|Year : 2015 | Volume
| Issue : 1 | Page : 57-61
Is prostate-specific antigen a reliable marker for uterine leiomyoma detection?
Department of Pathology, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
|Date of Web Publication||7-Jan-2015|
Keshavarz Blvd, Imam Hospitals Complex, Tehran
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Now it is accepted that prostate-specific antigen (PSA) is expressed extra prostatically and it is clear that many hormonally regulated female tissues show detectable PSA levels. This study was conducted due to differences of view between researchers about the role of PSA in some women diseases. This study was designed to evaluate the clinical implication of serum PSA measurement in diagnosis or management of patients with uterine myoma.
Materials and Methods: This was a case-control study. A total of 224 patients included in this study. Serum specimens were isolated and were stored at -70C until all specimens were completed. Wilcoxon's rank-sum test was used to identify statistically significant differences between the total PSA and free PSA measurements in patient groups.
Results: We noticed that there is no statistical significant correlation between total or free serum PSA level of cases with uterine myoma and control group (P = 0.433 and 0.700, respectively). Furthermore, no statistical difference was considered either in size or frequency of leiomyomas and free or total serum PSA (P = 0.126 and 0.433 and P = 0.997 and 0.442, respectively).
Conclusion: We concluded that serum PSA measurement has little clinical utility in diagnosis or management of uterine leiomyoma.
| Abstract in French|| |
Contexte: Maintenant, il est admis que l'antigène prostatique spécifique (PSA) est exprimé très prostatically et il est clair que de nombreux tissus femelles hormonalement réglementés montrent des niveaux PSA détectables. Cette étude a été réalisée en raison de divergences de vues entre les chercheurs sur le rôle du PSA dans certaines maladies de femmes. Cette étude visait à évaluer les implications cliniques de mesure de PSA sérique dans le diagnostic ou la gestion des patients atteints de myome utérin.
Matériaux et Méthodes: il s'agissait d'une étude cas-témoins. Un total de 224 patients inclus dans cette étude. Échantillons de sérum ont été isolés et ont été entreposées à -70° C, jusqu'à ce que tous les spécimens ont été achevés. Test de Wilcoxon rang-somme a servi à identifier des différences statistiquement significatives entre le PSA total et des mesures de PSA libres en groupes de patients.
Résultats: Nous avons remarqué qu'il n'y a aucune corrélation statistique significative entre le niveau de PSA sérique total ou libre de cas avec utérin myome et contrôle le groupe de (P = 0,433 et 0,700, respectivement). En outre, aucune différence statistique a été considérée en taille ou en fréquence des léiomyomes et libre ou total sérum PSA (P = 0,126 et 0,433 et P = 0,997 et 0,442, respectivement).
Conclusion: Nous avons conclu que la mesure de PSA sérique a petite utilité clinique dans le diagnostic ou la gestion du léiomyome utérin.
Mot cles: FEmme, sérum gratuitantigène prostatique spécifique, l'antigène prostatique spécifique total sérique, léiomyome utérin
Keywords: Female, free serum prostate-specific antigen, total serum prostate-specific antigen, uterine leiomyoma
|How to cite this article:|
Abdollahi A. Is prostate-specific antigen a reliable marker for uterine leiomyoma detection?. Ann Afr Med 2015;14:57-61
| Introduction|| |
Prostate-specific antigen (PSA) is a single chain glycoprotein, highly expressed in the epithelium of the human prostate gland  and is a well-established tumor marker in diagnosis and management of prostate cancer. ,
Although there was initial widespread belief that the expression of PSA is highly restricted to prostate gland, many studies showed that PSA can be expressed extra prostatically. ,, Using sensitive PSA assay, more than 50% of female sera have detectable PSA level.  It appears that hormonally regulated tissues in females can produce PSA. , Serum PSA level can be increased in many endocrine-dependent disorders, such as benign or malignant breast disease, uterine leiomyoma or hirsutism. ,,,
Mammary PSA is identical to seminal PSA regarding to molecular weight and mRNA sequence. ,
The ratio of free/total PSA (fPSA/tPSA) is also considered as an important valuable distinguishing factor between benign and malignant prostate disease.  While it is noticed that the predominant form of PSA in sera of women with breast cancer is the complex form (bound to antichymotrypsin [ACT]), , dominancy of fPSA appears to be unique to breast carcinoma. ,
Leiomioma is of higher incidence in women and is diagnosed by chance through some symptoms like hemorrhage. Therefore, if a screening marker is available these tumors would be diagnosed sooner for treatment.
Regarding the mentioned consideration, it seems logical that hormonally regulated tissue would be able to produce PSA in response to steroid hormones. Hence, we speculated that free or total serum PSA may show correlation to the size or numbers of uterine myomas and measurement of these markers may have some clinical implication in diagnosis or management of uterine leiomyoma.
| Materials and Methods|| |
A case-control study was conducted from May 2012 to May 2013, a total of 224 serum specimens including 113 cases and 111 controls admitted to gynecologic clinic of ValiAsr Hospital affiliated to Tehran University of Medical Science were collected. Vali-e Asr Hospital is a credited education, health care and research center in Iran and patients from across the country refer to it.
The control group selected from the patients admitted due to complaints other than uterine myoma. Both groups were examined by sonography in order to evaluate the number, size and location of uterine myomas in case group and exclude the presence of myoma in the control group.
Endocrine disorders such as diabetes, hirsutism, pregnancy, malignancy or taking medications including oral contraceptive pill or atorvastatin were considered as exclusion criteria. Furthermore, both groups were evaluated by breast mammography and sonography in order not to include patients suffering from significant benign or malignant disease.
Serum specimens were isolated and were stored at −70°C until all specimens were completed. The assay was performed according to the manufacturer's instruction.
A volume of 5 ml of blood were taken from these individuals, centrifuged 10 to 15 min at 3000 g and the serum achieved in this way was measured for tPSA and fPSA. The demographic specifications of these patients including their age, social conditions, and family history were gathered in a questionnaire.
Prostate-specific antigen was measured by applying sandwich chemiluminescence immunoassay and using kit DiaSorin Deutschland GmbH (LIAISON). fPSA was measured by applying the same method and using kit Diasorin S.P.A, Italy (LIAISON).
Principle of the procedure
The method for the quantitative determination of PSA is a sandwich chemiluminescence immunoassay.
A specific mouse monoclonal antibody is coated on the magnetic particles (solid phase); another monoclonal antibody is linked to an isoluminol derivative (isoluminol-antibody conjugate).
Free and ACT-complex-bound PSA are detected equimolarly.
During first incubation, PSA present in calibrators, samples or controls binds to the solid phase monoclonal antibody, and subsequently after a washing step in a second incubation the antibody conjugate reacts with the PSA already bound to the solid phase.
After incubation, the unbound material is removed with a wash cycle.
Subsequently, the starter reagents are added and a flash chemiluminescence reaction is thus induced, the light signal, and hence the amount of isoluminol-antibody conjugate, is measured by a photomultiplier as relative light units and is indicative of PSA concentration present in calibrators samples or controls.
Analytical sensitivity is defined as the minimum detectable dose distinguishable from zero by two standard deviations. The detection limit is <0.04 ng/ml.
The assay trueness has been checked by the dilution and recovery tests.
Analytical sensitivity for fPSA is defined as the minimum detectable dose distinguishable from zero by two standard deviations. The detection limit is <0.09 ng/ml.
The functional sensitivity (defined as the lowest analyte concentration that can be determined with an inter-assay coefficient of variation <20%) is <0.15 ng/ml.
At the end based on aims of study, serum levels of PSA and fPSA compared in the case and control groups. Before the study began blood specimens were taken, the patients were explained everything in detail and written consent was obtained.
This study has been endorsed by the Ethics Committee of the Hospital and the University.
Wilcoxon's rank-sum test was used to identify statistically significant differences between the tPSA and fPSA measurements in the patient group.
All PSA measurements below the detection limit of the methods were adjusted to 0. Statistical analysis was done using Statistical Package for Social Sciences (SPSS) software version 18.0 for Windows (Chicago, Illinois, Company).
| Results|| |
A total of 224 cases and controls included in this study and the mean ages of the case and control groups were 42.7 ± 7.1 and 41.1 ± 9.9 year old, respectively. The frequency of leiomyomas is summarized in [Figure 1].
In 52 cases, the greatest diameter of the largest leiomyoma was <30 mm, in 49 cases about 30-80 mm and in remaining 14 cases it was >80 mm. The serum level of tPSA and fPSA in the case and control groups is summarized in [Table 1]. We noticed no statistical significant correlation between total or free serum PSA level of cases with uterine myoma and control group (P = 0.433 and 0.700, respectively). Furthermore, no statistical difference was considered either in size or frequency of leiomyomas and free or total serum PSA (P = 0.126 and 0.433 and P = 0.997 and 0.442, respectively).
| Discussion|| |
Prostate-specific antigen is a 330 kDa serine protease with chymotrypsin-like enzymatic activity. 
Despite the original belief that PSA was a prostate tissue-specific marker, now it is accepted that PSA is expressed extra prostatically. ,, The periurethral (Skene's gland) was the first female tissue that were suggested to be able of producing PSA. ,, However, now it is clear that many hormonally regulated female tissues, including breast, endometrium, ovary or body fluids such as amniotic fluid, milk, breast cyst fluid show detectable PSA level. ,,,,,,,,,,,, The probable source of circulating PSA in females is the mammary ductal system. Female serum PSA is 100-500 times lower than male serum PSA.  Androgens up-regulate the expression of the PSA gene through androgen receptors,  meaning that serum PSA concentration show association with circulating steroid hormone level. 
For example, postmenopausal women have lower serum PSA concentration than premenopausal women, presumably due to the plunge in the hormone level or progesterone peak in the menstrual cycle, lead to rise in serum PSA level. 
Pregnancy or some endocrine-dependent disorders are associated with an increased level of serum PSA in females. , It appears that slight increase in tPSA in the serum of women with breast malignancy,  benign breast disease or uterine leiomyoma is due to impaired hormonal balance, which triggers the aberrant expression of hormone-dependent genes such as PSA. 
Prostate-specific antigen is involved in cell detachment, suggesting a role in tumor progression or metastasis.  Moreover, it has been noticed that PSA plays a role in extracellular matrix degradation.  In breast cancer, level of serum PSA is affected by tumor size. , Lymphnode involvement or adjuvant therapy. ,
In this study, we considered no statistical correlation between neither the size nor the numbers of uterine myoma and serum PSA level. Indeed, respect to fPSA and tPSA level, there was no significant statistical correlation between case and control group. In a study by Black et al.  they compared serum level of tPSA and fPSA in 107 patients with uterine fibroma with 99 cases in the control group. The median, range of tPSA in the case and control group were 1.0, 0-81 ng/L and 0, 0-55 ng/L, respectively. They found significant higher tPSA level in patients with uterine fibroma. They used sandwich type ELISA method for PSA quantification. The detection limit of the assay was 1 ng/L (0.001 ng/ml), which is more sensitive than the method we used.
The difference in results is attributed to different specimen volumes, measurement methods, race or genetics.
Regarding the hormonally dependent level of serum PSA, in a study by Melegos et al.,  they demonstrated that the average level of serum PSA (median) and 3α-AG (mean) were significantly higher in hirsute women than in normal women (P = 0.001 and 0.002, respectively). They used a sandwich time-resolved immunofluorometric assay. The lowest detection limit of the assay was 1 pg/ml (0.001 ng/ml). They believed that PSA can be considered as a marker of androgen action n female peripheral tissue. 
The majority of serum PSA in males is in complex with the ACT and only a minor component (<30%) is in free form.  In addition to total serum PSA level, the ratio of fPSA/tPSA is of great value to distinguish between benign and malignant prostatic pathology.  Although it is believed that in female with endocrinopathology PSA-ACT is the dominant form, in breast cancer fPSA appears to be the major form. , Thus, fPSA is unique to breast carcinoma. 
While the slight decrease in serum tPSA after breast cancer surgery, indicates that the complex form of PSA is produced by normal breast tissue not tumor cells.  Significant decrease in fPSA after breast cancer tumor removal shows this form is produced by the tumor. , In this study, we noticed that the dominant form of PSA in patients with leiomyoma was complex PSA, which is in agreement with the findings reported by Black and Diamandis,  emphasizing that fPSA can be considered as a specific marker for breast carcinoma. 
The volume of specimen and measurement methods is among the restrictions of this study. Moreover, the patients included in the study were from a single hospital. It is recommended that a study would be conducted with a large number of samples, applying measurement methods of higher sensitivity and specificity and using patients from more healthcare centers.
Finally, we concluded serum PSA measurement has little clinical utility in diagnosis or management of uterine leiomyoma. However, we think complementary studies by using more sensitive assays are necessary to confirm our findings.
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