Reproductive challenges of endometrial polyps: The influence of women's age and associated risk factors

/ Aim: Endometrial polyps (EPs) are abnormal benign growths that originate from the endometrium. Risk factors associated with EPs are hormonal changes related to ageing, Tamoxifen use, hor- mone replacement therapy, overweight or obesity. The exact causal relationship between EPs and infertility remains unclear, but multi - ple mechanisms including mechanical obstruction and biochemical changes are proposed. The “gold standard” for diagnosing and treat- ing EPs is hysteroscopy. This study aims to provide comprehensive understanding of the interplay between EP , age and infertility.

Our study included 301 women undergoing hysteroscopic polypectomy due to infertility treatment, which were divided into two groups based on their age (age ≤ 35 and age > 35).  Data were collected from patients’ medical histories and pathology reports. Study variables included infertility type, type 2 diabetes mel- litus, insulin resistance, polycystic ovary syndrome, endometriosis, hypothyreosis, previous unsuccessful intrauterine insemination and in vitro fertilization (IVF), menstrual cycle irregularities and abnormal uterine bleeding, polyp size and histopathology type.

At least one out of five participants had insulin resistance, polycystic ovary syndrome and abnormal uterine bleeding. Endome- triosis, insulin resistance and primary infertility were more common in the younger group then in the older group. Previous history of unsuccessful IVF cycles, hypothyreosis and secondary infertility were associated with older age.

The prevalence of EPs tends to increase with advanced women’s age, period marked by natural decline in ovarian reserve, hormonal changes and changes in endometrial health. Addressing EPs through appropriate diagnostic and therapeutic measure and understanding the hormonal influence on EPs and EM is crucial for improving fertility outcomes.

endometrial polyps, infertility, hysteroscopy Cite this article as: Mihajlovic S, Vujovic S, Hagen M, Lackovic M, Milic S, Sojat A. S, Saravinovska K, Antic N, Kalicanin Dj, Marina Lj. V. Reproductive challenges of endometrial polyps: the influence of women’s age and associated risk factors; Medicinska istraživanja 2025; 58(2):125-131 DOI: 10.5937/medi58-53292 ISSN 0301-0619 | E-ISSN 0301-0619 https://medicalresearch.med.bg.ac.rs/ 126 | Medicinska istraživanja 2025; 58(2):125-131

Endometrial polyps (EPs), also known as uterine polyps, are abnormal growths that originate from the endometri - um. They consist of glands, stroma, and blood vessels. The size of EPs can range significantly, they can be as small as 5 mm, but they can also fulfill the entire uterine cavity. Based on their attachment to the uterine surface, there are two main types of EPs. If an EP is attached by a narrow-elon - gated pedicle, then it is known as pedunculated. Howev - er, if they have a large flat base, they are known as sessile. The gross morphological appearance of these polyps can vary, but they often present as smooth structures with a tan to yellow coloration. EPs are quite common among women, with estimates suggesting they affect about 25% of women. While EPs can occur at any age, they are sta - tistically more prevalent in women aged 40 to 49 years, primarily due to hormonal changes and fluctuations that this age group tends to experience (1,2). Estrogen’s role in stimulating endometrial growth and thickening each month makes it a significant factor in the development of EPs. Understanding and managing conditions that result in elevated estrogen levels are essential in minimizing the risk of polyp formation and ensuring reproductive health (3). Aside from hormonal changes related to aging, other risk factors associated with EPs have also been identified, such as Tamoxifen use and hormone replacement therapy (HRT). There is an increased risk of EPs in women who are overweight or obese as well. Higher levels of adipose tissue can lead to increased estrogen production, which may contribute to the development of polyps (3,4).   EPs are typically asymptomatic but they can manifest as abnormal uterine bleeding (AUB). The AUB include irregular menstrual periods (unpredictable timing and flow), unusually heavy flow during menstrual period, bleeding or spotting between periods, vaginal spotting or bleeding after menopause. AUB may be the prima - ry symptom of EPs, occurring in more than a half of all women with the condition, and its incidence appears to increase with age (5,6).   Correlation between EPs and infertility is a special concern. While the exact causal relationship between EPs and infertility remains unclear, multiple mechanisms in - cluding mechanical obstruction and biochemical changes are proposed. EPs may induce an inflammatory response in the endometrium, which could disturb embryo im - plantation, similar to the effects seen with an intrauter - ine device. Also, EPs have been found to exhibit altered levels of matrix metalloproteinases (MMPs), cytokines like interferon gamma, and proteins such as glycodelin and placenta protein 14. These biochemical changes can interfere with sperm function, inhibit embryonic devel - opment, and affect the endometrial environment needed for successful implantation (1,7).    Hysteroscopy with guided biopsy not only serves as the definitive method for diagnosing EPs but also fa - cilitates precise localization and allows for immediate therapeutic intervention through simultaneous resec - tion. These advantages underscore its status as the “gold standard” in clinical practice for managing EPs. While there is still disagreement in the literature regarding the routine removal of EPs before attempting pregnancy (both natural and assisted), there is a tendency towards removing polyps before initiating assisted reproductive technologies (ART) such as intrauterine insemination (IUI) and in vitro fertilization (IVF). Therefore, the de - cision-making process should involve a thorough assess - ment of each patient’s unique circumstances and prefer - ences, guided by current evidence-based practices and clinical judgment (8).   This study aims to provide comprehensive under - standing of the interplay between EP, age and infertility, ultimately guiding more effective diagnostic and ther - apeutic strategies to enhance reproductive success for women experiencing such challenges.

Study design and participants  The study was performed in the Clinical Hospital Cen - tre (CHC) “Dr Dragisa Misovic - Dedinje” in Belgrade, Serbia. It included 301 women undergoing hysteroscopic polypectomy due to infertility treatment. The age ranged from 24 to 44 (mean 35.91 ± 4.63). Patients were treated at the Hospital of Gynecology and Obstetrics and recruit - ed from 2019 to 2024. The study was approved by the CHC’s Institutional Review Board (No 18328/4-2024, Date: 29.08.2024).   Study participants were divided into two groups based on their age.   The first, younger group (age ≤ 35) consisted of 131 participants where age ranged from 24 to 35 (mean 31.50 ± 3.00). Second, older group (age > 35) included 170 par- ticipants, with age ranging from 36 to 44 (mean 39.31 ± 2.12).   Study inclusion and exclusion criteria  Study included women aged between 18 and 45 who were treated during a five year long time frame at the CHC “Dr Dragisa Misovic - Dedinje”. Women older than 45 or younger than 18 were excluded from the study. All wom - en included in the study were normal weight and had body mass index (BMI) of between 18.5 and 24.9 kg/m2. Obese women were excluded.     Study variables  Data on infertility type (primary or secondary), type 2 diabetes mellitus, insulin resistance, polycystic ovarian | 127 Reproductive challenges of endometrial polyps: the influence of women’s age and associated risk factors syndrome, endometriosis, hypothyreosis, previous un - successful intrauterine insemination and in vitro fertil - ization, previous hysteroscopic polypectomy, menstrual cycle irregularities and abnormal uterine bleeding, were collected from patients’ medical histories. Data on polyp size and histopathology type were collected from pathol - ogy reports. Statistical analysis  Descriptive statistics are presented as frequencies and percentages for categorical data, and  as mean, medi - an, SD and range for continuous data. The descriptives were presented for the total sample, and for the younger and older group of participants. To test the relationship between age groups and other relevant variables in our study, we used Fisher’s Exact Test for categorical data and Mann-Whitney U test for continuous data. A significance level of p < 0.05 was set. Statistical analysis was conduct - ed using IBM SPSS version 23.0.

The characteristics and prevalence of comorbid- ities, previous ART and hysteroscopy procedures and menstrual cycle disorders in the sample   In order to describe the characteristics of the age groups regarding significant variables related to infertility, we calculated the number of conditions within two groups and in the total sample. In order to examine the relation - ship between age groups and significant variables, we performed Fisher’s Exact test. The results including fre - quencies, percentages and p values (two-tailed) are dis - played in Table 1.  Looking at the results for the whole sample present - ed in Table 1, we can observe that at least one out of five participants have insulin resistance, PCOS and abnormal uterine bleeding – and those were the most common con - ditions. The majority of the sample (85.4%) had a regular menstrual cycle. Inspecting the differences between the age group, we can see that in the younger group (age ≤ 35), the more common conditions are endometriosis (p = 0.011), in - sulin resistance (p = 0.021) and primary infertility (p = 0.017). The prevalence for endometriosis in the younger group was 8.4% compared to the 1.4% in the older group. Insulin resistance was present in 30.5% of cases in the younger group, compared to the 18% in the older group. Regarding primary infertility, there were 90.1% diag - nosed participants in the younger group, compared to the 79.4% in the older group. In the older group there was a significantly higher number of cases with hypothyroidism (p = 0.014), previ - ous unsuccessful IVF (p < 0.001) and secondary infertil - ity (p = 0.017). Every fourth patient had hypothyroidism (25.3%) in the older group compared to every sixth patient (13.7%) in the younger group. The prevalence of previous unsuccessful IVF was 18.8% in the older group compared to the 4.6% in the younger group. Regarding secondary infertility there were 20.6 % diagnosed women in the old - er group compared to the 9.9% in the younger group. The characteristic polyp size and histopathology type in the sample The size of EPs can vary significantly; they can be as small as 5mm, but they can also fulfill the entire uterine cavity. EPs are usually benign, but in some cases, they can be associated with a risk of malignancy, especially in post - menopausal women or in those with abnormal bleeding   total sample (n = 301) age ≤ 35 (n = 131) age > 35 (n = 170) p   N. yes (%) N. yes (%) N. yes (%) endometriosis 14 (4.7) 11 (8.4) 3 (1.8) 0.011 insulin resistance 72 (23.9) 40 (30.5) 32 (18 . 8) 0.021 PCOS 73 (2 4. 3) 38 (29.0) 35 (20.6) 0.104 hypothyroidism 61 (20. 3) 18 (13.7) 43 (25. 3) 0.014 IUI 3 (1.0) 3 (2 . 3) 0 (0) 0.081 IVF 38 (12 . 6) 6 (4.6) 32 (18 . 8) <0.001 previous hysteroscopic polypectomy 4 8 (15 .9) 16 (12 . 2) 32 (18 . 8) 0.153 regular menstrual cycle 257 (85.4) 115 (87.8) 142 (83. 5) 0.327 abnormal uterine bleeding 79 (26.2) 33 (25.2) 4 6 (27.1) 0.792 primary infertility 2 52 (8 4.1) 118 (9 0 .1) 135 (79.4) 0.017 secondary infertility 4 8 (15 .9) 13 (9.9) 35 (20.6) 0.017 Table 1. Frequencies, percentages of participants with endometriosis, insulin resistance, PCOS, hypothyroidism, unsuccessful IUI and IVF, previous hysteroscopic polypectomy, regular menstrual cycle, abnormal uterine bleeding withing total sample and subsamples and statistical significance (p value, two tailed) of Fisher’s Exact test. Note: PCOS – polycystic ovarian syndrome; IUI – unsuccessful intrauterine insemination; IVF – unsuccessful in vitro fertilization  128 | Medicinska istraživanja 2025; 58(2):125-131 patterns. In the total sample the size of the polyp ranged from 2 mm to 50 mm (M = 12.88; SD = 6.57; Median = 10). We used Mann-Whitney U test to discover whether there was a significant difference in average size between the age groups. There were no significant differences (p = .813) between the Mean Rank in the younger group (149.67) compared to the older group (152.03). We also checked the histopathology type and com - pared the groups. In the total sample in 96.7% of cases it was confirmed polyp, and in 3.3% cases other diagnosis. In the younger group the prevalence of other diagnosis was 3.1% whereas in the older group was 3.5%. The re - sults of Fisher’s Exact test showed that these differences were not statistically significant (p = 1.000). Association Between Endometriosis and Type of Infertility To investigate the potential association between endome- triosis prevalence and the type of infertility (primary vs. secondary), we performed Fisher’s Exact Test. The prev - alence of endometriosis was 5.1% among patients with primary infertility and 2.1% among those with secondary infertility. However, this difference was not statistically significant (p = 0.706).

Our study included 301 women dealing with infertility, who were diagnosed with EPs. Subjects were divided in two subgroups, based on age, which was defined for the purpose of this study as older or younger than 35. A to - tal of 12 variables related to EP and infertility treatment were assessed, but statistical relevance was found for only two parameters, concomitant presence of endometriosis and the history of previous IVF failure.   The age for the diagnosis of type 2 diabetes mellitus (T2DM) has decreased over the last few decades (9). Guidelines specifically created for this group of patients are still lacking, and recommendations are primarily ex - trapolated from the evidence in older people (10). How - ever, only three cases of T2DM were observed in the group of women who were older than 35, and there were no participants with T2DM among participants in the first group (35 or younger) so therefore statistical com - parison between the two groups was not performed. Women’s fertility starts to decline after the age of 30, and after the age of 35 the fertility decline rate accelerates. The underlying etiology is associated with the oocyte number and quality depletion, and this is the primary reason why women over 35 are more commonly seeking fertility counselling and are more commonly exposed to the methods of assisted reproduction (11). The highest number of ART procedures in the United States (US) are actually carried out among women aged between 35 and 40. Centers for Disease Control and Prevention (CDC) reported the average age of women undergoing ART pro - cedures to be 36.2 years. Women aged between 35 and 40 represent 43.3% of all women undergoing ART proce - dures in the US (12).  Advanced women’s age is a well-known risk factor for prolonged time to conception. Without involvement of ART techniques before the age of 30 women have approx- imately 85% chance to conceive within one year, while after the age of 35 these chances drop to 66%, and go further down reaching a probability of 44% by the age of 40. Unfortunately, reproductive challenges at this age are not limited only to the conception difficulties. At this age women deal with other burdens of unfavorable pregnancy outcomes as well, such as a miscarriage. More than a quar- ter of all clinical pregnancies terminate as a miscarriage at the age of 40, compared to 16% at the age of 30 (11,13).  Our results are in unison with the fact that advanced women’s age is associated with higher number of unsuc - cessful IVF cycles (14), and this is the most probable ex - planation why women over 35 in our study did undergo IVF procedures more often compared to the group of women who were 35 years or younger.  Our study showed higher prevalence of endometriosis in younger patients with EP. Both EP and endometriosis are conditions related to the uterine lining, but they are distinct in their nature and presentation. While EP are growths that occur in the endometrium, endometriosis is a condition where endometrial tissue grows outside the uterus, causing pain, irregular bleeding and fertility issues. Even though EP and endometriosis are two dif - ferent conditions, there’s often an overlap in clinical pre - sentation and possibly in the pathophysiological mecha - nism leading to it. Although the exact pathophysiological mechanism is not completely understood yet, several re - search groups have reported increased prevalence of EP in women with endometriosis dealing with infertility si - multaneously (15,16).   It is known that adhesions associated with anatomi - cal disturbances are the leading mechanism resulting in infertility in endometriosis patients, but the importance of endocrine and immunological disturbances should not be neglected either, especially since the exact pathophys - iological mechanism explaining endometriosis is so far not fully understood (17).  Endometriosis and EP are influenced by hormon - al changes, particularly those related to estrogen, but they do so in different manners. Estrogen stimulates the growth of the endometrial lining resulting in the de velopment of EP, and estrogen fluctuations affect the growth of EP in a more complex manner. Estrogen recep - tor pattern and aromatase activity expression are altered in both EP and endometriosis patients, and estrogen fluc - tuation levels are the probable intrinsic factor linking EP, endometriosis and infertility (18-20). Furthermore, vas - cular changes associated with Endometriosis could be | 129 Reproductive challenges of endometrial polyps: the influence of women’s age and associated risk factors in relationship with the evolution of the EP vessel’s axis as well. Machado et al. have found that levels of inflam - matory markers in endometrium, such as vascular endo - thelial growth factor (VEGF), matrix metalloproteinases (MMP) and angiogenesis factors 1 and 2, are higher in patients with EP who suffer from endometriosis at the same time (21). Additionally, Wang et al. have reported significant association between endometriosis and EP in their research and emphasized that all patients dealing with endometriosis should be carefully evaluated for the concomitant presence of EP, regardless of the ultrasonog - raphy findings (22).  Unlike EP which have a peak incidence between the age of 40 and 49 (23), endometriosis typically affects women during their 30s. Even though between 10 and 15% of all women of reproductive age are affected by en - dometriosis, and despite all the improvements and prog - ress in technology and diagnostics, there is still a shock - ing average delay of nearly seven years in establishing endometriosis diagnosis (24).  Estrogen levels reach their peak during women’s late 20s. By the age of 50 there is a 50% decline in estrogen lev- els compared to their peak levels, with further dramatical decrease during and after perimenopause (25). Endome - triosis is known to be highly dependent on estrogen, but it is known that even if estrogen level would decline, endo - metriosis symptoms would not necessarily decrease (26). In this context, younger age, 35 or less, is beyond doubt related with higher estrogen levels and consequently with higher endometriosis incidence, and our result supports this interdependence.  Endometriosis affects women’s quality of life in a sim - ilar manner as Crohn’s disease, T2DM and rheumatoid arthritis, and despite a significant percentage of women of reproductive age living with it, therapeutic approaches for endometriosis are still limited exclusively to the man - agement of symptoms caused by endometriosis. In fact, treatment options are oriented only to infertility or pelvic pain treatment, without any targeted therapy designated for the treatment of endometriosis (27). Endometriosis is defined as an inherited, autoimmune, long-life diseases, which has to be treated from the time of diagnosis, con - tinuously with the individually tailored treatment ac - cording to patients’ overall status, age and complaints, in order to control the pain and further dissemination (28). Therefore, associations between endometriosis and EP, as well as the role of estrogen and its receptors, must be demystified, and more comprehensive and causal treat - ment offered to patients affected by it.

The prevalence of EPs tends to increase with advanced women’s age, a period marked by natural decline in ovarian reserve, hormonal changes and changes in en - dometrial health. Addressing EPs through appropriate diagnostic and therapeutic measures and understanding the hormonal influence on EPs and EM is crucial for im - proving fertility outcomes. Ongoing research and clinical practice must continue to focus on optimizing treatment strategies to address EP pathology, ultimately supporting better reproductive outcomes for women across various age groups. The interplay between EPs, age and infertil - ity underscores the importance of comprehensive repro - ductive evaluation and tailored interventions to enhance fertility perspectives and support women towards their journey to better reproductive outcomes.

The authors express sincere gratitude to the Clinical Hospital Centre “Dr Dragisa Misovic - Dedinje” for providing the necessary resourc - es and facilities, as well as to all employees working at the Hospital for Gynecology and Obstetrics “Dr Dragisa Misovic - Dedinje”. Funding information: The authors reported no funding associated with the work featured in this article. Conf lict of Interest Statement: No conflict of inter - est to report. Author contributions: S. M, Lj. M, S. V, and M. H, conceptualization, supervision, methodology, investiga - tion, formal analysis, and writing—original draft; M. L, S. M, and Dj. K, methodology, formal analysis, visualiza - tion, and writing—original draft; A. S. S, K. S, and N. A, conceptualization, visualization, writing- original draft. All authors have read and agreed to the published version of the manuscript. Ethical approval: The study was approved by the In- stitutional Review Board (IRB) of the University Hospi - tal “Dragisa Misovic” in Belgrade, Serbia, (No. 18328/4, Date: 29.08.2024).

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PMID: 30044147. | 131 Reproductive challenges of endometrial polyps: the influence of women’s age and associated risk factors REPRODUKTIVNI IZAZOVI KOD ŽENA SA ENDOMETRIJALNIM POLIPIMA: UTICAJ STAROSTI I POVEZANIH FAKTORA RIZIKA Slađana Mihajlović1,2, Svetlana Vujović2,3, Mina Hagen4, Milan Lacković1, Sanja Milić1, Antoan Stefan Šojat 3, Kristina Saravi- novska2,3, Natalija Antić3, Đurđica Kaličanin1, Ljiljana V. Marina2,3 Sažetak Uvod / Cilј: Endometrijalni polipi (EP) predstavlјaju be- nigne tumore poreklom iz endometrijuma. Najčešći faktori rizika koji dovode do pojave EP su hormonske promene povezane sa starenjem, upotreba tamoksi - fena, supstituciona hormonska terapija, prekomerna težina i gojaznost. Tačna uzročna veza između EP-a i infertiliteta ostaje nejasna, ali najčešće predlagani patofiziološki mehanizmi jesu mehaničke prepreke i biohemijske promene na nivou endometrijalnog tki - va. „Zlatni standard“ dijagnostike i lečenja EP je histe - roskopija. Cilј ove studije je da se ispita povezanost godina starosti, endometrijalnih polipa i infertiliteta. Materijal i metode: Istraživanje je obuhvatilo 301 paci- jentkinju podvrgnutu histeroskopskoj polipektomiji radi lečenja infertiliteta, koje su podelјene u dve grupe na osnovu starosti (starost ≤ 35 i starost > 35 godina).  Po - daci su prikuplјeni iz istorija bolesti i histopatoloških iz - veštaja, i analizirane su sledeće varijable: tip infertiliteta, prisustvo insulinske rezistencije, sindroma policističnih jajnika, endometrioze, hipotireoze, prethodni neuspešni pokušaji intrauterine inseminacije i vantelesne oplodnje (IVF), nepravilnosti menstrualnog ciklusa i abnormalno krvarenje iz materice, veličina polipa i histopatološki tip.  Rezultati: Najmanje jedna od pet ispitanica imala je in - sulinsku rezistenciju, sindrom policističnih jajnika i ab - normalno krvarenje iz materice. Endometrioza, insulin - ska rezistencija i primarni infertilitet bili su češći u mlađoj grupi nego u starijoj. Prethodna istorija neuspešnih IVF ciklusa, hipotireoza i sekundarni infertilitet bili su pove - zani sa uznapredovalim godinama. Zaklјučak: Prevalencija EP ima tendenciju rasta sa godi- nama starosti žene, periodom koji je obeležen prirodnim padom rezerve jajnika, hormonskim promenama, kao i promenama u strukturi endometrijuma. Primena odgo - varajućih dijagnostičkih i terapijskih mera, kao i razume- vanje uticaja godina, hormonskog statusa i povezanosti EP i endometrioze, klјučni su u lečenju EP , kao i u sveu - kupnom pobolјšanju ishoda lečenja infertiliteta. Ključne reči: endometrijalni polip, infertilitet, histeroskopija Primljen: 25.10.2024. I Revidiran: 04.06.2025. I Prihvaćen: 06.06.2025. I Objavljen: 30.06.2025. Medicinska istraživanja 2025; 58(2):125-131