GYNECOLOGIC ONCOLOGY 36, 219-225 (1990)
Human Chorionic Gonadotropin, Follicle-Stimulating Hormone, and Luteinizing Hormone in Patients with Epithelial Ovarian Carcinoma CARL-GUSTAV MAHLCK,
M.D., PH.D., KJELL GRANKVIST, M.D., PH.D., OLLE KJELLGREN, M.D., TORBJGRN B~CKSTR~M, M.D., PH.D.
Departments of Obstetrics and Gynecology, Clinical Chemistry, Gynecologic Oncology, and Physiology, University of Umed, Ume& Sweden Received
Plasma levels of human chorionic gonadotropin (hCG), folliclestimulating hormone (FSH), and luteinizmg hormone (LH) were studied in patients with epithelial ovarian carcinoma prior to and during chemotherapy. Blood samples were drawn for radioimmunoassay at monthly intervals. Plasma concentrations were compared to those of three different control groups: healthy postmenopausal women (PM), fertile women in the follicular phase of the menstrual cycle (FPh), and postmenopausal women with nongynecologic disseminated malignant disease(DMD). The hCG level was elevated in women with great tumor burden, such as large tumor volume, FIGG stage IV, and histologic type V. LH and FSH levels showed the reverse pattern. hCG concentration decreased during chemotherapy, whereas LH increased. Initial plasma concentrations were not found to have prognostic importance. We discuss the possibility that hCG is produced by the tumor, which stimulates steroid hormone production by the stroma, which, in turn, exerts negative feedback on FSH proAcademic R~SF, inc. duction by the pituitary. o 1990 INTRODUCTION
Some ovarian tumors are known producers of steroid hormones; for instance, granulosa-theta cell tumors produce estrogens and arrhenoblastomas produce androgens. These tumors occur rarely. However, common epithelial ovarian carcinoma, which constitute the vast majority of ovarian malignant tumors (about 83%), have generally been considered “nonendocrine,” i.e., not producing hormones. In recent studies it has been shown that progesterone, androstenedione, estradiol, and to some degree 20a-OH-progesterone and testosterone are produced in small amounts by these ovarian tumors [l61. Furthermore, it was found that plasma concentrations of progesterone, androstenedione, and estradiol are related to tumor volume and follow the effect of chemotherapy on tumor volume, and increase prior to relapse of the disease . These steroids have been found in
higher concentration in the ovarian vein draining the tumor than in the contralateral ovarian vein or peripheral blood . An interesting case has been reported, in which the injection of human chorionic gonadotropin (hCG) into a patient with a mutinous ovarian tumor (histologically IIB) yielded’a dramatic increase in the concentrations of progesterone, androstenedione, and especially estradiol in the ovarian vein draining the tumor [93. This raises a question concerning the factors involved in promoting steroidogenesis in ovarian tumors. Since 1975 hCG has been known to be present not only in placenta, but in various tissues in both males and nonpregnant females [lo-121. The highest concentrations have been found in testes and ovaries, with an inverse correlation between hCG concentration and age after age 15 . Small amounts have been found in urine and plasma of normal postmenopausal women [14-161. Previous studies have revealed that lo-20% of patients with carcinoma of the lung, pancreas, colon, or other malignant disease have elevated levels of hCG or its subunits [17,18]. cr-hCG chains have been found to be secreted in high percentages among patients with carcinoid , while functioning pancreatic islet cell carcinoma showed elevated levels of p-hCG chains in a high frequency [19,20]. Increased concentration of the intact hCG molecule has been reported in a case of virilizing hepatoblastoma . Vaitukaitis er al. have shown that hCG-producing tumors secrete intact hCG as the predominant form of that hormone . Some investigations into the presence of hCG in peripheral blood in cases of ovarian carcinoma have been performed. Donaldson and co-workers found hCG to be present in 5 of 20 cases of epithelial adenocarcinoma of the ovary 1231.In a small number of patients, Tsalacopoulos and Bloch found P-hCG chains to be detectable
219 Copyright 0 1590 by Academic Press, Inc. AU rights of reproduction in any form reserved.
in 4 of 6 cases of cystadenocarcinoma of the ovary . Carenza et al. found small amounts of P-hCG in peripheral blood in 7 of 17 women with ovarian carcinoma . Measurable amounts of &hCG chains were also found in subjects without clinical evidence of neoplasm, and the authors concluded that the findings reduced its usefulness in the management of nontrophoblastic tumors. However, these studies were usually performed with the intention of achieving a diagnostic or monitoring tool in the clinical management of the patient. The present investigation is merely a descriptive study. By analyzing plasma levels of hCG, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in the same patients as previously reported, where steroid hormones were studies [2-71, the intention is to clarify some of the biology and nature of hormone production in women with epithelial ovarian carcinoma. METHOD Patients
With the IO-fold difference in the order of magnitude of the dividing points, it was easy to decide to which of the three categories a patient should belong. Thus, it has been possible not only to compare the entire patient group with controls, but also to make comparisons between subgroups of patients, especially between those with large and small tumor volumes. Whether the tumors were solid or cystic was diagnosed at operation, at autopsy, by bimanual palpation, and by ultrasound examination. Of the large and medium tumors, 2 were large cysts, 8 were multiple small cysts with thick tissue septa, and 18 were solid. This study was approved by the Ethical Committee of the University Hospital of UmeH. Controls
Eighteen postmenopausal (PM) women with no malignant or internal disease or any medication (hormonal or other) served as a control group (mean age 60.3 years, range 51-78 years). These controls were recruited among patients suffering from uterine prolapse before starting estrogen medication. Another control group (mean age 29.3 years, range 20-45 years) consisted of 16 healthy fertile women from whom blood was sampled during early follicular phase (FPh) of the menstrual cycle. These controls were recruited among the hospital personnel. Finally, a third control group (mean age 76.2 years, range 64-92 years) consisted of 13 postmenopausal women with a nongynecologic disseminated malignant disease (DMD).
The material comprised 51 patients recruited at the Department of Gynecologic Oncology, University Hospital, Umel, Sweden. The diagnosis was carcinoma ovarii in all cases, with histologic types IC (n = 21), IIC (n = 6), IIIC (n = 12), and V (n = 12). The number of cases with clear cell tumor (histologically IVC) was too small to make statistic evaluation possible. Thus, they were excluded from the study. Staging was in accordance with the classification of the International Federation of Obstetrics and Gynecology (FIGO). The patients were in stage I (n = 6), stage II (n = 12), stage Blood Sampling III (n = 17), and stage IV (n = 15). Mean age was 60.8 Blood samples were drawn monthly for peptide horyears with a range of 33-83 years. The patients were mone radioimmunoassays on four occasions, the first either naturally postmenopausal (PM) (80%) or had sample being drawn on the first admission to the hospital undergone a radical bilateral oophorectomy before enbefore chemotherapy was started. All samples were tering the study (1 l/51, 22%; 50% of the small tumor taken between noon and 1 PM. In 13 patients, samples group). None of the patients had any other malignant or were drawn for a longer period at regular intervals prior endocrine disorder. to diagnosis of recurrence of the disease. Tumor volume was estimated once a month using bimanual rectovaginal palpation under anesthesia. The ma- Biochemical Assays terial was divided into three categories-large, medium, Directly after centrifugation plasma was frozen in and small tumor volume-with dividing points at 1000 and 100 ml. The small tumor group included those pa- small aliquots, which were thawed only for assay. All tients who were radically operated on and who had no samples from the same patient were assayed in duplicate palpable tumor. The estimated tumor volume was in the same run. Plasma FSH and LH were assayed with radioimmuchecked occasionally by ultrasound examination and computerized tomography. The error in the rated di- noassay kits from Farmos Diagnostica, Turku, Finland. The FSH standard was WHO 69/104 and that for LH ameter was + 1 cm on those occasions. was WHO 68140.Within- and between-assay coefficients Evaluation of tumor volume was carried out by clinical of variation (CV) were 8.5 and 10.5% for FSH and 8.7 means. The evaluation of tumor volume in this investiand 8.7% for LH. Plasma hCG was assayed employing gation is not claimed to be precise; the main intention was to divide the material into large, medium, and small a solid-phase enzyme immunoassay from Abbot Diagtumor volume, with dividing points at 1000 and 100 ml. nostics products GmbH, Wiesbaden-Delkenheim, West
hCG, FSH, AND LH IN OVARIAN CARCINOMA
Germany. The procedure measures the p-specific subunit by adding two different anti-&antibodies, which allows detection of 1.0 IU p-hCGlliter plasma. Cross-reactivity with LH is reduced to 0.4%. hCG was calibrated against WHO Second International Standard (IS) for hCG. The interassay CV was 6.7% and the intraassay CV was 4.4%.
Statistics The mean values between several groups were tested using the Kruskal-Wallis test and serial measurements from the same individuals, using Friedman’s test. If significance was found between the groups, the MannWhitney U test was used to test for significance between independent groups. All group values are given as means -C standard errors of the mean (SE), unless otherwise stated. Nonparametric statistical methods have been used to avoid assuming normal distribution. Because of multianalysis within areas of investigation, significance should be considered at P 5 0.01, rather than P 5 0.05. RESULTS
I HC6 •I FSH . LH
FIG. 1. Plasma concentrations of hCG, FSH, and LH (mean -rSE) in women with large, medium, and small ovarian tumor volume and in postmenopausal (PM) and follicular phase (FPh) controls and a control group of postmenopausal women with nongynecologic disseminated malignant disease (DMD). “Large is significantly higher than small, medium, and PM, FPh, and DMD controls (P < 0.0005, 0.01, 0.005, O.OOOOOl, and 0.005, respectively). bLarge is significantly lower than medium and PM controls (P < 0.001 and 0.001, respectively). ‘FPh is significantly lower than small, medium, and PM and DMD controls (P < 0.0005, 0.005, 0.001, and 0.005, respectively). “FPh is significantly lower than small, medium, large, and PM and DMD controls (P < 0.000001, 0.001, O.OOOOO1, 0.001, and 0.001, respectively). ‘FPh is significantly lower than small, medium, large, and PM and DMD controls (P < 0.000005, 0.001, 0.000005, 0.001, and 0.001, respectively). ‘DMD is significantly lower than PM controls (P < 0.01).
Volume Significant heterogeneity was found in mean plasma concentrations within the tumor volume groups and the control groups with respect to hCG, FSH, and LH: H (5,97) = 38.63, 48.69, and 37.20, respectively (KruskalWallis, P < 0.001 for all). When the tumor volume groups were investigated alone, significant heterogeneity was also found, as for hCG and FSH, H (2,48) = 13.84 and 10.28, respectively (P < 0.001 and 0.01). The same heterogeneity was found when PM controls were added, H (3,68) = 17.20 and 13.79 for hCG and FSH, respectively (Kruskal-Wallis, P < 0.001 for both. When the large tumor group was excluded, however, the heterogeneity disappeared, H (2,47) = 0.075 and 0.95, respectively, NS. No significant heterogeneity was found when LH was investigated. When the groups were tested individually, the large tumor volume group had a significantly higher plasma hCG concentration than all other groups, including controls, whereas FSH concentration was lower in the large tumor group than in the medium and small tumor groups. No difference in LH concentration was found within the tumor volume groups, H (2,48) = 0.03, NS. For detailed analysis, see Fig. 1. Patients with solid tumors in the large and medium tumor groups did not show any significant difference, with respect to plasma concentration of hCG, FSH, or LH, compared to those with unicystic or multicystic tumors (Mann-Whitney U test, NS).
Histologic Type When the material was divided into different histologic types, significant heterogeneity was found within the tumor group and the control groups, H (5,97) = 31.15, 47.33, and 37.37 for hCG, FSH, and LH, respectively (P < 0.001 for all). Excluding the control groups, no significant heterogeneity was found. When the groups were tested individually, the anaplastic tumors (histologically type V) had a significantly higher hCG concentration than type IIIC and the control groups. As for FSH, type V was found to be lower than IC and PM controls. For further details, see Fig. 2. Stage Investigating the tumor stage groups and the controls, significant heterogeneity was found for hCG, FSH, and LH, H (6,97) = 34.62, 49.19, and 41.74, respectively (P < 0.001 for all). Excluding the control groups, no significant heterogeneity was found within the tumor group for any of the hormones investigated. When tested individually, tumor stage IV was found to have a significantly higher hCG concentration than stage II and the control groups; the stage II group had a higher FSH level than other tumor stage groups and a higher LH level than DMD control group. For statistical evaluation between groups, see Fig. 3.
FIG. 2. Plasma concentrations of hCG, FSH, and LH (mean ? SE) in women with ovarian tumor and histologic types IC, IIC, IIIC, and V as well as postmenopausal (PM) and follicular phase (FPh) controls and a control group of postmenopausal women with nongynecologic disseminated malignant disease (DMD). “V is significantly higher than IIIC and PM, FPh, and DMD controls (P < 0.01, 0.005, 0.001, and 0.001, respectively). bV is significantly lower than IC and PM controls (P < 0.01 and 0.001, respectively). “FPh is significantly lower than IC, IIC, IIIC, and PM and DMD controls (P < 0.00005, 0.01, 0.001, 0.001, and 0.001, respectively). ‘FPh is significantly lower than IC, IIC, IIIC, V, and PM and DMD controls (P < 0.000001, 0.001, 0.001, 0.001, 0.001, and 0.001, respectively). ‘FPh is significantly lower than IC, IIC, IIIC, V, and PM and DMD controls (P < 0.000005, 0.001, 0.001, 0.001, 0.001, and 0.001, respectively). IDMD is significantly lower than PM controls (P < 0.01).
Effect of Chemotherapy Patients with large tumor volume were monitored once a month, with blood sampling and bimanual estimation of tumor volume being carried out under general anesthesia. Fourteen women who showed a 50% reduction I q
in tumor volume within 3 months were grouped together. The reason for doing so is that in many clinical trials 50% tumor mass reduction is considered a standard of effectiveness of the investigated therapy. Mean plasma concentration of hCG decreased concomitantly with reduction of tumor volume, with the mean value at 2 months being significantly lower than the mean value before any chemotherapy had been given. As for LH, a significant decrease in the mean plasma concentration was seen after 1 month of chemotherapy, but afterward a significant increase was seen, as compared to the mean value at 1 month but not in comparison to the initial mean LH concentration. No significant change in the mean plasma FSH concentration was seen during chemotherapy. For details, see Fig. 4. Prognostic Value The women were divided into two groups depending on 30-month survival. Thirty months was chosen because at that time 50% of the initial group (n = 51) was still alive. No statistically significant difference in the initial plasma concentrations of hCG, FSH, and LH was found between patients surviving 30 months from onset of therapy as compared with those not surviving 30 months. The same procedure was carried out with 6 months as the dividing point. Neither in this comparison was any statistical difference found in mean plasma concentrations (Wilcoxon’s matched-pairs signed-ranks test). Prognostic value in terms of early detection of recurrence of disease was investigated in 13 postmenopausal women with malignant ovarian tumor who showed signs of disease recurrence. Plasma levels of hCG, FSH, and LH at diagnosis of recurrence were compared to the preceding values sampled at monthly intervals. No sig-
PIG. 3. Plasma concentrations of hCG, FSH, and LH (mean 2 SE) in women with ovarian tumor in FIG0 stages I-IV as well as postmenopausal (PM) and follicular phase (FPh) controls and a control group of postmenopausal women with nongynecologic disseminated malignant disease (DMD). “II is significantly higher than I, III, and IV (P < 0.01, 0.01, and 0.01, respectively). ?I is significantly higher than DMD controls (P < 0.01). ‘IV is significantly higher than II, III, and PM, FPh, and DMD controls (P < 0.01, 0.01, 0.005, 0.001, and 0.01, respectively). ‘FPh is significantly lower than II, III, and PM and DMD controls (P < 0.001, 0.001, 0.001, and 0.005, respectively), ‘FPh is significantly lower than I, II, III, IV, and PM and DMD controls (P < 0.001 for all). fFPh is significantly lower than I, II, III, IV, and PM and DMD controls (P < 0.01, 0.001, 0.001, 0.001, 0.001, and 0.001, respectively). sDMD is significantly lower than PM controls (P < 0.01).
FIG. 4. Plasma concentrations of hCG, FSH, and LH (mean * SE) in 14 patients with large tumor volume and with at least 50% mass reduction within 3 months during chemotherapy. “Mean at 2 months of chemotherapy is significantly lower than mean plasma concentration before any chemotherapy was given (P < 0.01). ?Same as for a, but at 1 month of therapy (P < 0.01). ‘Mean at 3 months of chemotherapy is significantly higher than that 1 month after therapy (P < 0.01) (Wilcoxon’s matched-pairs signed-ranks test).
hCG, FSH, AND LH IN OVARIAN
nificant change in mean plasma concentration was ob- . The reason for their different results as compared served in either determination (Mann-Whitney U test). to ours is probably assay cross-reactivity versus LH, as A comparison was made between plasma levels of elevated hCG titers were found only among postmenohCG, FSH, and LH on the day of largest registered pausal women and where the majority of the patients tumor volume prior to death and on the day of smallest also had raised plasma LH levels. They did not exclude registered tumor volume during the course of therapy. ectopic production of hCG in a minority of patients, though. A significant rise in plasma concentration of hCG (P I Interestingly, plasma concentrations of FSH showed 0.01) and a concomitant fall in plasma concentration of FSH (P i 0.01) were found when tumor volume was a pattern opposite that of hCG, with lower levels in the increasing prior to death (Wilcoxon’s matched-pairs large tumor group than in medium and small tumor signed-ranks test). A slight, though not statistically sig- groups. The plasma level of FSH in the large tumor group nificant, decrease in LH concentration was found. was also lower than that in the PM control group. This is of special interest, since in previous investigations [241 plasma levels of progesterone, androstenedione, and DISCUSSION estradiol have been shown to be higher in the large tumor The results of the present investigation indicate that group than in the medium and small tumor groups as the plasma level of hCG in patients with epithelial ovar- well as the PM control group. During chemotherapy a ian carcinoma is related to the volume of the tumor. It decrease in hCG concentration was seen in this investigation, concomitantly with the reduction of tumor volis to our knowledge the first time that such a relationship has been demonstrated. When the material is divided ume (see Fig. 4). This is similar to what has been deinto different FIG0 stages, the same relationship can be scribed for steroid hormones , but dissimilar to FSH and LH levels in this investigation, where an opposite seen. This is not surprising since an advanced FIG0 stage of the disease merely reflects a high degree of tumor tendency was found. An explanation of these results would be that hCG is burden. Concerning cysticity, the majority of the large tumors were found to be solid. Interestingly, no differ- produced by the tumor, which stimulates the ovarian ence in hormone concentration was found between solid stroma to produce steroid hormones, which in turn could and cysticlmulticystic tumors for any of the peptide hor- exert an inhibiting effect on peptide hormone production mones investigated. The significance of this finding is by the pituitary. This opinion is further supported by the still not clear. It is obvious that the content of the tumor fact that hCG levels in the various subgroups show a volume has had no influence on the peptide hormone pattern similar to what has been shown for steroid horconcentration in plasma in the present investigation. This mones . As has been pointed out previously, prois in accordance with the results of previous investiga- gesterone [8,9,27,28], androstenedione [9,27], and estradiol [8,9,27] have been demonstrated in higher levels in tions on steroid hormones in the same patients [251. When the material was divided according to histologic the ovarian vein draining the tumorous ovary than on differentiation, women with anaplastic tumors (histolog- the contralateral side and peripheral blood. Furthermore, ically type V) were shown to have the highest hCG con- hCG concentration in DMD controls did not differ from centration in plasma. The same tendency was seen for that in PM controls, indicating that the elevated hCG group IC, though it was not statistically significant (P < level is not a general reaction to malignant disease. The 0.025) in this investigation, where a higher degree of small amount of hCG found in the plasma of PM controls significance is required. On analysis of the distribution is normal [14-161. It is interesting though that the LH of tumor types, the large tumor group was found to level in the DMD control group was significantly lower comprise mainly histologically IC and V tumors, which than that in the PM control group. The reason for this makes tumor volume the most important determinant of finding is not clear. plasma hormone concentration. This conclusion is furOf the extragenital tumors producing hCG, a surpristher supported by the fact that the significant hetero- ingly large number have been found to originate from geneity among patient groups and PM controls disap- the gastrointestinal tract, especially the stomach, liver, peared when the large tumor group was excluded. and pancreas. In many cases, transition from adenocarDonaldson et al. found elevated levels of hCG almost cinomatous to trophoblastic elements was observed exclusively in patients with serous cystadenocarcinoma [17,29,301, which indicates a morphologic differentiation (histologically IC) of the ovary . The reason for their of the adenocarcinoma toward choriocarcinoma [3 1,321. different results in this context as compared to the pres- As not every gastrointestinal tumor with an elevated hCG ent investigation is their smaller patient material. Mon- level showed foci of trophoblastic cells, it is possible that teiro et al. found raised hCG levels in half of the material, primary gastrointestinal tract tumors themselves are caan increase that was neither stage nor tumor type related pable of producing chorionic gonadotropin. This may
explain the finding of stromal luteinization in ovaries containing metastases from tumors of the gastrointestinal tract . Secreting small amounts of chorionic gonadotropin, gastrointestinal tract neoplasms may cause high local concentrations within the ovaries, which induce stromal luteinization. Some primary cystadenocarcinomas have been described as “ovarian tumors with functioning stroma”  due to the presence in the stroma of cells that simulated the theta externa cells of a developing follicle. In some cases in the present investigation, the same cell type was found in the tumorous stroma, which cannot be distinguished from cells with known steroid hormone-producing capacity (Mahlck, Cajander, Kjellgren, and Backstrom, unpublished data). The hCG measured in this investigation is the p subunit. For biological activity to occur, the entire hCG molecule must be present, however. Even though some of the biology of ovarian tumors may be explained by the results of the present investigation, confirmation should be sought through complementary experiments studying the biologic activity of the analyzed chorionic gonadotropin. Such experiments are in progress. In conclusion, ovarian epithelial tumors seem to be capable of producing hCG, which induces steroid hormone production of the ovarian stroma, which in turn inhibits FSH and LH production by the pituitary. ACKNOWLEDGMENTS This work has been supported by the Swedish Cancer Society (Project p88-OZXA) and the Lions Research Foundation, University of Umei (Projects 382/85 and 509187).
REFERENCES 1. Mango, D., Scirpa, P., Battaglia, F., Sentinelli, S., and Menini, E. A case of mutinous cystadenocarcinoma of the ovary associated with virilization: Pre- and post-operative steroid plasma levels, J. Endocrinol. Invest. 8, 359-362 (1985). 2. Backstrom, T., Mahlck, C. G., and Kjellgren, 0. Progesterone as a possible tumor-marker for “non-endocrine” ovarian malignant tumors, Gynecol. Oncol. 16, 129-138 (1983). 3. Mahlck, C. G., Backstrom, T., and Kjellgren, 0. Androstenedione production by malignant epithelial ovarian tumors, Gynecol. Oncol. 25, 217-222 (1986). 4. MahIck, C. G., Backstrom, T., and Kjellgren, 0. Plasma level of estradiol in patients with ovarian malignant tumors, Gynecol. Oncol. 30, 313-320 (1988). 5. Mahlck, C. G., Backstrom, T., Kjellgren, O., and Selstam, G. Plasma Z&-OH-progesterone in women with malignant epithelial “non-endocrine” ovarian tumors, Acta Obstet. Gynecol. Stand. 64, 515-518 (1985). 6. Mahlck, C. G., Grankvist, K., Backstrom, T., and Kjellgren, 0. Testosterone, SHBG and albumin in patients with ovarian carcinoma, Acta Obstet. Gynecol. &and. 65, 533-538 (1986). 7. Mahlck, C. G., Backstrom, T., Kjellgren, O., and von Schoultz, B. Plasma progesterone and androstenedione in relation to changes
ET AL. in tumor volume and recurrence in women with ovarian carcinoma, Gynecol. Obstet. Invest. 22, 157-164 (1986). 8. Jeppsson, S., Kullander, S., and Rannevik, G. Peripheral and ovarian venous concentrations of gonadal steroids and CEA in women with ovarian tumors, Acta Obstet. Gynecol. Stand. 61, 209-212 (1982). 9. Quinn, M. A., Baker, H. W. G., Rome, R., Fortune, D., and Brown, I. B. Response of a mutinous ovarian tumor of borderline malignancy to human chorionic gonadotropin, Obstet. Gynecol. 61, 121-126 (1983). 10. Braunstein, G. D., Rasor, J., and Wade, M. E. Presence in normal human testes of a chorionic-gonadotropin-like substance distinct from human luteinizing hormone, N. Engl. J. Med. 293, 13391343 (1975). 11. Yoshimoto, Y., Wolfsen, A. R., and Odell, W. D. Human chorionic gonadotropin-like substances in non-endocrine tissues of normal subjects, Science 197, 575-577 (1977). 12. Carenza, L., Di Gregorio, R., Mocci, C., Moro, M., and Pala, A. Ectopic human chorionic gonadotropin: Gynecological tumors and nonmalignant conditions, Gynecol. Oncol. 10, 32-38 (1980). 13. Braunstein, G. D., Kamdar, V. V., Rasor, J., Swaminathan, N., and Wade, M. E. Widespread distribution of a chorionic gonadotropin-like substance in normal human tissues, J. Clin. Endocrinol. Metab. 49, 917-925 (1979). 14. Chen, H. C., Hodgen, G. D., Matsuura, S., Lin, L. J., Gross, E., Reichert, L. E., Jr., Birken, S., Canfield, R. E., and Ross, G. T. Evidence for a gonadotropin from nonpregnant subjects that has physical, immunological and biological similarities to human chorionic gonadotropin, Proc. Natl. Acad. Sci. USA 73, 2885-2889 (1976). 15. Ayala, A. R., Nisula, B. C., Chen, H. C., Hodgen, G. D., and Ross, G. T. Highly sensitive radioimmunoassay for chorionic gonadotropin in human urine, J. Clin. Endocrinol. Metab. 47, 767773 (1978). 16. Robertson, D. M., Suginami, H., Hernandez Montes, H., Puri, C. P., Choi, S. K., and Diczfalusi, E. Studies on a human chorionic gonadotrophin-like material present in non-pregnant subjects, Acta Endocrinol. 89, 492-505 (1978). 17. Braunstein, G. D., Vaitukaitis, J. L., Carbonne, P. P., and Ross, G. T. Ectopic production of human chorionic gonadotrophin by neoplasms, Ann. Intern. Med. 78, 39-45 (1973). 18. Hattori, M., Fukase, M., Yoshimi, H., Matsukura, S., and Imura, H. Ectopic production of human chorionic gonadotropin in malignant tumors, Cancer 42, 2328-2333 (1978). 19. Gberg, K., and Wide, L. hCG and hCG subunits as tumour markers, in patients with endocrine pancreatic tumours and carcinoids, Acta Endocrinol. 98, 256-260 (1981). 20. Kahn, C. R., Rosen, S. W., Weintraub, B. D., Fajans, S. S., and Gorden, Ph. Ectopic production of chorionic gonadotropin and its subunits by islet-cell tumors, N. Engl. J. Med. 297,565-569 (1977). 21. Braunstein, G. D., Bridson, W. E., Glass. A., Hull, E. W., and M&tire, K. R. In vivo and in vitro production of human chorionic gonadotropin and alpha-fetoprotein by a virilizing hepatoblastoma, .I. Clin. Endocrinol. Metab. 35, 857-862 (1972). 22. Vaitukaitis, J. L. Immunologic and physical characterization of human chorionic gonadotropin (hCG) secreted by tumors, J. Clin. Endocrinol. Metab. 37, 505-514 (1973). 23. Donaldson, E. S., van Nagell, Jr., J. R., Pursell, S., et al. Multiple biochemical markers in patients with gynecologic malignancies, Cancer 45, 948-953 (1980). 24. Tsalacopoulos, G., and Bloch, B. Ectopic production of the beta
hCG, FSH, AND LH IN OVARIAN CARCINOMA
subunit of human chorionic gonadotrophin by malignant ovarian neoplasms, S. Afr. Med. J. 62, 487-488 (1982). Mal-dck, C. G. Plasma steroid hormones in women with epithelial ovarian carcinoma, Acta Obstet. Gynecol. Stand. Suppl. 137, 131 (1986). Monteiro, J. C., Barker, G., Ferguson, K. M., Wiltshaw, E., and Neville, A. M. Ectopic production of human chorionic gonadotrophin (hCG) and human placental lactogen (hPL) by ovarian carcinoma, Eur. J. Cancer C/in. Oncol. 19, 173-178 (1983). Edwards, R. L., Nicholson, H. O., Zoidis, T., Butt, W. R., and Taylor, C. W. Endocrine studies in post-menopausal women with ovarian tumours, J. Obstet. Gynaecol. Brit. Commonw. 78, 467477 (1971). Heinonen, P. K., Koivula, T., and Pystynen, P. Elevated progesterone levels in serum and ovarian venous blood in patients with ovarian tumors, Acta Obstet. Gynecol. &and. 64, 649-652 (1985).
29. McKechnie, J. C., and Fechner, R. E. Choriocarcinoma and adenocarcinoma of the esophagus with gonadotropin secretion, Cancer 27, 694-702 (1971). 30. Ozaki, H., Ito, I., Sano, R., et al. A case of choriocarcinoma of the stomach, Japan. J. Clin. Oncol. 1, 83-94 (1971). 3l Schlagenhaufer, F. iiber das Vorkommen chorionepitheliom und ’ traubenmolenartiger Wucherungen in Teratomen, Wien. Klin. Wochenschr.
15, 571-580, 604-606 (1902).
32. Pick, L. iiber die Chorionepitheliomahnlich metastasierende Form des Magencarcinoms, Klin. Wochenschr. 5, 1728-1729 (1926). 33. Scully, R. E., and Richardson, G. S. Luteinization of the stroma
of metastatic cancer involving the ovary and its endocrine significance, Cancer 14, 827-840 (1961). 34. Morris, J. M., and Scully, R. E. Endocrine pathology Mosby, St. Louis (1958).
of the ovary,