each colonic region is multiplied by its weighting factor as follows: (%AC × 1 +%TC × 2 + %DC × 3 + %RS × 4 + % stool × 5)/100 =GC. Ascending colonic emptying was summarized as t1/2 from linear interpolation of data on the AC emptying curve.

Daily stool diaries  Each day, participants filled in standard validated questionnaires on paper diaries to document stool frequency, consistency (using the Bristol stool form scale), sense of evacuation and ease of stool passage, as in previous studies.27–29

Statistical analysis  The primary motility endpoints were ascending colonic emptying t1/2 and the colonic GC at 24 h. An analysis of covariance (ancova) based on the 2 × 2 factorial design was used to assess the overall main effects of progesterone and oestradiol and their potential (statistical) interaction incorporating age as a covariate. As a primary goal of this study was to examine the effect of progesterone, oestradiol and their combination vs placebo, the pairwise comparisons of active treatment groups with placebo were also assessed at an alpha level of 0.05.

The analyses were performed for measurements made on the day 5–7 study and separately for the changes following withdrawal of the treatments (i.e. value from the day 5–7 study minus the value from the day 11–13 study). A similar analysis approach was used for secondary response variables of t1/2 of gastric emptying of solids, colonic filling at 6 h, geometric centre (GC) 48 h, and bowel function. For bowel function, the daily diary data were first summarized per subject by averaging over the individual stool scores per day and then averaging over treatment days to obtain a mean stool frequency, mean stool consistency score and mean stool ease of passage score. These values were then analysed using an ancova as described above, including age and BMI as covariates.

The analyses of treatment effects included all randomized subjects based on the intent-to-treat principle. Missing data were assigned an ‘imputed’ value in the analyses using the corresponding endpoint overall mean value (using all subjects with non-missing data values for that endpoint). A corresponding adjustment to the error degrees of freedom in the ancova was made by subtracting one degree of freedom for each missing value imputed. This provides a more appropriate estimate for the error variance when the number of missing values is relatively small (<10%). All of the subjects completed the initial (day 5–7) physiology studies, although one subject did not participate in the day 11–13 studies and one additional subject did not complete the 48-h scan to obtain a GC 48 value (both subjects were in the placebo group); thus, no physiology data were imputed for the initial studies, but one to two missing values were imputed for the analysis of changes on withdrawal of treatments. There were a total of four subjects who did not provide daily diaries (one in the placebo group and three in the progesterone group) and one additional subject (placebo group) only filled in the stool frequency portion; thus, a total of four to five missing values were imputed for the analysis of bowel function.

A descriptive summary of subject characteristics (age and BMI) at baseline was compiled over all randomized subjects by treatment groups.

Sample size assessment  The proposed sample size (n = 12 per treatment arm) was estimated to provide 80% power to detect the effect sizes (Table 1) for the differences between pairs of treatment groups assuming the variance would be similar to that observed previously. The coefficients of variation (CV%) and corresponding standard deviation (SD) are from recent studies in healthy volunteers using the same measurement methodology.30,31 The current study actually had slightly smaller (pooled) SD values (0.75 for GC 24 h and 7.8 for AC t1/2) which would have provided the same power for somewhat smaller effect sizes.

Table 1.   Power calculation
ResponseMeanSDCV %n per groupEffect size (%)*Detectable difference
  1. SD, standard deviation; CV, coefficients of variation; GC, geometric centre; AC, ascending colon. *Effect size (%) is the estimated difference that could be detected with the stated power as a percentage of the overall groups’ mean value of the response. These estimates are based on a simple two-sample t-test at α = 0.05 (two-sided).

  2. †Individual treatment group comparisons (n = 12) from 2 × 2 factorial design. ‡Main effect comparisons based on marginal totals (n = 24) from 2 × 2 factorial design.

GC 242.671.074012†481.28
24‡330.88
AC t1/2 (h)12.89.357312†8711.1
24‡607.7

Table 1 summarizes the response variability (CV%) and ‘effect size’ (%) that could have been detected with 80% power assuming the prestudy planning values for response variability. These estimates were based on a simple two-sample t-test (e.g. placebo vs specific dose level) with n = 12 per group at an α-level of 0.05 (two-sided) corresponding to individual treatment group pairwise comparisons, and with n = 24 per group corresponding to tests for overall main effects based on the marginal totals from the 2 × 2 factorial design. The ancova was anticipated to provide similar power for somewhat smaller effect sizes by pooling the variation across four groups. For the primary efficacy parameters, colonic transit (GC 24) and ascending colonic emptying t1/2, the proposed study would detect changes in transit of a magnitude that would be of clinical significance as they would result in changes in bowel function based on prior studies in disease.32,33

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Subjects

Participant demographics are summarized in Table 2. The groups were balanced on age (<55 years vs≥55 years) by design and were similar in BMI, although the placebo group had somewhat larger values.

Table 2.   Demographics of postmenopausal female participants
  nAge (years)BMI (kg m−2)
  1. BMI, body mass index; P, progesterone; E, oestradiol.

Placebo1261 ± 229.2 ± 1.5
Progesterone1360 ± 126.7 ± 1.0
Oestradiol1260 ± 125.8 ± 1.0
Combined P & E1260 ± 225.6 ± 1.3

Gastric and small bowel transit

The overall drug effects on gastric emptying and small bowel transit (estimated by the t1/2 and the percent colonic filling at 6 h respectively, see Table 3) were not statistically significant and no interaction effect was detected. No significant differences between active treatment groups and placebo were observed.

Table 3.   Post-treatment gastric, small bowel, and colonic transit
  nGE t1/2 (min) nCF6 (%) nGC 8 nGC 24 nGC 48
  1. Data expressed as mean ± SEM; GE, gastric emptying t1/2; CF6, colonic filling at 6 h; GC, geometric centre at 8 (GC 8), 24 (GC 24), and 48 (GC 48) h; P, progesterone; E, oestradiol. *P < 0.05 vs placebo.

Placebo12122 ± 61235 ± 8121.0 ± 0.2122.1 ± 0.2123.2 ± 0.3
Progesterone13117 ± 61349 ± 9 131.3 ± 0.2132.3 ± 0.1133.9 ± 0.2*
Oestradiol12129 ± 111239 ± 7110.8 ± 0.2122.0 ± 0.3123.7 ± 0.3
Combined P & E12123 ± 51242 ± 7121.0 ± 0.2122.0 ± 0.1123.1 ± 0.3

Colon transit and ascending colon emptying

The ancova indicated a significant (statistical) interaction effect of progesterone and oestradiol on GC 48 (P = 0.012). Specifically, the effect of progesterone alone accelerated colonic transit (GC 48 = 3.9 for progesterone vs 3.2 for placebo, P = 0.039), but in the presence of oestradiol, taking progesterone in addition resulted in lower values of GC 48 compared with oestradiol alone (Table 3). A similar pattern was observed for GC 24, but the (statistical) interaction effect was not significant (P > 0.25).

Based on the 2 × 2 factorial design, the overall main effect of progesterone on AC emptying (Fig. 1) t1/2 was to significantly accelerate colonic emptying (P = 0.042), while the pairwise comparison of progesterone alone vs placebo was borderline significant (P = 0.099).

image

Figure 1.  Effect of female sex hormones on ascending colon (AC) emptying. Data show mean ± SEM. Combined P & E = combined progesterone (P) and oestradiol (E). The overall effect of progesterone was significant (P = 0.042), based on the 2 × 2 factorial design, i.e. P and P + E vs placebo and placebo + E. Change in AC emptying time after withdrawal was not significantly different among groups.

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Effects on bowel function

Pairwise comparisons of active treatment groups vs placebo (Table 4) indicated looser stool consistency scores with progesterone alone (P = 0.025) and oestradiol alone (P = 0.040) and greater ease of passage scores for oestradiol alone (P = 0.018). The ancova (incorporating age and BMI as covariates) indicated (statistical) interaction effects of progesterone and oestradiol on ease of passage scores (P = 0.028) and stool consistency scores (P = 0.071). No significant treatment effects on stool frequency (Table 4) or sense of incomplete evacuation were detected (P = 0.8 for interaction, P > 0.5 for both main effects, data not shown).

Table 4.   Least squares adjusted* mean (±SE) values from daily diary data
 Mean daily stool frequencyMean stool consistencyMean stool ease of passage
  1. *From analysis of covariance including imputed values. P, progesterone; E, oestradiol.

Placebo1.6 (±0.2)3.0 (±0.3)3.7 (±0.1)
Progesterone1.3 (±0.2)3.8 (±0.2)3.9 (±0.1)
Oestradiol1.3 (±0.2)3.8 (±0.2)4.0 (±0.1)
Combined P & E1.1 (±0.2)3.7 (±0.2)3.8 (±0.1)

Effect of withdrawal of sex hormones

Withdrawal of oestradiol and progesterone did not result in any significant change in GI or colonic transit with any treatment (Table 5), nor were treatment effects on changes in bowel function detected (data not shown).

Table 5.   Postwithdrawal gastric, small bowel, and colonic transit
  nGE t1/2 (min) nCF6 (%) nGC 8 nGC 24 nGC 48
  1. Data expressed as mean ± SEM; GE, gastric emptying t1/2; CF6, colonic filling at 6 h; GC, geometric centre at 8 (GC 8), 24 (GC 24), and 48 (GC 48) h; P, progesterone; E, oestradiol.

Placebo11124 ± 81131 ± 7111.0 ± 0.3112.1 ± 0.3103.3 ± 0.3
Progesterone13112 ± 51351 ± 9131.0 ± 0.2132.0 ± 0.2133.6 ± 0.3
Oestradiol12119 ± 61239 ± 8111.2 ± 0.3122.4 ± 0.4123.5 ± 0.3
Combined P & E12127 ± 51232 ± 7121.0 ± 0.2122.0 ± 0.1123.4 ± 0.2

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

This is the first study to document effects of female sex hormones on measured colon transit in postmenopausal women. The study shows that there is a significant acceleration of colonic transit by micronized progesterone measured as the rate of emptying of the AC, and overall colonic transit at 48 h. Accelerated colonic transit with progesterone was not observed compared with the placebo group at the 24-h mark, but this likely reflects the greater variation in the responses (and hence a potential exists for a type 2 error) compared with the lower variation at 48 h. The significant effect of micronized progesterone is also convincingly demonstrated by the effect of withdrawal, which was associated with a reduction of colonic transit to mimic the transit profiles with placebo treatment. Micronized progesterone was associated with a looser stool consistency, but no change in stool frequency or ease of passage. Oestradiol was also associated with a looser stool consistency and ease of passage, but no change in stool frequency. The combination of the two female sex hormones did not significantly alter colonic transit or bowel function. Accelerated colonic transit can only be proposed as a factor in the change of stool consistency in those treated with micronized progesterone. In this group, we observed acceleration of AC emptying time and overall colonic transit at 48 h.

The moderate acceleration of colonic transit was unexpected, given the body of evidence from studies of the effects of female sex steroids on colonic transit in experimental animals or in isolated muscle tissues. Thus, in myometrial and GI smooth muscle tissues, progesterone impairs muscle contraction and oestrogens have no direct effect other than to prime progesterone receptors.34,35 Although, many of these studies were performed using gall bladder or antral muscle strips, there are also data from canine colonic muscle showing inhibitory effects of progesterone on muscle contractility.36 It is unclear whether the response of colonic muscle to progesterone in the isolated denervated state might differ from the levels in tissue that are achieved in response to the clinically relevant situation where the colon is not extrinsically denervated and the sex steroid is administered orally or through a skin patch. In humans, there is evidence of prolongation of orocecal transit time during the luteal phase11 and during the second and third trimesters of pregnancy which normalizes after delivery.12 However, pregnancy presents several perturbations including the presence of the gravid uterus, and the effects of pregnancy cannot be attributed only to the effects of progesterone. Moreover, the results in orocecal transit cannot be assumed to reflect effects of sex steroids on colonic transit. Indeed, Hinds et al.8 demonstrated there were no significant differences in colonic transit between either phase of the menstrual cycle and that, although colonic transit in women was slower than in men, this was not statistically significant.

The mechanism for the oestradiol induced change in stool consistency and ease of passage is unclear, as we did not observe an acceleration of transit. Moreover, sex steroids, such as testosterone, progesterone and 17α-oestradiol, do not significantly increase colonic Cl- secretion in experimental studies of rat distal colonic epithelium.37 Similarly, the reason why the combined hormonal therapy did not result in any change of gut transit or bowel function is unclear.

Our data are consistent with the intriguing observations of Behar's group on the potential role of progesterone receptors and associated G proteins in severe constipation.38 Thus, Xiao et al.38 showed that disorders of G proteins (reduced Gαq and increased Gαs) in patients requiring colectomy for constipation were associated with the upregulation of progesterone receptors. The proteins Gαq and Gαs are usually associated with contraction and relaxation of muscle respectively, and the coordination of these muscle functions may facilitate colonic transit. Malfunction of these proteins results in lack of response to ligands that are coupled through G protein-coupled receptors and G proteins, and an increase in progesterone receptors may initially compensate for the lack of biological response. However, Xiao's data suggest that this eventually fails and results in lack of response to progesterone.38 In contrast, when the G proteins function normally, there is the potential to observe the effects of progesterone on colonic transit, as seen in our study.

In summary, progesterone does not slow human colonic transit, contrary to the prevailing hypothesis based on in vitro data using animal tissues. Loosening of stool consistency in postmenopausal females may suggest the acceleration of transit based on the two-tailed analysis and is worthy of further study. Oestradiol and combination sex steroids do not have this effect on transit, but oestradiol changes stool consistency and ease of passage through unknown mechanisms. Overall, these data suggest that formal clinical trials of progesterone in postmenopausal females with constipation would be of significant interest to the public's health and, specifically, to women's health.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

This study was sponsored by a grant from the American College of Gastroenterology, by Mayo General Clinical Research Center Grant no. M01-RR00585 from National Institutes of Health. Dr Camilleri is supported by grants R01 DK54681, DK67071 and K24 DK02638 from National Institutes of Health. We thank Lorraine Fitzpatrick, MD, for advice on experimental design and Cindy Stanislav for secretarial assistance.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
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