Effects of Cancer Chemotherapeutic Agents on Endocrine Organs and Serum Levels of Estrogens, Progesterone, Prolactin, and Luteinizing Hormone'

[CANCER RESEARCH 35, 1975-1980, August 1975]

Eric V. H. Kuo, Henry J. Esber, D. Jane Taylor, and Arthur E. Bogden

Department oflmmunobiology, Mason ResearchInstitute, Worcester,Massachusetts01608[E. Y. H. K., H. J. E., A. E. B.], and Division of Cancer Biology and Diagnosis,National CancerInstitute, Bethesda,Maryland 21.Xfl4[D.J. T.]

SUMMARY INTRODUCTION

The effects of the following cancer chemotherapeutic Many types ofneoplasms, both spontaneous and induced, agents on serum hormonal levels, estrous cycles, and are known to arise in the various endocrine organs as well as endocrine organs were studied in mature, normal in the target tissues of hormones. The growth of tumors Sprague-Dawley rats by radioimmunoassay, vaginal smear arising in endocrine-responsive tissues is frequently found to examination, and organ weight end point: estradiol mustard be hormone dependent or at least hormone responsive. (NSC 112259), testosterone mustard (NSC I 12260), phen Recent studies (9, 11) on gs antigen expression have estrin (NSC 104469), methotrexate (NSC 740), 5-fluo produced evidence suggesting that certain hormones may rouracil (NSC 19893), vinblastine (NSC 49842), vincristine also play a role in activating the oncogenic expression of (NSC 67574), nitrogen mustard (NSC 762), and l,3-bis(2- some RNA tumor virus genomes. While hormonal effects chloroethyl)-l-nitrosourea (NSC 409962). Following 2 are often associated with stimulation of tumor growth, an weeks of treatment, estradiol-17fi levels were markedly inhibitory effect on tumor growth may also be exerted by elevated by all compounds except testosterone mustard and hormones (14, 24). The use of androgens and estrogens in nitrogen mustard, which caused a decrease. Estrone levels the therapy of human prostatic and mammary cancers are were elevated by methotrexate, 5-fluorouracil, vinblastine, classical examples of such effects. vincristine, nitrogen mustard, and 1,3-bis(2-chloroethyl)-l - Since nonhormonal chemotherapeutic agents have been nitrosourea, but were lowered by estradiol mustard. Proges found to inhibit various hormone responsive neoplasms also terone levels were elevated only by estradiol mustard and (14, 24), it is a logical extrapolation to assume that, in testosterone mustard and were not affected by other corn addition to their direct effects on tumor cells, they may pounds. Prolactin surge during proestrus was suppressed by exert significant effects on the endocrine system of treated phenesterin and methotrexate. Luteinizing hormone levels subjects. For example, depression of ovarian function has were lowered by methotrexate and nitrogen mustard. Es been reported for myleran and N,N',Nâ€•-triethylenethio trous cycles of rats treated with estradiol mustard were phosphoramide in addition to their antitumor activity (8, arrested at proestrus, and the uterine and pituitary weights 20). However, relatively little information is available con of these rats markedly increased. Uterine weight loss was cerning the changes in endocrine organs, and especially in significant following treatment with testosterone mustard, serum hormonal levels, in response to treatment with 5-fluorouracil, and nitrogen mustard. Thyroid weight was chemotherapeutic agents. Such information is necessary reduced by all compounds except methotrexate and vinblas if the actions of chemotherapeutic agents are to be fully tine. Significant increases in pituitary weights occurred understood and exploited effectively in planning drug corn following treatment with all compounds except l,3-bis(2- binations and therapeutic modalities to be used in the chloroethyl)-l-nitrosourea. The effects on ovarian and adre therapy ofcancers arising in hormone-responsive tissues. nal weights were minimal although significant by some As I facet of a research effort designed to determine the compounds. Thus, in addition to their direct antiturnor chemotherapy responsiveness of animal mammary tumor effects, these agents also produce changes in endocrine models, 9 representative anticancer chemotherapeutic system which may be synergistic or antagonistic to the agents were tested in female rats to determine their effects chemotherapy of endocrine-responsive neoplasms. on the estrous cycle, the endocrine organs, and the serum levels of PRL,2 LH, E1, E3, and PRG. The results of these tests are presented in this report.

1 This study was supported by Contract NOI-CB-50006 from Breast Cancer Program Coordinating Branch, Division of Cancer Biology and 2Theabbreviationsusedare:PRL, prolactin;LH, luteinizinghormone; Diagnosis, National Cancer Institute. An abstract of this study has been 5-FU, 5-fluorouracil; BCNU, l,3-bis(2-chloroethyl)- 1-nitrosourea; E,, published (15). estrone; E,, estradiol-l7@; PRG, progesterone; ACTH, adrenocortico Received February 24, 1975; accepted April 14, 1975. tropic hormone.

AUGUST 1975 1975

MATERIALS AND METHODS Antimetabolites. (a) Methotrexate (NSC 740), N-[p-[(2,4- diamine-6-pteridinyl)methyl]methylamino@benzoyl glu Experimental Animals. Forty-five ARS-Sprague-Dawley tamic acid, 0.2 mg/kg, 3 times weekly, p.o.; (b) 5-FU (NSC stock female rats, 100 days of age, were used for the control 19893), 25 mg/kg/day, p.o. and for each compound tested. Animals were housed in an Vinca Alkaloids. (a) Vinblastine (NSC 49842), yin environment with controlled light and dark cycles of 12 hr caleukoblastine sulfate, 0.05 mg/kg/day, s.c.; (b) vincris and were maintained on a regular diet of Wayne Lab Blox tine (NSC 67574), leucocristine sulfate, 0.02 mg/kg/day, (Allied Mills Inc., Chicago, Ill.) and tap water ad !ibitum. s.c. Upon arrival at this laboratory, rats were numbered and Alkylating Agents. (a) Nitrogen mustard (NSC 762), allowed to acclimatize to the environment for I week before methylbis(2-chloroethyl)amine, or mechlorethamine hydro being placed on test. Body weights were recorded 3 times chloride, 0. 1 mg/kg/day, s.c.; (b) BCNU (NSC 409962), weekly, and animals showing signs of respiratory infection 0.2 mg/kg/day, s.c. or weight loss were excluded from the experiment. Radioimmunoassays of PRL and LH Estrous Cycle Observation, Drug Treatment, and Serum Collection The methods for radioiodination of rat PRL and LH, and the double antibody radioimmunoassay used in this study, The estrous cycles of each rat were followed by daily have been reported in detail elsewhere ( 16). Hormones and examination of its vaginal smear between 2:00 to 5:00 p.m. antihormone sera were kindly provided by the National for 10 days prior to the initiation of drug treatment. Rats Institute of Arthritis and Metabolic Diseases as rat PRL that did not exhibit regular cycling were excluded from the and rat LH radioimmunoassay kits which included purified experiment. Daily determination of the estrous stage for hormone for radioiodination (NIAMD-Rat Prolactin-I-l each rat was continued during the treatment period. and NIAMD-Rat LH-I-2), reference preparation to be used Chemotherapy was initiated on Day 11. Compounds were for standards (NIAMD-Rat Prolactin-RP-l and NIAMD administered in the morning over a 14-day period, either s.c. Rat LH-RP-l) and antihormone sera (NIAMD-Anti-Rat or p.o., and either daily or 3 times weekly (Monday, Prolactin Serum-I and NIAMD-Anti-Rat LH Serum-l). Wednesday, and Friday). On the last day of treatment, Goat anti-rabbit â€˜y-globulin, obtained from Antibodies, between 2:00 and 5:00 p.m., following determination of Inc., Davis, Calif., was used as the 2nd antibody. Purified estrous stages, all rats were sacrificed. In order to minimize hormones were radioiodinated with 1311in this laboratory. the effect of stress on hormonal levels, rats were gently removed from the cage and quickly decapitated for blood collection. Blood was allowed to clot at 4Â°for at least I hr Radioimmunoassays of Estrogens and Progesterone and then centrifuged to separate serum. Since the quantity of serum obtainable from each individual rat was not To each 2-mI serum sample, 1000 cpm of tritiated E1, E2, sufficient for the simultaneous measurement of 5 hormones and PRG were added for recovery estimation. The serum (PRL, LH, E1, E2, and PRG), the sera from 2 to 4 rats in was then extracted 3 times with 5 volumes of cold diethyl the same estrous stage were pooled and stored at â€”20Â°. ether from a freshly opened can. The ether layer was Subsequently, hormonal levels were determined on these recovered, washed once with distilled water, and evaporated pools and their mean values were calculated. to dryness under a stream of nitrogen. The residue was Immediately after exsanguination, the pituitary, ovaries, dissolved in benzene:methanol (9:1) and applied to Sepha uterus, adrenals, and thyroids were removed from each rat dcx LH-20 microcolumns for chromatographic separation and examined for gross morphological changes, and weights of the different steroids according to a modification of the were recorded. The organ weights were then converted to procedure described by M ikhail et a!. ( 17) and by Murphy mg/ 100 g body weight. (1 9). The different chromatographic fractions containing E1, E2, and PRG were dried down under nitrogen and resuspended in absolute ethanol. E1, E3, and PRG were CompoundsTested, Dose Levels, andTreatment Regimens3 quantitated by radioimmunoassay procedures patterned after the methods reported by Abraham (1), Knobil (13), Steroid Alkylating Agents. (a) Estradiol mustard (NSC and Abraham et a!. (2), respectively. The antiserum to E3 112259), estra- I,3,5( I0)-triene-3, I7$-diol, bis@p-[bis(2- was kindly provided by Dr. B. V. Caldwell of Yale chloroethyl)amino]phenyl$acetate, 5 mg/kg, 3 times University School of Medicine, New Haven, Conn. weekly, p.o.; (b) testosterone mustard (NSC I 12260), an drost-5-en- I 7-one, 3f3-hydroxy@p-[bis(2-ch1oroethyl)- amino]phenyflacetate, 10 mg/kg, 3 times weekly, p.o.; (c) RESULTS phenesterin (NSC I04469) (cholest-5-en-3$-ol@p-[bis(2- chloroethyl)aminoJphenyl@acetate, 10 mg/kg, 3 times weekly, p.o. Summarized in Table 1 are the results showing the effect of chemotherapeutic agents on the relative wet weights of

$ Chemotherapeutic agents were obtained from the Division of Cancer endocrine organs with respect to final body weight. The Biology and Diagnosis of the National Cancer Institute. effects of treatment on the estrous cycles and the serum

I976 CANCER RESEARCH VOL. 35

Effects ofAntitumor Agents on Endocrine System

Table I Efftct of chemotherapeutic agents on body and endocrine organ weights Organ weights were recorded at sacrifice following 2 weeks of treatment, as described in text. Each value represents mean, or mean Â±S.D. of 45 rats.

(mg)UterusOvaryThyroidPituitaryAdrenalControl wt/ I00 g of final body wt

Test compoundFBW:IBWaOrgan

Â±41.2 Â±6.0 Â±17.5 Â±1.3 Â±3.4 Estradiol 0.97 239.3 Â±30.8Â° 45.9 Â±6.2 22.4 Â±9.3k' 7.8 Â±0.9Â° 33.0 Â±5.0â€• mustard Testosterone 0.97 150.2 Â±31.8Â° 43.2 Â±6.6 40.2 Â±13.5Â° 5.3 Â±0.8Â° 28.4 Â±3.9 mustard Phenesterin 0.99 178.9 Â±32.3 43.0 Â±5.3 69.1 Â±16.5Â° 5.1 Â±0.8Â° 29.9 Â±3.9Â° Methotrexate 1.03 197.1 Â±43.2c 49.7Â±5.1â€• 100.0Â±17.0â€• 5.9Â±0.7Â° 29.9 Â±3.2Â° 5-FU 0.97 161.8Â±36.lc 38.5 Â±5.3Â° 21.9Â±5.2Â° 5.1 Â±1.0â€• 27.3Â±3.8 Vinblastine 1.01 179.9 Â±37.6 44.1 Â±5.3 81.9 Â±14.3 5.5 Â±0.9â€• 27.8 Â±3.4 Vincristine 1.02 174.9 Â±37.9 41.5 Â±5â€¢4c 66.0 Â±17.4Â° 5.1 Â±0.8Â° 27.8 Â±3.8 Nitrogen 0.91 136.5Â±46.0Â° 4l.0Â±5.8c 51.4Â± 13.9Â° 5.0Â±0.8Â° 29.0Â±3.5c mustard BCNU1.02 1.00178.6177.0Â±46.343.9 45.2Â±8.478.4 70.5Â±25.6Â°4.1 4.5Â±1.027.3 30.7Â±7.6Â° aRatiooffinalbodyweighttoinitialbodyweight.

S Significant difference (p < 0.01) from the control.

C Significant difference (p < 0.05) from the control.

@50 0 final body weight to initial body weight reflect little change hi,, 116 in body weights of these animals as a result of treatment, indicating little or no drug toxicity. @ 0 ..-...â€˜.,.@â€˜...... @.,. ....â€˜â€”â€˜ Estradiol Mustard (NSC 112259). Treatment with this [1@ compound produced a significant increase in uterine, pitui 440 400 tary, and adrenal weights, and a marked decrease in thyroid 360 weight. No significant change in ovarian weight was ob 320 served. Examination of vaginal smears showed that all rats @ 260 â€”200 failed to cycle and remained in proestrus during the latter @ 180 part of the treatment period. Radioimmunoassay of serum 20 80 hormonal levels revealed an extremely high E2, a lowered 40 E1, and high PRL and PRG levels. No significant change occurred in LH levels. 240 Testosterone Mustard (NSC 112260). Treatment with this 220 200 compound caused a mild decrease in relative uterine weight, II 8060 a marked decrease in thyroid weight, and a slight increase in F 40 pituitary weight. Ovarian and adrenal weights were not @ 120 @ 00 affected. The treated rats were able to proceed with their @ 80 estrous cycling. No significant changes occurred in serum @e0 40 LH and PRG levels. In contrast to the very high E2:E1 20 ratios observed following administration of estradiol mus @ L@ PEMO PEPVV â€˜PEMO â€˜PEMO PEMO p@p@ â€˜PEMD PEMO â€˜PEMO PEMO' tard, treatment with testosterone mustard resulted in a lowered E2:E1 ratio. Serum E2 levels were lowered, and @o a ! @ d a@ @- 1;; serum E1 and PRG levels were increased above control levels. @ U W@ i Phenesterin (NSC 104469). No significant changes in Chart I . Effect of chemotherapeutic agents on estrous cycle and serum ovarian and uterine weights were observed following the levels of prolactin and luteinizing hormone in the rat. P. E. M, and D, administration of this compound. There was, however, a proestrus, estrus, metestrus and diestrus, respectively. Numbers above bars, number of serum pools obtained from rats at each estrous stage. slight increase in adrenal and pituitary weights and a slight Hormonal levels of these pools were determined by radioimmunoassay and decrease in thyroid weight. The number of rats in estrus their mean values were plotted. ND, not determined. increased and that in metestrus decreased, suggesting a prolongation in the duration of estrus. There were increases hormonal levels are illustrated in Charts I and 2. An overall both in serum E1 and E2 levels. summary of the results is also presented in Table 2. Methotrexate (NSC 740). Administration of methotrex Except in the case of nitrogen mustard treatment, which ate seemed to be stimulatory to all endocrine organs caused a significant decrease in body weight, the ratios of measured, causing a mild increase in the relative weights of

AUGUST 1975 I977

E. Y. H. Kuo et a!.

the ovaries, uterus, thyroid, adrenals, and pituitary. The were considerably higher than the levels found in the control number of rats at proestrus increased, but the serum PRL group. levels at proestrus and the serum LH levels at all estrous 5-FU (NSC 19893). Moderate decreases in ovarian and stages were lower than those of the control group. No uterine weights and a very marked decrease in thyroid change was seen in the serum PRG level, but both E1 and E3 weight were observed following treatment with 5-FU. Both E1 and E2 levels were several times higher in these treated 220 animals than in those in the control group. As a result of the 200 ieo higher E1 and E2 levels, greater numbers of rats were at @ieo proestrus or estrous stages on the day of sacrifice. @l40 ,g120 @1@@ Vinblastine (NSC 49842) and Vincristine (NSC 67574). Wloo The only organ affected by vinblastine was the pituitary, g eo @eo which showed a mild weight increase. Vincristine, on the U 40 other hand, caused a mild decrease in thyroid weight and a 20 L slight increase in pituitary weight. Vinblastine caused a 2- to @ II .., hiftifirâ€¢____, 5-fold increase in serum E1 and a 3- to 5-fold increase in 4200 kÂ°@ serum E2 during metestrus-diestrus stages and, interest 200 ingly, caused decreases in both serum E1 and E2 levels at I80 I leo proestrous stage. However, the number of rats reaching @ 140 proestrus and estrus increased, compared with the control 120 group. Vincristine, on the other hand, caused a 2- to 5-fold @I00 increase in serum E1 at all estrous stages and a 4- to 10-fold @ 60 increase in serum E2 at proestrus and estrus. Despite such lii 40 20 marked increases in serum E1 and E2 levels, uterine growth and the PRL surge at proestrus were not stimulated, and there was no increase in ovarian weight. Similar results were leo also observed in the group treated with 5-FU. 40 30 Nitrogen Mustard (NSC 762). Administration of this 20 prototype alkylating agent caused marked decreases in 10 uterine and thyroid weights, an effect similar to that PEMD â€˜PEMD â€˜PEMO â€˜PEMD â€˜PEMO â€˜ MO' ,.tan., - â€˜-câ€•L'- P.t@i) - produced by the testosterone mustard. In addition, it caused z Uz a slight decrease in ovarian weight and a slight increase in

4 U) adrenal weight. Serum PRL and PRG levels and the cycling @ -I @ 9- z pattern of the treated animals were apparently not affected. a @, 5 > @ ft iI@ Serum LH and E2 levels were markedly lowered and the Chart 2. Effect of chemotherapeutic agents on serum levels of estrone, serum E1 level was greatly elevated. estradiol-17fl and progesterone in the rat. P, E. M, and D, proestrus, estrus, metestrus, and diestrus, respectively. Each plotted value represents BCNU (NSC 409962). Treatment with this alkylating the mean hormonal level of the serum pools obtained from rats at each agent caused only a slight decrease in thyroid weight and a estrous stage. The number of serum pools for each estrous stage is slight increase in adrenal weight. However, its effect on indicated in Chart I . ND, not determined. serum estrogen levels was quite marked: E1 was elevated 2-

Table 2 Summary of the effects of chemotherapeutic agents on serum hormonal levels and endocrine organ weights

wtE2E1PRGPRLÂ°LHUterusOvaryThyroidPituitaryAdrenalEstradiolSerumhormonal levelOrgan wt/unit body

mustard

Testosterone â€” 0 + 0 0 â€” 0 â€” + 0 mustard

Phenesterin + 0 0 â€” 0 0 0 â€” + + Methotrexate + + 0 â€” â€” + + + + + 5-FU + + 0 0 0 â€” â€” â€” + 0 Vinblastine + + 0 0 0 0 0 0 + 0 Vincristine + + 0 0 0 0 â€” â€” + 0 Nitrogen â€” + 0 0 â€” â€” â€” â€” + + mustard BCNU+Â° +â€” ++ 00 00 0+ 00 0â€” -+ 0+ +

a Only the proestrous surge ofserum PRL level ofeach treated group was compared with that ofthe control.

Â° + and â€” , hormonal levels and organ weights significantly higher or lower, respectively, than the control. 0, no significant difference from the control.

I978 CANCER RESEARCH VOL. 35

to 5-fold, and E2 was elevated 2- to 10-fold during the van tested. Interestingly, methotrexate was, again, the only ous estnous stages, compared with the serum estrogen levels compound that exerted a stimulatory effect on the thyroid. in the control group. As a result, the number of rats in es Although serum levels of thyroid hormones were not trus was double that of the control group on the day of measured in this study, it was unlikely that the treated sacrifice. The serum levels of LH and PRG were not sig animals could have maintained the same concentrations of nificantly affected, but the PRL surge at proestrus was thyroid hormones in their blood after their thyroids were lower than that of the control. These results are rather reduced to less than one-third of their normal sizes. Recent similar to those produced by 5-FU, which is an anti in vitro (22, 25) studies have shown that thyroid secretion @ metabolite, and are in contrast to the results produced by from mouse thyro glands in response to thyroid-stimu another alkylating agent, nitrogen mustard, which caused lating hormone was inhibited by colchicine and vinblastine. only E1 increase. This observation was confirmed by in vivo studies (4) that showed that vinblastine caused an inhibition of the thyroid DISCUSSION stimulating hormone-induced endocytosis ofthe thyroid and the release of thyroid hormone. Table 2 summarizes the effects of chemothenapeutic Hypothyroid condition has been found to increase the agents on serum hormonal levels and organ weights. Of the incidence of 7, 12-dimethylbenzanthracene-induced rat 9 compounds tested, 7 increased serum E2 levels, 6 elevated mammary tumors (5, 21). It has also been found to be serum E1 levels, 8 stimulated pituitary weights, 7 markedly associated with massive virginal breast hypertrophy (10) decreased thyroid weights, and 5 increased adrenal weights. and breast cancer in humans (3). In estrogen-primed rats, These results clearly indicate that chemotherapeutic agents, thyroidectomy induced a marked stimulation of mammary both hormonal and nonhormonal in nature, produce various development which was completely suppressed by replace degrees of changes in the endocrine system of treated ment doses ofthyroxin (18). In view ofthese findings, it may subjects. he of value to attempt to determine, experimentally and It is of interest to note that all tested compounds except clinically, whether the thyroid suppression produced by testosterone mustard caused increases in serum levels of these drugs reduces their anti-mammary tumor efficacy, either E2, E1, or both. Judging from the lack of increase in and if so, whether such undesirable effect can be overcome ovarian weight following treatment with most compounds, by the addition of thyroxine to the treatment regimen to it can be speculated that the increases in serum estrogen prevent possible mammary stimulation due to thyroid levels were probably not the results of increased ovarian suppression. secretion of estrogens but, rather, were due to a generalized Although small in magnitude, adrenal weights were decrease in estrogen utilization by target tissues, resulting in stimulated by 5 compounds. It is not known whether these the accumulation of circulating estrogens. This view is weight increases were due to direct drug effect, the effect of supported by the absence of uterotropic effect following stress, or to the elevated serum estrogen levels. In this treatment with most compounds, despite the increased respect, estrogen has been clearly shown to stimulate serum levels of estrogens, which are known to stimulate ACTH release from the pituitary and a simultaneous uterine growth. In fact, treatment with 5-FU suppressed increase in adrenal weight (12). Also unclear is whether the uterine weight while serum levels of both E1 and E2 were significant increases in pituitary weights following treat elevated. These results suggest that one of the anticancer ments with 8 of the 9 compounds were direct drug effects or activities of these compounds may lie in their ability to the result of hormonal interaction. A practical concern is interfere with the uptake of estrogens by target tissues. A whether these pituitary weight increases were accompanied recent work by Everson et a!. (6) has clearly shown that by an increased ACTH release and subsequent stimulation estradiol mustard inhibits the binding of tnitiated E2 to its on adrenals, resulting in elevated levels of glucocorticoid receptors in rat uterine cytosol. hormones. This concern is prompted by a recent report (7) Two exceptions were estradiol mustard and methotrex that glucocorticoids enhanced the replication in vitro of ate, which stimulated uterine growth. Being an estrogen mouse mammary tumor virus. The adrenal stimulation analog itself, estradiol mustard apparently exerted a direct observed in the present study suggests that ACTH release uterotrophic effect (23), resulting in an increase in uterine may have been stimulated by some compounds. However, weight while ovarian weight remained unchanged. Thus, further studies that measure the changes in ACTH and methotrexate was the only compound that produced a glucocorticoids are necessary to verify such therapeutic normal pattern of stimulatory effects, namely, increased effects. ovarian weight, elevated serum estrogen levels, increased uterine weight, and a suppressed serum LH level. Of the endocrine organs examined, the greatest change in REFERENCES organ weight following treatment was observed in the thyroid. For example, administration of estradiol mustard I. Abraham, G. E. Solid-phase Radioimmunoassay of Estradiol-l7beta. and 5-FU reduced the thyroid weights (mg/kg body weight) J. Clin. Endocrinol. Metab., 29: 866â€”870, 1969. to 22.4 Â±9.3 and 21.9 Â±5.2, respectively, compared with 2. Abraham, G. E., Swerdloff, R., Tulchinsky, D., and Odell, W. D. 78.4 Â± 17.5 for the control group. Substantial decreases in Radioimmunoassay of Plasma Progesterone. J. Clin. 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Eric Y. H. Kuo, Henry J. Esber, D. Jane Taylor, et al.

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