Effect of sex on the outcomes of peroral endoscopic myotomy for the treatment of achalasia

Abstract

BACKGROUND

Peroral endoscopic myotomy (POEM) has emerged as the first-line therapy for achalasia. However, large-scale studies which examine sex-related differences in symptoms and outcomes remain limited.

AIM

To evaluate the impact of sex on achalasia symptoms, diagnostic findings, and postoperative improvement following POEM.

METHODS

We conducted a retrospective review of achalasia patients who underwent POEM at a large center between 2010 and 2020, analyzing demographics and variables collected before, during, and after the procedure for both female and male cases.

RESULTS

Our study included 526 cases in total, with the female group experiencing more severe chest pain (P = 0.008). After stratifying age, we found that women aged 40 to 60 showed higher chest pain scores compared to their male counterparts. In female cases, the severity of dysphagia before POEM was lowest among those aged 60 and older (P = 0.033). Preoperatively, the integrated relaxation pressure (IRP) and resting lower esophageal sphincter pressure (LESP) were higher in the female group compared to the male group (P < 0.001 and P = 0.001, respectively). However, no differences in postoperative IRP and LESP were observed between two groups. The overall efficiency of POEM was 96.52%, with a significant improvement in chest pain scores noted in female cases (P = 0.043).

CONCLUSION

Sex may influence the severity and frequency of chest pain, with female cases exhibiting higher LESP and IRP compared to male cases. POEM is proven to be a safe and effective procedure for both sexes, with female cases potentially experiencing greater benefits.

Key Words: Sex difference; High-resolution esophageal manometry; Eckardt score; Peroral endoscopic myotomy; Achalasia

Core Tip: This is the first study that aimed to evaluate the impact of sex on achalasia symptoms, diagnostic findings, and postoperative improvement following peroral endoscopic myotomy (POEM). Our study drew a conclusion that sex may influence the severity and frequency of chest pain, with female cases exhibiting higher lower esophageal sphincter pressure and integrated relaxation pressure compared to male cases. POEM is proven to be a safe and effective procedure for both sexes, with female cases potentially experiencing greater benefits.

INTRODUCTION

Achalasia, first documented by Sir Thomas Willis in 1674, is a rare esophageal motility disorder characterized by impaired relaxation of the lower esophageal sphincter (LES) and the absence of normal peristalsis[1]. The condition poses significant diagnostic challenges due to its nonspecific presentation. Common clinical manifestations include chest pain, dysphagia, unintentional weight loss, and heartburn[2], which often overlap with other gastrointestinal disorders. The incidence of achalasia in adults varies worldwide, ranging from 0.3 per 100000 to 1.63 per 100000 annually[3]. Endoscopy is the first recommended diagnostic examination, aiming to exclude conditions such as erosive gastroesophageal reflux disease (GERD), esophageal squamous cell carcinoma, and structural lesions[4]. Gastroesophageal endoscopy and high-resolution esophageal manometry are essential diagnostic tools for patients with a strong clinical suspicion of achalasia[5]. High-resolution esophageal manometry, considered as the gold standard for diagnosing achalasia, it is widely utilized to evaluate the inability of the LES to relax and has become the most commonly employed technique in clinical trials[6].

A recent study has provided valuable insights into the underlying mechanisms of achalasia, suggesting it may involve a neurodegenerative motility disorder of the esophagus[7]. Despite these advancements, the exact pathophysiology remains unclear, highlighting the need for further investigation. Peroral endoscopic myotomy (POEM), a minimally invasive procedure, has recently gained widespread adoption, particularly in Asia and other regions, due to its high efficacy and reduced invasiveness in accessing and treating the esophagus[8].

Numerous non-randomized studies have explored the clinical outcomes of POEM from various perspectives[9]. However, due to the rarity of achalasia, these studies have typically involved small patient cohorts, limiting their generalizability. In addition, while sex-related differences in conditions like GERD have been extensively investigated[10]. Studies investigating the influence of sex on preoperative and postoperative differences associated with POEM for achalasia remains scarce, with only a few studies available[11]. Therefore, our study aims to investigate the effect of sex on symptoms, diagnostic evaluation, and postoperative improvement following POEM for achalasia.

MATERIALS AND METHODS

Participants and study design

A total of 1111 consecutive cases diagnosed with achalasia between December 2010 to February 2020, at Chinese PLA General Hospital were treated with POEM by skilled physicians. Inclusion criteria: (1) Diagnosis of achalasia; and (2) Treated by POEM. Exclusion criteria: (1) Cases who were unable to complete follow-up assessments, later evaluations, or those who were unwilling to cooperate with the researchers were excluded from the study; and (2) Cases with a history of esophagus or stomach surgery, pregnancy, contraindications to endoscopy, or severe general illness. Ultimately, 526 cases were included in this study.

Achalasia was diagnosed by a combination of endoscopy, lipiodol radiography, and esophageal high-resolution manometry (HRM). During the post-POEM period, all cases received standardized treatment, dietary guidance, and consistent follow-up care. The cases were divided into 2 groups based on sex: A male group (n = 238) and a female group (n = 288). Each group was further subdivided into three subgroups based on age (< 40 years, 40-60 years, ≥ 60 years).

The differences among the three groups were retrospectively analyzed in terms of the following parameters: (1) Demographic and clinical characteristics, including age, sex, body mass index (BMI), disease duration, Chicago Classification, and the American Society of Anesthesiologists physical status classification; (2) Pre-POEM and post-POEM variables, such as Eckardt score, lipiodolography parameters, HRM findings and rate of clinical success; and (3) Operative findings, including tunnel length, myotomy length, and intraoperative complications. Postoperative complications observed included pleural effusion and infection. Clinical success was defined as achieving an Eckardt score of ≤ 3 without requiring additional treatment. This retrospective study received approval from the Ethics Committee of the Chinese PLA General Hospital (No. S2021-239-01). Informed consent was obtained from all cases prior to their inclusion in the study.

The menopausal status of female cases was recorded and categorized as premenopausal, perimenopausal, or postmenopausal based on clinical history. Additionally, serum estrogen levels were measured preoperatively in all female cases to assess potential hormonal influences on achalasia symptoms and esophageal motility. These data were analyzed to explore possible associations between estrogen levels, symptom severity, and HRM parameters.

POEM procedures

All cases with a preoperative diagnosis of achalasia underwent standard routine examinations prior to undergoing POEM. The procedure involved the creation of a submucosal bleb using a saline solution mixed with methylene blue dye solution, followed by a 2 cm longitudinal mucosal incision made with a specialized knife. A submucosal tunnel was subsequently created using a forward-viewing endoscope equipped with a transparent distal cap, allowing access to the circular muscle fibers and enabling the myotomy. An endoscopic submucosal dissection knife was utilized to extend the submucosal tunnel and perform the muscle dissection, ensuring the longitudinal muscle layers remained intact. After completing the myotomy, the submucosal tunnel was carefully inspected for any signs of bleeding before the mucosal incision was closed with endoscopic clips.

Eckardt symptom score

Achalasia-related symptoms were evaluated both preoperatively and postoperatively using the Eckardt score, a composition measure of achalasia symptom severity that incorporates score for dysphagia, regurgitation, chest pain, and weight loss. The severity of each symptom was rated as follows: 0 (no symptoms), 1 (mild), 2 (moderate), 3 (severe), and 4 (very severe). This score was also employed to determine the therapeutic effect of POEM[12]. To quantify symptom improvement, the postoperative score was subtracted from the preoperative score, with the resulting difference representing the improvement score.

HRM

HRM is a sophisticated technique for diagnosing specific esophageal motor disorders and is now regarded as the gold standard for evaluating esophageal motility[13]. The standard HRM protocol includes a baseline quiescent period of at least 30 seconds, followed by a sequence of 5-10 mL water swallows at room temperature. The procedure utilizes a water-infused catheter and a transducer catheter equipped with closely spaced pressure sensors, allowing for precise measurement of intraluminal pressure changes[14]. Inadequate relaxation of the LES results in esophageal pressure exceeding normal levels. HRM is routinely applied during the perioperative period and follow-up assessments to evaluate both resting and residual pressures.

Radiographic examination

In this study, lipiodolography was selected as an adjunctive diagnostic tool to assess inadequate esophageal motility and rule out any signs of esophageal perforation. This technique provides a structural evaluation of the esophagus by measuring the height and diameter of the lipiodol column using a calibrated ruler while the patient is in an upright position.

Statistical analysis

Normally distributed data are presented as the mean ± SD, while skewed data are reported as the median and interquartile range. Continuous variables were analyzed using Student’s t-test, and categorical variables were analyzed with the χ² test and Fisher’s exact test, as appropriate. The Spearman test was used to assess correlations between age, Eckardt scores, integrated relaxation pressure (IRP), and lower esophageal sphincter pressure (LESP); A P value < 0.05 was considered statistically significant. All statistical analysis were performed using SPSS version 25.0 (IBM, Chicago, IL, United States).

RESULTS

Baseline characteristics before POEM

Follow-up assessment was conducted from December 2010 to May 2020 on 526 cases in this study, with a median age of 45.01 ± 13.78 years. Among these cases, 288 cases were women (54.75%) and 238 were men (45.25%). Although a significant difference was observed in the BMI between men (22.27 ± 3.29 kg/m²) and women (20.85 ± 3.04 kg/m²), no weight loss was noted in either group. No significant differences were observed between the male and female groups regarding tunnel length, myotomy length, or intraoperative complications. In addition, the length of the intraoperative incision in the muscular layer of the esophagus and stomach showed no significant differences between the two groups (Table 1).

Table 1 Baseline characteristics of the cases, mean ± SD/n (%).

Characteristics	Total (n = 526)	Male (n = 238)	Female (n = 288)	P value
Age, year	45.01 ± 13.78	43.23 ± 13.54	46.48 ± 13.82	0.007
BMI, Kg/m2	21.49 ± 3.23	22.27 ± 3.29	20.85 ± 3.04	< 0.001
Course of disease, month (median IQR)	48 (24, 120)	48 (22.5, 120)	48 (24, 96)	0.584
ASA classification	Total (n = 496)	Male (n = 221)	Female (n = 275)	0.506
1	55 (11.1)	23 (10.4)	32 (11.6)
2	428 (86.3)	191 (86.4)	237 (86.2)
3	13 (2.6)	7 (3.2)	6 (2.2)
Chicago classification	Total (n = 437)	Male (n = 199)	Female (n = 238)	0.219
1	65 (14.9)	36 (18.1)	29 (12.2)
2	343 (78.5)	149 (74.9)	194 (81.5)
3	29 (6.6)	14 (7.0)	15 (6.3)
Follow-up period, month (median IQR)	41.0 (21.3, 64.6)	37.7 (19.9, 66.6)	43.0 (22.5, 64.3)	0.226
Previous treatment				0.584
Pneumatic dilation	58 (11.03)	29 (12.18)	29 (10.07)
Botox injection	27 (5.13)	10 (4.20)	17 (5.90)
laparoscopic heller myotomy	11 (2.09)	6 (2.52)	5 (1.74)
Tunnel length, cm (median IQR)	12 (10, 12)	12 (9.75, 12)	12 (10, 12)	0.074
Myotomy length, cm (median IQR)	7 (5.6, 9)	7 (6, 9)	7 (6, 9)	0.492
Myotomy length of esophagus, cm (median IQR)	5 (4.7)	5 (4, 7)	5 (4, 7)	0.369
Myotomy length of stomach, cm (median IQR)	2 (2, 2)	2 (2, 2)	2 (2, 2)	0.948

BMI: Body mass index; ASA: American Society of Anesthesiologists; IQR: Interquartile range.

Outcome of Eckardt scores, manometry and radiography

The Eckardt scores significantly reduced after POEM [mean, 1 (current) vs 7 (perioperative), P < 0.001], accompanied by simultaneous improvements in dysphagia, regurgitation, chest pain, and weight loss. The overall short-term success rate of POEM, defined as achieving an Eckardt score ≤ 3, was 96.52%. Perioperatively, chest pain was more severe in the female group compared to the male group; however, no differences were observed in postoperative outcomes. Further analysis of the four symptoms revealed that only chest pain and weight loss were significantly correlated with BMI. Weight loss showed significant associations with BMI, LESP, and IRP (P < 0.001, P = 0.02, and P = 0.012, respectively). In addition, IRP and LESP were not correlated with ages in either sex.

Only 437 cases (199 men and 238 women) underwent HRM before POEM. We recorded the pressure of the upper and lower esophagus and compared IRP and LESP between different groups. These two pressures were both slightly higher in the female group preoperatively. The height or the width of the lipiodol column dramatically decreased after POEM (Table 2).

Table 2 Comparison of pre-peroral endoscopic myotomy and post-peroral endoscopic myotomy clinical characteristics between male and female subgroups.

Variables	Pre-POEM			Post-POEM
	Male (n = 238)	Female (n = 288)	P value	Male (n = 238)	Female (n = 288)	P value
Eckardt scores
Dysphagia			0.237			0.407
0	0	5		111	138
1	28	30		109	136
2	43	50		8	9
3	167	203		10	5
Regurgitation			0.734			0.858
0	34	44		158	196
1	53	62		69	82
2	77	82		9	9
3	74	100		2	1
Chest pain			0.008 (female > male)			0.052
0	132	120		181	197
1	74	112		54	90
2	24	34		2	1
3	8	22		1	0
Weight loss			0.850			1.000
0	49	62		230	277
1	35	47		7	9
2	67	84		1	1
3	87	95		0	1
Total Eckardt scores (median IQR)	7 (5, 9)	7 (5, 9)	0.393	1 (0, 2)	1 (0, 2)	0.761
HRM
LESP, mmHg (median IQR)	27.6 (20.5, 36.5)	32.8 (23.6, 42.2)	< 0.001 (female > male)	14.0 (10.1, 18.4)	14.8 (10.3, 21.4)	0.296
IRP, mmHg (median IQR)	22.3 (16.7, 29.7)	25.5 (19.6, 33.1)	0.001 (female > male)	8.2 (5.4, 14.1)	11.1 (7.8, 15.4)	0.084
Length of LES, cm (median IQR)	2.5 (2.0, 3.0)	2.6 (2.0, 3.1)	0.631	2.0 (1.7, 2.3)	1.8 (1.5, 2.7)	0.648
Iodipin column, mm (median IQR)
Height	86.0 (58.4, 126.5)	97.5 (67.1, 148.6)	0.127	50.5 (33.1, 77.3)	57.3 (33.1, 94.6)	0.601
Diameter	48.5 (35.5, 65.2)	41.9 (30.9, 53.1)	0.012 (female > male)	27.5 (16.1, 29.3)	24.6 (17.4, 34.0)	0.627

IQR: Interquartile range; POEM: Peroral endoscopic myotomy; HRM: High-resolution manometry; LESP: Lower esophageal sphincter pressure; IRP: Integrated relaxation pressure; LES: Lower esophageal sphincter.

Age-related changes in the female group

The male and female groups were each divided into 3 subgroups based on age (male: Group 1: Age < 40 years; Group 2: 40-60 years; Group 3: Age > 60 years; Female: Group 4: Age < 40 years; Group 5: 40-60 years; Group 6: Age > 60 years). The male subgroups were then compared to their corresponding female subgroups of the same age in terms of Eckardt scores, HRM results, and lipiodol column parameters. Prior to age-based subgrouping, perioperative chest pain was found to be more severe in the female group. When the subgroups were compared, we found that only women aged 40 to 60 had higher chest pain scores and total Eckardt scores. There was no difference in other subgroups (Table 3). The dysphagia scores in group 6 were lower than those in the other female subgroups (P = 0.033). Regarding the perioperative IRP and LESP, the older female subgroups (group 5 and group 6) had higher values than the male subgroups. (Table 4 and 5). Correlation tests showed that the Eckardt scores was negatively related with BMI and positively related with LESP and IRP.

Table 3 Comparison of clinical characteristics between male and female subgroups (year < 40).

Variables	Pre-POEM			Post-POEM
	Group 1: Male, year < 40 (n = 111)	Group 4: Female, year < 40 (n = 96)	P value	Group 1: Male, year < 40 (n = 111)	Group 4: Female, year < 40 (n = 96)	P value
Eckardt scores
Dysphagia			0.744			0.772
0	0	1		54	44
1	9	9		49	48
2	17	17		4	2
3	85	69		4	2
Regurgitation			0.535			0.722
0	13	10		78	71
1	25	30		29	24
2	34	24		2	0
3	39	32		2	1
Chest pain			0.394			0.147
0	54	36		78	59
1	39	43		31	37
2	12	10		1	0
3	6	7		1	0
Weight loss			0.450			0.665
0	19	22		109	93
1	19	14		2	3
2	30	31		0	0
3	43	29		0	0
Total Eckardt scores (median IQR)	7.17 (6, 9)	6.99 (5, 9)	0.411	1 (0, 2)	1 (0, 2)	0.611
Chicago classification	n = 97	n = 82	0.370	n = 97	n = 82	0.370
1	17	10		17	10
2	73	69		73	69
3	7	3		7	3
HRM (median IQR)
LESP, mmHg (median IQR)	29.5 (20.7, 38.5)	32.0 (22.8, 40.7)	0.252	13.8 (8.1, 18.5)	11.8 (8.1, 21.7)	0.889
IRP, mmHg (median IQR)	24.1 (17.9, 31.4)	26.1 (19.4, 33.8)	0.168	6.4 (5.2, 12.4)	10.0 (5.3, 16.6)	0.452
Length of LES, cm (median IQR)	2.5 (2.0, 3.0)	2.6 (2.0, 3.2)	0.351	1.9 (1.9, 2.6)	1.7 (1.4, 2.4)	0.374
Iodipin column, mm (median IQR)
Height	93.3 (65.1, 127.5)	88.8 (52.1, 156.5)	0.692	54.8 (44.6, 92.4)	46.4 (17.5, 94.3)	0.745
Diameter	49.1 (36.2, 59.7)	41.1 (31.4, 53.6)	0.746	28.6 (21.8, 44.5)	21.0 (10.9, 30.2)	0.230

IQR: Interquartile range; POEM: Peroral endoscopic myotomy; HRM: High-resolution manometry; LESP: Lower esophageal sphincter pressure; IRP: Integrated relaxation pressure; LES: Lower esophageal sphincter.

Table 4 Comparison of clinical characteristics between male and female subgroups (40 ≤ year < 60).

Variables	Pre-POEM			Post-POEM
	Group 2: Male, 40 ≤ year < 60 (n = 101)	Group 5: Female, 40 ≤ year < 60 (n = 136)	P value	Group 2: Male, 40 ≤ year < 60 (n = 101)	Group 5: Female, 40 ≤ year < 60 (n = 136)	P value
Eckardt scores
Dysphagia			0.270			0.862
0	0	0		43	62
1	15	14		51	67
2	19	19		3	4
3	67	103		4	3
Regurgitation			0.680			0.774
0	17	26		61	88
1	19	23		35	43
2	38	43		5	5
3	27	44		0	0
Chest pain			0.001			0.236
0	64	56		80	96
1	28	51		20	39
2	9	20		1	1
3	0	9		0	0
Weight loss			0.733			0.865
0	23	28		97	130
1	11	21		4	6
2	31	37		0	0
3	36	50		0	0
Total Eckardt scores (median IQR)	6.5 (5, 8)	7.1 (5, 9)	0.029	1 (0, 2)	1 (0, 2)	0.632
Chicago classification	n = 83	n = 108	0.430	n = 83	n = 108	0.430
1	13	11		13	11
2	63	90		63	90
3	7	7		7	7
HRM (median IQR)
LESP, mmHg (median IQR)	25.5 (20.6, 36.6)	33.2 (23.9, 43.5)	0.001	14.2 (10.9, 18.3)	16.6 (11.8, 21.5)	0.092
IRP, mmHg (median IQR)	21.6 (16.2, 27.1)	25.5 (20.2, 33.3)	0.003	9.4 (5.4, 15.3)	11.1 (8.6, 15.1)	0.266
Length of LES, cm (median IQR)	2.6 (2.0, 3.0)	2.5 (2.0, 3.0)	0.795	2.0 (1.7, 2.2)	1.8 (1.5, 2.9)	0.126
Iodipin column, mm (median IQR)
Height	81.3 (51.9, 106.6)	99.9 (68.7, 141.1)	0.061	47.8 (17.9, 84.9)	59.1 (42.2, 82.6)	0.645
Diameter	50.8 (38.2, 70.3)	42.3 (31.8, 55.7)	0.397	20.2 (14.1, 30.8)	24.8 (19.4, 39.5)	0.430

IQR: Interquartile range; POEM: Peroral endoscopic myotomy; HRM: High-resolution manometry; LESP: Lower esophageal sphincter pressure; IRP: Integrated relaxation pressure; LES: Lower esophageal sphincter.

Table 5 Comparison of clinical characteristics between male and female subgroups (year ≥ 60).

Variables	Pre-POEM			Post-POEM
	Group 3: Male, year ≥ 60 (n = 26)	Group 6: Female, year ≥ 60 (n = 56)	P value	Group 3: Male, year ≥ 60 (n = 26)	Group 6: Female, year ≥ 60 (n = 56)	P value
Eckardt scores
Dysphagia			0.663			0.295
0	0	4		14	32
1	4	7		9	21
2	7	14		1	3
3	15	31		2	0
Regurgitation			0.307			0.857
0	4	8		19	37
1	9	9		5	15
2	5	15		2	4
3	8	24		0	0
Chest pain			0.874			0.243
0	14	28		23	42
1	7	18		3	14
2	3	4		0	0
3	2	6		0	0
Weight loss			0.918			0.378
0	7	12		24	54
1	5	12		1	0
2	6	16		1	1
3	8	16		0	1
Total Eckardt scores (median IQR)	6.38 (5, 8.25)	7.0 (5, 8)	0.605	1 (0, 2)	1 (0, 2)	0.076
Chicago classification	n = 19	n = 48	0.195	n = 19	n = 48	0.195
1	6	8		6	8
2	13	35		13	35
3	0	5		0	5
HRM (median IQR)
LESP, mmHg (median IQR)	24.1 (11.2, 30.4)	31.6 (24.6, 39.4)	0.032	10.0 (7.9, 20.8)	16.6 (5.6, 21.7)	0.699
IRP, mmHg (median IQR)	16.7 (10.4, 22.8)	25.2 (17.3, 30.6)	0.028	10.7 (1.4, 15.2)	13.9 (5.8, 18.0)	0.546
Length of LES, cm (median IQR)	2.4 (1.9, 3.7)	2.6 (2.0, 3.3)	0.616	1.6 (1.5, 3.0)	2.1 (1.7, 2.7)	0.697
Iodipin column, mm (median IQR)
Height	84.9 (57.3, 133.4)	91.4 (67.8, 152.6)	0.638	41.2 (39.4, 89.8)	59.4 (38.0, 101.9)	0.688
Diameter	42.5 (32.4, 96.8)	36.1 (28.5, 50.7)	0.395	28.3 (27.6, 36.9)	32.3 (17.3, 35.8)	0.961

IQR: Interquartile range; POEM: Peroral endoscopic myotomy; HRM: High-resolution manometry; LESP: Lower esophageal sphincter pressure; IRP: Integrated relaxation pressure; LES: Lower esophageal sphincter.

In female cases, subgroup analysis revealed that perioperative chest pain scores were significantly higher in perimenopausal and postmenopausal women compared to premenopausal women (P < 0.05). Additionally, lower estrogen levels were correlated with increased IRP and LESP, suggesting a potential hormonal influence on esophageal motility. Notably, estrogen levels showed a negative correlation with chest pain scores (r = -0.32, P = 0.014), further indicating a possible role of estrogen in modulating visceral pain perception in achalasia. These findings suggest that menopause-related hormonal changes may contribute to variations in achalasia presentation and treatment response.

Improvement in Eckardt scores

Our results showed that chest pain scores significantly improved in female groups (P = 0.043) (Table 6).

Table 6 Comparison of improvement in Eckardt scores between male and female subgroups.

Improved scores	Male (n = 238)	Female (n = 288)	P value	Improved scores	Male (n = 238)	Female (n = 288)	P value
Dysphagia				Chest pain
-2	1	0	0.567	-2	0	0	0.043
-1	1	3		-1	14	7
0	18	22		0	150	159
1	44	54		1	53	84
2	103	108		2	16	29
3	71	101		3	5	9
Regurgitation				Weight loss
-2	1	1	1.000	-2	0	1	0.741
-1	9	9		-1	1	0
0	49	49		0	50	65
1	60	60		1	37	46
2	70	70		2	65	86
3	49	49		3	85	90

Perioperative and postoperative complications

The number of perioperative complications, including mucosal tears, mucosal perforation, mucosal injury, pneumoperitoneum, pneumothorax, mediastinal emphysema, subcutaneous emphysema, and their possibility of emergence were both greater postoperatively than postoperatively. The occurrence of complications, whether preoperatively or postoperatively, was minimal. The most frequent perioperative complication was mucosal injury, with an incidence of 4.1%. After the operation, the most likely complication was infection, with an incidence of 3.5%.

DISCUSSION

Achalasia is a rare disease and equal distribution between men and women[15]. Our study included a substantial cohort of achalasia cases and aimed to explore the impact of sex on symptoms, diagnostic evaluations, and postoperative outcomes. Although some previous studies have reported that female cases are more vulnerable to chest pain[15], they did not further analyze the sex differences by classifying female cases into distinct age groups. In contrast, a recent study found no significant difference in chest pain between male and female cases[15]. However, in our cohort, a clear sex difference in chest pain was evident, with female cases reporting more chest pain before POEM. Upon further comparisons on subgroups of female and male cases, we found that perimenopausal female cases (aged 40-60 years) had higher chest pain scores and total Eckardt scores compared to males in the same age. Perimenopause, a natural physiological transition, typically occurs in women within this age range. The World Health Organization defined it as the permanent cessation of menstruation and a decline in ovarian steroid hormone levels resulting from the loss of ovarian follicular function. We assumed that the sex difference in chest pain was due to low serum estrogen levels, as no such difference was observed between the other female group and the males. A previous study confirmed the presence of estrogen receptors in the mid- and lower esophagus[15]. Since the majority of female cases aged 40 to 60 are perimenopausal, their esophagus may be influenced by estrogen. Demirbilek et al[16] demonstrated that the esophagus of rats with alkali burns had delayed healing and collagen formation due to treatment with estrogen and progesterone. It has been suggested that the symptoms may be caused by prolonged contractions occurring 5 cm above the LES (in-text citation). However, current research has yet to provide a conclusive explanation regarding the estrogenic effect on esophageal motility. In addition, studies have suggested that being perimenopausal is associated with an increased risk of more severe symptoms of depression or anxiety[17]. An explanation for highlighted symptoms of depression or anxiety in perimenopausal female may provide insight into their higher chest pain scores. Some previous studies on achalasia also noted that chest pain decreased significantly with age[18]. However, our study did not find a significant difference between younger cases and older cases in terms of chest pain. We observed a significant sex difference preoperatively, with female cases being more likely to report chest pain (Table 2). To assess the improvement in chest pain between men and women, we subtracted the postoperative score from the preoperative score, and the difference was considered the improvement score. Consequently, we observed a significant improvement in chest pain in female cases (P = 0.043). Based on these findings, we concluded that POEM treatment can significantly improve clinical symptoms in cases, with female cases experiencing greater benefits.

While some studies have reported a significant sex difference in dysphagia, with female cases exhibiting more severe symptoms[18], the present study did not find such a discrepancy. This inconsistency could be attributed to differences in sample sizes, patient demographics, or variations in the criteria used to assess symptom severity across studies. Additionally, prior research has suggested that chest pain in achalasia cases tends to decrease with age[18], whereas our findings indicated that the severity of chest pain in female cases was more pronounced in the perimenopausal group (40-60 years) rather than uniformly declining with age. This divergence may be due to variations in hormonal influences, psychological factors, or differences in esophageal motility, which were not uniformly accounted for in previous studies. Furthermore, while some reports have failed to establish a direct correlation between HRM parameters and achalasia symptoms, the present study found significant associations between LESP, IRP, and weight loss. This discrepancy highlights the complexity of achalasia pathophysiology and suggests that factors beyond manometric measurements, such as esophageal compliance and neural dysfunction, may contribute to symptom severity. Future multicenter studies with standardized methodologies are necessary to elucidate these conflicting findings and further clarify the role of sex differences and hormonal influences in achalasia symptomatology.

Some previous studies found no significant difference was observed between men and women, whereas one study did report a sex difference, noting that dysphagia was more severe in women[18].

Our results are similar to the former study; no sex difference in dysphagia was observed when comparing the male group with the female group. Jia et al[7] reported that dysphagia, chest pain, and heartburn would significantly decrease with aging. Indeed, when we compared the old female group (> 60 years) to the younger female group (< 60 years) separately, we found that dysphagia was milder in the latter than in the former group. A decrease in estrogen may explain the milder dysphagia in the older women.

In our study, we recorded the pressure parameters of the upper and lower esophagus, including the IRP and LESP. Dantas et al[19] concluded that sex may influence esophageal motility. According to the HRM results, the LESP and IRP in the female group were significantly higher compared to those in the male group. After age subgrouping, we found that only women above 40 years of age exhibited higher LESP and IRP. Although no significant difference was found in the Eckardt score between the two sex-classified groups in our study, except for the chest pain score, the female group displayed notably higher scores in various aspects of LES pressure. This suggests that the LES pressure may have a limited impact on the severity of uncomfortable symptoms.

The Eckardt score was closely related to BMI, LESP and IRP. After subdividing the score into four indicators, we found that weight loss was the most significant factor. Previous studies have shown that the IRP is positively correlated with the total Eckardt score, regurgitation score, and weight loss score, indicating that the IRP reflects the severity of achalasia[20-22]. However, some studies have found no relationship between HRM metrics and achalasia symptoms[23]. In our research, we found that weight loss and the Eckardt total score were positively correlated with LESP and IRP, respectively. Symptom severity in achalasia cases was assessed by Eckardt scores. The weight loss score was more objective. The LESP is a component of the resting pressure at the esophagogastric junction. Previous research has considered the LESP an objective indicator of symptom severity and used it to evaluate treatment effectiveness[24]. Thus, we concluded that resting pressure and residual pressure could be indicators of the severity of symptoms. Cases with higher resting pressure or higher residual pressure before POEM are considered to have more serious symptoms.

The common agreement of failed symptom control or clinical recurrence is an Eckardt score > 3. In our study, the short-term success rate of POEM treatment was 96.52%, indicating that POEM should be considered as a first-line therapy for achalasia due to its high effectiveness.

Limitations

Although this retrospective study involved a large sample size, several limitations should be acknowledged. First, being a single-center study, it may be subject to selection bias. Additionally, we found that the chest pain score in the male group was significantly lower than that in the female group, particularly among perimenopausal women aged 40 to 60 years. However, we did not assess the cases’ menopausal status or estrogen level; therefore, the association of sex with symptoms cannot be precisely analyzed. In addition, this retrospective, long-term study focusing on achalasia cases with various examination outcomes and symptoms. However, after the critical first postoperative follow-up, routine examinations were difficult to conduct at later follow-up; thus, we could not evaluate the long-term efficiency of POEM. Furthermore, postoperative follow-up assessments were not uniform across all cases, as some cases were lost to follow-up or did not undergo regular postoperative evaluations. This may have led to incomplete data on long-term symptom relief and potential complications. Additionally, variations in follow-up duration among cases could have influenced the observed outcomes, limiting the ability to draw definitive conclusions regarding the sustained effectiveness of POEM.

CONCLUSION

In conclusion, our study suggests that sex may play a critical role in influencing the severity and frequency of chest pain in cases with achalasia. Female cases have higher LESP and IRP values compared to male cases. POEM is a safe and effective method for both men and women, with female cases experiencing greater benefits.