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What do we know about the origin of CA 125?
European Journal of Obstetrics & Gynecology and Reproductive Biology, 49 (1993)93-98 @ 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved. 0028-2243/93/%06.00
93
EUROBS 01589
What do we know about the origin of CA 125? P. Bischof Hormone Laboratory,
Department
of Obstetrics
and Gynecology,
University of Geneva, Mater&P
1211, Geneva 14, Switzerland
Summary
The murine monoclonal antibody OC 125 recognizes an epitope on a molecule called Cancer Antigen 125 (CA 125). The CA 125 antigen is expressed in amnion and its derivatives of fetal coelomic epithelia (such as Mtillerian epithelia, peritoneum, pleura and pericardium) and in many adult tissues (such as the epithelium of fallopian tubes, endometrium, endocervix, pleura and peritoneum). The normal endometrium produces CA 125 and this production can contribute significantly to the level of circulating CA 125 at the time of menstruation. During peritoneal irritation (hyperstimulation, salpingitis, ruptured ectopic pregnancy, laparotomy) peritoneally derived CA 125 significantly contributes to circulating CA 125 concentrations, giving elevated CA 125 values. The use of the CA 125 serum assay as a single diagnostic tool is restricted by the fact that the antigen CA 125 is produced by normal epithelia (of peritoneum, endometrium and benign ovarian cysts) and not only by the ovarian cancer cell. CA 125; Tumor marker; Menstruation; Peritoneum; Endometrium
Introduction OC 125 is a murine monoclonal antibody which was raised against an ovarian carcinoma cell line derived from a patient with a serous cystadenocarcinema [l]. This antibody recognizes an epitope on a molecule called Cancer Antigen 125 (CA 125) which however remains unknown so far despite important efforts to characterize it biochemically. In 1984 a CA 125 immunoradiometric assay became commercially available [2] and the antibody was largely distributed so that at the present time, CA 125 assays are produced by many companies (Centocor, Cis, Abbott, Amersham). This Correspondence IO: P. Bischof, Hormone Laboratory, Dept. of Obstetrics and Gynecology, University of Geneva, MaternitC 1211, Geneva 14, Switzerland.
,permitted the publication of many clinical studies. The important message that emerged was that 80-95% of patients with a clinically demonstrable ovarian cancer have elevated (above 35 U/ml) serum levels of CA 125. This was, and still is, an absolute record of detection for a tumor marker in one specific malignancy. The reader wanting an overview on these clinical studies is referred to an excellent review published by Jacobs and Bast [3]. It is now widely accepted that CA 125 is an very good marker for the monitoring of ovarian cancer, but like all other cancer markers it has restricted diagnostic value. In other words, CA 125 measurements performed in asymptomatic women or in patients presenting with an abdominal mass will not provide the clinician with a diagnosis of ovarian cancer. The reason for this is due to the fact that CA 125 is also increased in several physi-
94
ological and pathological conditions such as: during menses [4,5] in early pregnancy [6,7], in women with endometriosis [8,9], in endometrial cancer [lo], in pelvic inflammatory disease [ 111, in uterine fibroids [12] and in various other benign and malignant disorders [3]. This, by no means exhaustive, list of conditions where CA 125 levels are elevated, demonstrates that CA 125 measurements should be used only when a clinical diagnosis of ovarian cancer is available. The fact that low but detectable levels of CA 125 are present under physiological conditions prompted us and other groups to search for the source of CA 125 in normal women. The distribution of CA 125 In their original immunohistochemical study, Kabawat et al. [ 131 showed that CA 125 was localized in the amnion and its derivatives of fetal coelomic epithelia such as Miillerian epithelia, peritoneum, pleura and pericardium. In adult tissues, immunoreactive CA 125 was found in the epithelium of fallopian tubes, endometrium and cervix. It was also detected in pleura, peritoneum and pericardium. Interestingly, CA 125 was not detected on the surface epithelium of the ovaries. However, subsequent reports indicated that CA 125 was expressed in normal ovarian epithelium as well as in epithelia of the pancreas, colon, gall bladder, stomach, lung and kidney [14,15]. In pregnant women, CA 125 localized in decidua and amniotic epithelium but not in the placenta [16]. Finally, CA 125 is also found to be a common constituent of normal cervical mucus [ 171. Taken together the results of these immunohistochemical studies indicate as shown in Fig. 1, that CA 125 is an antigen expressed essentially by epithelia covering the body’s cavity. As summarized in Table I, the quantitative measurements of CA 125 largely confirm the notion of CA 125 being a marker of the covering epithelia. The origin of CA 125 in pregnant women As can be seen from Table I, the highest serum levels of CA 125 in normal patients are reached during early pregnancy. The highest tissue levels
Fig. 1. Distribution of CA 125 in normal women. Positive tissues include: pleura, pericardium, peritoneum, epithelium of the cervix, endometrium, fallopian tube, epithelium covering the colon, kidney, stomach and the ovaries.
(non-malignant) are found in decidua also during early pregnancy. This observation prompted Jacobs and coworkers [ 181 to suggest that during pregnancy, circulating CA 125 could be of decidual origin. In view of the fact that amniotic fluid levels are 2-3 orders of magnitude higher than in the serum [19,20] and that amniotic cells release CA 125 in vitro [21] it cannot be excluded that some amniotic CA 125 reaches the peripheral circulation, although this seems improbable when the molecular size (> 700 kDa) of CA 125 is considered. We tend to think that circulating CA 125
95 TABLE I CA 125 in different biological compartments (range) L Serum U/ml
Normal women Patients with: Endometriosis Type I-II Type III-IV Leiomyoma Endometritis Salpingitis Pregnant patients 5-l 1 weeks 12-23 weeks 24-36 weeks 37-40 weeks Cord blood Postpartum Extrauterine pregnancies Unruptured Ruptured
Peritoneal fluid U/ml
7.5-30
50-311
75-40 15-52 13-72 5-15 20-280
98-167 69-375
10-140 12-26 13-30 14-42 220 30-420
Amniotic fluid U/ml
8800-82 000 1300-7600
Endometrium U/g
Follicular fluid U/ml
Vaginal Mucous U/ml
28600-150000
5-130
14200-15 300
3400-209 000
640-3400
6-136 1l-500
From Refs. 4-9, 11, 12, 17-20, 24.
is of decidual origin and amniotic fluid CA 125 is produced by the amnion. There is however, one noticeable exception to this. In extrauterine pregnancies, we observed significant differences in maternal serum CA 125 between ruptured and unruptured ectopic pregnancies [7]. Every time that in early pregnancy clinical signs of peritoneal irritation were present (hyperstimulation, hydrosalpinx, salpingitis or ruptured ectopic), CA 125 levels were highly increased. Under those pathological conditions we propose that peritoneally derived CA 125 significantly contributes CA 125 concentrations. The origin of CA 125 in non-pregnant women The ovary
There are 3 reports suggesting an ovarian origin for CA 125. Jlger and coworkers [22] observed an increase of CA 125 which paralleled the rise in follicular diameter and estradiol secretion in 6 out of 13 normal women in whom blood was sampled
at daily intervals. Zweers and colleagues 1231 measured CA 125 in different groups of women: in normal cycles, in pill-suppressed cycles and in stimulated cycles for intrauterine insemination or oocyte retrieval. In the first 2 groups no changes in CA 125 levels were observed between the first and the second half of the cycle. However, in women with stimulated cycles, luteal phase CA 125 concentrations, were higher than in the follicular phase. That this increase was not due to the laparoscopy procedure was shown by the fact that in women undergoing operative laparoscopy, CA 125 levels were not higher 7- 10 days after laparoscopy than before. The authors conclude that during the luteal phase of stimulated cycles, increased CA 125 levels are either of luteal or of endometrial origin. Finally, CA 125 levels have been found in measurable quantity in follicular fluid and the levels were higher when the oocyte was present as compared to those cases were the oocyte could not be found [24]. In contrast to these studies, Lanzone et al. [25]
96
and Lehtovirta et al. [26] found no correlation between ovarian steroid concentrations and CA 125 levels under different physiological conditions. These results argue against an ovarian origin for CA 125. Our own results, show that CA 125 levels do not increase during ovarian stimulation (as compared to normal cycles). However, as soon as a laparoscopy is undertaken, CA 125 concentrations increase dramatically. Furthermore, in 10 premenopausal and in 14 postmenopausal women, there was no difference in the CA 125 concentration between the peripheral blood, the blood draining the active (high estradiol and/or progesterone) or the inactive ovary (Bischof, unpublished observations). In the absence of a concentration gradient from the ovaries to the periphery and with the observed effects of laparoscopy we would conclude that under normal conditions, the ovary does not produce CA 125 into the circulation and that intervention on the abdominal wall (laparoscopy) increases briskly and transiently (5-6 days) the circulating levels of CA 125. The endometrium It is widely accepted that the decidua is a source of CA 125 (see above) however, it is still unclear if the normal endometrium produces CA 125 and if this production contributes significantly to the circulating CA 125. Relatively high levels of CA 125 have been measured in non-decidualized eutopic endometria [ 18,191. In contrast, no CA 125 was found in ectopic endometrial implants in women with endometriosis despite elevated serum levels [27]. In order to have some insight into a possible endometrial origin for CA 125 we conducted in vitro studies with explants and primary endometrial cell cultures [28-301. Explants of decidua released high amounts of CA 125 when cultured in vitro. In presence of cycloheximide, an inhibitor of protein synthesis, the release of CA 125 was significantly inhibited [28,29] demonstrating that the decidua is capable of producing CA 125. Endometrial stromal cells, when cultured separately from glandular cells secreted also CA 125 but in concentration 4-10 times smaller than glandular cells alone [30]. This low secretion could well be due to the contamination of stromal cell cultures by epithelial cells which was estimated to be at about 5%. CA
125 production by endometrial cells was inhibited by medroxyprogesterone acetate and this inhibition could be overcome by the coincubation with the antiprogestin RU 486 [28]. These in vitro studies were compared with immunohistochemical data. It was shown that CA 125 was localized in the infranuclear region of epithelial cells during the proliferative phase and to the apical luminal border during the secretory phase. No staining was observed in stromal cells. The results of these in vitro studies led us to conclude that CA 125 was indeed an endometrial product and that its secretion was exocrine, into the uterine cavity. In order to verify this statement in vivo, we collected endometrial aspirations (jet washes of the uterine cavity) and measured CA 125. CA 125 levels were very high and a significant increase was observed from the proliferative to the secretory phase [30], indicating that in vivo also, CA 125 was excreted by the epithelium of the endometrium. Taken together, these experiments demonstrate that the human endometrium produces and secretes CA 125 and that this secretion is regulated by ovarian hormones. This conclusion was also reached by others using endometrial explant cultures [31]. If it does seem apparent that the endometrium produces CA 125, its contribution to the circulating CA 125 pool remains unknown. To answer this question we measured CA 125 in a cohort of women with uterine fibroids who underwent a hysterectomy or a treatment with GnRH analogues [12]. We observed that about one-third of the women with uterine fibroids had increased circulating levels of CA 125 and that removal of the uterus or treatment with GnRH significantly decreased peripheral concentrations of CA 125 below those observed in normal women. The origin of this increased CA 125 in women with uterine fibroids is a matter of speculation. The uterus probably only partially contributes to circulating CA 125 since after hysterectomy the peripheral levels of CA 125 are only slightly lower than during the normal cycle. However, since the levels are still measurable after hysterectomy, a contribution from yet another source has to be considered. The peritoneum There is some indirect evidence to suggest that
91
the peritoneum is probably an important source of CA 125. As discussed before, intervention on the abdominal wall (laparoscopy) increases CA 125 quite dramatically. In pregnant women, CA 125 is highly increased when clinical signs of peritoneal inflammation such as: hydrosalpinx, ruptured ectopic pregnancy, ovarian hyperstimulation are present [7]. In non-pregnant women also pelvic inflammatory disease has been shown to increase CA 125 [32]. Since Kabawat et al. [13] have clearly shown that CA 125 is localized in the mesothelial cells of the peritoneum, we speculate that the peritoneum is probably the main source of CA 125. If it is true, then the mechanical distension of the peritoneum due to the presence of uterine fibroids, peritoneal inflammation and surgery on the abdominal wall represent non-specific inducers of the CA 125 secretion. This hypothesis is currently under study in our laboratory.
I
8
9
10
11
12
13
Concluding remarks 14
It is hoped that this brief review of what is known about the origin of CA 125, will help the clinician to prescribe and interpret a CA 125 blood test. Because CA 125 is produced by normal epithelia and not only by ovarian cancer cells, the use of CA 125 serum assay as a single diagnostic tool is both useless and expensive.
15
16
References Bast RC, Fenney M, Lazarus H, Nadler LM, Colvin RB, Knapp RC. Reactivity of a monoclonal antibody with Clin human ovarian carcinoma. J Invest 1981;68:1331-1337. Klug TL, Bast RC, Niloff JM, Knapp RC, Zurawski VR. Monoclonal antibody immunoradiometric assay for an antigenic determinant (CA 125) associated with human epithelial ovarian Cancer carcinomas. Res 1984;44:1048-1053. Jacobs I, Bast RC. The CA 125 tumor-associated antigen: A review of the literature. Hum Reprod 1989;4:1-12. Takahashi K, Yoshino K, Araki Y, Nishigaki A, Shirai T, Stribukawa T, Kitao M. Alteration in levels of CA 125 during the menstrual cycle. Jpn J Fertil Steril 1986;31:392-396. Pittaway DE, Fayez JA. Serum CA 125 antigen levels inGynecol crease during menses. Am J Obstet 1987;156:75-16. Haga Y, Sakamoto K, Egami H, Yoshimura R, Agaki M. Evaluation of serum CA 125 values in healthy individuals and pregnant women. Am J Med Sci 1986;292:25-29.
17
18
19
20
21
Bischof P, Mignot TM, Cedard L. Are pregnancyassociated plasma protein A (PAPP-A) and CA 125 measurements after IVF-ET possible predictors of early pregnancy wastage? Hum Reprod 1989; 4843-847. Giudice LC, Jacobs A, Pineda J, Bell CE, Lippmann L. Serum levels of CA 125 in patients with endometriosis: A preliminary report. Fertil Steril 1986;45:876-878. Fedele L, Vercellini P, Arcaini L, Grazia de Dalt M, Candini GB. CA 125 in serum, peritoneal fluid, active lesions and endometrium of patients with endometriosis. Am J Obstet Gyneeol 1988;158:166-170. Duk JM, Aalders JG, Fleuren GJ, de Bruijn HWA. CA 125: A useful marker in endometrial carcinoma. Am J Obstet Gynecol 1986; 155:1097-l 101. Takahashi K, Nagata H, AbuMusa A, Shibukawa T, Yamasaki H, Kitao M. Clinical usefulness of CA 125 levels in the menstrual discharge in patients with endometriosis. Fertil Steril 1990;54:360-362. Bischof P, Galfetti MA, Seydoux J, von Hospenthal JU, Campana A. Peripheral CA 125 levels in patients with uterine fibroids. Hum Reprod 1992;7:35-38. Kabawat SE, Bast RC, Bhan AK, Welch WR, Knapp RC, Colvin RB. Tissue distribution of a coelomic epitheliumrelated antigen recognized by the monoclonal antibody OC 125. Int J Gynecol Pathol 1983;2:275-285. Dietel M, Arps H, Klapdor R, Muller-Hagan S, Sieck M, Hoffmann L. Antigen detection by monoclonal antibodies CA 19-9 and CA 125 in normal and tumor tissue and patients’ sera. J Cancer Res Clin Oncol 1986;111:257-265. Nowen EJ, Pallet DE, Eerdekens MW, Hendrix PG, Briers TW, de Broe ME. Immunohistochemical localization of placental alkaline phosphatase, carcinoembryonic antigen and cancer antigen 125 in normal and neoplastic human lung. Cancer Res 1986;46:866-876. Itahashi K, Inaba N, Fukazawa I, Takamizawa H. Immunohistochemical study of tissue polypeptide antigen (TPA) and cancer antigen 125 (CA 125) in the human and cynomolgus monkey placenta, umbilical cord and decidua. Arch Gynecol Obstet 1988; 243:145-155. de Bruijn HWA, van Beeck Calkoen-Carpay T, Jager S, Duk JM, Aalders JG, Fleuren GJ. The tumor marker CA 125 is a common constituent of normal cervical mucus. Am J Obstet Gynecol 1986; 154:1088-1091. Jacobs IJ, Fay TN, Stabile I, Bridges JE, Oram DH. Grudzinskas JG. The distribution of CA 125 in the reproductive tract of pregnant and non pregnant women. Br J Obstet Gynaecol 1988;95:1190-1194. Quirk JG, Brunson GL, Long CA, Bannon GA, Sanders MM, O’Brien TJ. CA 125 in tissues and amniotic fluid during pregnancy. Am J Obstet Gynecol 1988;159:644-649. Barbati A, Anceschi MM, Alberti P, Pomili G, Dilenzo GC, Cosmi MD. Ontogeny of CA 125 antigen in pregnancy: Immunoradiometric determination in amniotic fluid and immunohistochemical localization in fetal membranes. Am J Obstet Gynecol 1989;160:514-517. Barbati A, Anceschi MM, Broccuci L, Cosmi E. CA 125 is released by human amnion cells in culture. Am J Obstet Gynecol 1990;162:266-268.
22
23
24
25
26
27
Jiiger W, Meier C, Wildt L, Saverlrei W, Lang N. CA 125 serum concentrations during the menstrual cycle. Fertil Steril 1988;50:223-227. Zweers A, Boever J, Serreyn R, Vandekerckhove D. Correlation between peripheral CA 125 levels and ovarian activity. Fertil Steril 1990;54:409-414. Alneida Santos A, Torgal MI, Regateiro F, Moreira M, Nunes I. CA 125, prolactine et hormones steroides dans le liquide folliculaire. Actual Gynecol 1990;20:45-50. Lanxone A, Fulghesu AN, Guida C, Muscatello R, Caruso A, Mancuso S. Serum CA 125 levels do not depend on ovarian steroidogenesis. Fertil Steril 1990;54:415-418. Lehtovirta P, Apter D, Stenman UH. Serum CA 125 levels during the menstrual cycle. Br J Obstet Gynaecol 1990,97:930-933. Fedele L, Arcaini L, Baglioni A, Bianchi S, Menard S. What is the source of elevated serum levels of CA 125 in patients with endometriosis? Eur J Obstet Gynecol Reprod Biol 1989;33: 247-252.
28
29
30
31
32
Bischof P, Tseng L, Brioschi PA, Herrmann WL. Cancer antigen 125 is produced by human endometrial stromal cells. Hum Reprod 1986;1:423-426. Bischof P, Tseng L, Brioschi PA, Hemnann WL. CA 125 (Cancer antigen 125): Production endometriale et utilite clinique pour suivre les endometrioses. Actual Gynecol 1987;18:101-105. Weintraub J, Bischof P, Tseng L, Redard M, Vassilakos P. CA 125 is an excretory product of human endometrial glands. Biol Reprod 1990;42:721-726. Brumsted JR, McBean JH, Deaton JL, Gibson M. CA 125 secretion by luteal phase endometrium in vitro. Hum Reprod 1990,5: 682-684. Paavonen J, Miettinen A, Heinonen PK, Aaran RK, Teisala K, Aine R, Punnonen R, Laine S, Kallioniemi OP, Lehtinen M. Serum CA 125 in acute pelvic inflammatory disease. Br J Obstet Gynaec 1989;96:574-579.
93
EUROBS 01589
What do we know about the origin of CA 125? P. Bischof Hormone Laboratory,
Department
of Obstetrics
and Gynecology,
University of Geneva, Mater&P
1211, Geneva 14, Switzerland
Summary
The murine monoclonal antibody OC 125 recognizes an epitope on a molecule called Cancer Antigen 125 (CA 125). The CA 125 antigen is expressed in amnion and its derivatives of fetal coelomic epithelia (such as Mtillerian epithelia, peritoneum, pleura and pericardium) and in many adult tissues (such as the epithelium of fallopian tubes, endometrium, endocervix, pleura and peritoneum). The normal endometrium produces CA 125 and this production can contribute significantly to the level of circulating CA 125 at the time of menstruation. During peritoneal irritation (hyperstimulation, salpingitis, ruptured ectopic pregnancy, laparotomy) peritoneally derived CA 125 significantly contributes to circulating CA 125 concentrations, giving elevated CA 125 values. The use of the CA 125 serum assay as a single diagnostic tool is restricted by the fact that the antigen CA 125 is produced by normal epithelia (of peritoneum, endometrium and benign ovarian cysts) and not only by the ovarian cancer cell. CA 125; Tumor marker; Menstruation; Peritoneum; Endometrium
Introduction OC 125 is a murine monoclonal antibody which was raised against an ovarian carcinoma cell line derived from a patient with a serous cystadenocarcinema [l]. This antibody recognizes an epitope on a molecule called Cancer Antigen 125 (CA 125) which however remains unknown so far despite important efforts to characterize it biochemically. In 1984 a CA 125 immunoradiometric assay became commercially available [2] and the antibody was largely distributed so that at the present time, CA 125 assays are produced by many companies (Centocor, Cis, Abbott, Amersham). This Correspondence IO: P. Bischof, Hormone Laboratory, Dept. of Obstetrics and Gynecology, University of Geneva, MaternitC 1211, Geneva 14, Switzerland.
,permitted the publication of many clinical studies. The important message that emerged was that 80-95% of patients with a clinically demonstrable ovarian cancer have elevated (above 35 U/ml) serum levels of CA 125. This was, and still is, an absolute record of detection for a tumor marker in one specific malignancy. The reader wanting an overview on these clinical studies is referred to an excellent review published by Jacobs and Bast [3]. It is now widely accepted that CA 125 is an very good marker for the monitoring of ovarian cancer, but like all other cancer markers it has restricted diagnostic value. In other words, CA 125 measurements performed in asymptomatic women or in patients presenting with an abdominal mass will not provide the clinician with a diagnosis of ovarian cancer. The reason for this is due to the fact that CA 125 is also increased in several physi-
94
ological and pathological conditions such as: during menses [4,5] in early pregnancy [6,7], in women with endometriosis [8,9], in endometrial cancer [lo], in pelvic inflammatory disease [ 111, in uterine fibroids [12] and in various other benign and malignant disorders [3]. This, by no means exhaustive, list of conditions where CA 125 levels are elevated, demonstrates that CA 125 measurements should be used only when a clinical diagnosis of ovarian cancer is available. The fact that low but detectable levels of CA 125 are present under physiological conditions prompted us and other groups to search for the source of CA 125 in normal women. The distribution of CA 125 In their original immunohistochemical study, Kabawat et al. [ 131 showed that CA 125 was localized in the amnion and its derivatives of fetal coelomic epithelia such as Miillerian epithelia, peritoneum, pleura and pericardium. In adult tissues, immunoreactive CA 125 was found in the epithelium of fallopian tubes, endometrium and cervix. It was also detected in pleura, peritoneum and pericardium. Interestingly, CA 125 was not detected on the surface epithelium of the ovaries. However, subsequent reports indicated that CA 125 was expressed in normal ovarian epithelium as well as in epithelia of the pancreas, colon, gall bladder, stomach, lung and kidney [14,15]. In pregnant women, CA 125 localized in decidua and amniotic epithelium but not in the placenta [16]. Finally, CA 125 is also found to be a common constituent of normal cervical mucus [ 171. Taken together the results of these immunohistochemical studies indicate as shown in Fig. 1, that CA 125 is an antigen expressed essentially by epithelia covering the body’s cavity. As summarized in Table I, the quantitative measurements of CA 125 largely confirm the notion of CA 125 being a marker of the covering epithelia. The origin of CA 125 in pregnant women As can be seen from Table I, the highest serum levels of CA 125 in normal patients are reached during early pregnancy. The highest tissue levels
Fig. 1. Distribution of CA 125 in normal women. Positive tissues include: pleura, pericardium, peritoneum, epithelium of the cervix, endometrium, fallopian tube, epithelium covering the colon, kidney, stomach and the ovaries.
(non-malignant) are found in decidua also during early pregnancy. This observation prompted Jacobs and coworkers [ 181 to suggest that during pregnancy, circulating CA 125 could be of decidual origin. In view of the fact that amniotic fluid levels are 2-3 orders of magnitude higher than in the serum [19,20] and that amniotic cells release CA 125 in vitro [21] it cannot be excluded that some amniotic CA 125 reaches the peripheral circulation, although this seems improbable when the molecular size (> 700 kDa) of CA 125 is considered. We tend to think that circulating CA 125
95 TABLE I CA 125 in different biological compartments (range) L Serum U/ml
Normal women Patients with: Endometriosis Type I-II Type III-IV Leiomyoma Endometritis Salpingitis Pregnant patients 5-l 1 weeks 12-23 weeks 24-36 weeks 37-40 weeks Cord blood Postpartum Extrauterine pregnancies Unruptured Ruptured
Peritoneal fluid U/ml
7.5-30
50-311
75-40 15-52 13-72 5-15 20-280
98-167 69-375
10-140 12-26 13-30 14-42 220 30-420
Amniotic fluid U/ml
8800-82 000 1300-7600
Endometrium U/g
Follicular fluid U/ml
Vaginal Mucous U/ml
28600-150000
5-130
14200-15 300
3400-209 000
640-3400
6-136 1l-500
From Refs. 4-9, 11, 12, 17-20, 24.
is of decidual origin and amniotic fluid CA 125 is produced by the amnion. There is however, one noticeable exception to this. In extrauterine pregnancies, we observed significant differences in maternal serum CA 125 between ruptured and unruptured ectopic pregnancies [7]. Every time that in early pregnancy clinical signs of peritoneal irritation were present (hyperstimulation, hydrosalpinx, salpingitis or ruptured ectopic), CA 125 levels were highly increased. Under those pathological conditions we propose that peritoneally derived CA 125 significantly contributes CA 125 concentrations. The origin of CA 125 in non-pregnant women The ovary
There are 3 reports suggesting an ovarian origin for CA 125. Jlger and coworkers [22] observed an increase of CA 125 which paralleled the rise in follicular diameter and estradiol secretion in 6 out of 13 normal women in whom blood was sampled
at daily intervals. Zweers and colleagues 1231 measured CA 125 in different groups of women: in normal cycles, in pill-suppressed cycles and in stimulated cycles for intrauterine insemination or oocyte retrieval. In the first 2 groups no changes in CA 125 levels were observed between the first and the second half of the cycle. However, in women with stimulated cycles, luteal phase CA 125 concentrations, were higher than in the follicular phase. That this increase was not due to the laparoscopy procedure was shown by the fact that in women undergoing operative laparoscopy, CA 125 levels were not higher 7- 10 days after laparoscopy than before. The authors conclude that during the luteal phase of stimulated cycles, increased CA 125 levels are either of luteal or of endometrial origin. Finally, CA 125 levels have been found in measurable quantity in follicular fluid and the levels were higher when the oocyte was present as compared to those cases were the oocyte could not be found [24]. In contrast to these studies, Lanzone et al. [25]
96
and Lehtovirta et al. [26] found no correlation between ovarian steroid concentrations and CA 125 levels under different physiological conditions. These results argue against an ovarian origin for CA 125. Our own results, show that CA 125 levels do not increase during ovarian stimulation (as compared to normal cycles). However, as soon as a laparoscopy is undertaken, CA 125 concentrations increase dramatically. Furthermore, in 10 premenopausal and in 14 postmenopausal women, there was no difference in the CA 125 concentration between the peripheral blood, the blood draining the active (high estradiol and/or progesterone) or the inactive ovary (Bischof, unpublished observations). In the absence of a concentration gradient from the ovaries to the periphery and with the observed effects of laparoscopy we would conclude that under normal conditions, the ovary does not produce CA 125 into the circulation and that intervention on the abdominal wall (laparoscopy) increases briskly and transiently (5-6 days) the circulating levels of CA 125. The endometrium It is widely accepted that the decidua is a source of CA 125 (see above) however, it is still unclear if the normal endometrium produces CA 125 and if this production contributes significantly to the circulating CA 125. Relatively high levels of CA 125 have been measured in non-decidualized eutopic endometria [ 18,191. In contrast, no CA 125 was found in ectopic endometrial implants in women with endometriosis despite elevated serum levels [27]. In order to have some insight into a possible endometrial origin for CA 125 we conducted in vitro studies with explants and primary endometrial cell cultures [28-301. Explants of decidua released high amounts of CA 125 when cultured in vitro. In presence of cycloheximide, an inhibitor of protein synthesis, the release of CA 125 was significantly inhibited [28,29] demonstrating that the decidua is capable of producing CA 125. Endometrial stromal cells, when cultured separately from glandular cells secreted also CA 125 but in concentration 4-10 times smaller than glandular cells alone [30]. This low secretion could well be due to the contamination of stromal cell cultures by epithelial cells which was estimated to be at about 5%. CA
125 production by endometrial cells was inhibited by medroxyprogesterone acetate and this inhibition could be overcome by the coincubation with the antiprogestin RU 486 [28]. These in vitro studies were compared with immunohistochemical data. It was shown that CA 125 was localized in the infranuclear region of epithelial cells during the proliferative phase and to the apical luminal border during the secretory phase. No staining was observed in stromal cells. The results of these in vitro studies led us to conclude that CA 125 was indeed an endometrial product and that its secretion was exocrine, into the uterine cavity. In order to verify this statement in vivo, we collected endometrial aspirations (jet washes of the uterine cavity) and measured CA 125. CA 125 levels were very high and a significant increase was observed from the proliferative to the secretory phase [30], indicating that in vivo also, CA 125 was excreted by the epithelium of the endometrium. Taken together, these experiments demonstrate that the human endometrium produces and secretes CA 125 and that this secretion is regulated by ovarian hormones. This conclusion was also reached by others using endometrial explant cultures [31]. If it does seem apparent that the endometrium produces CA 125, its contribution to the circulating CA 125 pool remains unknown. To answer this question we measured CA 125 in a cohort of women with uterine fibroids who underwent a hysterectomy or a treatment with GnRH analogues [12]. We observed that about one-third of the women with uterine fibroids had increased circulating levels of CA 125 and that removal of the uterus or treatment with GnRH significantly decreased peripheral concentrations of CA 125 below those observed in normal women. The origin of this increased CA 125 in women with uterine fibroids is a matter of speculation. The uterus probably only partially contributes to circulating CA 125 since after hysterectomy the peripheral levels of CA 125 are only slightly lower than during the normal cycle. However, since the levels are still measurable after hysterectomy, a contribution from yet another source has to be considered. The peritoneum There is some indirect evidence to suggest that
91
the peritoneum is probably an important source of CA 125. As discussed before, intervention on the abdominal wall (laparoscopy) increases CA 125 quite dramatically. In pregnant women, CA 125 is highly increased when clinical signs of peritoneal inflammation such as: hydrosalpinx, ruptured ectopic pregnancy, ovarian hyperstimulation are present [7]. In non-pregnant women also pelvic inflammatory disease has been shown to increase CA 125 [32]. Since Kabawat et al. [13] have clearly shown that CA 125 is localized in the mesothelial cells of the peritoneum, we speculate that the peritoneum is probably the main source of CA 125. If it is true, then the mechanical distension of the peritoneum due to the presence of uterine fibroids, peritoneal inflammation and surgery on the abdominal wall represent non-specific inducers of the CA 125 secretion. This hypothesis is currently under study in our laboratory.
I
8
9
10
11
12
13
Concluding remarks 14
It is hoped that this brief review of what is known about the origin of CA 125, will help the clinician to prescribe and interpret a CA 125 blood test. Because CA 125 is produced by normal epithelia and not only by ovarian cancer cells, the use of CA 125 serum assay as a single diagnostic tool is both useless and expensive.
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