Endocrine factors in common epithelial ovarian cancer.

0163-769X/91/1201-0014$03.00/012 Endocrine Reviews Copyright © 1991 by The Endocrine Society

Vol. 12, No. 1 Printed in U.S.A.

Endocrine Factors in Common Epithelial Ovarian Cancer* B. RAMANATH RAO AND BEREND J. SLOTMAN Department of Endocrinology, Academisch Ziekenhuis Vrije Uniuersiteit, 1081 HV Amsterdam, The Netherlands

I. II. III. IV. V. VI.

Introduction Etiology Plasma Hormone Levels Endocrine Therapy Hormone Receptors Steroid Hormone Receptors and Clinicopathological Parameters VII. Steroid Hormone Receptors and Prognosis VIII. Steroid Hormone Receptors and Therapy IX. Conclusions and Future Prospects

based combination chemotherapy (2). Although the majority of patients respond to this therapy, survival of ovarian cancer patients has not really improved during the last decades. Only 5-15% of patients with advanced disease [International Federation of Gynecology and Obstetrics Cancer Committee (FIGO) stage III and IV] survive 5 yr or longer (3). The 5-yr survival rates of other stages vary between 45% for stage II to 72% for stage la (3). Since most of the patients have stage III or IV disease at the time of diagnosis, the overall survival rate of ovarian cancer is low. New approaches to ovarian cancer are direly needed to improve this poor prognosis. In this paper, the available information on the role of hormones in ovarian cancer is reviewed. Data from epidemiological studies, from studies on the effect of endocrine therapy, and from studies on the presence and importance of steroid hormone receptors are discussed.

I. Introduction

T

HE OVARIES are specialized organs of reproduction, liberating gametes for fertilization and producing hormones, which may act in various genital and nongenital tissues. A number of different cell types are present in the functioning ovary: epithelial cells, stromal cells, and germ cells. Although all cell types may undergo malignant transformation, the vast majority of neoplastic ovarian tumors are of the epithelial type, and it is this type of tumor that will be discussed in this paper. Epithelial ovarian tumors are derived from the surface epithelium of the ovary, which is the adult equivalent of the mesothelium of the embryonic gonad (Miillerian epithelium). There is a close relationship between epithelial tumors and the Miillerian epithelium. Serous tumors resemble the epithelium of the Fallopian tube; endometrioid and clear cell tumors resemble the endometrium; and mucinous tumors resemble the endocervical epithelium. In females, ovarian cancer accounts for 4% of cancers and 6% of cancer deaths (1). The mortality rate from ovarian cancer is higher than for cervical and endometrial cancer combined. Current treatment of ovarian cancer consists of surgery, usually followed by cisplatin-

II. Etiology Chronic administration of estrogens, progestins, and androgens has been shown to result in the formation of malignant ovarian tumors in animal studies (4-6). High levels of gonadotropins have also been correlated with ovarian neoplasms in animal experiments (7). However, most of these animal tumors arose from stromal cells and not from the epithelium. The results from several case-control and cohort studies strongly suggest that endocrine factors play an important role in human ovarian cancer. Among women with ovarian cancer, an increased incidence of nulliparity and a lower mean number of pregnancies were detected (8-12). In women with one or two children, the risk of developing ovarian cancer is reduced by about 50%, as compared to nulliparous women, and the relative risk decreases further with increasing parity. A decreased incidence of ovarian cancer was observed after the use of oral contraceptives (13-16). Women who used oral contraceptives have a 40% lower chance of developing ovarian cancer, compared to those who never used them.

Address requests for reprints to: B. R. Rao, Ph.D., Department of Endocrinology, Academisch Ziekenhuis Vrije Universiteit, De Boelelaan, 117,1081 HV Amsterdam, The Netherlands. * This work was supported by the Dutch Cancer Society and Maurits en Anna de Kock Stichting, The Netherlands.

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February, 1991

HORMONES IN OVARIAN CANCER

The protective effect of pregnancy and the use of oral contraceptives might be explained by the concept of 'incessant ovulation' (17). It was hypothesized that each ovulation causes a minor trauma of the ovarian surface by the formation of inclusion cysts. Aberrations in the repair mechanism might lead to unrestrained proliferation and neoplasia (17, 18). The risk of ovarian cancer has also been related to gonadotropin levels. High levels of gonadotropins in women in the early postmenopause have been suggested to play a role in the development of ovarian neoplasms (19, 20). This is supported by the dramatically increased incidence of ovarian cancer in women above the age of 45 yr when gonadotropins reach high levels. In this connection, elevated levels of androstenedione, the precursor of estrogen, in the postmenopausal years may also have a role in the development of ovarian cancer (21). Interestingly, in the last decade a number of case reports appeared in the literature concerning the association between induction of ovulation with gonadotropins and the development of ovarian cancer (22-24). Estrogen replacement therapy does not seem to increase the risk of developing ovarian cancer (25-27). In another study, a 40% decrease in risk of developing ovarian cancer was observed in women who used estrogens during menopause (28). An increased incidence of ovarian cancer after menopausal hormonal replacement therapy has also been reported (29), although the increased risk was not correlated with the duration of use and the doses given. A 2- to 3-fold excess of ovarian carcinoma was found in women who used diethylstilbestrol (DES) (30). In animal studies, exposure to DES in utero was found to induce cystadenocarcinoma of the ovary (31). To date, no relationship has been demonstrated between intrauterine DES exposure and ovarian cancer in humans. Epidemiological studies further suggest that ovarian cancer shares some common etiological factors with cancer of the breast and endometrium. Women with breast cancer have a 2-fold increased risk of subsequently developing ovarian cancer, while a 3- to 4-fold increase in the frequency of breast and endometrial cancer is observed in women with ovarian cancer (32-34).

III. Plasma Hormone Levels Elevated plasma levels of 17j8-estradiol, estrone, progesterone, 20a-hydroxyprogesterone, dehydroepiandrosterone (DHEA) sulfate, androstenedione, and testosterone have been observed in patients with ovarian cancer (21, 35-46). In addition, plasma levels of 17/3-estradiol, progesterone, 20a-hydroxyprogesterone, and androstenedione were found to be correlated with tumor volume and stage of disease (38, 42-45). During chemotherapy, plasma levels of these hormones decreased with the

15

concurrent reduction in tumor volume (38, 42-45). The initial levels of androstenedione and progesterone were found to be correlated with survival and tumor recurrence (38, 43). In a follow-up study of 51 ovarian cancer patients, the combination of high initial testosterone levels and a high androstenedione-albumin ratio was found to be associated with poor prognosis (46). Progesterone levels have also been related to tumor histology, showing mucinous tumors to be associated with the highest progesterone levels (40). In addition to elevated steroid hormone levels, decreased levels of LH and FSH, as compared to normal postmenopausal values, have also been observed in postmenopausal ovarian cancer patients (36, 41). Production of human CG by ovarian tumors has also been reported (47-49). Recently, it was suggested that human CG produced by the tumor might stimulate steroid production in the stromal cells (49). The hypothesis that 17/3-estradiol, progesterone, and androstenedione may be produced by ovarian tumors is supported by the increased levels of these steroids observed in the ovarian vein draining the affected ovary, as compared with the contralateral ovarian vein and the peripheral blood (35, 36, 40). The elevated levels of androstenedione and progesterone, which are both 54steroids, may result from conversion of adrenal 5-5steroids [DHEA(sulfate) and5-pregnenolone(sulfate)] or from de nouo synthesis in the tumor tissue (39). It has been demonstrated that conversion of pregnenolone and 17-a-hydroxypregnenolone to DHEA and of progesterone to androstenedione and testosterone can take place in ovarian tumors in vitro (50). Elevated estrogen levels may also result from peripheral aromatization of androstenedione (21). The results from studies of hormone levels in ovarian cancer must be analyzed with caution. Plasma testosterone levels were found to be increased in ovarian cancer patients with large tumor masses (44). The unbound fraction of the testosterone, however, was not increased. In the patients with bulky ovarian tumors, elevated levels of sex hormone binding globulin (SHBG) were also observed. This suggests that the increased testosterone levels result from higher SHBG concentrations and that testosterone bound to SHBG remains in the blood for a longer period of time. This situation results in an apparent increase in testosterone synthesis (44). The elevated levels of SHBG in ovarian cancer may be due to increased 17j8-estradiol levels, which in turn may result in an increased production of SHBG (45). Carlstrom and coworkers (39) reported an inverse correlation between total estrone levels and tumor stage. Estrone, in contrast to 170-estradiol and testosterone, does not bind to SHBG but only to albumin (51). It is well known that albumin levels are frequently decreased in advanced ovarian can-


RAO AND SLOTMAN

16

cer. As a result, estrone is conjugated and readily excreted.

IV. Endocrine Therapy In the early 1960s, new information led some workers to consider female hormones, and in particular estrogens, as possible factors in the genesis of some pelvic and breast cancers. This has resulted in the use of progestins to counteract the estrogenic action in a variety of pelvic malignancies, including ovarian cancer (52-54). In these 3 studies, 3 of 27 patients with advanced ovarian cancer showed an objective response. In most studies on the use of progestins in patients with advanced ovarian cancer, response rates of 0-15% were recorded (54-62). In some studies, however, much higher response rates were observed (63-65). This considerable variation in the reported response rates may be due to the limited number of patients in most of these studies, differences in patient selection criteria, and differences in the treatment regimens. When the results of all studies are summarized, true objective response was recorded in about 15% of the patients, with an additional 10% of patients having stabilization of disease (2). Mangioni et al. (57) concluded on the basis of a prospective randomized study that im administration of medroxyprogesterone acetate (MPA) is more effective than oral administration. In 4 studies on the use of oral MPA an average response rate of 3% was recorded (54, 55, 57, 58), while in 7 studies where MPA was administered im (56, 57, 59-61, 63) on average 17% of the patients responded (Table 1). In a study of 33 patients with advanced endometrioid ovarian cancer treated with im MPA, 18 responses (55%) were recorded (64). It must be noted, however, that 79% of these tumors were well differentiated. In the same study, 10 patients with well differentiated early stage endometrioid ovarian carcinomas were treated with MPA. Five of them had a complete response (64). Geisler (65) recorded six complete and 4 partial responses among 22 patients treated with megestrol acetate (MGA). Survival of patients who achieved a complete response was 5-36 months. Patients with partial remissions survived 4-10 months (65). Progestins have also been used in combination with estrogen, antiestrogens, and chemotherapeutic drugs. On a theoretical basis, the combination of estrogen and progestins might be more effective than progestins alone, since estrogens induce progesterone receptors and thereby facilitate progesterone to function (66). Freedman et al. (67) studied the effect of a sequential combination of MPA and ethinylestradiol in 65 patients with refractory ovarian carcinomas (67). Nine (14%) patients responded, and 13 (20%) had stable disease. The combination of progestins with antiestrogens is anticipated to

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TABLE 1. Response to treatment with MPA and MGA in advanced ovarian cancer Investigators

Ref.

Agent

Route0

Response rate

Kaufman, 1966 Malkasian et al., 1977 Bergqvist et al., 1981" Slayton et al., 1981 Mangioni et al., 1981 Mangioni et al., 1981 Aabo et al., 1982 Rendina et al., 1982 Trope et al., 1982 Hamerlynck et al., 1985 Landoni et al., 1985 Geisler, 1985 Sikic et al., 1986

(54) (55)

MPA MPA

p.o. p.o.

1/11 (9%) 1/19 (5%)

(63)

MPA

im

3/4 (75%)

(56) (57)

MPA MPA

im im

0/19 (0%) 5/33 (15%)

(57)

MPA

p.o.

0/30 (0%)

(58) (64) (59) (60)

MPA

p.o.

MPA MPA

im im im

1/27 (4%) 18/33 (55%) 1/25 (4%) 1/41 (2%)

(61) (65) (62)

MPA MGA MGA

im p.o. p.o.

9/67 (7%) 10/22 (45%) 4/47 (9%)

MPA

°p.o., Per os. 6 All stages.

result in increased progesterone receptor levels and also a better response rate (68, 69). However, in a phase II study of cyclic therapy with MPA and tamoxifen, no objective responses were recorded (70). Belinson et al. (71) investigated the effect of MGA and the combination of MGA and tamoxifen in a randomized study comprising 33 patients. No objective responses were seen. Among the 14 patients who received MGA, 3 (21%) had stable disease, while 10 (53%) of 19 patients treated with the combination regimen showed stabilization of the disease. The 2 groups did not differ as to progression-free interval (71). In another study, the effect of adding progestins and tamoxifen to a conventional cytostatic drug regimen, used as first-line therapy in patients with stage III and IV disease, showed no differences in 2-yr survival rate (72). However, the use of progestins seemed to have a beneficial effect on the quality of life and on hematological parameters (72). The synthetic antiestrogen tamoxifen has also been used as single agent therapy in the treatment of ovarian cancer (61, 73-77). Landoni et al. (61) recorded no responses among 55 patients with advanced disease treated with tamoxifen. However, 19 patients (35%) had stable disease. Similarly, in another study no objective responses were seen, but stabilization of disease was observed in 80% of 22 refractory patients treated with tamoxifen daily (75). In a study of 31 patients with recurrent disease, one complete and two partial responses were seen (77). Six patients (19%) had stable disease. Median survival was 16 months for responders and 7 months for nonresponders. In a prospective randomized study of 100 ovarian


February, 1991


cancer patients with advanced disease, no beneficial effect of the addition of tamoxifen to standard chemotherapy, consisting of cisplatin and adriamycin, could be demonstrated (78). Neither aminoglutethimide nor androgen treatment showed objective responses in patients with advanced ovarian cancer (79, 80). LHRH-agonists have also been used in the therapy of ovarian cancer (81-85). In a study of 10 women in whom agonist therapy was started after failure of chemotherapy, tumor stabilization or shrinkage was seen in 50% of the cases (82). In another study, comprising 39 patients with advanced ovarian cancer, responses were observed in 6 patients (15%), and 5 patients (13%) had stable disease (83). Kavanagh et al. (84) recorded 4 (17%) partial responses among 23 patients treated with leuprolide acetate (84). There were six patients with well differentiated tumors and 3 of them responded, while 2 other patients had stable disease (84). Jager and coworkers (85) evaluated the effect of an LHRH agonist by measuring CA125 levels. In 9 of 11 patients, in whom LHRH agonist therapy was continued for at least 3 months, stabilization of disease with a slower increase of CA125 levels, as compared to untreated controls, was observed (85). A literature review in 1988 found that a response rate of about 15% was recorded among patients treated with progestins (2). Duration of response was usually short. Stabilization of disease was seen in approximately 10% of the patients. The combination of progestins with estrogen or antiestrogen has not shown therapeutic advantages. A response rate of only 4% was noted in six studies on tamoxifen therapy. The combination of tamoxifen with chemotherapy did not result in better survival. However, other studies reported stabilization of the disease in up to 80% of the patients treated with tamoxifen. The use of LHRH agonist therapy has resulted in a response rate of approximately 15%. The modest response rates using endocrine therapy may partly be due to the fact that this therapy was often initiated after failure of other therapeutic approaches as a last resort and on an empirical basis.

V. Hormone Receptors Receptors for estrogens (ER), progesterone (PR), and androgens (AR) are present in normal ovaries, as well as in benign ovarian tumors (63, 86-95). Steroid hormone receptors have also been detected in malignant epithelial ovarian tumors (Table 2). In malignant tumors, the concentration of ER is generally found to be higher as compared to benign tumors or normal ovaries, while the concentration of PR is generally lower in malignant lesions (63, 90-93, 95).

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The criteria for positivity vary among the series listed in Table 2. Furthermore, differences in reported frequencies may be due to different assay methods, different tumor types, and the limited number of tumors studied. If the criteria of the authors are accepted and the overall frequencies are analyzed, ER are seen in 62%, PR in 49%, and AR in 69% of the malignant ovarian tumors (2). The presence of both ER and PR is seen in 36% of the ovarian carcinomas. ER without PR are found in 26% of the cases, whereas in 25% neither ER nor PR are present. The presence of PR in the absence of ER is seen in only 12% of the tumors (Table 3). Compared to ER and PR, the presence of AR has been investigated in a relatively small number of studies (Table 2). In the largest studies about 90% of the tumors were found to contain AR (115,116,124). Ovarian cancer is predominantly seen in postmenopausal women. It is known that the postmenopausal ovaries produce little or no estrogen but continue to produce androgens (127, 128). Since AR are regulated by androgens, the predominance of AR in ovarian tumors could be due to the shift in androgen to estrogen ratio in postmenopause. In ovarian tumors a local accumulation of androgens may take place, due to decreased or absent activity of the enzyme aromatase (129,130), which is involved in the conversion of androgen to estrogen. It has been demonstrated that ovarian cancers without aromatase activity are AR-positive (129). In these tumors androgens are not converted to estrogens and may influence the tumor cells through AR. In metastases or recurrences of ovarian carcinomas, steroid receptors are rarely seen when the primary tumor is receptor-negative (89, 90, 99, 102, 108, 109,112, 131). Recently, binding sites for gonadotropic hormones (132,133) and LHRH (134) have also been demonstrated in ovarian tumors. Although the presence of receptors for steroids and other hormones suggests that hormones may play a role in ovarian cancer, the biological and clinical significance of these observations remains to be elucidated.

VI. Steroid Hormone Receptors and Clinicopathological Parameters Several authors correlated the presence of steroid receptors with prognostic factors such as histology, stage, and age. In most studies, no correlation between receptor content and stage of disease could be demonstrated (96, 102, 104, 109, 113,114, 117, 118, 122, 124). The relationship between receptor content and tumor histology is less clear. Some workers found no correlation between presence of ER and histological type or grade of differentiation (89, 96, 102, 104, 109, 111, 117, 120, 122, 124, 125). Others reported endometrioid tumors to con-


RAO AND SLOTMAN

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Vol. 12, No. 1

TABLE 2. Presence of ER, PR, and AR in epithelial ovarian cancer Investigator

Ref.

n

% ER-positive

Bibro et al, 1979 Dapunt et al, 1979 Friedman et al, 1979 Janne et al, 1980 Holt et al, 1981 Hahnel et al, 1982 Quinn et al, 1982 Quinn et al, 1982 Quinn et al, 1982 Rendina et al, 1982 Schwartz et al, 1982 Ford et al, 1983 Jones et al, 1983 Kauppila et al, 1983 Leibach et al, 1983 Pollow et al, 1983 Spona et al, 1983 Teufel et al, 1983 Teufel et al, 1983 Vieriko et a/., 1983 Willcocks et al, 1983 Wurz et al, 1983 Geyer et al, 1984 Gronroos et al, 1984 Lantta, 1984 Richman et al, 1985 Schwartz et al, 1985 Schwartz et a/., 1985 Iversen et al, 1986 Sutton et al, 1986 Sutton et al, 1986 Toppila et al, 1986 Kuhnel et a/., 1987 Kiihnel et al, 1987 Anderl et al, 1988 Bizzi et al, 1988 Jakobsen et al, 1988 Nestok et a/., 1988 Masood, 1988 Friedlander et al, 1989 Slotman and Rao, 1989 Slotman et al, 1989 Harding et al, 1990 Rao et al, 1990

(96) (97) (98) (86) (99) (100) (101) (101) (101) (64) (102) (103) (104) (105) (106) (89) (107) (108) (108) (90) (91) (92) (109) (110) (93) (HI) (112) (112) (113) (114) (114) (95) (115) (116) (117) (118) (119) (120) (121) (122) (123)

29 57 34 21 29 22 37 36 31 43 30 39 42 68 21

100 51 100 71 83 45 46

(124) (125) (126)

% PR-positive

-4

32 100 38

•4

14

• \

31

•*.

32 81 53 38 83 88 62

15 43 81 62

43

72

47

68 153 150 45 49 32 171 21 50 52 113 99 31 32 20 60 94 103 51 97 37 50 31 92 20

59 63

40

52 69

82 89 34

56 53 50

tain more frequently PR, often in association with ER (98, 103, 105, 108, 114), while serous tumors were more frequently found to be ER-positive (101, 108, 118). In mucinous (101, 103, 105) and in clear cell tumors (108, 109) lower amounts of steroid receptors were detected. Nestok et al. (120) did not find a correlation between the presence of ER and PR and histological features. However, detailed analysis showed that tumors with a solid growth pattern were more frequently PR-positive and that tumors with a high degree of fibrosis and/or inflammation were frequently PR-negative (120). Some investigators found an association between positivity for ER and poor differentiation (98,108). Others found that well

% AR-positive

89 57 88 64 62 48 73 51

7

72

4

46 91 29 28 49 57 44

A

i • 31

A

-4

51

45 55 52 63 56 51 54 74 55

4

48 35 53 52 51 37 65 43 48 58 42

90 91 4

90 57 39 53

92 88

differentiated tumors more frequently contained ER (103,113) or both ER and PR (101,135). No correlation between the presence of AR and tumor histology was found (116,124). This controversy may be explained by differences in the assay methods and the criteria for positivity for steroid receptors, the fact that within one tumor the population may be heterogeneous with respect to receptor content (131,136), and the small number of cases in most studies. Furthermore, the lack of uniformity and poor reproducibility of the various grading systems in ovarian cancer (137) may contribute to this. Therefore, the assessment of more objective and reproducible tech-



February, 1991

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TABLE 3. Presence of ER and PR in combinations in epithelial ovarian cancer Investigator

Ref.

n

ER+ PR+

ER+ PR-

ERPR+

ERPR-

Janne et al., 1980 Quinn et al., 1982 Jones et al., 1983 Kauppila et al., 1983 Leibach et al., 1983 Pollow et al., 1983 Spona et al., 1983 Teufel et al., 1983 Willcocks et al., 1983 Wurz et al., 1983 Geyer et al., 1984 Lantta, 1984 Iversen et al., 1986 Toppila et al., 1986 Kuhnel et al., 1987 Bizzi et al., 1988 Jakobsen et al., 1988 Masood, 1988 Friedlander et al., 1989 Slotman et al., 1989 Harding et al., 1990

(86) (101) (104) (105) (106) (89) (107) (108) (91) (92) (109) (93) (113) (95) (115) (118) (119) (120) (122) (124) (125)

21 32 42 68 21 43 68 150 49 32 171

38 25 36 76 43 40 32 36 20 28 39

33 25 48 13 19 33 26 29 37 59 28 20 19 11 22 11 27 23 28

0 10 7 5 19 7 7 11

29 41 10 7 19 21 34 24 14 13 22 36 32 34 26 24 30 19 29 23 40

50

28

31 60 94 97 37 31 92 82 89

32 33 33 44 24 52 27 37 33

niques, such as the measurement of nuclear DNA content and morphological features in the histological examination of ovarian tumors, has been advocated (137). It has been demonstrated that the DNA content and quantitative morphological features of ovarian tumors are correlated with patient survival (138-145). Recently, we (146) as well as others (122) have demonstrated a correlation between the PR status and the nuclear DNA content. Diploid tumors are frequently PR-positive, while aneuploid tumors are frequently PR-negative. No such correlation was detected for ER and AR. However, when a cut-off value of 30 fmol/mg cytosol protein was used, we found most diploid tumors to contain high AR concentrations, while aneuploid tumors were frequently AR-negative or contained only low AR concentrations (146). The tumor steroid receptor status has also been correlated with menopausal status. ER-positive tumors are seen more often among postmenopausal women, whereas PR-positive tumors are more frequently seen in premenopausal women (92, 98, 109,114).

VII. Steroid Hormone Receptors and Prognosis In the two most common hormone-related malignancies in women, cancer of the breast and uterine corpus, it has been demonstrated that the presence of ER and PR has both prognostic and therapeutic implications (147-150). Information on the prognostic importance of steroid receptors in ovarian cancer is less known. Early reports, suggesting a relationship between presence of

20 20

8 0 11

16 16 20 19 21 19 6 15 20 7

PR and a better prognosis, were hampered by the fact that the number of cases were small and that only the patient status (dead or alive) or median survival time of receptor-positive and receptor-negative cases were evaluated (92, 107, 113, 135). We have correlated the tumor ER, PR, and AR content and aromatase activity with patient survival (124). No significant differences in survival were observed between patients whose tumors were positive and those whose tumors were negative for ER, PR, AR, and aromatase activity (124). It should be emphasized, however, that the cut-off values used for positivity of receptors in ovarian cancer are arbitrary. In general, a concentration of 10 fmol/mg cytosol protein is used as the cut-off point. For endometrial cancer and postmenopausal breast cancer, it has been demonstrated that the cut-off values for steroid receptor positivity should be much higher (50 fmol/mg) to obtain the maximum prognostic information (150-152). We also analyzed the survival data of the ovarian cancer patients using a higher cut-off point for receptor positivity and found that patients with tumor PR levels >50 fmol/mg had significantly longer survival than those with lower PR values (124). This difference could not be explained by differences in age, stage, or tumor histology between the two groups. In an extended study on the prognostic relevance of steroid receptors, comprising 100 ovarian cancer patients, with a mean follow-up period of more than 5 yr, patients with AR-positive tumors were found to have significantly longer survival than those with AR-negative tumors (153). Tumor PR content was identified as an


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independent indicator of prognosis by Cox's proportional hazards analysis. The tumor AR status, although significant in the univariate analysis, was not independently correlated with survival (153). The correlation that was found between stage of disease and AR concentration may have contributed to this. Unlike Bizzi et al. (118), we found that the tumor ER status did not correlate with survival (124, 153). Differences in patient characteristics may be responsible for this. In the group of patients studied by Bizzi and coworkers, all patients had advanced disease, 75% had serous tumors, and 63% had poorly differentiated tumors. These factors are all known to be associated with poor survival (154-156). When patients were stratified according to the amount of residual disease after laparotomy, the beneficial effect of ER positivity was only observed in the group with bulky residual disease (118). In the same study, PR was not found to be an independent prognostic factor, but in case of negativity for PR, positivity for ER had no longer a beneficial influence on survival. In our study, all stages were included and only 44% of the patients had serous tumors, while 39% of the patients had poorly differentiated tumors (153). It appears that positivity for ER is only a relevant prognostic indicator in patients with unfavorable other prognostic factors (advanced stage, poorly differentiated, serous tumors, and bulky residual disease). VIII. Steroid Hormone Receptors and Therapy It would be immensely useful to determine which patients are likely to respond to different forms of endocrine therapy. In breast cancer, it is known that about one-third of the patients with ER-positive tumors fail to respond to tamoxifen therapy, while about 10% of the patients with ER-negative tumors respond. An important difference in the treatment of cancer of the breast and ovary is that in ovarian cancer surgery is almost invariably followed by chemotherapy. In ovarian cancer endocrine therapy is only used after failure of first and second line chemotherapy (when there is progressive or recurrent disease), while in breast cancer postmenopausal woman, especially those with ER-positive tumors, frequently receive adjuvant antiestrogen treatment. As far as we are aware adjuvant endocrine therapy has never been used in ovarian cancer. In endometrioid cancer of the ovary, the presence of ER and PR is reported to be a reliable criterion in the selection of patients for progestin therapy (64). No correlation was found between response to tamoxifen therapy and the tumor ER and PR content (75, 77, 78). Agarwal and co-workers (157) reported that patients with low concentrations of ER and PR in the tumor had a better response to chemotherapy, whereas the tumors

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with high receptor levels showed a definite response to progestins in vitro. However, further studies are required to determine the correlation between receptor content and response to therapy in ovarian cancer. In these studies, not only the presence or absence of receptors should be considered, but also the receptor concentrations should be taken into account when comparing the response to therapy. Differences in results of receptor studies and in the relationship between receptor presence and response to therapy may partly be due to the fact that within one tumor the cell population can be heterogeneous for hormone binding (131,136). Probably, only the proliferation of receptor-containing cells can be influenced by a specific endocrine therapy and not the proliferation of receptor-negative cells. Another reason for the discrepancy between hormone responsiveness and receptor status of the tumor might be due to a change in the receptor phenotype of the tumor during the course of the disease. Furthermore, it must be realized that binding of the steroid to its receptor is only the first step in the complex pathway of the biological hormonal response. Since endocrine therapy is most frequently used after failure of chemotherapy, it is of importance to know the effect of chemotherapeutic agents on receptor levels. Although some found ER levels to be decreased after chemotherapy (114), others have reported that ER continues to be expressed after chemotherapy, while PR levels are decreased after chemotherapy (108, 109, 111, 114). If failure of progestin therapy is due to low concentrations of PR, induction of PR might increase response (114). Tamoxifen may increase the number of PR and decrease the number of ER. From this point of view, alternating therapy with tamoxifen and progestins might be useful (114, 158). However, as discussed previously, in a trial of 29 patients with advanced disease, no beneficial effect of this combination could be demonstrated (70). The hormonal responsiveness of ovarian cancer cells has also been investigated by in vitro cell culture techniques. It has been shown that ovarian cancer cells cultured in vitro are a suitable model for the study of this tumor (159-167). One of the agents tested is the LHRH agonist Buserelin (168). The chronic administration of LHRH agonists has recently been shown to have some effect in the treatment of ovarian cancer (81-85). However, the mechanism of action of this therapy is still unknown. It has been proposed that, apart from an effect on the hypothalamic-pituitary-gonadal axis, LHRH agonists may exert a direct cytotoxic action (169). Our findings, however, do not support the hypothesis that Buserelin exerts a direct antitumor action, since only minimal inhibitory effects


February, 1991


were observed in human ovarian and breast cancer cells at concentrations that are unlikely to be achievable in humans (168). It appears that the observed responses to chronic administration of LHRH agonists in ovarian cancer patients must be attributed to other mechanisms of action. One of these alternative mechanisms could be the reduction of gonadotropin levels. Gonadotropins may stimulate tumor cell proliferation directly via specific receptors or indirectly by influencing the steroid production in the tumor cells. Further investigations are needed to clarify this. The demonstration of AR in the vast majority of the ovarian carcinomas prompted us to investigate whether the proliferation of established ovarian cancer cell lines in vitro could be inhibited by antiandrogens. In an ARpositive cell line, a dose-dependent inhibitory effect of antiandrogens was observed (170). The proliferation of this cell line was not stimulated by androgens. However, the addition of gonadotropins resulted in increased cell proliferation. The proliferation of two AR-negative cell lines was not markedly inhibited by antiandrogens (170). The three ovarian cancer cell lines were also cultured in the presence of dihydrotestosterone for 14 weeks and, after this period, low concentrations of AR were present in all of them. Moreover, an increased sensitivity to some of the antiandrogens was observed after such a treatment (170). Culturing the AR-positive cell line in the presence of the antiandrogen flutamide for 14 weeks resulted in a decreased sensitivity to antiandrogens. Furthermore, the stimulatory effect of gonadotropins was no longer observed. These results suggest that the observed inhibitory effects in these cell lines are indeed mediated via AR, even though the measured AR levels were low (170). Furthermore, it appears that only a subpopulation of cells responds to antiandrogens, since after long term culturing with antiandrogens, the sensitivity for antiandrogens was decreased, suggesting that the surviving cells were not sensitive to these agents. The effect of the 3/3-hydroxysteroid dehydrogenase inhibitor epostane on ovarian cancer cell proliferation has also been investigated (170). The addition of epostane resulted in a significantly decreased cell proliferation in two of three ovarian cancer cell lines. The inhibitory effect of epostane increased after culturing of the cell lines in the presence of dihydrotestosterone and the detection of AR in them. Since in a number of nonovarian cancer cell lines no cytotoxic effect of epostane was observed, it is unlikely that the inhibitory effect of epostane is due to a nonspecific action. Epostane is a potent inhibitor of the enzyme 3(S-hydroxysteroid dehydrogenase, involved in the metabolism of pregnenolone to progesterone, 17a-hydroxypregnenolone to 17a-hydroxyprogesterone, and DHEA to androstenedione. Epostane effectively inhibits the synthesis of progesterone, but it

21

has also been reported that it may increase the serum levels of 17a-hydroxyprogesterone and androstenedione (171). Thus far, epostane has never been shown to have an antiandrogenic action. However, our in vitro results suggest that androgen synthesis may also be affected by epostane, although we failed to demonstrate changes in hormone levels in the culture media during epostane treatment. Alternative explanations for the observed effect of epostane include the reduction of progesterone synthesis and accumulation of 17a-hydroxyprogesterone in the tumor cells. Further investigations on the mechanism of action of epostane in ovarian cancer cells are required. Although the use of established cancer cell lines has been proven to be a useful technique in studies on the role of hormones in cancer, investigations on the effect in primary cultures might be more meaningful. We have investigated the effect of androgens, pure antiandrogens, estrogen, antiestrogen, and progesterone in 24 primary ovarian cancer cultures, initiated from ascitic fluid and tumor tissue. A dose-dependent inhibitory effect of antiandrogens was observed in about two thirds of the cultures (172). AR-positive cases more frequently responded as compared to AR-negative cases. Progesterone and tamoxifen were effective in only about 15% of the cases (172). The response to progesterone was correlated with the response to tamoxifen. Furthermore, cultures initiated from tumors of younger patients more frequently responded to these agents than tumors from older patients. Although this is suggestive for estrogenic action on tumor cell proliferation in younger patients, no correlation was observed between the in vitro response to progesterone and tamoxifen and the tumor ER and PR status. These results are in agreement with those reported by other investigators (110, 173, 174). In two cases, the culture was initiated from tumors that had persisted or recurred after chemotherapy. Neither responded to any of the agents investigated (172). Although no data on the steroid receptor status of these tumors were available, this observation tends to suggest that, in order to be effective, endocrine therapy should be used early in the course of the disease. Our results showed that about 60% of the ovarian cancers in vitro respond to antiandrogens (172). Therefore, the initiation of clinical investigations on the effect of antiandrogens in ovarian cancer patients was suggested (175). Recently, the Gynecologic Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer (EORTC) initiated a clinical trial on the effect of flutamide in advanced or recurrent ovarian cancer. In this trial, as in most studies on endocrine therapy for ovarian cancer, the effectiveness is being


RAO AND SLOTMAN

22

evaluated in patients with progressive disease after chemotherapy and in patients who cannot tolerate chemotherapy or radiotherapy. This may not be an optimal approach with which to investigate the effect of antiandrogens. Ideally, the drugs should be tested earlier in the course of the disease, e.g. in combination with initial chemotherapy, or as adjuvant treatment in patients with no or minimal residual disease at second-look laparotomy. In these studies, attempts should be made to correlate patient response with the amount of steroid receptors in the tumor and with the in vitro responsiveness to various agents, in order to develop methods to be used in the selection of the most effective therapy. An interesting new approach in this area might be the use of radiolabeled ligands for imaging and treatment of receptor-rich cancers (176-178).

IX. Conclusions and Future Prospects New approaches are needed to improve the poor survival of ovarian cancer patients. Epidemiological studies have shown that hormonal factors play a role in ovarian cancer. ER and PR are detected in about half of the ovarian cancers. The presence of both ER and PR is seen in about one third of the cases. The use of progestins and synthetic antiestrogen tamoxifen has resulted in a response rate of about 15%. This modest response rate was achieved using (anti-)hormonal agents on an empirical basis and as last resort therapy in progressive or recurrent advanced ovarian cancer. Studies on the prognostic importance of steroid hormone receptors have clearly shown a prognostic advantage of PR-positive tumors. The prognostic value of PR was found to be independent of age, stage of disease, and tumor histology. AR have been detected in the vast majority of ovarian cancers. In vitro studies on the use of pure antiandrogens in ovarian cancer have shown that two thirds of the ovarian tumors can be significantly inhibited by antiandrogens. The clinical efficacy of antiandrogens in ovarian cancer treatment is currently being investigated by the EORTC Gynecological Cancer Cooperative Group. Further investigations will also focus on the combination of various hormonal approaches. Recent results on the use of antiandrogen alone are encouraging (179). It is also worthwhile to explore the possibilities of using combined chemo-endocrine therapy. A study on the effect of combining endocrine therapy with current standard chemotherapy as first line treatment for ovarian cancer will be conducted in the near future.

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115. Kiihnel R, de Graaff J, Rao BR, Stolk JG 1987 Androgen receptor predominance in human ovarian carcinoma. J Steroid Biochem 26:393-397 116. Kiihnel R, Delemarre JFM, Rao BR, Stolk JG 1987 Correlation of multiple steroid receptors with histological type and grade in human ovarian cancer. Int J Gynecol Pathol 6:248-256 117. Anderl P, Fuith LC, Daxenbichler G, Marth C, Dapunt 0 1988 Correlation between steroid hormone receptors, histological and clinical parameters in ovarian carcinoma. Gynecol Obstet Invest 25:135-140 118. Bizzi A, Codegoni AM, Landoni F, Marelli G, Mansoni S, Spina AM, Torri W, Mangioni C 1988 Steroid receptors in epithelial ovarian carcinoma: relation to clinical parameters and survival. Cancer Res 48:6222-6226 119. Jakobsen A, Hansen V, Poulsen HS 1988 DNA profile and steroid receptor content of human ovarian cancer. Eur J Gynaecol Oncol 9:461-463 120. Nestok BR, Masood S, Lammert N 1988 Correlation of hormone receptors with histologic differentiation in ovarian carcinoma. J Fla Med Assoc 75:731-733 121. Masood S 1988 The potential value of imprint cytology in cytochemical localization of steroid hormone receptors in ovarian cancer. Diagn Cytopathol 4:42-47 122. Friedlander ML, Quinn MA, Fortune D, Foor MS, Toppila M, Hudson CN, Russell P 1989 The relationship of steroid receptor expression to nuclear DNA distribution and clinicopathological characteristics in epithelial ovarian tumors. Gynecol Oncol 32:184-190 123. Slotman BJ, Rao BR 1989 The presence of a hitherto undefined high-capacity androgen binding macromolecule in human ovarian cancer tissue. J Steroid Biochem 33:105-109 124. Slotman BJ, Kiihnel R, Rao BR, Dijkhuizen GH, De Graaff J, Stolk JG 1989 Importance of steroid receptors and aromatase activity in the prognosis of ovarian cancer: high tumor progesterone receptor levels correlate with longer survival. Gynecol Oncol 33:76-81 125. Harding M, Cowan S, Hole D, Cassidy L, Kitchener H, Davis J, Leake R 1990 Estrogen and progesterone receptors in ovarian cancer. Cancer 65:486-491 126. Rao BR, Slotman BJ, Geldof AA, Dinjens WNM 1990 Correlation between steroid receptors, tumor histology and adenosine deaminase complexing protein immunoreactivity in ovarian cancer. Int J Gynecol Pathol 9:47-54 127. Greenblatt RB, Colle ML, Mahesh VB 1976 Ovarian and adrenal steroid production in the postmenopausal woman. Obstet Gynecol 47:383-387 128. Vermeulen A 1976 The hormonal activity of the postmenopausal ovary. J Clin Endocrinol Metab 42:247-253 129. Kiihnel R, Delemarre JFM, Rao BR, Stolk JG 1986 Correlation of aromatase activity and steroid receptors in human ovarian carcinoma. Anticanctr Res 6:889-892 130. MacLusky NJ, Voit R, Lazo JS, Schwartz PE, Merino MJ, Eisenfeld AE, Naftolin F 1987 Aromatase activity in human ovarian cancer. Steroids 50:423-433 131. Quinn MA, Rome RM, Cauchi M, Fortune DW 1988 Steroid receptors and ovarian tumors: variation within primary tumors and between primary tumors and metastases. Gynecol Oncol 31:424-429 132. Kammerman S, Demopoulos RI, Raphael C, Ross J 1981 Gonadotropic hormone binding to human ovarian tumors. Hum Pathol 12:886-8% 133. Rajaniemi H, Kauppila A, Ronnberg L, Selander K, Pystynen P 1981 LH(hCG) receptor in benign and malignant tumors of human ovary. Acta Obstet Gynecol Scand [Suppl] 101:83-86 134. Emons G, Pahwa GS, Brack C, Sturm R, Oberheuser F, Knuppen R 1989 Gonadotropin releasing hormone binding sites in human epithelial ovarian carcinomata. Eur J Cancer Clin Oncol 25:215221 135. Creasman WT, Sasso RA, Weed Jr JC, McCarty Jr KS 1981 Ovarian carcinoma: histologic and clinical correlation of cytoplasmic estrogen and progesterone binding. Gynecol Oncol 12:319-327

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136. Rao BR, Meyer JS 1977 Estrogen and progestin receptors in normal and cancer tissues. In: McGuire WL, Raynaud J-P, Baulieu E-E (eds) Progress in Cancer Research and Therapy: Progesterone Receptors in Normal and Neoplastic Tissues. Raven Press, New York, vol 4:155-169 137. Baak JPA, Langley FA, Talerman A, Delemarre JFM 1987 The prognostic variability of ovarian tumor grading by different pathologists. Gynecol Oncol 27:166-172 138. Erhardt K, Auer G, Bjorkholm E, Moberger B, Silversward C, Wicksel G, Zetterberg A 1984 Prognostic significance of nuclear DNA content in serous ovarian tumors. Cancer Res 44:2198-2202 139. Friedlander ML, Hedley DW, Taylor IW, Russell P, Coates AS, Tattersall MHN 1984 Influence of cellular DNA content on survival in advanced ovarian cancer. Cancer Res 44:397-400 140. Volm M, Briiggemann A, Giinther M, Kleine W, Pfleiderer A, Vogt-Schaden M 1985 Prognostic relevance of ploidy, proliferation, and resistance-predictive tests in ovarian carcinoma. Cancer Res 45:5180-5185 141. Rodenburg CJ, Cornelisse CJ, Hermans J, Fleuren GJ 1988 DNA flow cytometry and morphometry as prognostic indicators in advanced ovarian cancer: a step forward in predicting the clinical outcome. Gynecol Oncol 29:176-187 142. Rutgers DH, Wils IS, Schaap AHP, van Lindert ACM 1987 DNA flow cytometry, histological grade, stage, and age as prognostic factors in human epithelial ovarian carcinomas. Pathol Res Pract 182:207-213 143. Baak JPA, Schipper NW, Wisse-Brekelmans ECM, Ceelen Th, Bosman FT, van Geuns H, Wils J 1988 The prognostic value of morphometrical features and cellular DNA content in cis-platin treated late ovarian cancer patients. Br J Cancer 57:503-508 144. Iversen O-E 1988 Prognostic value of the flow cytometric DNA index in human ovarian carcinoma. Cancer 61:971-975 145. Murray K, Hopwood L, Volk D, Wilson JF 1989 Cytofluorometric analysis of the DNA content in ovarian carcinoma and its relationship to patient survival. Cancer 63:2456-2460 146. Slotman BJ, Baak JPA, Rao BR 1990, Correlation between nuclear DNA content and steroid receptor status in ovarian cancer. Eur J Obstet Gynecol Reprod Biol, 38:221-227 147. McGuire WL 1980 Steroid hormone receptors in breast cancer treatment strategy. Recent Prog Horm Res 36:135-149 148. Bonomi P, Johnson P, Anderson K, Wolter J, Bunting N, Strauss A, Roseman D, Shorrey W, Economou S 1985 Primary hormonal therapy of advanced breast cancer with megestrol acetate: predictive value of estrogen receptor and progesterone receptor levels. Semin Oncol 12:48-54 149. Chambers JT, MacLusky N, Eisenfield A, Kohorn El, Lawrence R, Schwartz PE 1988 Estrogen and progestin receptor levels as prognosticated for survival in endometrial carcinoma. Gynecol Oncol 31:65-77 150. Palmer DC, Muir IM, Alexander AI, Cauchi M, Bennett RC, Quinn MA 1988 The prognostic importance of steroid receptors in endometrial carcinoma. Obstet Gynecol 72:388-393 151. Mercer RJ, Bryan RM, Bennett RC, Rennie GC, Lie TH, Morgan FJ 1984 The prognostic value of oestrogen receptors in breast cancer. Aust NZ J Surg 54:7-10 152. Quinn MA, Cauchi M, Fortune D 1985 Endometrial carcinoma: steroid receptors and response to medroxyprogesterone acetate. Gynecol Oncol 21:314-319 153. Slotman BJ, Nauta JJP, Rao BR 1990 Survival of ovarian cancer patients: apart from stage and grade, tumor progesterone receptor content is a prognostic indicator. Cancer 66:740-744 154. Barber HRK, Sommers SC, Snyder R, Kwon TH 1975 Histologic and nuclear grading and stromal reactions as indices for prognosis in ovarian cancer. Am J Obstet Gynecol 121:795-807 155. Sorbe B, Frankendal B, Veress B 1982 Importance of histologic grading in the prognosis of epithelial ovarian carcinoma. Obstet Gynecol 59:576-582 156. Malkasian Jr GD, Melton III LJ, O'Brien PC, Greene MH 1984 Prognostic significance of histologic classification and grading of epithelial malignancies of the ovary. Am J Obstet Gynecol 149:274-284 157. Agarwal N, Rao DL, Murgeshan K, Vermall U, Mittal S, Buckshee


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158. 159. 160.

161. 162.

163.

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RAO AND SLOTMAN K, Chapeker TN 1987 Clinical evaluation of steroid receptors in ovarian neoplasms. Int J Gynaecol Obstet 25:145-149 Hamilton TC, Behrens BC, Louie KG, Ozols RF 1984 Induction of progesterone receptor with 17/?-estradiol in human ovarian cancer. J Clin Endocrinol Metab 59:561-563 Woods LK, Morgan RT, Quinn LA, Moore GE, Semple TU, Stedman KE 1979 Comparison of four new cell lines from patients with adenocarcinoma of the ovary. Cancer Res 39:4449-4459 Hamilton TC, Young RC, McKoy WM, Grotzinger KR, Green JA, Cha EW, Whang-Peng J, Rogan AM, Green WR, Ozols RF 1983 Characterization of a human ovarian carcinoma cell line (NIH-OVCAR-3) with androgen and estrogen receptors. Cancer Res 43:5379-5389 Buick RN, Pullano R, Trent JM 1985 Comparative properties of five human ovarian adenocarcinoma cell lines. Cancer Res 45:3668-3676 Hill BT, Whelan RDH, Gibby EM, Sheer D, Hosking LK, Shellard SA, Pupniak HT 1987 Establishment and characterisation of three new human ovarian carcinoma cell lines and initial evaluation of their potential in experimental chemotherapy studies. Int J Cancer 39:219-225 Langdon SP, Lawrie SS, Hay FG, Hawkes MM, McDonald A, Hayward IP, Schol DJ, Hilgers J, Leonard RCF, Smyth JF 1988 Characterization and properties of nine human ovarian adenocarcinoma cell lines. Cancer Res 48:6166-6172 Hills CA, Kelland LR, Abel G, Siracky J, Wilson AP, Harrap KR 1989 Biological properties of ten human ovarian carcinoma cell lines: calibration in vitro against four platinum complexes. Br J Cancer 59:527-534 Geisinger KR, Kute TE, Pettenati MJ, Welander CE, Dennard Y, Collins LA, Berens ME 1989 Characterization of a human ovarian carcinoma cell line with estrogen and progesterone receptors. Cancer 63:280-288 Nash JD, Ozols RF, Smyth JF, Hamilton TC 1989 Estrogen and antiestrogen effects on the growth of human epithelial ovarian cancer in vitro. Obstet Gynecol 73:1009-1016 Poels LG, Jap PHK, Ramaekers FFCS, Scheres JMJC, Thomas CMG, Vooys PG, Croes HJE, Mungyer G 1989 Characterization of a hormone-producing ovarian carcinoma cell line. Gynecol Oncol 32:203-214

Vol. 12, No. 1

168. Slotman BJ, Poels LG, Rao BR 1989 A direct LHRH-agonist action on cancer cells is unlikely to be the cause of response to LHRH-agonist therapy. Anticancer Res 9:77-80 169. Miller WR, Scott WN, Morris R, Fraser HM, Sharpe RM 1985 Growth of human breast cancer cells inhibited by a luteinizing hormone-releasing hormone agonist. Nature 313:231-233 170. Slotman BJ, Rao BR 1989 Response to inhibition of androgen action of human ovarian cancer cells in vitro. Cancer Lett 45:213220 171. Crooij MJ, de Nooyer CCA, Rao BR, Berends GT, Gooren LJG, Janssens J 1988 Termination of early pregnancy by the 3/3hydroxysteroid dehydrogenase inhibitor epostane. N Engl J Med 319:813-817 172. Slotman BJ, Rao BR 1989 Primary human ovarian adenocarcinoma: response to steroids and anti-hormones in vitro. Cancer J 2:373-377 173. Runge H-M, Teufel G, Neulen J, Geyer H, Pfleiderer A 1986 In vitro responsiveness of ovarian epithelial carcinomas to endocrin therapy. Cancer Chemother Pharmacol 16:58-63 174. Schieder K, Bieglmayer Ch, Kolbl H 1989 Uber die Hormonabhangigkeit maligner Ovarialtumoren: ein In-vitro-Modell. Geburtshilfe Frauenheilkd 49:437-441 175. Rao BR, Slotman BJ 1989 Action and counter-action of hormones in human ovarian cancer. Anticancer Res 9:1005-1008 176. Lorincz MA, Holt JA, Greene GL 1985 Monoclonal antibody recognition of multiple forms of estrogen receptor tagged with [125I]methoxy-iodovinyl estradiol in ovarian carcinoma. J Clin Endocrinol Metab 61:412-417 177. Hochberg RB, MacLusky NJ, Chambers J, Eisenfeld AJ, Naftolin F, Schwartz PE 1986 Concentration of [16a-125I]iodoestradiol in human ovarian tumors in vivo and correlation with estrogen receptor content. Steroids 46:775-788 178. McLaughlin WH, Milius RA, Pillai KMR, Edasery JP, Blumenthal RD, Bloomer WD 1989 Cytotoxicity of receptor-mediated 16a-[125I]iodo-estradiol in cultured MCF-7 human breast cancer cells. J Natl Cancer Inst 81:437-440 179. Rao BR, Dijkhuizen GH, Slotman BJ Endocrine factors in ovarian cancer etiology and a rationale for considering endocrine therapy. Proceedings of the Biology and Therapy of Ovarian Cancer Conference. Marble Island Resort, VT, 1990, (abstract 12)

Endocrine Society Members In Remembrance John P. Allen, MD Leela S. Craig, MD, FACP Larry L. Ewing, PhD Norbert Freinkel, MD Masanobu Honda, MD Jerrold D. Hydovitz, MD Anthony J. Izzo, MD Richard Scott Jaeckle, MD Joseph P. Kriss, MD

*Grant W. Liddle, MD Juan Carlos Penhos, MD Rosaline V. Pitt-Rivers, PhD Ora Mendelsohn Rosen, MD Diane H. Russell, PhD Sheila F. Stewart, PhD Diana E. Van Orden, MD Frank G. Young, DSc *Past President


Risk factors for epithelial ovarian cancer in Beijing, China.

Epithelial ovarian cancer: the molecular genetics of epithelial ovarian cancer.

Characterization of fusion genes in common and rare epithelial ovarian cancer histologic subtypes.

Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC).

Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.

Skeletal Muscle Depletion and Markers for Cancer Cachexia Are Strong Prognostic Factors in Epithelial Ovarian Cancer.

Alcohol and epithelial ovarian cancer.

Epithelial ovarian cancer: An overview.

Targeted therapies in epithelial ovarian cancer.

Chemokine receptors in epithelial ovarian cancer.

CA125-response assessment in epithelial ovarian cancer.

Ha-ras polymorphisms in epithelial ovarian cancer.

Adjuvant therapy in epithelial ovarian cancer.

Growth factors in ovarian cancer.

Aetiological factors in ovarian cancer.

Estrogen signaling crosstalk: Implications for endocrine resistance in ovarian cancer.

Reproductive factors and epithelial ovarian cancer survival in the EPIC cohort study.

Recent Advancements in Prognostic Factors of Epithelial Ovarian Carcinoma.

Prognostic factors for ovarian epithelial cancer in the elderly: a case-control study.

Screening of potentially crucial genes and regulatory factors involved in epithelial ovarian cancer using microarray analysis.

Serum levels of IL-6, IL-8 and CRP as prognostic factors in epithelial ovarian cancer.

The anti-cancer effects of itraconazole in epithelial ovarian cancer.

Epithelial ovarian cancer: the role of radiotherapy.

Menstrual pain and epithelial ovarian cancer risk.