9 Sex hormones and pancreatic cancer A, K E A N D R I ~ . N - S A N D B E R G PIA LENA BACKMAN

A role for steroid hormones in pancreatic cancer development is suggested by epidemiological data. Exocrine pancreatic cancer is more common in men than in women. The male to female sex ratio in most countries lies between 1.25 and 1.75:1, and the ratio decreases with increasing age. In Sweden, this ratio is 1.75:1 below the age of 50 years and decreases with age so that there is no significant difference after the age of 70 years. A similar observation has been made in most other countries with a high incidence of pancreatic cancer (Bourhis et al, 1987). Moreover, prior oophorectomy appears to be significantly commoner in women with pancreatic cancer than in controls (Lin and Kessler, 1981). Hormonal treatment is in routine clinical use for prostatic (Torti, 1984; Waxman, 1985), breast (Hubay et al, 1984), endometrial and ovarian carcinomas (Kauppila, 1984), and there has been some success with renal carcinoma (Mukamel et al, 1984; Nakano et al, 1984). There is evidence that a similar approach may prove to be of value in the treatment of pancreatic cancer (Andr6n-Sandberg, 1986a, b; Greenway, 1987). Even if the benefit is small such an approach would be of significance given the overall prevalence of the disease and the relatively poor result achieved with current methods of treatment. OESTROGEN AND THE OESTROGEN RECEPTOR

Steroid hormone receptors were first described in 1962 by Jensen and Jacobsen in breast cancer. Since then there has been a considerable increase in the knowledge of the structure and function of these receptors. The current consensus is that steroid receptors, including the receptor of oestradiol, are present in the nucleus (King, 1989). The steroid-binding domain of the receptor is separated from the DNA-binding domain by a region called the 'hinge' domain. The oestrogen receptor is normally loosely attached to a major groove of the chromatin DNA via projections termed 'zinc' fingers. Oestradiol crosses the cell membrane by an unknown mechanism and reaches the nucleus perhaps in association with an oestrogen-binding protein, which because of its low affinity cannot be defined as a receptor. The binding of oestradiol to the steroid-binding domain leads to a much Bailli&e's Clinical Gastroenterology-Vol. 4, No. 4, December 1990 ISBN 0-7020--1470-2

941 Copyright © 1990, by Bailli~re Tindall All rights of reproduction in any form reserved

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stronger binding by the zinc fingers. This results in a range of transcription events to produce several types ofmRNA. The resulting translations produce progesterone receptor and a variety of other proteins and peptides (Rochfort et al, 1989). These oestrogen-regulated agents include: (1) classical growth factors, such as transforming growth factor o~, insulin-like growth factors I and II, fibroblast growth factors a and b and epidermal growth factor-like protein, which when secreted can activate membrane receptors on the same cells; (2) proteases such as plasminogen activator and precursors of cathepsins which stimulate cell proliferation by an unknown mechanism as well as enhance invasiveness by breaking down the extracellular matrix; (3) a variety of other partly characterized proteins of as yet unknown function. The extent to which these growth factors are involved in pancreatic cancer is discussed in this volume by Lemoine and Hall (Chapter 2). Of further interest is that the oestrogen receptor has close similarities with other soluble steroid receptors, including those for progesterone, glucocorticoid, vitamin D and retinoic acid, homologies being particularly high between the DNA-binding domains (King, 1989). Moreover, the steroid receptor homologies are similar to those of the viral oncogene v-erb A and its cellular equivalent c-erb A. This has inevitably raised questions as to the oncogenic potential of steroid receptors, particularly since c-erb A has been found to be a thyroid hormone receptor (Sap et al, 1986). Since the DNA-binding domains of this receptor family are similar there is the possibility of interaction (either competitive or synergistic) between their respective ligands at the DNA level (King, 1989). Although much of the work relating to steroids has inevitably centred on the breast, there is increasing attention on the effects of steroid hormones on the structure and function of the exocrine pancreas (Grossman et al, 1969, 1983; Beaudoin et al, 1986). Specific sex-steroid binding sites have been demonstrated in the pancreas of dogs (Sandberg and Rosenthal, 1979; Singh et al, 1986a), rats (Sandberg and Rosenthal, 1974; Rosenthal and Sanberg, 1978; Boctor et al, 1983; Singh et al, 1986b), hamsters (Saydjari et al, 1988), humans (Pousette et al, 1982, 1985) and guinea-pigs (Guo and Singh, 1989). Various effects of other steroid hormones on the exocrine pancreatic functions have also been reported (Logsdon et al, 1965; Sandberg and Rosenthal, 1979; Morisset and Jolicoeur, 1980; Gullo et al, 1982; Logsdon and Williams, 1983; Singh et al, 1987). In this chapter the detailed evidence for the involvement of oestrogens and androgens in pancreatic cancer shall be described, along with the results of clinical studies. THE INFLUENCE OF OESTROGENS ON THE EXOCRINE PANCREAS

More than twenty years ago Ullberg and Bengtsson (1963) reported increased accumulation of radiolabelled oestrogen in the exocrine part of the pancreas. Radioactively labelled oestradiol or oestriol has also been found to be selectively retained in the pancreas of male dogs, rats and

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baboons in relation to other organs including the kidney, prostate, testis, muscle and thyroid (Sandberg and Rosenthal, 1979; Grossman et al, 1983). Such selective concentration in the pancreas was unaffected by testosterone or cortisol. Using autoradiography Sandberg and Rosenthal (1974) confirmed that the oestrogen was predominantly localized in the cytosol of the acinar cells. Moreover, normal human pancreatic tissue has been shown to be capable of converting both oestrone and oestrone sulphate into the biologically active oestrogen 1713-oestradiol at a rate comparable with that of established oestrogen target tissue, such as breast cancer (Fernstad et al, 1987). Exogenous testosterone has also been found to localize selectively in the pancreas (Sandberg and Rosenthal, 1979). In 1983 Boctor and colleagues reported that the accumulation of zymogen granules which occurred after adrenalectomy in male rats was reversed by giving 17[3-oestradiol. A putative receptor for 17[3-oestradiol was also identified which was distinct from the uterine receptor. Evidence that this receptor was restricted to the exocrine pancreas was based on experiments using streptozotocine which selectively destroys islet cells but did not affect the oestrogen receptors (Grossman et al, 1985). The binding of steroid hormone to pancreatic acinar tissue requires the presence of a co-ligand (Boctor et al, 1981), one possible candidate being somatostatin (Band et al, 1983). Somatostatin, however, also inhibits the translocation of proteins into the endoplasmic reticulum which might explain how somatostatin reduces exocrine secretion. Oestrogen appears to be necessary for the synthesis of pancreatic digestive enzymes. Following adrenalectomy in male rats and adrenalectomy and oophorectomy in female rats, there is a marked depletion of zymogen granules in the acinar cells. Treatment with either triamcinolone or oestradiol reverses this effect, whilst there is no infleunce by testosterone (Grossman et al, 1983). Moreover, oestrogen administration results in decreased secretion of zinc and bicarbonate in pancreatic juice, whilst amylase and lipase are increased; in pancreatic tissue triglycerides and total lipids are increased (Sandberg and Rosenthal, 1979; Tiscornia et al, 1986a, 1986b). In contrast to the effects on pancreatic enzyme synthesis, oestrogens appear to have an inhibitory effect on pancreatic growth. Lhoste and colleagues (1987) showed that the pancreatic weight of normal male rats was 35% higher than that of normal females, even when corrected for body weight. Guo and Singh (1989) demonstrated that chronic treatment of guineapigs with oestradiol resulted in a significant reduction in pancreatic weight, and amylase content compared with that in castrated control animals, without an associated change in body weight. The pancreatic weight loss with oestradiol treatment was primarily due to reduced pancreatic growth in terms of cell numbers, as the DNA content per unit pancreatic weight was identical between treated and control groups. In contradistinction to oestrogens male gonadal hormones appear to have a trophic affect on the pancreas. Orchidectomy was found to decrease significantly pancreatic weight in male rats, which was reversed by testosterone administration (Lhoste et al, 1987). The role of corticosteroids in

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pancreatic growth is less clear. While some have shown that glucocorticoids produce an significant increase in pancreatic weight, total DNA, RNA and protein content in the rat (Morisset and Jolicoeur, 1980; Werlin and Stefanick, 1982), others have shown that corticosteroids produce a decrease in pancreatic weight, protein, DNA content (Grossman et al, 1983; Leung et al, 1987) and cell proliferation (Rail et al, 1977; Leung et al, 1987), in the same species. The action of oestrogens appears to be different and independent from that of corticoids on amylase levels in the pancreas. Beaudoin and colleagues (1986) reported that dexamethasone replacement therapy is castrated and adrenalectomized rats, partially restored the level of pancreatic amylase, whilst oestradiol had no effect on the amylase content and was associated with the presence of unusual 'halo' granules. Apparent discrepancies in some of the experimental results of the effects of steroids on the pancreas may be explained to some extent by differences in experimental design. Measurement of pancreatic weight alone without measurement of total DNA content, cannot produce useful conclusions as to pancreatic growth as the effect could be due to alteration in protein content. On the other hand, measurement of protein or amylase content alone without measurement of pancreatic weight, or DNA content, cannot be reliably interpreted as reflecting differences in enzyme synthesis (or release) as this does not exclude an effect on pancreatic growth. Of interest is that Guo and Singh (1989) have shown increased release of amylase by cholecystokinin (CCK) in oophorectomized guinea-pigs treated with oestradiol. Although the total amount of amylase released was less in the latter due to a reduction in the amount of acinar tissue, the proportional release of amylase was significantly greater. This appeared to be due to specific up-regulation of the pancreatic CCK receptors as the receptor density for vasoactive intestinal polypeptide (VIP) was unaltered. That the oestrogenic effect on the CCK receptor was organ specific was suggested by the finding of normal receptor density for both CCK and VIP in the gallbladder. The mechanism by which oestradiol mediates its multiple effects on pancreatic growth, enzyme production and release remain uncertain. At least some of these effects, however, may be due to a direct interaction of oestradiol with oestradiol-binding protein observed in the rat pancreas (Sandberg and Rosenthal, 1974; Boctor et al, 1983; Saydjari et al, 1988). OESTROGEN RECEPTORS AND OESTROGEN-BINDING PROTEINS IN THE PANCREAS

Receptors for oestrogen have been identified in pancreatic adenocarcinoma as well as the healthy pancreas of humans (Greenway et al, 1981; Andr6nSandberg et al, 1982; Petersen et al, 1986). That such receptors may be important was suggested by the finding of progesterone receptors in human pancreatic tissue (Corbishley et al, 1984) since these require activated oestrogen receptors for their expression (McGuire, 1978).

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Oestrogen-binding protein has been separated from the nuclear and the microsomal fractions of the rat pancreas and characterized by Boctor et al, (1983). It is a protein with a sedimentation constant of 4S that binds oestradiol with a high binding capacity of about 1 × 103 fmol oestradiol/mg pancreatic tissue and a low affinity with a dissociation constant, Kd > 1 riM. This oestrogen binding protein has a distinctly lower affinity, but a capacity of approximately 1 × 103 higher than that of the oestrogen receptor. Oestrogen-binding protein has been identified in a healthy pancreatic tissue of several species, including man, and also in human pancreatic cancer (Rosenthal and Sandberg, 1978; Andr6n-Sandberg et al, 1982; Pousette et al, 1982; Andr6n-Sandberg et al, unpublished). This protein has not been found in tumours nor in normal tissues other than the pancreas. Proteins of a similar size, binding steroids with a lower capacity but a higher affinity (Kd < 1 nM) are, however, characteristically present in uterine, prostatic and breast tissue (Clark et al, 1978; Panko et al, 1981). Oestrogen-binding protein from the pancreas unlike that from the uterus requires a co-ligand for maximum binding. The physiological action of pancreatic oestrogenbinding protein may also be different since it does not appear to translocate oestradiol to the nucleus, and may be involved in the process of acinar cell secretion (Boctor et al, 1983). THE INFLUENCE OF OESTROGENS IN EXPERIMENTAL PANCREATIC CANCER Evidence for a role for oestrogen in promoting pancreatic cancer comes from studies both in vivo and in vitro. Lacaine et al (1986) reported that the in vivo growth of a grafted hamster ductular pancreatic cancer cell line which binds 1713-oestradiol and dihydrotestosterone was significantly reduced in oestrogen-treated animals. Recently it has been shown that oestradiol treatment was highly effective in a dose-dependent manner in inhibiting the development and growth of preneoplastic pancreatic lesions in rats treated with azaserine (Sumi et al, 1989). In a series of in vitro experiments, Benz and co-workers (1986) compared the steroid responsiveness of four human and one rodent pancreatic tumour cell line with an oestrogen receptor-positive breast cancer cell line. They found that all four human pancreatic tumours cell lines contained measurable levels of specific oestradiol binding sites with a Kd that ranged from 1 to 9 riM, which contrasted with the higher affinity found in the breast cancer cell line, with a Ko < i nM. Growth of one of the pancreatic tumour cell lines was stimulated by about 40% following exposure to nM concentrations of oestradiol. Moreover, both glucocorticoids and androgen also stimulated the proliferation of the pancreatic tumour cell lines by as much as 30%. The growth of the other pancreatic tumour lines was inhibited by varying degrees following exposure to micromolar concentrations of oestrogen, anti-oestrogen, anti-androgen, progesterone and inhibitors of steroid-metabolizing enzymes but with little relationship to the oestrogen receptor content of the tumours. In general, progesterone was slightly more

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growth inhibiting to these pancreatic tumour lines than the other endocrine agents, including tamoxifen. An inhibitor of 5a-reductase with minimal affinity for androgen receptors inhibited the growth of the pancreatic tumour cell lines to less than 40% of controls, whereas a potent androgen receptor antagonist with no direct influence on 5a-reductase inhibited growth of two cell lines but not the others. This suggests that the steroiddependent growth-inhibitory mechanisms of some pancreatic cancers may involve both receptor antagonism and direct inhibition of steroidal oxidoreductases. In 1982 Benz et al using the oestrogen receptor expressing human pancreatic cancer cell line COLO-357 found that the binding of oestradiol to the receptor could be inhibited with diethylstilboestrol. When cytotoxic concentrations of 5-fluorouracil were combined with oestradiol, progesterone or tamoxifen there was a five-fold increase in cytotoxicity. In 1982 Wilking et al described the distribution of radioactively labelled tamoxifen given intravenously to oophorectomized mice. Rather low amounts of uptake were found in normal oestrogen target tissues, such as breast and uterus, but high concentrations of tamoxifen were detected in the lung, adrenals and pancreas. This observation coupled with the in vitro effects of tamoxifen in pancreatic cancer cells would suggest a benefit for tamoxifen in vivo. Nevertheless, tamoxifen had no effect on the growth of human pancreatic cancer xenographs in nude mice (Greenway et al, 1982a). In this study, however, neither was there any effect with the synthetic non-steroidal oestrogen stilboestrol. An analogous situation to breast cancer may pertain in which hormone manipulation with antioestrogens is much more likely if the pancreatic cancer expresses oestrogen receptor. Thus, in a recent study of xenografted human pancreatic cancer cell lines in nude mice, growth was significantly reduced by somatostatin given alone or as a combined regimen with tamoxifen (Poston et al, 1990). Also the DNA, RNA and protein content in the tumours was reduced. In one of the cell lines tamoxifen alone was effective.

ESTRAMUSTINE-BINDING PROTEIN

Estramustine is the nor-nitrogen mustard derivative of oestradiol and is an effective cytotoxic agent used for treating advanced prostatic cancer. Of particular interest is that an estramustine-binding protein has been found in human pancreatic tissue; this binds estramustine and its metabolite estromustine but not oestradiol or tamoxifen (Bj6rk et al, 1983; Andr6nSandberg, 1986b). Estramustine binds with an affinity 20 times greater than the affinity with which oestrogen-binding protein binds oestradiol. estramustine-binding protein has not been identified in other malignancies, including breast and renal cancers, malignant melanoma and, surprisingly, prostatic cancer. Recently Bj6rk et al (in press) reported that estramustine phosphate (Estracyt®), estramustine and estromustine, were bound with a relatively high affinity (Kd--~ 10nmol/1) to protein binding sites (mol. wt

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24-30 kDa) constituting 0.02 to 0.03% of total protein in the rat pancreas. Similar binding sites were present in two human pancreatic cancers that were examined but absent in the only histopathologically normal pancreas examined. THE INFLUENCE OF ANDROGENS ON PANCREATIC CANCER An androgen receptor has been tentatively identified in the rat pancreas (Pousette, 1976) and is likely to be present in human healthy and malignant pancreatic tissue (Corbishley et al, 1984). Adequate characterization of these receptors is, however, lacking. Hayashi and Katayama (1981) found that aminoquinoione-induced pancreatic tumours were increased by injections of testosterone proprionate in female and male rats following bilateral oophorectomy and orchidectomy respectively. On the other hand, oophorectomy alone gave a decreased incidence of pancreatic tumours. Similarly, Lhoste et al (1987) reported that 4 months after azaserine administration, preneoplastic atypical acinar cell loci and nodules were smaller and less numerous in female and castrated male rats, compared with intact males. Although testosterone treatment partly reversed the effect of orchidectomy, no high-affinity androgen receptors were detected. Greenway et al (1982a) reported that testosterone stimulated the growth of human pancreatic cancer xenografts in nude mice, whilst growth was inhibited by cyproterone acetate and anti-androgen. In human studies Greenway et al (1982b, 1983) reported significantly lower serum concentrations of testosterone in patients with pancreatic cancer compared with patients with benign disease or with other types of gastrointestinal cancer. Since normal or low levels of FSH and LH were also found in association with these low levels it was assumed that there might be a dysfunction of hypothalamic-hypophyseal feedback (Militello et al, 1984; Shearer et al, 1984) but this was subsequently contradicted by the finding of similar levels of FSH and LH in patients with chronic pancreatitis (Pasquali et al, 1985). Robles-Diaz et al (1986) found a low ratio of serum testosterone to 5oL-dihydrotestosterone in comparison with patients with other gastrointestinal malignancies and chronic pancreatitis and attributed this to increased 5~-reductase activity in pancreatic tumour tissue. The role of androgens and androgen receptors in human pancreatic cancer remains unclear. An alternative explanation for the reported findings relating to serum testosterone is that these are secondary to cancer cachexia rather than a primary cancer effect (Todd, 1988). CLINICAL TRIALS WITH TAMOXIFEN Four phase II clinical trials of tamoxifen treatment in patients with advanced pancreatic cancer have been published. Theve, Pousette and Carlstr6m (1983) found a mean survival of 8.5 months in 14 patients (8 women, 6 men)

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with unresectable and histologically proven adenocarcinoma of the pancreas given tamoxifen 20 mg (0 b.d). In three of the men survival extended to 22 months. The overall survival was significantly better when compared with an historical control group whose median survivial time was only 2.5 months. T6nnesen and Kamp-Jensen (1986) similarly reported a median survivial of 7 months in 10 patients (6 men, 4 women) treated with tamoxifen 10mg (0 t.d.s). Crowson et al (1986) failed to demonstrate any effect by tamoxifen. Based on serial computerized tomography studies the mean interval for disease progression was 3 months (range 1-8 months). In this study a loading dose of 160 mg tamoxifen was given followed by 40 mg (0 daily). Only one of the patients survived more than 6 months. Wong et al (1987) treated 24 patients with tamoxifen 20 mg (0 b.d). with a median survival of 7 months. In men the median survival was 4 months and in women (all of whom were postmenopausal) this was 10 months. Six of these women survived for more than 1 year and three survived for more than 2 years. There have been two phase III studies of tamoxifen treatment in pancreatic cancer published. In the prospective controlled clinical trial reported by Keating et al (1989), 108 patients with pancreatic adenocarcinoma were randomly allocated to receive daily tamoxifen 20rag, cyproterone acetate 100 mg or no active treatment. The median survival of those receiving tamoxifen was 5.3 months compared with 4.3 months for the cyproterone acetate group. There was no survival benefit for either of these groups compared with the control group which had a median survival of 3 months. Cox regression analysis of 12 clinical and biochemical features showed, not surprisingly, that for the entire group of patients survival was significantly longer in younger patients, those undergoing surgical bypass and those with better initial performance status. Adjustment for the distribution of these prognostic variables confirmed the lack of benefit in the treatment groups. In the recently published Norwegian multicentre study 173 patients with pancreatic cancer were randomized to receive tamoxifen 30 mg (0 daily) or placebo (Bakkevold et al, 1990). Treatment was continued until death or 10 months after accrual into the trial. The median survival in the tamoxifen group was 115 days compared with 122 days in the placebo group. Although there was no difference in survival between men and women, a retrospective analysis of women with stage III cancer (any T, N1, M0)the median survival was 195 days in the treatment group compared with 45 days in the control group (P = 0.011). Three women (7%) were still alive after 2.5 years in the treatment group and none in the control group; no men survived after this time. The data of the Norwegian study relating to women with stage III cancer might be conceived as supporting the view of Wong et al (1987) that tamoxifen is beneficial in postmenopausal women. It would be incorrect to do so, however, because of the inherent bias involved in retrospective subgroup analysis. To answer the question of whether tamoxifen is of benefit in postmenopausal women with pancreatic cancer will require further phase III trials.

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CONCLUSIONS

A role for oestrogens and androgens in the control of pancreatic acinar function is suggested by experimental studies as well as the finding of receptors for oestrogen, progesterone and androgen and binding proteins for oestrogen and estramustine in human pancreatic cancer. Although experimental studies have again suggested that hormonal manipulation may have a therapeutic potential in pancreatic cancer, clinical trials with tamoxifen have shown no clear benefit. Such an approach, however, should not be abandoned, particularly since pancreatic cancer has far-reaching effects on the metabolism of the host which seem to extend beyond the simple limits of tumour burden. Rather, better and more consistent characterization of these receptors and binding proteins needs to be undertaken as well as an understanding of how they relate to other growth-regulating factors and oncogenes. In so doing a more rational approach to treatment either by hormonal manipulation per se or by novel agents targeted at oestrogen-regulated proteins and peptides may be possible.

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Bourhis J, Lacaine R, Augusy M & Huguier M (1987). Protective effect of oestrogen in pancreatic cancer. Lancet ii: 977. Clark JH, Hardin JW, Upchurch S & Eriksson H (1978) Heterogenity of estrogen binding sites in the cytosol of the rat uterus. Journal of Biological Chemistry 253: 7630-7634. Corbishley TP, Iqbal M J, Johnson PJ & Williams R (1984) Progesterone receptors in malignant and foetal pancreatic tissue. IRCS Medical Science 12: 575-583. Crowson MC, Dorrell A, Rolfe EB & Fielding JW (1986) A phase II study to evaluate tamoxifen in pancreatic adenocarcinoma. European Journal of Surgical Oncology 12: 335-336. Fernstad R, Pousette ~, & Carlstr6m K (1987) Metabolism of esterone sulfate by normal human pancreatic tissue in vitro. Scandinavian Journal of Gastroenterology 22: 644-648. Greenway BA (1987) Carcinoma of the exocrine pancreas: a sex hormone responsive tumour? British Journal of Surgery 74: 441-442. Greenway B, Iqbal MJ, Johnsson PJ & Williams R (1981) Oestrogen receptor protein in malignant and fetal pancreas. British Medical Journal 283: 751-755. Greenway B, Duke D, Pym B, Iqbal MJ, Johnson PJ & Williams R (1982a) The control of human pancreatic adenocarcinoma xenografts in nude mice by hormone therapy. British Journal of Surgery 69: 595-597. Greenway B, Iqbal M J, Johnson PJ & Williams R (1982b) Serum sex-steroid concentrations in patients with pancreatic carcinoma. British Journal of Surgery 69: 293-296. Greenway B, Iqbal MJ, Johnson PJ & Williams R (1983) Low serum testosterone concentrations in patients with carcinoma of the pancreas. British Medical Journal 286: 93-95. Grieg RG & Schein PS (1986) Therapy of gastrointestinal cancer. In Polack JM, Bloom SR, Wright NA, Butler AG (eds) Basic Science in Gastroenterology. Diseases of the Gut, pp 329-345. Herts, UK: Glaxo Group Research. Grossman A, Boctor AM & Lane B (1969) Dependence of pancreatic integrity on adrenal and ovarian secretions. Endocrinology 85: 956-959. Grossman A, Boctor AM, Band P & Lane B (1983) Role of steroids in secretion-modulating effect of triamcinolone and estradiol on protein synthesis and secretion from the rat exocrine pancreas. Journal of Steroid Biochemistry 19: 1069-1081. Grossman A, Richardson SB, Altszuler N & Lane B (1985) Evidence that the (3)H-oestradiol binding protein in pancreas is localized in the exocrine cells. Endocrinology 116: 22212226. Gullo L, Priori P & Labo G (1982) Influence of adrenal cortex on exocrine pancreatic function. Gastroenterology 83: 92-96. Guo YS & Singh P (1989) Effect of estradiol on pancreatic amylase and cholecystokinin binding in ovariectomized guinea pigs. Journal of Steroid Biochemistry 33: 459-464. Hayashi Y & Katayama H (1981) Promoting effect of testosterone propionate on experimental exocrine pancreatic tumors by 4-hydroxyaminoquinoline-l-oxide in rats. Toxicological Letters 9: 349-354. Hubay CA, Arafah B, Gordon NH, Guyton SP & Crowe JP (1984) Hormone receptors. An update and application. Surgical Clinics of North America 64: 1155-1172. Hudd C, LaRegina M, Palmer D, Herbold D, Devine J & Johnson F (1985) Effect of cholecystokinin (CCK) on growth and metabolism of human pancreatic and gastric carcinoma in nude mice. Proceedings of the Annual Meeting of the American Society of Clinical Oncology 4: 218. Jensen EV & Jacobson HI (1962) Basic guides to the mechanism of estrogen action. Recent Progress in Hormone Research 18: 387-392. Kauppila A (1984) Protestin therapy of endometrial, breast and ovarian carcinoma. A review of clinical observations. Acta Obstetricia et Gynecologica Scandinavica 63: 441-450. Keating J J, Johnson PJ & Cochrane AMG (1989) A prospective randomized controlled trial of tamoxifen and cyproterone acetate in pancreatic carcinoma. British Journal of Cancer 60: 789-792. King RJB (1989) Oestrogen receptors: advances in their structure and function. In Berk JS (ed.) Oestrogen and the human breast. Proceedings of the Royal Society of Edinburgh 95B: 133-144. Lacaine F, Houry S, Clough K, Lointier P & Huguier M (1986) Is pancreatic tumor growth inhibited by sex steroid hormones? An experimental study in hamster (meeting abstract). Digestive Disease and Sciences 31: 68S.

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