The association of ovarian hyperstimulation syndrome in the early ovulation induction and procalcitonin in patients with polycystic ovary syndrome

Authors

Abstract

Aim This study investigates the potential role of procalcitonin (PCT) as a predictive biomarker for ovarian hyperstimulation syndrome (OHSS) in patients with polycystic ovary syndrome (PCOS) undergoing ovulation induction.
Materials and Methods Sixty patients undergoing assisted reproductive techniques (ART) were enrolled. Group I included 30 patients with PCOS, and Group II included 30 patients without PCOS. Baseline demographic data, antral follicle count, and hormonal parameters were recorded on the second day of menstruation. Blood samples were collected before ovulation induction and on the fifth day of stimulation to measure PCT levels. The development of OHSS was monitored and correlated with PCT levels.
Results No significant difference was found in demographic characteristics or prior ART history between the groups. The development rate of OHSS in Group I patients is significantly higher than in Group II patients. The procalcitonin levels measured prior to and on the fifth day of ovulation induction do not significantly differ between the groups. Of the 60 patients included in the study, 8 developed OHSS. The procalcitonin value assessed on the fifth day of induction is considerably higher when compared to the procalcitonin levels recorded before induction in 8 patients who developed OHSS and 52 individuals who did not. Procalcitonin level is shown to be greater in OHSS patients whose pregnancies were planned to use assisted reproductive procedures than in OHSS-free patients. This finding suggests that procalcitonin may be utilized as a marker to assess the risk of developing OHSS.
Discussion Although procalcitonin levels did not differ significantly between PCOS and non-PCOS groups overall, the significant rise observed on the fifth day of stimulation in patients who developed OHSS suggests that procalcitonin may serve as an early biomarker for identifying high-risk patients. These findings highlight its potential clinical utility in ART cycles.

Keywords

Introduction

The prevalence of polycystic ovary syndrome (PCOS), the most prevalent hormonal illness seen in women of reproductive age, ranges between 6–8% [1]. Specific standards for the diagnosis of PCOS were adopted during the 1990 National Institutes of Health (NIH) PCOS conference in the United States. These have been recognized as being clinical and/or biochemical signs of hyperandrogenism, chronic anovulation, and the exclusion of other disorders that are linked [2].
The definition of PCOS was updated and broadened in Rotterdam in 2003 by the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology (ASRM/ESHRE). Oligoovulation and/or anovulation are suggested as clinical and/or biochemical symptoms of hyperandrogenism, and at least one ovary must show polycystic ovaries on ultrasonography [3, 4].Polycystic ovary: According to Adams et al., this condition is characterized by larger ovaries from increased stromal tissue on USG and the presence of more than 10 follicles that are 2–8 mm in size and positioned peripherally, resembling pearl necklaces [5]. Infertility occurs in 40–70% of people with PCOS conditions [6].
In recent years, because it is simple to use, affordable, efficient, trustworthy in terms of adverse effects, and does not necessitate stringent follow-up, Clomiphene Citrate (CC) is the first choice of medication [7, 8]. Although treatments including extending the induction period with CC, adding dexamethasone to CC, adding bromocriptine, and pituitary desensitization have been tried, the switch to exogenous gonadotropins is frequently performed in cases of non-response to CC. Higher rates of pregnancy (24% vs 40%) and more frequent mono follicular development (27% vs 74%) can be achieved by using step-up, stepdown, or consecutive step-up, step-down modified protocols with chronic and low-dose FSH rather than standard treatment in patients with PCOS [9].Following stimulation with gonadotropins in PCOS, Ovarian Hyperstimulation Syndrome (OHSS) may arise as an iatrogenic complication and is characterized by cystic growth of ovaries and protein-rich fluid leaving the intravascular space as a result of increased capillary permeability [10].The immune system, vascular endothelial growth factor (VEGF), TNF-alpha, IL-6, ovarian-derived renin- angiotensinogen system, hCG, and estradiol (E2) are highlighted in the etiology; however, the pathophysiological events underlying these changes have not been fully described [11]. In IVF cases, the incidence of OHSS has been published between 3% and 6% in the moderate form and between 0.1% and 2% in the severe form. In previous cycles, a history of OHSS, age, BMI, a history of allergies, the presence of polycystic ovaries are among the factors that increase the risk of OHSS of the patient but there has been found no association between the presence of primary or secondary infertility of the patient and OHSS [12]. Golan et al. [13] have classified OHSS into three categories as mild, moderate, and severe. OHSS was defined according to the Golan criteria. Diagnosis of mild OHSS required the presence of abdominal distension and discomfort with or without nausea, vomiting, and/or diarrhea. Moderate OHSS was diagnosed when ultrasonographic ascites was present in addition to the above features. Several OHSS were diagnosed when there was clinical evidence of ascites and/or hydrothorax or breathing difficulties with or without hemoconcentration, coagulation abnormalities, and decreased renal function.
Early and late OHSS are both clinical types. The acute consequence of exogenous hCG injection within 9 days of oocyte collection is early OHSS, which is connected to ovarian response to stimulation of early OHSS. On the contrary, late OHSS manifests beyond 10 days and is more dependent on hCG administered for luteal phase support or endogenous hCG production by embryo implantation than on ovarian response [14].
Various chemicals have been implicated in the development of OHSS, including histamine, serotonin, prostaglandins, prolactin, and others [15, 16].Procalcitonin (PCT) is the precursor of calcitonin and is a prohormone affected by sepsis-induced inflammatory responses. PCT is also activated in sepsis, particularly in bacterial inflammation [17]. In viral infections, autoimmune disorders, neoplastic diseases, and surgical injuries, PCT increases just slightly or not at all. This is why PCT is used to differentiate between bacterial and non-bacterial inflammation [17]. Procalcitonin levels in healthy individuals are either very low (<0.15 ng/ml) or undetectable. Any PCT value greater than 0.5 ng/ml should be considered abnormal. In general, values between 0.5-2 ng/ml are regarded as mildly high. A rise of between 2 and 5 ng/ml is regarded as moderate. High PCT values are those that are greater than 5 ng/ml. Indicators of severe sepsis and septic shock are above 10ng/ml [18]. It is believed that a rise in PCT levels is linked to disease severity and mortality, and that PCT may be a crucial factor in determining the prognosis of sepsis [19, 20]. One of the significant side effects of ovulation induction is OHSS, and the purpose of our study is to determine whether PCT could be used to predict this condition.

Materials and Methods

This single-center prospective study was conducted by evaluating eligible individuals who applied to our clinic for ART between January 2014 and February 2015. A total of 60 individuals have been enrolled in the study between January 2014 and February 2015, including 30 PCOS-positive infertile patients (Group I) who registered to our clinic for assisted reproductive methods (ART) and 30 patients (Group II) who are PCOS-negative and planned for ART other than this indication. The Ethics Committee of Necmettin Erbakan University Meram Faculty of Medicine has given its approval for this study. The patients have been chosen from among those between 20 and 42 years old who need ART but do not exhibit symptoms of an active infection. Additionally, each patient taking part in the trial has provided their informed consent.
Following the exclusion of alternative etiologic factors, the diagnosis of PCOS has been determined using the combination of two of the following three criteria. (The Rotterdam ESHRE/ ASRM; 2003):
1. Oligo-anovulation,
2. Clinical and/or biochemical signs of hyperandrogenism,
3. Polycystic ovaries on ultrasonography.
On the second day of menstruation in every case, ovulation induction has been begun using daily doses of 75–300 IU r-FSH (Gonal F Merck Serono Turkey, Puregon MSD Turkey) based on the patient’s age, weight, the number of antral follicles present, and basal FSH readings. Measurements of estradiol and ultrasonography have been used to monitor the ovarian response. Following ovulation induction, patients have been monitored for OHSS development. In order to determine the association between OHSS and PCT, before ovulation induction and 5th day, blood has been drawn from patients. The blood collected has been passed through a centrifuge, and the serum has been separated. The serums have been placed in Eppendorf. Until all samples are collected, Eppendorf tubes have been kept at -80°C. The research has found that when the PCT samples are kept at -80°C, the PCT level does not change considerably [21].Following the collection of all the samples, the blood was defrosted to room temperature from -80°C and then examined with the Maglumi equipment using the chemoluminescence technique. Comparing the progression of OHSS and PCT readings has allowed researchers to assess the usefulness of PCT as a marker in OHSS.
Statistical Analysis
The SPSS 16.0 program has been utilized to evaluate the statistical analysis. Data analysis of the conformity distribution was done. The comparison between the groups has been made with the Student 7 t-test. For pre- and post-comparison, the Paired T test has been used. The Pearson Correlation has been used to look at how the parametric data relate to one another. The Sperm Correlation has been used to evaluate Non-parametric tests. In all analyses, the significance level is accepted as p< 0.05.
Informed Consent
This study was conducted in accordance with the ethical principles of the Declaration of Helsinki, and informed consent was obtained from all participants.
Ethical Approval
This study was approved by the Ethics Committee of Necmettin Erbakan University Meram Medical Faculty (Date: 2015-04-15, No:151518009).

Results

There are no discernible variations between the groups when the demographic details of the study’s participants are compared (Table 1). The average age of group 1 patients is 30.1±5.6 (min 20, max 42), and the average age of group 2 patients is 27.0±4 (min 22, max 41). There is no discernible difference in the median ages of the patients in the two groups (p>0.05). The BMI of both groups is similar to each other (mean BMI of Group 1 patients is 25.3±6.6, mean BMI of Group 2 patients is 23.3±5.3). The number of developing follicles is similar in both groups (Group 1 patients have 15.1, 4, 6, and Group 2 has 14.4, 8.1, respectively). Additionally, there are no appreciable differences between the two groups in the previous history of ART cycles (Group 1: 1,7,0,8; Group 2: 2,0,0,8).One of the Group I study participants and two of the Group II participants both have a history of OHSS. 13 patients in Group I and 5 patients in Group II have progressed to OHSS. When compared to patients in Group II, participants in Group I have progressed to OHSS at a considerably greater rate (p 0.05). Table 2 provides details on the degree of OHSS that patients experienced. When PCT levels are evaluated between Group I and Group II patients on day 0, there is no statistically significant difference between them (Group I median 0.140 ng/mL, Group II 0.146 ng/mL, p>0.05). There is no discernible difference in the PCT levels between the groups on the fifth day of stimulation (Group I median 0.158 ng/mL, Group II median 0.151 ng/mL, p>0.05). No significant difference between the 0- and 5-day values of the same patients is discovered when both groups are assessed individually (Group I p: 0.86, Group 2 p: 0.89) (Table 2).Eight patients (13%) out of the 60 research participants experienced severe OHSS (Table 2). When the day 0 PCT levels of the 8 patients who have progressed severe OHSS and the 52 patients who have not progressed OHSS have been compared amongst themselves, a statistically significant difference has been found between the PCT values on the fifth day in the group with severe OHSS (0.142 on the stimulation onset day, 0.280 ng/dl, p=0.02 on the fifth day). There was no difference between the groups in terms of PCT values for the group that did not have OHSS (0.149-0.153, p: 0.85). There is no statistically significant change between day 0th and day 5th PCT levels when the two groups are compared to one another (p values, 0.56 and 0.73, in turn) (Table 3).

Discussion

Although diagnostic standards and prevalence vary by population, PCOS is the most prevalent hormonal condition seen in women of fertility age [1]. When CC is insufficient to stop anovulation in PCOS, gonadotropin therapy is moved to. Use of gonadotropins may result in issues such as multifollicular development, OHSS that goes along with it, and the possibility of multiple pregnancies. The World Health Organization calculated the OHSS incidence as 0.2% -1% for all stimulation cycles [12]. OHSS is characterized by cystic enlargement of the ovaries and increased capillary permeability, which causes protein-rich fluid to exit the intravascular space. Typically, distention and abdominal tautening are the first symptoms to be reported. Nausea, vomiting, and diarrhea can be added to these. A rise in morbidity is indicated by shortness of breath and a decrease in urine production. As clinical findings, rapid weight gain, oliguria or anuria, hemoconcentration, leukocytosis, hypovolemia, electrolyte disorder, acid, pleural or pericardial effusion, such as hypercoagulability, a broad-spectrum picture may be encountered [22].
According to research that has been done, PCOS is a risk factor for the emergence of OHSS. In the research conducted by Delvigne et al. [23], patients with PCOS have a higher incidence of progressing OHSS. Kunter et al. [24], a research study reveals that PCOS multiplies the risk of developing OHSS by 7.6 times. 63% of severe OHSS cases in the 1992 research by MacDougall et al. [25], and 37% of 128 OHSS patients and 15% of 256 control patients in the 1993 research by Delvigne et al. [23] both had PCOS. In spite of being stimulated by the identical protocol, it was discovered by Dor et al. [6], Buyalos and Lee [9], that patients with PCOS generated three times as many oocytes and follicles as women who were normoovulatory. In patients with PCOS, Kamat et al. found that the ovarian stroma expressed more VEGF mRNA. The combined odds ratio for OHSS in PCOS cases has been estimated to be 6.8 in a meta-analysis of 10 studies carried out by Tummon in 2005 (95% confidence interval 4.9-9.6).In a 1997 study by Fulghesu et al. [18], it was discovered that hyperinsulinemic PCOS patients have a greater risk of OHSS than those who are normoinsulinemic. In our study, OHSS has progressed in 5 patients without PCOS and 13 patients with PCOS. It has been observed that mild, moderate, and severe OHSS were present in 6%, 16%, and 20%, respectively, of women with PCOS who have OHSS. In the non-PCOS patient group, 6% of the patients who had OHSS had mild cases, 3% had moderate cases, and 6% had severe cases. Patients with PCOS have a considerably increased risk of progressing to OHSS than patients who do not with PCOS (p<0.05).
There has not been a study investigating the association between PCT and OHSS before. Within the patient groups with and without PCOS, there has been no statistically significant difference between day 0 and day 5 PCT levels (p values, 0.86 and 0.89, respectively). There has been no discernible difference between the two groups’ PCT levels on days 0th and 5th, according to p values of 0.71 and 0.83, respectively. A total of 8 out of 60 patients in groups I and II progressed to severe OHSS (13%). When these individuals have been compared to 52 patients who do not experience severe OHSS at days 0th and 5th, a statistically significant difference has been discovered (p values of 0.02 and 0.85, respectively). There has been no discernible difference between the PCT levels on days 0 and 5 between the 8 patients who have experienced OHSS and the 52 patients who have not (p values, 0.56 and 0.73, respectively).

Limitations

The sample size is relatively small, particularly the number of patients who developed OHSS. Moreover, only two time points were assessed for PCT measurement. Future studies with larger cohorts and serial PCT measurements may provide more robust data on its predictive utility.

Conclusion

The significant increase in PCT levels in patients who developed OHSS supports its potential use as a predictive biomarker. PCT monitoring during ART cycles may enhance clinical decision- making, particularly in high-risk populations such as those with PCOS. Further prospective studies are warranted to validate these findings and establish clinical thresholds.

References

1. AZZiZ R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, YildiZ BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004;89(6):2745-9.
   PubMed Google Scholar
2. Chang S, Dunaif A. Diagnosis of polycystic ovary syndrome: which criteria to use and when? Endocrinol Metab Clin North Am. 2021;50(1):11-23.
   PubMed Google Scholar
3. Sultan C, Paris F. Clinical expression of polycystic ovary syndrome in adolescent girls. Fertil Steril. 2006;86(Suppl.1):S6.
   PubMed Google Scholar
4. Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS). Hum Reprod. 2012;27(1):14-24.
   PubMed Google Scholar
5. Adams J, Polson DW, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J. 1986;293(6543):355-9.
   PubMed Google Scholar
6. Nastri CO, Ferriani RA, Rocha IA, Martins WP. Ovarian hyperstimulation syndrome: pathophysiology and prevention. J Assist Reprod Genet. 2010;27(2- 3):121-8.
   PubMed Google Scholar
7. White DM, Polson DW, Kiddy DS, et al. Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab. 1996;81(11):3821-4.
   PubMed Google Scholar
8. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356(6):551-66.
   PubMed Google Scholar
9. Buyalos RP, Lee CT. Polycystic ovary syndrome: pathophysiology and outcome with in vitro fertiliZation. Fertil Steril. 1996;65(1):1-10.
   PubMed Google Scholar
10. Ata B, Tulandi T. Pathophysiology of ovarian hyperstimulation syndrome and strategies for its prevention and treatment. Expert Rev Obstet Gynecol. 2009;4(3):299-311.
    PubMed Google Scholar
11. Humaidan P, Papanikolaou EG, Kyrou D, et al. The luteal phase after GnRH- agonist triggering of ovulation: present and future perspectives. Reprod Biomed Online. 2012;24(2):134-41.
    PubMed Google Scholar
12. Durul C. Ovaryan Hiperstimülasyon sendromu görülen ve yaş kriteri olarak 35 yaş altı ve üzeri seçilen hastalarda, BMI’nin endometriyum kalınlığıyla, implantasyon oranıyla, fertilizasyon ve embriyo’nun gelişimiyle olan bağlantısı [The relation of OHSS with endometrial thickness, implantation, fertiliZation and embryo development by BMI and age]. Gülhane Med J. 2016;58(2):123-9.
    PubMed Google Scholar
13. Golan A, Ron-El R, Herman A, Soffer Y. Ovarian hyperstimulation syndrome: an updated review. Obstet Gynecol Surv. 1989;44(6):430-40.
    PubMed Google Scholar
14. McClure N, Leya J, Radwanska E, Rawlins R, Haning RV Jr. Luteal phase support and severe ovarian hyperstimulation syndrome. Hum Reprod. 1992;7(6):758-64.
    PubMed Google Scholar
15. Engel T, JewelewicZ R, Dyrenfurth I, Speroff L, Van Wiele RL. Ovarian hyperstimulation syndrome: report of a case with notes on pathogenesis and treatment. Am J Obstet Gynecol. 1972;112(8):1052-60.
    PubMed Google Scholar
16. Schenker JG. Clinical aspects of ovarian hyperstimulation syndrome. Eur J Obstet Gynecol Reprod Biol. 1999;85(1):13-20.
    PubMed Google Scholar
17. KarZai W, Oberhoffer M, Meier-Hellmann A, Reinhart K. Procalcitonin—a new indicator of the systemic response to severe infections. Infection. 1997;25(6):329- 34.
    PubMed Google Scholar
18. Fulghesu AM, Villa P, Pavone V, Guido M, Mancini A, LanZone A. The impact of hyperinsulinemia on ovarian hyperstimulation syndrome. Gynecol Endocrinol. 1997;11(3):211-8.
    PubMed Google Scholar
19. Ehrmann DA, KasZa K, AZZiZ R, Legro RS, GhaZZi MN. Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90(1):66-71.
    PubMed Google Scholar
20. Demirdağ K, Özden M, Gödekmerdan A, Cihangiroğlu M, Kalkan A. Sepsis olgularında prokalsitonin, TNF-α ve C-reaktif protein düzeylerinin değerlendirilmesi [Evaluation of procalcitonin, TNF-α and C-reactive protein levels in sepsis cases]. Klimik Derg. 2003;16(1):21-4.
    PubMed Google Scholar
21. SchuetZ P, Christ-Crain M, Huber AR, Müller B. Long-term stability of procalcitonin in froZen samples and comparison of Kryptor® and VIDAS® automated immunoassays. Clin Biochem. 2010;43(3):341-4.
    PubMed Google Scholar
22. Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril. 2015;103(6):e44-e50.
    PubMed Google Scholar
23. Delvigne A, Demoulin A, SmitZ J, et al. The ovarian hyperstimulation syndrome in in-vitro fertiliZation: a Belgian multicentric study. I. Clinical and biological features. Hum Reprod. 1993;8(9):1353-60.
    PubMed Google Scholar
24. Tatar HK, Ürünsak İF, Khatib G, Güleç ÜK, Çetin T, Seydaoğlu G. Kontrollü overyan hiperstimülasyon uygulanan olgularda overyan hiperstimülasyon sendromu görülme insidansı ve risk faktörleri [Incidence and risk factors of OHSS in controlled ovarian stimulation cycles]. J Clin Obstet Gynecol. 2013;23(3):176- 85.
    PubMed Google Scholar
25. MacDougall MJ, Tan SL, Jacobs HS. In vitro fertiliZation and the ovarian hyperstimulation syndrome. Hum Reprod. 1992;7(5):597-600.
    PubMed Google Scholar

Declarations

Additional Information

Publisher’s Note
Bayrakol MP remains neutral with regard to jurisdictional and institutional claims.

Rights and Permissions

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). To view a copy of the license, visit https://creativecommons.org/licenses/by-nc/4.0/

View full license details →

About This Article