THE INFLUENCE OF PITUITARY HORMONES ON ADJUVANT ARTHRITIS ISTVAN BERCZI, EVA NAGY, SYLVIA L. ASA, and KALMAN KOVACS Adjuvant arthritis was induced in female Fisher rats by injecting their right hind paw with 0.1 ml Freund’s complete adjuvant. The development of adjuvant arthritis was inhibited by hypophysectomy and by daily treatment of intact animals with the dopaminergic agent bromocriptine. Adjuvant arthritis developed normally if hypophysectomized or bromocriptine-suppressed animals were treated with either prolactin or growth hormone. Additional treatment with adrenocorticottopic hormone inhibited this restoration. Treatment of hypophysectomized rats with follicle-stimulating hormone, luteinizing hormone, aud thyroidstimulating hormone had no effect. These results indicate that prolactin and/or growth hormone are necessary for the development of adjuvant arthritis, whereas adrenocorticotropic hormone has an inhibitory effect. Women are more prone to autoimmune disease than men. Approximately 90% of patients with systemic lupus erythematosus (SLE) are female (1). Rheumatoid arthritis (RA) is 2-3 times more frequent From the University of Manitoba. Winnipeg. Manitoba, Canada and the University of Toronto, Toronto. Ontario, Canada. Supported by the Arthritis Society of Canada. Dr. Asa is a Fellow of the Medical Rescarch Council. Istvan Berczi, DVM, PhD: Department of Immunology, Faculty of Medicine, University of Manitoba; Eva Nagy, MD: Department of Immunology. Faculty of Medicine. University of Manitoba; Sylvia L. Asa, MD: Department of Pathology, St. Michael’s Hospital, University of Toronto; Kalman Kovacs, MD. Phl): Department of ‘Pathology, St. Michael’s Hospital, University of Toronto. Address reprint requcsts to Dr. I. Berczi, Immunology Department, Faculty of Medicine, University of Manitoba, 795 McDerrnot Avenue, Winnipeg, Manitoba. Canada R3E OW3. Submitted for publication June 15. 1983; accepted in revised form January 26, 1984. Arthritis and Rheumatism, Vol. 27. No. 6 (June 1984) in females than in males (2). Hormonal factors may be responsible, at least in part, for this notable difference in the sexes regarding autoimmune disease. Patients affected by SLE appear to have abnormal sex hormone metabolism, which leads to a net increase in estrogens and/or decrease in androgens (3-6). Oral contraceptives containing estrogens, but not those with progesterone, often induce exacerbation of SLE activity (7). Rheumatoid arthritis is also influenced by hormonal factors. The immunosuppressive effect of adrenocorticotropic hormone (ACTH) and of corticosteroids was discovered by Hench and coworkers during the treatment of rheumatoid arthritis (8,9). These hormones are still in use for the management of RA. Structural changes in the adenohypophysis have been observed in RA patients, along with altered adrenal corticosteroid metabolism (10-13). Oral contraceptives and testosterone may alter the course of RA (14,15). All thc above findings arc compatible with the idea that hormonal factors are involved in the pathogenesis of autoimmune disease. Pcarson reviewed the various animal models of RA and concluded that adjuvant arthritis has a number of features making it a suitable model, although certain characteristics are different from the human disease (16). Hormonal factors seem to influence adjuvant arthritis. Rats developing adjuvant arthritis show hypertrophy of their adrenal glands, and the plasma corticosterone concentration may reach 145% of that in control rats at the time of maximum inflammation (17). Pretreatment of rats with hydrocortisone led to the aggravation of arthritis, possibly because of the elimination of suppressor cells (18). Female LEW/N rats are highly susceptible to PITUITARY HORMONES streptococcal cell wall-induced polyart hritis, whereas males are relatively resistant. It was suggested that androgens enhance and estrogens depress clearance and sequestration of streptococcal cell wall fragments by the reticuloendothelial system, which correlates directly with the severity of the disease (19). The development of adjuvant arthritis is inhibited by thyroidectomy, and susceptibility can be restored by thyroid replacement therapy (20). We have also observed a sex difference in the susceptibility of Fisher rats to adjuvant arthritis, females being more susceptible. Furthermore. neither female nor male animals developed adjuvant arthritis after hypophysectomy. Hypophysectomized animals did develop adjuvant arthritis after grafting with syngeneic pituitary gland, or if treated daily with prolactin. The possible role of prolactin in the development of adjuvant arthritis was supported further by the finding that treatment of normal animals with bromocriptine (which inhibits the secretion of prolactin) also inhibited adjuvant arthritis (21). In this paper, we present further studies on the role of pituitary hormones in adjuvant arthritis. It seems clear that the pituitary gland has thc potential of regulating adjuvant arthritis since it secretes both enhancing (prolactin and growth hormone) and inhibitory (ACTH) hormones. MATERIALS AND METHODS Animals. Inbred, pathogen-free female Fisher rats weighing 150-170 gm were purchased from Canadian Breeding Farm Laboratories Ltd., Montreal, Canada. The animals were maintained on a standard diet (Wayne’s Laboratory Blocks with 6% fat content, Chicago, IL) and on water supplied ad libitum. Hypophysectomy. The hypophysis was removed by the parapharyngeal approach (22). The completeness of hypophysectomy was determined for each animal by autopsy at the end o f the experiment. Animals with residual pieces of hypophysis were excluded from the final evaluation of the results. Induction of arthritis. Three weeks after hypophysectomy, the experimental and control groups of animals were administered 0.1 ml Freund’s complete adjuvant that contained 5 mg/ml of Mycobacterirrtn trrberculosis. injected into the right hind paw. Sham operated controls had been used earlier, and their immune reactivity was found to be comparable with that of unoperated animals (23). Therefore, only unoperated control animals were used in the present experiments. Bromocriptine (BRC) treatment ( 5 mg/kg/day subcutaneously) was started 1 week prior to adjuvant injection and was maintained until the end of the experiment. Hormone treatment was initiated on the day of adjuvant arthritis induction (3 weeks after hypophysectomy) and maintained until termination of the experiment (18 days). The doses used are discussed below. 683 Control A HypoxtTSH Right Hind Lc-, 0 Hypox T , WIIII riA) 12 10 h E E Y a 6 81 Forelegs 6 4 t h 6 I I I 1 12 15 18 DAYS Figure 1. Restoration of hypophysectomized (Ilypox) rats’ susceptibility to adjuvant arthritis after hormone treatment (measured by mean paw diameter). Susceptibility was restored by growth hormone (GH) and prolactin (PRL). Female Fisher rats were divided into groups of 10; final evaluation included 9 or 10 from each group. For all 3 measurements (right and left hind legs, forelegs) controls, Hypox f G H , Hypox + PRL. and Hypox f all hormones were not different from each other, but were significantly different ( P < 0.01) from Hypox, Hypox + ACTH, Hypox + FSH. Hypox + LH. and Hypox + TSH, days 3-18, The latter groups did not differ significantly from each other at any time. ACTH = adrenocorticotropic hormone: FSH = follicle-stimulating hormone: LH = luteinizing hormone; TSH = thyroid-stimulating hormone; FCA = Freund‘s complete adjuvant. See text for additional details. 0 9 The extent of adjuvant arthritis was determined by measuring the horizontal diameters of the feet with a caliper every third day. Because of the nonspecific inflammation that developed quickly in the injected foot of all animals, data obtained for the left and right hind paws were averaged separately, whereas the diameters of forefeet were pooled. Hormone and drug treatment. Treatment was initiated on the day of immunization as follows: ACTH (purified cortrophin, Sterivet Laboratories, Ltd., porcine, potency I 1U/mg); follicle-stimulating hormone (FSH: NIAMDD-rat FSH-B2, activity 3 x NIH-FSH-SI); growth hormone (GH: NIH-GH B18, bovine, biopotency 0.81 IUimg); luteinizing hormone (LH: NIAMDD-bLH-4, bovine, biopotency 2.4 BERCZI ET AL 684 <0.5%; TSH <0.1%; FSH <0.5%; LH <0.5% by weight (determined by RIA). We were unable to obtain similar estimates regarding the purity o f ACTH and TSH. All the hormones were administered subcutaneously-GH, PRL, and TSH in saline, and ACTH, FSH, and LH in oil. Effective doses of ACTH, GH, PRL, and BRC had been titrated in previous experiments (24-26). Immune reactivity of hypophysectomized animals can be restored by daily subcutaneous injections of 100-200 pg/kg of GH or PRL. Similar doses of ACTH (assuming that 1 IU = I mg) were found to be immunosuppressive both in normal and in hormone-restored animals. However, as much as 500 pglkg of GH o r PKI, was necessary for the restoration of immune reactivity of BRC-suppressed animals, probably because ACTH secretion is intact in this latter situation, which tends to antagonize restoration. Other reasons are also conceivRight Hind Leg 16 /" 0 Control o HY~OX 0 3 6 9 12 15 18 Figure 2. Mean paw diameters, showing that the restoration by PRL of adjuvant arthritis in hypophysectomized rats was inhibited by additional treatment with ACTH. Groups of 10 female Fisher animals were used; final evaluation included 8-10 from each group. Hypophysectomy and hormone treatment were carried out as described in the text. For the forelegs and right hind legs, the control and Hypox t PRI, groups were significantly different ( P < 0.01) from the Hypox and Hypox + PRI, + ACTH groups on days 6-18. For the left hind legs, the above groups differed significantly on days 9-18. Controls differed from Hypox A PRL occasionally, but not regularly. See Figure 1 for abbreviations. unitshg); prolactin (PRL: NIAMDD, BPRL-6, bovine, biopotency 30 IU/mg); thyroid-stimulating hormone (TSH: thyrotron, Nordic Pharmaceuticals, Ltd., human, potency 10 IUD-5 ml). Contamination of the hormone preparations received from NIAMDD with other pituitary hormones was as follows. Rat FSH: LH activity 0.0045 x NIH-LH-S1 (ovarian ascorbic acid depletion method); TSH activity 0.5 IU (bovine) TSH/mg (McKenzie method); GH and PRL activity < 1% by weight (determined by radioimmunoassay [RIA]). Bovine GH: TSH C0.05 USP unitshg (P-32 uptake method using baby chicks); LH <0.025 NIH-LH-S1 unitdmg (ovarian ascorbic acid depletion assay); PRL <0.50 IU/mg (pigeon-crop sac weight method). Bovine L H : TSH activity 0.3%; GH 0.1%; PRL 0.1%; FSH 0.5% by weight (determined by RIA); ACTH not determined. Bovine PRL: GH tGH " t " tACTH ** A 1 DAYS A Hind Leg 12 a a " I 0 3 I I I I I 9 12 1k 18 DAYS Figure 3. Mean paw diameters, showing that the restoration by growth hormone of adjuvant arthritis in hypophysectomized rats was inhibited by additional treatment with ACTH. Groups of 10 female Fisher animals were used; final evaluation included 8-10 from each group. Hypophysectomy and hormone treatment were carried out as described in the text. For the forelegs and right hind legs, controls and Hypox + GH differed significantly ( P < 0.01) from Hypox and from Hypox t GH + ACTH on days 6-18 and for the left hind legs, on days 9-18. No consistently significant differences occurred between control and Hypox + GH or between Hypox and Hypox + GH + ACTH. See Figure I for abbreviations. PITUITARY HORMONES Right Hind Leg . L 16.- 685 (injected with FCA) ,4] X ly” by 2 qualified pathologists; histologic changes were graded on a scale of 0-3. Specimens with no detectable morphologic abnormality were given a score of 0; mild edema and minimal infiltration of subcutaneous tissue and synovium by mononuclear inflammatory cells were assessed as grade I ; significant inflammation and synovial hyperplasia were classified as grade 2; the presence of tissue necrosis or abscess formation qualified the specimen for a grade of 3. RESULTS ” “ +PRL + “ +ACTH Forelegs 0 3 6 9 15 15 l’a DAYS Figure 4. Prevention of adjuvant arthritis by bromocriptine (BRC), restoration by prolactin. and inhibition of restoration by ACTH, shown by mean paw diameters of rats. Groups of 10 female Fisher animals were used. Treatment with bromocriptine (5 mg/kg/day subcutaneously) was started I week before the induction of arthritis and continued throughout the experiment. Prolactin was given at I 0 0 pg/rdt/day and ACTH at 0.02 IU/rat/day, both subcutaneously, starting on the day of arthritis induction and continuing until termination of the experiment. For the forelegs and right hind legs. controls and BRC + PRL differed significantly from BRC and from BRC + PRL + ACTH on days 6-18. and for the left hind legs, on days 9-18. Only occasional differences occurred between control and BRC + PRL, and between BRC and BRC + PRL + ACTH. See Figure 1 for abbreviations. able. We consulted the literature with regard to the doses of other pituitary hormones (27,223). I n the present studies hormones were given to hypophysectomized animals at a daily dosage of 40 pg (except 0.66 IU dose of TSH and 0.02 IU dose of ACTH). BRC-suppressed animals received 100 pg daily doses of PRL and GH and 0.02-0.1 IU doses of ACTH as specified for the individual experiments. Bromocriptine (Sandoz, Basel, Switzerland) was dissolved in ethyl alcohol (70%) and brought to volume with phosphate buffered saline, pH 7.2. Histology. Tissues from the forelegs were excised from some animals in control and treated groups and were fixed in 10% buffered formalin. The specimens were embedded in paraffin and 4-6-pm thick sections were stained with hematoxylin and eosin. Coded slides were examined “blind- In the first experiment, the various groups of hypophysectomized animals were treated with ACTH, FSH, G H , L H . PRL, and T S H , respectively. An additional group was treated with all the above hormones. As illustrated by the results plotted in Figure 1 , PRL and G H restored the ability of hypophysectomized animals to develop arthritis. The animals treated with all the hormones also responded as well as the untreated controls. ACTH, FSH, L H , and TSH treated rats showed no reactivity in this experiment. In the second experiment (Figure 2), the restoration by PRL of adjuvant arthritis in hypophysectomized rats was inhibited by additional treatment with ACTH. The restoration by GH of hypophysectomized rats was inhibited by ACTH in a similar fashion (Figure 3). When normal animals were treated with BRC, the development of adjuvant arthritis was strongly inhibited (Figure 4). Arthritis developed. however, if the BRC-suppressed animals were also given daily injections of prolactin. ACTH treatment again antagonized the restoring effect of prolactin in such animals. BRC-suppressed animals’ ability to develop adjuvant arthritis could also be restored by GH treatment. It could again be antagonized by ACTH administration (Figure 5). Control animals showed histologic changes of adjuvant arthritis: subcutaneous tissues overlying the bones, joints, and tendons were intensely infiltrated by mononuclear inflammatory cells; there was focal inflammatory infiltration into skeletal muscle near involved bones and joints. The synovium was hyperplastic, edematous, and inflamed. Similar changes were seen in hypophysectomized rats treated with PRL and in intact rats given the combination of BRC and PRL. A less intense inflammatory reaction was seen in hypophysectomized rats given G H therapy. Biopsy specimens from hypophysectomized rats with no pituitary hormone treatment showed minimal inflammatory cell infiltration and mild edema of the subcutaneous tissue. Normal rats treated with BKC showed no evidence of inflammatory changes on histologic examination, and those given the combination of BRC and ACTH showed minimal edema and inflammation. BERCZI ET AL 686 Right Hind Leg (injected with FCA) 16 12 0 3 6 9 12 15 18 DAYS Figure 5. Prevention of adjuvant arthritis by bromocriptine (BRC), restoration by growth hormone, and inhibition of restoration by ACTH, shown by mean paw diameters of rats. Groups of 10 female Fisher animals were used. Treatment with BRC and with hormones was carried out as described in Figure 4. Daily subcutaneous dosages of ACTH and GH were 0.1 IU and 100 pg, respectively. For the forelegs and right hind legs, controls and BKC + GH differed significantly ( P < 0.01) from BRC and from BRC + G H + ACTH on days 6-18 and for the left hind legs, on days 9-18. See Figure I for abbreviations. DISCUSSION The results presented in this paper confirm our earlier findings that prolactin plays a role in the development of adjuvant arthritis (21). However, it is clear from the present results that growth hormone is equally potent in this respect. In our preliminary experiments, we administered GH together with ACTH, TSH, and human chorionic gonadotropin to hypophysectomized animals, and no restoration of immunocompetence resulted from this treatment. It is suggested that in that case ACTH antagonized the restorative effect of growth hormone. ACTH was quite effective in this respect in our present experiments also. LH, FSH, and TSH showed no influence on the immune reactivity of hypophysectomized animals, when given either alone or in combination with other hormones. One possible reason for this may be that the doses given were not optimal for the alteration of immune reactivity. This possible explanation cannot be discounted. However, BRC-treated animals are just as immunodeficient as hypophysectomized rats, as can easily be determined from the data presented here and also from our previous experiments (26). BRC inhibits the secretion of PRL and may also have some effect on GH, but otherwise the pituitary gland functions normally. This has been evaluated extensively in experimental animals and supported also by clinical experience (29-32). As a matter of fact, hyperprolactinemic women often become fertile again after BRC treatment, which shows that the secretion of gonadotropins and ovarian function become normal after treatment (30). At this stage we have not designed our experiments to study the role of thyroid hormones in adjuvant arthritis and cannot draw any firm conclusions in this regard. However, Fabris (33) showed that rats whose thyroids were removed as young adults had an impaired antibody response 35-60 days after the operation. On the basis of this finding, immunologic impairment could be expected after 5-9 weeks, if thyroid function ceased because of hypophysectomy. Thus, in our study, the impaired reactivity of animals 4-5 weeks after hypophysectomy was probably not due to the lack of thyroid hormones. Previous investigators emphasized the importance of growth hormone in the development and maintenance of normal immune function (34-37). Recently it was found that isolated growth hormone deficiency in humans may be associated with hypogammaglobulinemia (38). These indications, together with our results, strongly suggest that GH does indeed have a role in immunoregulation. Others have found that lactation and prolactin treatment alter the resistance of rats and mice to certain parasites (39-41). A malignant rat lymphoma which is dependent on prolactin for growth has also been described (42). These findings are compatible with our results indicating that PRL plays a role in the maintenance of immunocompetence. Interestingly, PRL and GH proved to be interchangeable with regard to the restoration of immune reactivity of hypophysectomized and BRC-suppressed animals in these and also in earlier experiments (24-26,43). Growth hormone and prolactin are related peptides exhibiting a considerable structural homology PITUITARY HORMONES (44). Some cross-reactivity at the receptor level has also been demonstrated (45). Furthermore, there is a lot of overlap in t h e biologic activities of GH a n d P R L , especially in lower vertebrates (46). Therefore, it is not entirely unexpected that both hormones are involved in the maintenance of immunocompetence, which is of vital importance for survival. There is much evidence of the immunosuppressive effect of ACTH (47), which w a s discovered through the treatment of rheumatoid patients. Our findings suggest that ACTH acts on the immune system as an antagonist of PRL a n d GH. Earlier experiments yielded similar results (25,26). 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