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Keywords:

  • gastroparesis;
  • menstrual cycle

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Background  Gastroparesis, a chronic gastric motility disorder with symptoms of nausea, vomiting, early satiety, postprandial fullness and bloating, predominantly affects women. Some studies suggest that gastric emptying may be slower in females especially during the luteal phase of the menstrual cycle when estrogen and progesterone levels are elevated. In females with irritable bowel syndrome, symptoms may worsen during the luteal phase. The aim of this study was to determine if symptoms of gastroparesis vary along the menstrual cycle and to determine the effect of oral contraceptive agents (OCPs) on symptoms.

Methods  Thirty-nine premenopausal women were studied (10 gastroparesis patients not on OCPs, 10 gastroparesis on OCPs, nine healthy women not on OCPs and 10 healthy women on OCPs). The Gastroparesis Cardinal Symptom Index Daily Diary was used to assess daily symptoms (0 = none and 5 = very severe).

Key Results  Gastroparesis patients not on OCPs had significantly worse symptoms during the luteal phase compared to the follicular phase for nausea (2.25 ± 0.68 vs 1.58 ± 1.06; < 0.001) and early satiety (2.80 ± 0.50 vs 1.70 ± 1.50; < 0.001), but not for vomiting, bloating, abdominal pain, fullness, or loss of appetite. Gastroparesis patients on OCPs showed little day-to-day variation of symptoms. Vomiting was more severe in patients off OCPs (2.00 ± 0.80 vs 1.20 ± 0.83; = 0.040). Healthy women exhibited little to no symptoms regardless of OCP use.

Conclusions & Inferences  Increased symptoms, particularly nausea and early satiety, occurred in the luteal phase of the menstrual cycle in female patients with gastroparesis. A variation in symptoms was not seen in gastroparesis female patients on hormonal contraception.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Gastroparesis, a chronic gastric motility disorder characterized by symptoms of nausea, vomiting, early satiety, postprandial fullness and bloating, predominantly affects women.1 In normal subjects, gastric emptying may be affected by gender.2 Some studies suggest that gastric emptying is slower in females than males.3–5

Hormonal influence has been proposed as a possible contributor to variability. In vitro studies have shown that estrogen and progesterone have inhibitory effects on smooth muscle of the lower esophageal sphincter, pylorus and small bowel muscle strips resulting in decreased gastrointestinal contractility.6 Some studies suggest gastric emptying is slower in females during the luteal phase of the menstrual cycle when estrogen and progesterone levels are elevated,4,7,8 whereas others do not.9,10

Whether symptoms change during the menstrual cycle in gastroparesis patients has not been determined. There are studies reporting exacerbation of symptoms during the luteal phase in patients with irritable bowel syndrome.11 The aim of this study, therefore, was to determine: (i) if symptoms of gastroparesis vary along the menstrual cycle, and (ii) the effect of oral contraceptive agents (OCPs) on symptoms of gastroparesis.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Study participants

Patients with gastroparesis and normal volunteers were recruited for participation in this study from the patients seen in the Digestive Disease Center of Temple University Hospital and Internal Medicine Residency Clinic. Women were asked if they would be interested in participating in a women’s health study that seeks to determine if there are changes in gastrointestinal symptoms throughout the menstrual cycle and the study would assess their symptoms, on a daily basis. This study was IRB approved by the Institutional Review Board of Temple University, Philadelphia, PA (IRB protocol #12555; July 2009).

In each group, subjects were recruited so that half were not taking oral contraception and half were taking oral contraception. Thirty-nine pre-menopausal women were studied (10 gastroparesis patients not on OCPs, 10 gastroparesis on OCPs, 9 non-gastroparesis volunteers not on OCPs, and 10 non-gastroparesis volunteers on OCPs).

Control women were defined as those without prior history of peptic ulcer disease, functional dyspepsia, irritable bowel syndrome, or gastrointestinal surgeries. Control women also had a normal physical examination, no gastrointestinal (GI) symptoms, and were on no medications for GI disorders. All subjects studied denied psychiatric illnesses, use of alcohol, tobacco or narcotic drug use.

Patients with gastroparesis had (i) delayed gastric emptying (defined as greater than 60% retention at 2 h, and greater than 10% retention at 4 h) on a 4 h gastric emptying scintigraphy test;2,12 (ii) etiology can be either diabetic or idiopathic; (iii) chronic (>6 months) symptoms; (iv) stable symptoms on current medications; (v) on no narcotics.

Of twenty gastroparetic patients, seventeen carried a diagnosis of idiopathic gastroparesis. The other three patients were diagnosed with diabetic gastroparesis. For gastroparesis patients taking OCPs, there was one insulin-dependent diabetic and one diet-controlled diabetic. There was one insulin-dependent diabetic off hormonal contraception. All three diabetic patients reported both stable symptoms and blood sugars on their current diabetes regimens (mean hemoglobin A1c was 7.9 ± 0.4).

Subjects not taking hormonal contraception (off hormonal contraception) had regular 28–30 days menstrual cycles. Subjects on OCPs used continuous 90 days contraception and did not have menses. Hormonal contraception consisted of both low dose estrogen and progesterone. Nine out of 10 gastroparesis patients were taking low dose estrogen-progesterone combination pills (i.e., LoEstrin) with 20–35 μg of an estrogen derivative and 0.5–1.0 μg of a progesterone derivative, and one patient was taking Depo Provera (medroxyprogesterone, 104 mg injection every 3 months). Subjects were asked to not begin, end or switch any hormonal contraception during this study.

The menstrual cycle

For the purpose of this study, the menstrual cycle was divided into two phases, a follicular phase (days 1–14) and a luteal phase (days 15–28). The follicular phase was then further subdivided into two stages; the menses (generally days 1–6) and then the proliferative phase (days 7–14). During menses, levels of estrogen and progesterone fall and the endometrial lining is shed because fertilization and implantation of an ovum did not occur.13 After menses, the next cycle of follicular recruitment occurs and levels of estrogen and progesterone begin to rise. Estrogen at this time rises higher than progesterone and contributes to follicular development. Just before ovulation, estrogen levels peak and then slowly fall. A dominant follicle emerges and leads to follicular rupture and ovulation. Progesterone at this time continues to rise and lead to alterations in the endometrial lining to prepare for ovum implantation. Ovulation typically occurs midcycle (during days 15–18) and marks the beginning of the luteal phase.

Biphasic changes in basal body temperature are characteristic of the ovulatory cycle and occurs secondary to alterations in progesterone. A temperature change of 0.5–1.0°F signifies ovulation and the beginning of the luteal phase.14 Daily basal body temperature (BBT) recordings have been performed by women as a way to assess for ovulation and thus days they are most fertile.13 Compared to fertility kits measuring urinary levels of luteinizing hormone (LH, a hormone secreted from the pituitary gland to stimulate ovarian follicular rupture and ovulation) or plasma levels of progesterone, BBT has a positive predictive value of 0.94 with an overall accuracy of 0.77 to detect ovulation.14 Although more superior forms of ovulation detection exist over BBT recording, such as urinary LH surge testing kits or plasma progesterone levels, BBT provides a convenient, inexpensive and acceptable form of ovulation detection.14

Study protocol

Subjects not on hormonal contraception were asked to record daily basal body temperatures as a marker of ovulation.13 The participants recorded their temperatures orally using a special basal body temperature thermometer graded in one-tenth of degree increments (CVS Digital Basal Thermometer; CVS Corporation, Woonsocket, RI, USA) at the same time every day before getting out of bed, eating or drinking. Generally a temperature shift of at least 0.5 F reflects ovulation.13,14

On the first visit, subjects filled out a Biographical Information questionnaire asking about their medical history, current medications, women’s health history, etc. Each subject also filled out two validated questionnaires: (i) The Menorrhagia questionnaire15 regarding cycle length and menorrhagia (heavy menses) was used as a screening tool to ensure all patients enrolled had regular 28–30 days cycles, normal menstrual flow and no disabling effect of their menses on their life. If subjects reported irregular cycle length (<28 days, >30 days), menorrhagia (>4 tampons per day) or disabling symptoms (confined to home or bed secondary to menorrhagia), they were not enrolled as these patients may experience irregular levels of estrogen and progesterone or have undiagnosed endometriosis (which could be a confounding cause of abdominal pain that worsens with ovulation); (ii)16 patient assessment of upper GI symptoms (PAGI-SYM) validated questionnaire, was used as a baseline for gastrointestinal symptoms (regarding symptoms of nausea, retching, vomiting, fullness, satiety, appetite, bloating, distension, abdominal pain, heartburn, regurgitation, acid sensation) over the past 2 weeks. Lower GI symptoms of diarrhea and constipation were also asked in the PAGI-SYM.

All subjects were also given the Gastroparesis Cardinal Symptom Index (GCSI) Daily Diary,17 derived from the PAGI-SYM questionnaire, that asked subjects to rate their symptoms (including: nausea, vomiting, stomach fullness, loss of appetite, bloating, upper and lower abdominal pain, heartburn, constipation, diarrhea, which of the aforementioned is the most prominent symptom, as well as, pelvic cramping, and vaginal bleeding) on a 5 point scale (0 = no symptoms to 5 = very severe) daily over the course of 2 months.

On the second visit, 1 month later, symptoms were reassessed and subjects were asked if there have been any changes in their medical history, medications, recent hospitalizations, etc. They reassessed their symptoms with the PAGI-SYM questionnaire for the last 2 weeks and updated their biographical information.

Sample size assessment

A sample size of approximately six in each group was calculated to be needed. This was determined using the GCSI scores for females with gastroparesis (average score 2.9), normal female subjects (average score <0.9) and the standard deviations. A minimum of a 1 point difference in symptoms among the groups was able to be detected using the GCSI scoring system and this sample size.

Statistical analysis

Data are reported as mean ± SEM or mean ± SD where indicated.

The first sign of menstrual bleeding was defined as day 1 of the menstrual period. The first day of ovulation (days 15–18 for our subjects) defined the luteal phase of the menstrual cycle. We accounted for symptom alignment throughout the menstrual cycles by determining Day 1 as the first day of menstruation in women off hormonal contraception. For women on continuous hormonal contraception Day 1 was considered the first day of enrollment as their hormonal levels essentially do not fluctuate, any day can be considered Day 1. Scores were individually aligned to account for the first day of ovulation (marking the first day of the luteal phase) as indicated by the BBT recordings.

The daily symptom score (graded from 0 to 5) for each subject was taken for each symptom. This daily symptom score was then averaged among all the other daily symptom scores for each patient in that group. From this, we were able to derive a cumulative daily symptom score for each group. These daily cumulative symptom scores were plotted daily across the menstrual cycle and analyzed for trends throughout the month among groups.

Data were analyzed looking at each phase of the menstrual cycle: during the menses (when estrogen and progesterone levels are the lowest), the proliferative stage of the follicular phase (where estrogen and progesterone levels are still very low but estrogen levels are increasing more so than progesterone) and the luteal phase (where estrogen and progesterone levels are elevated and progesterone becomes the dominant hormone). The symptom scores for the follicular phase and the luteal phase were compared using paired Student’s t-tests.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Subjects

The demographics for the study (age, menarche, cycle length, gastric emptying scans) subjects are shown in Table 1. Ages of the gastroparesis patients ranged from 20 to 34 in the hormonal contraceptive group and 21–44 in the ovulation group. In the healthy control groups, ages ranged from 19 to 31. There were no statistically significant demographical differences among the groups, except for ethnicity. There were also no statistical significant differences in BMI in gastroparesis not taking OCPs (25.2 ± 1.8) compared to gastroparesis taking OCPs (24.9 ± 1.2; = 0.09) among the two groups.

Table 1.   Demographic information of study subjects: gastroparesis patients and non-gastroparesis women
GroupGastroparesis women not taking OCPsGastroparesis women taking OCPsNon-gastroparesis women not taking OCPsNon-gastroparesis women taking OCPsP value
  1. NA, not applicable.

Age32.3 ± 1.4 years28.9 ± 1.0 years24.5 ± 1.3 years25.8 ± 2.1 years= 0.09
BMI25.2 ± 1.824.9 ± 1.223.1 ± 1.921.5 ± 1.3
Diabetes20% (2 of 10)10% (1 of 10)10% (0 of 10)0% (0 of 10)
Race
 Caucasian100% (10 of 10)100% (10 of 10)0% (0 of 10)0% (0 of 10) 
 African American0% (0 of 10)0% (0 of 10)100% (10 of 10)100% (10 of 10)
Age at menarche, years (Mean ± SD)13.0 ± 1.8512.50 ± 1.5313.1 ± 1.0313.25 ± 0.99= 0.16
Length of cycles, days (Mean±SD)28.75 ± 2.10NA27.6 ± 2.70NA= 0.49
Length of menses, days (Mean ± SD)5.1 ± 0.138.2 ± 0.225.4 ± 0.127.1 ± 0.07= 0.42
Menstruation severity9 of 10, mild10 of 10, mild8 of 10, mild10 of 10, mild
1of 10, moderate2 of 10, moderate
Gastric electric stimulator10% (1 of 10 patients)40% (4 of 10 patients)NANA 
Hospitalizations per year1.5 ± 0.64 (Range: 0–6)3.600 ± 1.76 (Range: 0–12)NANA= 0.41
Years since diagnosis2.38 ± 0.75 (Range: 1–4 years)2.9 ± 0.71 (Range: 3–9 years)NANA= 0.47
Gastric emptying (% retention) (Mean ± SEM)2 h: 64% ± 5.4 (Range: 53–81%)2 h: 56% ± 3.5 (Range: 37–95%)NANA2 h = 0.47
4 h: 37% ± 2.7 (Range: 18–60%)4 h: 42% ± 4.3 (Range: 16–90%)4 h = 0.48

Of twenty patients with gastroparesis, three were diabetic. For gastroparesis patients on OCPs, there was one insulin-dependent diabetic and one diet-controlled diabetic. There was one gastroparesis patient off hormonal contraception with insulin dependent diabetes. All three diabetic patients reported both stable diabetes symptoms and good blood sugar control on their current diabetes regimen. The mean Hemoglobin A1c was 7.93 ± 0.40.

Of twenty patients with gastroparesis, five had gastric electric stimulators. Results were analyzed with and without patients with gastric electric stimulators for which there were no statistically significant changes. There was no significant differences among the two groups of gastroparesis patients with respect to frequency of hospitalizations per month (= 0.40).

Initial results of PAGI-SYM questionnaires for all participants are show in Table 2. The main symptoms of the patients with gastroparesis were stomach fullness, nausea, bloating, and loss of appetite.

Table 2.   Results of the initial PAGI-SYM validated questionnaire in patients with gastroparesis and non-gastroparesis subjects
SymptomsGastroparesis women not taking OCPs = 10 patientsGastroparesis women taking OCPs = 10 patientsNon-gastroparesis women not taking OCPs = 10 patientsNon-gastroparesis women taking OCPs = 9 patients
  1. NA, not applicable.

  2. Results expressed as mean ± SD.

Nausea2.67 ± 0.602.43 ± 0.730.50 ± 0.080.30 ± 0.06
Retching1.20 ± 0.761.43 ± 0.630 ± 00 ± 0
Vomiting1.67 ± 1.100.86 ± 0.630 ± 00 ± 0
Stomach fullness3.11 ± 1.123.02 ± 1.230.10 ± 0.030.20 ± 0.04
Unable to finish a normal-sized meal2.25 ± 0.542.18 ± 0.600.10 ± 0.030.10 ± 0.03
Excessive fullness with meals2.49 ± 1.422.21 ± 0.850.04 ± 0.070.03 ± 0.04
Loss of appetite2.33 ± 1.302.57 ± 0.730.04 ± 0.050.20 ± 0.04
Bloating2.11 ± 1.232.57 ± 0.920.80 ± 0.070.50 ± 0.05
Stomach visibly larger1.43 ± 0.951.30 ± 0.250.65 ± 0.050.50 ± 0.04
Upper abdomen pain1.97 ± 0.292.75 ± 1.040.30 ± 0.050.20 ± 0.04
Upper abdominal discomfort2.35 ± 0.382.73 ± 1.040.30 ± 0.050.20 ± 0.04
Lower abdominal pain2.50 ± 0.382.85 ± 1.010.30 ± 0.050.20 ± 0.04
Lower abdominal discomfort1.90 ± 0.382.65 ± 0.160.30 ± 0.050.20 ± 0.04
Heartburn during the day1.75 ± 0.281.95 ± 0.280 ± 00 ± 0
Heartburn when lying down1.73 ± 1.201.85 ± 0.950.10 ± 0.030 ± 0
Chest discomfort during the day1.90 ± 0.381.60 ± 0.250 ± 00 ± 0
Chest discomfort at night2.10 ± 0.281.80 ± 0.190.10 ± 0.030 ± 0
Regurgitation during the day1.64 ± 1.231.85 ± 0.920 ± 00 ± 0
Regurgitation when lying down1.85 ± 0.882.08 ± 0.980 ± 00 ± 0
Acid taste1.95 ± 0.851.44 ± 1.200.10 ± 0.030 ± 0
Constipation0.87 ± 0.571.17 ± 0.920.40 ± 0.020.30 ± 0.05
Diarrhea1.14 ± 0.791.44 ± 1.200 ± 00 ± 0
Predominant symptomNausea-40%Vomiting-30%NANA
Vomiting-20%Abdomen pain-20%
Fullness-20%Nausea-20%
Heartburn-10%Heartburn-10%
Bloating-10%Early satiety-10%
Episodes of vomiting per day2.12 ± 2.102.3 ± 0.380 ± 00 ± 0
Number of bowel movements per day1.14 ± 0.161.63 ± 0.511.03 ± 0.140.97 ± 0.11

Menstrual cycle

All study subjects successfully completed the daily diaries of their symptoms. The symptom scoring during each phase of the menstrual cycle between each group is show in Table 3. Gastroparesis patients not on OCPs had significantly worse symptom scores during the luteal phase compared to the follicular phase for nausea (2.25 ± 0.68 vs 1.58 ± 1.06; < 0.001) and early satiety (2.84 ± 0.50 vs 1.74 ± 1.50; < 0.001), but not for vomiting (2.11 ± 0.78 vs 2.02 ± 0.68; = 0.26), bloating (2.46 ± 0.96 vs 2.11 ± 0.79; = 0.78), abdominal pain (1.97 ± 1.39 vs 2.18 ± 1.38; = 0.38), fullness (2.50 ± 0.77 vs 2.21 ± 0.55; = 0.17), or loss of appetite (2.31 ± 0.89 vs 2.23 ± 0.84; = 0.57). No other significant differences were found.

Table 3.   GCSI daily diary symptom scoring during each phase of the menstrual cycle for gastroparesis patients and for non-gastroparesis women depending on the use of oral contraceptive agents
SymptomGastroparesis women not taking OCPsGastroparesis women taking OCPs (D = days)Healthy women not taking OCPsHealthy women taking OCPs (D = days)
  1. Results expressed as mean ± SD.

NauseaMenses: 1.44 ± 1.13D1–9: 1.88 ± 0.82Menses: 0.03 ± 0.06D1–9: 0.15 ± 0.09
Follicular:1.58 ± 1.06D10–19: 1.81 ± 0.97Follicular: 0.14 ± 0.06D10–19: 0.18 ± 0.12
Luteal: 2.25 ± 0.68D20–28: 1.80 ± 0.99Luteal: 0.12 ± 0.13D20–28: 0.09 ± 0.06
VomitingMenses: 1.92 ± 0.95D1–9: 1.80 ± 0.99Menses: 0 ± 0D1–9: 0 ± 0
Follicular: 2.02 ± 0.68D10–19: 1.15 ± 0.67Follicular:0 ± 0D10–19: 0 ± 0
Luteal: 2.11 ± 0.78D20–28: 1.36 ± 0.83Luteal: 0 ± 0D20–28: 0 ± 0
BloatingMenses: 2.40 ± 0.64D1–9: 2.44 ± 1.32Menses: 0.02 ± 0.31D1–9: 0.01 ± 0.01
Follicular: 2.11 ± 0.79D10–19: 2.38 ± 1.30Follicular: 0.01 ± 0.09D10–19: 0.02 ± 0.03
Luteal: 2.46 ± 0.96D20–28: 2.50 ± 1.45Luteal: 0.01 ± 0.06D20–28: 0.01 ± 0
Early satietyMenses: 1.52 ± 0.46D1–9: 2.67 ± 1.40Menses: 0.02 ± 0.006D1–9: 0.01 ± 0.01
Follicular: 1.74 ± 0.46D10–19: 2.3 ± 1.70Follicular:0.08:±0.31D10–19: 0.04 ± 0.03
Luteal: 2.84 ± 0.54D20–28: 2.32 ± 1.50Luteal: 0.04 ± 0.003D20–28: 0.01 ± 0.01
FullnessMenses: 2.04 ± 0.49D1–9: 2.91 ± 1.17Menses: 0.03 ± 0.09D1–9: 0.01 ± 0.01
Follicular: 2.21 ± 0.55D10–19: 2.61 ± 1.59Follicular:0.05 ± 0.006D10–19: 0.02 ± 0.03
Luteal: 2.50 ± 0.77D20–28: 3.00 ± 1.40Luteal: 0.02 ± 0.003D20–28: 0.01 ± 0.02
Loss of appetiteMenses: 2.12 ± 0.99D1–9: 2.65 ± 1.38Menses: 0.06 ± 0.003D1–9: 0.05 ± 0.03
Follicular: 2.23 ± 0.84D10–19: 2.65 ± 1.44Follicular: 0.04 ± 0.06D10–19: 0.07 ± 0.06
Luteal: 2.31 ± 0.89D20–28: 2.57 ± 1.55Luteal: 0.05 ± 0.006D20–28: 0.08 ± 0.06
Abdominal painMenses: 2.42 ± 1.32D1–9: 1.69 ± 0.90Menses: 0.03 ± 0.06D1–9: 0.06 ± 0.03
Follicular: 2.18 ± 1.38D10–19: 1.67 ± 0.99Follicular: 0.01 ± 0.03D10–19: 0.04 ± 0.03
Luteal: 1.97 ± 1.39D20–28: 1.77 ± 1.40Luteal: 0.02 ± 0.03D20–28: 0 ± 0
HeartburnMenses: 2.16 ± 1.20D1–9: 1.52 ± 1.10Menses: 0.04 ± 0.06D1–9:0.08 ± 0.06
Follicular: 2.52 ± 0.72D10–19: 1.42 ± 1.10Follicular: 0.06 ± 0.03D10–19: 0.08 ± 0.06
Luteal: 2.41 ± 0.70D20–28: 1.46 ± 1.10Luteal: 0.04 ± 0.09D20–28: 0.14 ± 0.09
DiarrheaMenses: 0.04 ± 0.80D1–9: 0.21 ± 0.23Menses: 0.01 ± 0.09D1–9: 0.01 ± 0.01
Follicular: 0.08 ± 0.10D10–19: 0.37 ± 1.08Follicular: 0.05 ± 0.13D10–19: 0.02 ± 0.02
Luteal: 0.08 ± 0.11D20–28: 0.40 ± 0.73Luteal: 0.02 ± 0.06D20–28: 0.01 ± 0.003
ConstipationMenses: 0.50 ± 0.47D1–9: 0.86 ± 0.96Menses: 0.03 ± 0.06D1–9: 0.07 ± 0.06
Follicular: 0.29 ± 0.25D10–19: 0.84 ± 0.90Follicular: 0.04 ± 0.03D10–19: 0.18 ± 0.13
Luteal: 0.25 ± 0.12D20–28: 0.47 ± 0.50Luteal: 0.20 ± 0.03D20–28: 0.10 ± 0.06

Fig. 1 shows the average daily symptom scores for nausea in gastroparesis patients. In the gastroparesis patients not taking OCPs there was an increase in nausea severity in the second portion of the menstrual cycle (luteal phase) (Fig. 1A); whereas in patients taking OCPs, the symptoms were relatively stable (Fig. 1B). Fig. 2 shows the average daily symptom scores for early satiety in gastroparesis patients. In the gastroparesis patients not taking OCPs there was an increase in early satiety severity in the second portion of the menstrual cycle (luteal phase) (Fig. 2A); whereas in patients taking OCPs, the symptoms were relatively stable (Fig. 2B).

image

Figure 1.  Nausea throughout the menstrual cycle in female patients with gastroparesis. Fig. 1A represents patients not taking oral contraceptive agents. Fig. 1B represents patients taking oral contraceptive agents.

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image

Figure 2.  Early satiety throughout the menstrual cycle. Fig. 2A represents patients not taking oral contraceptive agents. Fig. 2B represents patients taking oral contraceptive agents.

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Eight of 10 gastroparesis patients off hormonal contraception reported nausea in their GCSI daily diary as the most predominant symptom during the luteal phase. During the proliferative stage of the follicular phase (days 7–14), the most predominant symptoms included bloating (4 of 10), nausea (3 of 10), heartburn (2 of 10) and abdominal pain (1 of 10).

Gastroparesis patients on OCPs, regardless of gastric pacemaker presence, showed little day-to-day variation of symptoms with average scores for nausea, 1.83 ± 0.92 and early satiety, 2.43 ± 1.53 (Figs 1B and 2B). Vomiting was more severe in patients off OCPs compared with patients not taking OCPs (2.05 ± 0.80 vs 1.44 ± 0.83; = 0.040).

Healthy control women exhibited little to no symptoms regardless of OCP use and regardless of their menstrual period. Average daily symptom scores for all normal subjects throughout the menstrual cycle were <0.5, on a 0 (none) to 5 (severe) point scale (Table 3).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

This prospective study sought to evaluate differences in gastroparetic symptoms throughout the menstrual cycle in female patients with gastroparesis. This study shows that some gastroparesis symptoms, particularly nausea and early satiety, vary along the menstrual cycle in female patients with gastroparesis. Symptoms increased in the luteal phase of the menstrual cycle when estrogen and progesterone levels are typically elevated. In contrast, although nausea and early satiety were increased in gastroparetic patients on oral contraceptives compared with normal subjects, there were no cyclic variations.

The variation of symptoms among the menstrual cycle is of importance in gastroparesis, a condition where most patients with gastroparesis are women.18,19 Why gastroparesis has a predilection for young female subjects is not known. Gastric emptying is affected by gender, menopausal status, and even phase of the menstrual cycle. Stanghellini et al. reported female sex was associated with delayed gastric emptying in patients with functional dyspepsia even when sex-specific normal ranges in which females were slower than males.20 The exact mechanism responsible for the effect of female gender on gastrointestinal motility is unknown.21 Studies also suggest that females may have more severe symptoms than males. In a series of patients with idiopathic gastroparesis, females had higher symptom severity scores than male patients for stomach fullness, inability to finish a meal, bloating, visible stomach distention and constipation.22 In a telephone survey study of 21 128 adults in the community, symptoms of early satiety and nausea were found to be more common in females than in males, by nearly a 2 : 1 ratio with nausea being present in 1.4% of males and 3.0% of females whereas early satiety was present in 3.7% of males and 5.7% of females.23

Interestingly, in our study, female gastroparesis patients had significantly worse symptoms during the luteal phase compared to the follicular phase of the menstrual cycle for nausea and early satiety, but not for vomiting, bloating, abdominal pain, fullness, or loss of appetite. The increased symptoms of nausea and early satiety occurring in the luteal phase suggest that estrogen and progesterone may be responsible as levels of these hormones are typically elevated during this phase of the menstrual cycle. Female reproductive hormones, especially progesterone, have inhibitory effects on gastric motility. Estrogen has also been shown to effect gastrointestinal motility. In vitro studies using exogenous estrogen has been suggested to prime and enhance the inhibitory effects of progesterone.6 However, studies by Knight et al. have shown that gastric emptying in normal young women is slower than in aged matched men, even in the first 10 days of the menstrual cycle when estrogen and progesterone levels are low.3 A recent study reported by Brennan et al.24 found rates of gastric emptying of glucose were slower during the follicular phase compared to the luteal phase of the menstrual cycle in healthy non-diabetic females. Gender-related differences have also been reported to be present in the proximal stomach affecting motility and perception.25 Estrogen and progesterone may also induce gastric dysrhythmias in the postprandial period.26

Traditionally, OCPs are packaged with 21 active (hormone-containing) pills and seven placebo pills (contain no hormones). During the week of placebo pills, withdrawal bleeding occurs and simulates an average 28-day menstrual cycle. Placebo pills may be skipped, going straight to the next pack of active pills to prevent the withdrawal bleeding. More recently, extended or continuous use of OCPs has been employed to treat endometriosis, dysmenorrhea, and menstruation-associated symptoms.27 OCPs have been used to avoid menstruation altogether. Synthetic estrogen and progesterone in each pill pack prevent both ovulation and menstruation. This occurs by mimicking the body’s own hormones and triggers a negative feedback loop to the hypothalamus and pituitary gland to suppress ovulation. Older research studying the effects of OCPs on gastric emptying and GI function generally assessed the effects of daily administration of OCPs and did not assess the newer extended or continuous hormonal contraception which were used by the patients in this study.

Oral contraceptive agents act by centrally suppressing endogenous ovarian sex hormones production. In this study, the patients on continuous hormonal contraception still experience symptoms, though with less variation. Perhaps this was due to suppression of both the LH surge and ovulation (associated with rising progesterone levels) caused by reducing cyclic variation in sex hormones and providing a more consistent hormonal level. Interestingly, vomiting was less severe in patients taking OCPs compared to patients taking OCPs. These findings suggest that it may be useful to investigate a role for hormonal contraception to limit variation of symptoms during the menstrual cycle in female patients with gastroparesis. These findings also raise the question as to whether a central mechanism for female sex hormones on the perception of gastrointestinal symptoms exists.

This study enrolled patients with gastroparesis from a tertiary medical center. This was helpful to accrue the number of patients with gastroparesis needed for the study. However, patients in a tertiary medical center may have more severe symptoms than the general community. There were some differences among the study groups with respect to ethnicity, BMI, presence of gastric electric stimulators; however, these did not appear to have an effect on the results of this study. In future studies, we plan to enroll more patients and lengthen the period of time we follow our patients. In this study, we used a convenient test, basal body temperature recordings, to assess for ovulation for which all patients were compliant; more superior forms of measuring LH and progesterone exist and could be used.

In summary, this study demonstrates that there are variations in symptoms of female patients with gastroparesis that occur along the menstrual cycle. Increased symptoms, particularly nausea and early satiety, occurred in the luteal phase of the menstrual cycle in female patients with gastroparesis. Interestingly, variations in symptoms were not seen in gastroparesis female patients on hormonal contraception.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
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