The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 9 3336-3343
Copyright © 1999 by The Endocrine Society
Interferon-
-2a Is a Potent Inhibitor of Hormone Secretion by Cultured Human Pituitary Adenomas
Leo J. Hofland,
Wouter W. de Herder,
Marlijn Waaijers,
Joke Zuijderwijk,
Piet Uitterlinden,
Peter M. van Koetsveld and
Steven W. J. Lamberts
Department of Internal Medicine III, Erasmus University, 3015 GD
Rotterdam, The Netherlands
Address all correspondence and requests for reprints to: L. J. Hofland, Ph.D., Department of Internal Medicine III, University Hospital Dijkzigt, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: hofland{at}inw3.azr.nl
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Abstract
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Interferon-
(IFN) may exert direct inhibitory effects on cell
proliferation and on the production of different peptide hormones. We
investigated the effect of IFN on hormone production by 15
GH-secreting pituitary adenomas, 4 clinically nonfunctioning or
gonadotroph pituitary adenomas, and 4 prolactinomas in
vitro. In the GH-secreting pituitary adenoma cultures, a short
term (72-h) incubation with IFN (50–100 U/mL) significantly
inhibited GH secretion in 3 of 7 cases and PRL secretion in 6 of 7
cultures. During prolonged incubation (14 days) with IFN, GH and/or
PRL secretion was significantly inhibited in 7 of 8 cultures (GH,
17–78% inhibition; PRL, 39–88% inhibition). In the clinically
nonfunctioning or gonadotroph cultures, incubation with IFN resulted
in inhibition of the secretion of gonadotropins and/or -subunit in
all cases (27–62%), whereas in the prolactinoma cultures PRL
secretion was inhibited by IFN in all cases (37–76%). The effect
of IFN was additive to the inhibitory effects of the dopamine
agonist bromocriptine (10 nmol/L) or the somatostatin
analog octreotide (10 nmol/L). The inhibition of hormone secretion by
IFN was accompanied by inhibition of the intracellular hormone
concentrations. The effect of IFN was dose dependent, with an
IC50 for inhibition of hormone secretion of 2.3 ± 0.3
U/mL (n = 5), which is relatively low compared with the
concentrations that are reached in patients treated with IFN for
various malignancies. In conclusion, the potent antihormonal effect of
IFN on cultured pituitary adenomas suggests that this drug might be
of benefit in the treatment of selected patients with secreting
pituitary adenomas. As treatment with IFN is associated with
considerable adverse reactions, studies with this drug should only be
considered in inoperable, invasive aggressive, and dopamine agonist-
and/or somatostatin analog-resistant functioning pituitary
macroadenomas.
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Introduction
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INTERFERONS (IFNs) are glycoproteins
produced in response to viral and certain nonviral stimuli. Apart from
having antiviral activity, IFNs are potent inhibitors of cell
proliferation as well. Because of these properties IFNs have been
approved for clinical use to treat certain viral diseases, autoimmune
diseases, and malignancies (1). During the past 10 yr evidence has
emerged that IFNs may play a regulatory role in pituitary hormone
secretion as well. Both stimulatory and inhibitory effects of IFNs
(IFN and IFN
) on the secretion of ACTH, PRL, and GH have been
reported (2, 3, 4, 5, 6). Apart from cells of the immune system, pituitary
endocrine cells may also contain IFN (7), providing further evidence
for a local regulatory role for this group of proteins at the pituitary
level. Moreover, Katahira et al. (8) recently showed that
prolonged incubation with IFN or IFN induces a potent inhibitory
effect on POMC gene expression in mouse AtT-20 pituitary tumor
cells.
Until now, IFN has been used with variable success in the treatment
of hormone-secreting gastroenteropancreatic tumors (mainly carcinoids).
Treatment with IFN may control tumor growth, but also reduces the
secretion of tumor-related products in patients harboring these tumors,
thereby improving clinical symptomatology (9, 10, 11). The decrease in the
production of different peptide hormones is caused by its blocking
effect on intracellular messenger ribonucleic acid formation (12) and
appears to be signalled via the JAK (Janus kinase)-STAT (signal
transducer and activator of transcription) pathway (13).
Medical therapy of human pituitary adenomas comprises the use of
dopamine (DA) agonists and somatostatin (SS) analogs. In patients with
prolactinomas, treatment with DA agonists effectively reduces
circulating PRL levels and tumor size in the majority of them, probably
due to an inhibitory effect on PRL synthesis. However, a small subgroup
of patients with prolactinomas is either resistant to DA agonist
therapy or cannot be treated due to intolerance to therapy with DA
agonists (14). In patients with acromegaly, good inhibition of
circulating GH levels has been achieved using SS analogs such as
octreotide, whereas tumor shrinkage is observed less frequently (15).
This is probably due to the absence of an inhibitory effect of SS
analogs on GH synthesis (16, 17). Finally, the effectiveness of the use
of DA agonists and/or SS analogs in the medical treatment of clinically
nonfunctioning pituitary adenomas (NFA) is still under discussion
(18).
The presence of IFN in pituitary endocrine cells, its modulating
effect on pituitary hormone secretion (and/or production), and the
observations that IFNs act at the transcriptional level suggest that
IFNs may also influence hormone secretion by pituitary adenomas. To
further explore the possibilities of medical therapy of pituitary
adenomas, we investigated in the present study the effect of IFN-2a
on hormone secretion by different types of cultured human pituitary
adenoma cells. In addition, the interrelationship between the effects
of IFN and octreotide and/or bromocriptine was studied.
Moreover, a comparison was made with the effects of IFN on hormone
secretion by primary cultures of three insulinomas and one
gastrinoma.
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Subjects and Methods
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Patients
Pituitary tumor samples were obtained by transsphenoidal
operation from 15 patients with GH-secreting pituitary adenomas, from 4
patients with clinically nonfunctioning (n = 2) or gonadotroph
(n = 2) adenomas, and from 4 patients with prolactinomas, as
described previously (19). Tumor samples of 3 insulinomas and 1
gastrinoma were obtained within 30 min after surgical removal of the
tumors. Diagnosis was made on the basis of clinical and biochemical
characteristics of the patients in combination with
(immuno)histochemistry of the tumor samples. The two patients with
gonadotroph adenomas had elevated preoperative levels of FSH. All
patients gave their informed consent for the use of tumor material for
research purposes.
Cell dispersion and cell culture
Single cell suspensions of the pituitary adenoma tissues were
prepared by enzymatic dissociation with dispase as described in detail
previously (19). Tumor tissue from the insulinomas and the gastrinoma
was dissociated as described (20). For short term incubation of
monolayer cultures, the dissociated cells were plated in 48-well plates
(Costar, Cambridge, MA) at a density of 105
(GH-secreting pituitary adenomas, prolactinomas, insulinomas, and
gastrinoma) or 2 x 105 (NFAs) cells/well·1 mL
culture medium. After 3–4 days the medium was changed, and 72-h
incubations without or with test substances were initiated. At the end
of the incubation the medium was removed and centrifuged for 5 min at
600 x g. The supernatant was collected and stored at
-20 C until analysis. For long term incubation studies in Transwells
(21), the isolated tumor cells were plated in Transwell-COL membranes
(Costar, Badhoevedorp, The Netherlands) at a density of
105 (GH-secreting pituitary adenomas, prolactinomas,
insulinomas, and gastrinoma) or 2 x 105 (NFAs)
cells/well. The Transwells were then placed into multiwell plates
(24-well; Costar) containing 1 mL culture medium. After
72 h the Transwells were transferred to wells containing fresh
medium (without or with test substances). Every 3–4 days the cells
were placed into fresh medium, and the incubation media were collected
and stored at -20 C until determination of hormone concentrations. In
some experiments, intracellular hormone concentrations were determined
in cell lysates obtained by lysis of the cells in 150 µL ammonia
solution (0.2%, vol/vol), followed by the addition of 1 mL assay
buffer (100 mmol/L NaCl, 10 mmol/L ethylenediamine tetraacetate, and 10
mmol/L Tris-HCl, pH 7.0), as described previously (22). In the NFA
cultures cell lysates were obtained by lysis of the cells in distilled
water containing 1 g/L BSA followed by repeated freezing and thawing,
as described previously (21).
The cells were cultured at 37 C in a CO2 incubator. The
culture medium consisted of MEM D-valine with Earle’s
salts supplemented with non essential amino acids, sodium pyruvate (1
mmol/L), 10% FCS, penicillin (1 x 105 U/L),
fungizone (0.5 mg/L), L-glutamine (2 mmol/L), and sodium
bicarbonate (2.2 g/L), pH 7.6. Unfortunately, generally not enough
tumor material was obtained to test each tumor for its responsiveness
to all of the above indicated drugs.
Hormone determinations
Human GH, PRL, LH, and FSH concentrations in the media and cell
extracts were determined by immunoradiometric assays (MedGenix
Diagnostics, Fleurus, Belgium) as described previously (19, 21).
Glycoprotein -subunit concentrations were determined using an
immunoradiometric assay from Immunotech S.A. (Marseille,
France). Insulin and gastrin concentrations were determined by double
antibody RIAs as previously described (20). Dilution of GH, PRL, LH,
FSH, -subunit, insulin, and gastrin in the media was parallel to
that of the respective standards supplied with kits.
Testsubstances
Octreotide (Sandostatin) and
bromocriptine were obtained from Novartis Pharma A.G.
(Basel, Switzerland). IFN-2a (Roferon-A) was obtained from
Hoffmann-La Roche B.V. (Mijdrecht, The Netherlands).
Measurement of DNA content
The DNA content in the cell lysates (see above) was measured
using the bisbenzimide fluorescent dye (Behring, La Jolla, CA) as
described in detail previously (22).
Statistical analysis of the data
All data for hormone release are expressed as the mean ±
SE (n = 4 wells/treatment group). All data were
analyzed by ANOVA to determine overall differences between treatment
groups. When significant differences were found by ANOVA, a comparison
between treatment groups was made using the Newman-Keuls test.
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Results
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Pituitary adenomas
First, tumor cell preparations from 15 acromegalics were studied.
IFN (50–100 U/mL) significantly inhibits GH secretion in 3 of 7
cultures (16–69% inhibition) and PRL secretion in 6 of 7 cultures
(21–56% inhibition) during a 72-h incubation (Fig. 1
, left panel). A
significantly higher number of cultures responded to IFN after
prolonged exposure. After 14 days of treatment, GH secretion was
significantly inhibited in 7 of 8 other tumor cell cultures (17–78%
inhibition), and PRL secretion was significantly inhibited in 4 of 4
cultures (39–88% inhibition), as shown in Fig. 1, right
panel.
In all prolactinoma (n = 4; Fig. 2)
and NFA or gonadotroph cultures (n = 4; Fig. 3) IFN significantly inhibited hormone
secretion after 14 days of treatment. The percent inhibition varied
between 37–76% in prolactinoma cultures and between 27–62% in NFA
and gonadotroph cultures after 14 days of treatment.
In the majority of the cultures the effects of IFN and octreotide or
bromocriptine on hormone secretion were additive. Figure 4 (GH-secreting pituitary adenoma cells)
and Fig. 5 (NFA cells) show the
increasing, time-dependent, additive effect of these drugs. Tables
1-3
show that significant additive effects on hormone secretion were found
in three of five GH-secreting pituitary adenoma cultures, in two of two
prolactinoma cultures, and in one NFA culture in which the combination
of these drugs was studied. IFN also significantly inhibited
intracellular GH concentrations in two of four GH-secreting adenoma
cultures (Table 1), whereas at the same time treatment with octreotide
or bromocriptine induced a statistically significant
accumulation of intracellular GH concentrations (Table 1), suggesting a
different mechanism of action between IFN, on the one hand, and
octreotide and bromocriptine, on the other hand. Both
bromocriptine and IFN significantly inhibited
intracellular PRL concentrations in the GH-secreting pituitary adenoma
cultures (n = 3; Table 1) and in the prolactinoma cultures (n
= 3; Table 2) and intracellular -subunit and/or FSH concentrations
in the NFA cultures (n = 2; Table 3).
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Table 1. The effect of long term treatment with IFN and/or
octreotide or bromocriptine on GH and PRL secretion and intracellular
concentrations by cultured human GH-secreting pituitary adenoma cells
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Table 2. The effect of long term treatment with IFN and/or
bromocriptine on PRL secretion and intracellular concentrations of
cultured human prolactinoma cells
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Table 3. The effect of long term treatment with IFN and/or
bromocriptine on -subunit and FSH secretion and intracellular
concentrations of cultured human clinically nonfunctioning (no. 1 and
2) or gonadotroph (no. 3 and 4) adenoma cells
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We also studied the effect of drug withdrawal on day 14 of treatment.
In the majority of the cases we found that withdrawal from IFN
treatment resulted in a recovery of hormone secretion, suggesting that
the inhibitory effect of IFN represents inhibition of hormone
secretion and/or production and not inhibition of cell proliferation or
any cytotoxic effect. Representative examples of the effect of drug
withdrawal are shown in Fig. 4
(GH-secreting pituitary adenoma), Fig. 5
(NFA), and Fig. 6 (prolactinoma). The
absence of any cytotoxic effect is further illustrated by the absence
of an effect of IFN on the DNA content of the pituitary adenoma
cells, which is shown in Fig. 7 for a
GH-secreting pituitary adenoma culture. No statistically significant
inhibition of IFN on the DNA content of the cells was demonstrated
in six additional pituitary adenoma cultures (data not shown).
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Figure 6. Recovery of PRL secretion by cultured human
prolactinoma cells (no. 2) after withdrawal of IFN treatment
(50 U/mL) on day 14 of treatment. Values are the mean ±
SE and are expressed as the percentage of control hormone
release at each time point.
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Figure 7. Dose-dependent inhibition of GH secretion
(upper panel) and intracellular GH concentrations
(middle panel) of cultured GH-secreting pituitary
adenoma cells (no. 15) by IFN. Cell number, as measured by
the DNA content of the cells, was not inhibited (lower
panel). Values are the mean ± SE. *,
P < 0.05 vs. control.
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Finally, the effect of IFN on hormone secretion was dose dependent,
with IC50 values between 1.7–3.3 U/mL (mean, 2.3 ±
0.3; Table 4). Data are shown in Fig. 7
(GH-secreting pituitary adenoma), Table 2 (prolactinoma), and Table 3
(gonadotroph adenomas).
Gastroenteropancreatic tumors
For comparison we also evaluated the effect of IFN on insulin
secretion by three insulinomas and on gastrin secretion by a
gastrinoma. In two of three insulinomas insulin secretion was inhibited
by 18% and 37% only at a high dose of IFN (50 U/mL), whereas in
the gastrinoma a more significant reduction of gastrin secretion was
found (45% inhibition by 50 U IFN U/mL), as shown in Table 5.
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Table 5. Effect of long term in vitro treatment
with IFN-2a on insulin or gastrin secretion by cultured insulinoma
and gastrinoma cells
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Discussion
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In the majority of patients with GH-secreting pituitary adenomas
medical treatment with SS analogs and/or DA agonists is, after
transsphenoidal surgery, the therapy of second choice (15). First
choice medical therapy of this type of pituitary adenomas is not
frequently applied because SS analogs and/or DA agonists induce only
slight tumor shrinkage in approximately 50% of the patients treated.
This is probably related to the fact that these drugs do not inhibit
hormonal synthesis in this type of pituitary adenomas (16, 17). In
contrast, medical therapy with DA agonists is the first choice therapy
in patients with prolactinomas (23). The majority of patients with
prolactinomas can be effectively treated with DA agonists, resulting in
lowered circulating PRL levels and a reduction of tumor volume due to a
potent inhibition of hormonal synthesis by the drug (23). On the other
hand, some patients with prolactinomas cannot be treated due to either
resistance or adverse reactions to DA agonists (14). Finally, at
present no effective medical therapy of patients with NFA is available
(18). Taken together, these data indicate that novel drugs that inhibit
both hormonal hypersecretion and/or synthesis by pituitary adenomas
might be beneficial along with current medical therapy.
During the past 10 yr evidence has emerged that IFNs may also play a
regulatory role in pituitary hormone secretion (2, 3, 4, 5, 6, 7, 8). IFN-2a is a
drug that has been used with variable success in the treatment of
several malignancies (1). In patients with neuroendocrine tumors such
as carcinoids, treatment with IFN may control tumor growth, but also
reduces the secretion of tumor-related products in patient harboring
these tumors, thereby improving clinical symptomatology (9, 10, 11). The
decrease in the production of different peptide hormones is caused by
its blocking effect on intracellular messenger ribonucleic acid
formation (12).
In the present study we found that IFN significantly inhibits both
hormone secretion and intracellular hormone concentrations in primary
cultures of human GH-secreting pituitary adenomas, prolactinomas, and
NFA or gonadotroph adenomas. In the GH-secreting pituitary adenoma
cultures in which octreotide and/or bromocriptine
significantly inhibited hormone secretion, intracellular GH
concentrations were concomitantly increased, as has been reported
previously (16). These data suggest that IFN, on the one hand, and
octreotide and bromocriptine, on the other hand, act via
different mechanisms of action. Although octreotide and
bromocriptine act to inhibit hormone secretion via
inhibition of adenylyl cyclase activity and/or inhibition of calcium
fluxes (24), IFN may inhibit hormone synthesis via inhibition of
transcription of the GH gene, as has been proposed for the effect of
the drug on peptide production in neuroendocrine tumors (12). As we
found that hormone secretion recovered after withdrawal of treatment
with IFN in vitro, and because the drug did not affect
the DNA content of the adenoma cell cultures, it is unlikely that
IFN inhibited cell proliferation or induced cytotoxic effects.
Moreover, we found that even very low concentrations significantly
inhibited both hormone secretion and intracellular hormone
concentrations in a dose-dependent manner.
In primary cultures of human prolactinomas, we found that both
bromocriptine and IFN significantly inhibited hormone
secretion and intracellular hormone concentrations. The observation
that bromocriptine increased intracellular GH
concentrations in human GH-secreting pituitary adenoma cultures,
whereas the same drug significantly inhibited intracellular PRL
concentrations in prolactinoma cultures suggests a different
responsiveness of hormonal synthesis to DA agonists between these two
types of pituitary adenomas. Of interest in this respect is that after
long term treatment in vitro both bromocriptine
and IFN significantly inhibited intracellular PRL concentrations in
the GH-secreting pituitary adenomas despite a concomitant rise in
intracellular GH levels induced by bromocriptine. The
inhibitory effect of IFN on intracellular PRL concentrations in
prolactinomas suggests that this drug might also induce tumor shrinkage
in patients with prolactinomas. Again of importance is our observation
that very low concentrations induced significant inhibition of
intracellular PRL concentrations. However, the four prolactinoma
cultures that were studied showed a high sensitivity to
bromocriptine in vitro. It remains to be
established, therefore, whether DA agonist-resistant prolactinomas
respond in a comparable manner to IFN. Of special interest is a case
report of a 45-yr old woman suffering from antihepatitis C
virus-positive chronic active hepatitis and amenorrhea-galactorrhea
syndrome due to a PRL-secreting microadenoma, in whom IFN treatment
resulted in normalization of plasma PRL levels and disappearance of
related symptoms (25).
Finally, in line with the observations in prolactinoma cultures, we
found that both bromocriptine and IFN significantly
inhibited both the secretion and intracellular hormone concentrations
of -subunit and/or FSH in the NFA cultures. The inhibitory effect of
prolonged treatment with bromocriptine on hormone
production is in agreement with our previous observations (21).
However, treatment with DA agonists infrequently induces (minor) tumor
shrinkage in patients with NFA despite an inhibitory effect on
circulating gonadotropin and/or subunit levels (18). This may be
related to the low hormonal activity of this type of pituitary adenoma,
and in this respect the effect of treatment with IFN on tumor volume
is more uncertain than that in secreting pituitary adenomas.
In the present study we showed that in the majority of the
cultures the inhibitory effects of IFN were clearly additive to the
inhibitory effects of octreotide and bromocriptine. These
observations seem in line with studies in patients with carcinoid
tumors, which showed that the combination treatment with octreotide and
IFN appears to be more effective, especially in controlling clinical
symptomatology rather than on tumor mass, than treatment with either
drug alone (26). Our observations suggest that IFN treatment does
not interfere in a negative manner with the effects of the drugs
currently used for medical treatment of prolactinomas and GH-secreting
pituitary adenomas and can thus be used in combination. Moreover, in
patients with carcinoid tumors IFN therapy was better tolerated when
used in conjunction with SS analogs (26).
Recently, Katahira et al. (8), showed that both IFN and
IFN have a potent inhibitory effect on POMC gene expression in mouse
AtT-20 pituitary tumor cells, thereby providing evidence for an
inhibitory action of this group of proteins at the level of
transcription. If such an inhibition also occurs in the human
corticotropic tumor cell, ACTH production by human corticotroph
adenomas may be influenced by IFN as well. This may be very
important, because at present no medical treatment for this type of
pituitary adenoma is available.
Although the inhibitory effects of IFN on hormone production in
secreting pituitary adenomas seems promising, several points for the
use of IFN have to be stressed. Treatment with IFN is associated
with considerable adverse reactions, including flu-like syndrome,
fatigue, anorexia, and depression (1). This is in sharp contrast with
the use of SS analogs and/or DA agonists, which have only mild adverse
reactions. On the other hand, we found in the present study that a very
low concentration IFN (<5 U/mL) induced significant inhibitory
effects on both hormone secretion and intracellular hormone
concentrations. This concentration is much lower than the
concentrations reached in patients currently treated with IFN for
various malignancies or viral infections (concentrations around 50–100
U/mL) (27, 28, 29). Therefore, lower dose, long term IFN treatment might
be considered. In this respect it is of interest that in treating other
malignancies lower dose treatment regimens have been suggested to be
more effective than high doses (30, 31). As a result, lower dosages may
be related to fewer adverse reactions. This may be related to the fact
that IFN is part of a physiologically active, complex biological
system and should thus not be considered as a conventional drug
(30).
In conclusion, the potent inhibitory effect of IFN on hormone
production by cultured pituitary adenomas suggests that the drug might
be a novel tool for medical treatment of pituitary adenomas. On the
other hand, considering the above-indicated adverse reactions of IFN
treatment, the use of this drug in the medical treatment of pituitary
adenomas should only be considered in inoperable, invasive aggressive,
DA agonist- and/or SS analog-resistant, secreting pituitary
macroadenomas. Of additional interest is that IFNs may have
antiangiogenic activity as well (31).
Received December 8, 1998.
Revised June 3, 1999.
Accepted June 10, 1999.
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Abstract
Introduction
, Control; 
, IFN
