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The influence of pituitary hormones on adjuvant arthritis.

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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). ACTH is known
to affect immune reactions through the stimulation of
adrenal corticosteroids (48), but it is not clear how
PRL and GH influence immunity. Further studies are
required for elucidation of the mechanism of action of
these hormones; this would hopefully lead to a better
understanding a n d more rational treatment of autoimmune disease.
687
7.
8.
9.
10.
11.
ACKNOWLEDGMENTS
The authors are indebted to Drs. H. G. Friesen and
A. H. Sehon for their continuous encouragement and advice.
Prolactin. growth hormone, follicle-stimulating hormone,
and luteinizing hormone were generously donated by Dr.
Salvatore Raiti, through the National Hormone and Pituitary
Program, Baltimore, MD. Some of the bromocriptine was
donated by Professor E. Fluckiger, Sandoz I.td., Basel.
Switzerland.
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