Materials
and Methods. The study was conducted from January to October 2023 at
Wahidin Sudirohusodo Hospital in Makassar using a cross-sectional design through
consecutive sampling of ovarium endometrioma patient confirmed by histopathological
examination. AMH levels were measured by ELISA technique, size and bilaterality were
determined based on abdominal ultrasound examination.
Results. A total of 50 women, with a mean age 32.24 ± 0.75 years, were enrolled in the
study. There was no difference in the effect of age, menarche age, education, parity, BMI,
endometrioma bilaterality, or tumor size on AMH levels(p > 0.05). In the correlation test, age
(r = -0.248) and tumor size (r = -0.276) were negatively correlated with AMH levels, while
menarche age (r = 0.067) was positively correlated with AMH levels, but all three variables
were statistically insignificant (p > 0.05).
Conclusions. There was no association anti mullerian hormone level with the size and
bilaterality of ovarium endometrioma. Further research is needed with a larger sample size
to confirm it.
K
eywords: Endometrioma, Anti-Mullerian Hormone, Unilateral, Bilateral, Tumor Size
Manuscript accepted for publication
2
Introduction
Endometriosis is an estrogen-dependent condition characterized by the presence of ectopic
endometrial-like tissue [1]. The most common sites of endometriosis are the ovaries,
followed by the Douglas pouch, the posterior leafs of the broad ligaments, and the
sacrouterine ligaments [2]. Ovarian endometriomas occur in 17–44% of patients with
endometriosis and account for 35% of all benign ovarian tumors [3]. Several studies have
indicated a correlation between endometriosis and a higher prevalence of obstetric
complications, including preterm births, placental disorder, gestational diabetes, cesarean
section (CS), and postpartum hemorrhage (PPH) [4]. Additionally, there is a correlation
between endometriomas and infertility, and it is now widely accepted that endometriomas
affect fertility. Although the mechanism is unclear, research suggests that it can negatively
affect spontaneous ovulation rates and reduce the number and activity of follicles in adjacent
ovarian tissue [5].
Anti-Mullerian Hormone (AMH) is a glycoprotein hormone with a molecular weight of 140
kDa linked by a disulfide chain [6]. It is produced by granulosa cells of non-growing follicles,
such as primary, secondary, preantral, and early antral follicles. It can predict the state of
ovarian reserve and follicular growth, which are critical to fertility [7]. AMH is commonly used
as a primary fertility marker, particularly in conditions or diseases that affect ovarian reserve,
such as polycystic ovarian syndrome [8].
The decline in AMH levels was found to be more rapid in women with endometriomas
compared to healthy women and women with other benign ovarian cysts [9]. The correlation
between AMH levels and endometrioma volume is not well known due to conflicting study
results. A study by Suardi et al. found a negative correlation between AMH levels and
ovarian endometrioma volume, but it was not statistically significant (r = -0.332; p=0.066).
The study also found significantly lower AMH levels in the endometrioma group compared to
controls, but this was not affected by laterality [10]. Another study which compared AMH
levels tested one month pre-surgery in the ovarian endometrioma group with controls, found
AMH levels were not significantly different between the two groups and serum AMH levels
were significantly positively correlated with ovarian endometrioma cyst volume (r
2=0.23; 95%
CI: 0.007-0.1; p=0.02) [11]. In addition, a meta-analysis also showed postoperative AMH
levels were affected by the bilaterality of the endometrioma but not preoperative AMH levels
[12].
Existing research about association between anti mullerian hormone levels with the size
and bilaterality of ovarium endometrioma is still controversial. Therefore, this study aims to
analyze the association between anti-Mullerian hormone levels and the size and bilaterality
of ovarian endometriomas through abdominal ultrasound examination especially in the
limited health facilities so the ovarian reserves can be predicted with a simple modality.
Materials and methods
This study was conducted at Wahidin Sudirohusodo Hospital, Makassar Indonesia, between
January until October 2023. The study received approval from the Health Research Ethics
Committee of the Faculty of Medicine, Hasanuddin University
(No.20/UN4.6.4.5.31/PP36/2023). Informed consent was obtained from all participants. The
participants were enrolled into the study by consecutive sampling technique. The inclusion
criteria were: 1) Diagnosed as endometrioma based on ultrasound examination, 2) >20
years old and not yet menopause. The exclusion criteria were: 1) Using hormonal
contraception in the last 1 year, 2) Taking vitamin D supplements, 3) History of previous
endometrioma surgery, pelvic inflamatory disease or polycystic ovarian syndrome, 4)
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3
Histopathological examination results not endometrioma. We excluded patients using
hormonal contraception and vitamin D supplements because contraception can reduce AMH
levels, while vitamin D can increase AMH levels [13,14].
All participants underwent transabdominal USG to assess the size and characteristics of
ovarian endometrioma. The ultrasonographic criteria for diagnosing endometrioma included
the presence of a cystic structure with uniform low-level internal echoes lacking papillary
proliferations and exhibiting poor vascularization, or a cystic structure with uniform low-level
internal echoes containing an echogenic portion devoid of detectable blood flow. The
endometrioma was measured in two dimensions,
The levels of AMH measured at the Clinical Pathology Laboratory of Hasanuddin University
Hospital using an enzyme-linked immunosorbent assay (ELISA) kit (AMH ELISA kit,
Bioassay Technology lab,Shanghai) according to the manufacturer’s instructions. The kit has
a sensitivity of 0.024 ng/mL and a detection range between 0.05 - 30ng/ml. It were
examined from vein blood specimens using the ELISA method and reported in ng/ml. The
samples were collected from venous blood in EDTA tubes from presurgical endometrioma
patients. After mix 10-20 minutes, sample was centrifuged for 20 minutes at 2000-3000
RPM then supernatant without sediment was collected. Samples were stored at 80°C,
waiting for histopathological examination. Serum AMH levels for fertile women range from
1.0 ng/ml to 4.0 ng/ml [15]; AMH levels below 1.0 ng/ml are considered low and indicate a
decrease in ovarian reserve [16]. The endometrioma was confirmed through
histopathological examination using hematoxylin-eosin staining.
Statistical analysis was conducted using the SPSS 24.0 for Windows software (IBM, USA).
Baseline characteristics were reported as frequencies and percentages. For normally
distributed data, the results were reported as Mean ± SD and analyzed with an independent
t-test. While in non-normally distributed data were reported as Median ± Interquartile Range
(IQR) and analyzed using the Mann-Whitney test. The differences in baseline characteristics
between the two groups will be analyzed using a chi-square test. A p-value of <0.05 was
considered significant.
Discussion
One of several method to assess the ovarian reserve is by measuring serum AMH levels,
which are produced by granulosa cells in small to medium-sized follicles. These follicles,
ranging from 4 to 8 mm in diameter, account for approximately 60% of circulating AMH [17].
AMH plays a crucial role in controlling ovarian function in the initial stages of follicle growth
by preventing the excessive activation of primordial follicles and slowing down their
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4
progression to the primary stage, thereby preserving the follicle pool[17,18]. Unlike FSH,
AMH levels stay consistent throughout the menstrual cycle [19]. Serum AMH levels are lower
in women with endometriomas, suggesting a decreased ovarian reserve in these women
[10]. .
In this study, an AMH value of <1 ng/mL was used as a benchmark for low AMH levels. For
the characteristic data, the variables of age, menarche age, education, parity, BMI,
endometrioma location, and tumor size were not found to be significantly different in the two
groups. AMH levels decrease with age, resulting in lower pregnancy rates in infertile
patients. Age is considered one of the factors that affect AMH levels [20]. Khan et al. found
that AMH levels decrease by about 6% per year, suggesting a direct relationship between
increasing age and decreasing follicular reserve [21]. However, in this study, age levels were
not found to be different in groups with low and normal AMH. Multivariate testing and
correlation tests were carried out, but no association was found with AMH. Feferkorn et al.'s
study found that AMH levels had a significant effect on endometriosis only in the age group >
35 years, but not in the age group under 35 years. According to this study, this is because at
the age of under 35 years, there are still many follicular reserves, so the increase in age
does not have a significant effect [22]. In Lie Fong's study, AMH concentration was positively
correlated with age until it peaked at 15.8 years, then remained stable, and inversely
correlated after the age of 25 years [23]. Normal AMH values vary by age group, which could
be a confounding factor when categorizing the low AMH group [24].
Menarche age, which also seems to play a role in follicular reserve, was found to be
unrelated to AMH levels in this study. Weghover's study found that the age at menarche is
associated with follicular reserve. The younger the patient is at menarche, the higher the risk
of having low AMH levels. This can be caused by several factors, such as the amount of
ovarian follicular reserve, the rate of follicular depletion, or a combination of both [25].
This study also found no significant difference between parity and AMH levels. Moini found
that women with higher parity had higher AMH levels compared to nulliparous women [26].
Different results were also found in a study of Filipino women, primiparous and multiparous
samples had significantly lower AMH levels than nulliparous [27].
In this study, there was no effect of BMI on AMH levels. This differs from Albu's study, which
reported a positive relationship between BMI and serum AMH levels in infertile patients. The
presence of overweight and obesity is associated with higher AMH levels compared to
patients with normal or lean BMI. Circulating androgens, insulin, and insulin resistance
increase with BMI. These parameters have also been shown to be positively associated with
serum AMH levels [28]. However, some other studies found that AMH levels are negatively
correlated in patients with older age (>35 years) or severe obesity (BMI ≥ 40 kg/m²)
[29,30].In addition, several previous studies have also found no relationship between BMI
and AMH levels [31–33].
There was no significant difference between tumor size and unilateral/bilateral tumor location
in this study. This is consistent with a study conducted at Hasan Sadikin Hospital, which
found a weak correlation between AMH levels and ovarian endometrioma volume but was
not statistically significant (r = -0.332, p = 0.066). However, the group with endometriosis
exhibited lower AMH levels compared to the non-endometriosis control group [10]. Another
study also found that patients with endometriomas had lower AMH levels compared to
patients with other benign ovarian cysts, especially in the 30-39 age group (3.77 ± 2.28 vs
6.58 ± 2.63, p < 0.05). This study also categorized endometriomas into four groups: single
unilateral, single bilateral, multiple unilateral, and multiple bilateral. However, there was no
significant difference in AMH levels among the four groups (p = 0.173). Total cyst diameter
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5
and the number of cysts were found to be negatively correlated with AMH, although the
correlation was not significant, which is consistent with the findings of this study[34]. The
study of Niewegloska et al. demonstrated that only bilateral tumor (p=0.003) and patient age
(p < 0.001) were significant factors. However, cyst volume was found to have a negative
correlation with AMH serum concentration, although it was not significant [35].
Serum AMH levels in women with endometriomas tend to be low due to chronic
inflammatory processes and massive reactive oxygen species (ROS) found in the ovaries.
Toxic factors, such as proteolytic enzymes, iron, and ROS can penetrate the tissue around
endometrioma cysts, causing fibrosis, smooth muscle metaplasia, and reduced follicles in
ovarian tissue [36]. The mechanisms underlying low serum AMH levels and decreased
ovarian reserve are inflammatory processes and immunomodulation abnormalities
associated with toxic endometriomas [37,38]. The inflammatory process causes follicular
damage and dysfunction so that follicular quality and quantity are also reduced [10]. As in
previous studies, AMH levels are not affected by endometrioma size, but AMH levels can
describe the severity/degree of endometrioma in patients and the extent to which
endometriomas cause damage and inflammation [39].
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Table 1. Demographic data of participant
AMH level P
Value Low ( n= 16) Normal ( n= 34)
Age ( Mean±SD; years) 33.81±4.02 31.64±5.8 0.186#
Menarch age(Median±IQR; years) 12(±11) 12(±0.25) 0.614+
Education [n (%)]
Senior High School 13 (26.0) 27 (54.0)
1.0*
Diploma 3 (6.0) 7 (14.0)
Parity [n (%)]
Nulipara 6 (12.0) 21 (42.0)
0.132* Primipara 3 (6.0) 7 (14.0)
Multipara 7 (14.0) 6 (12.0)
Bilaterality [n (%)]
Unilateral 12 (24.0) 22 (44.0)
0.687*
Bilateral 4 (8.0) 12 (24.0)
Body Mass Index [n (%)]
Normal 14 (28.0) 23 (46.0)
0.251*
Overweight 2 (4.0) 11 (22.0)
Table 2 Correlation test of variables to AMH levels
Variable Rho value P-value
Age
Menarch age
Endometrioma size
-0.248
0.067
-0.276
0.082
0.643
0.052
*Spearman Correlation
11
Manuscript accepted for publication