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Pituitary hormones and systemic lupus erythematosus.

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ARTHRITIS & RHEUMATISM
Vol. 52, No. 12, December 2005, pp 3701–3712
DOI 10.1002/art.21436
© 2005, American College of Rheumatology
REVIEW
Pituitary Hormones and Systemic Lupus Erythematosus
Jing Li, Warren May, and Robert W. McMurray
pituitary function (9,10) evoke the possibility that pituitary hormone abnormalities contribute to or synergize
with the altered sex steroids contributing to SLE disease
expression.
Investigations of pituitary hormones in SLE have
been relatively uniform in their enrollment of patients
and appropriately matched healthy controls. However,
small numbers of study participants, variability in interand intrastudy results, long time intervals over which
comparisons have been reported, and absence of sufficient statistical power to test respective hypotheses have
limited the conclusions and possibly obscured the identification of important relationships between SLE and
pituitary hormonal immunomodulation. Furthermore,
peptide hormone/steroid/cytokine feedback loops, hormonal interconversions (e.g., DHEA to testosterone
and/or estradiol), and the superimposed hourly, daily,
and monthly chronobiologic variations of menses, pregnancy, and/or hormone administration complicate a
simple interpretation of these cause-and-effect relationships as well as successful application of hormonal
immunotherapy.
We review herein the investigations of adenohypophyseal hormones—follicle-stimulating hormone
(FSH), luteinizing hormone (LH), adrenocorticotropic
hormone (ACTH), thyroid-stimulating hormone (TSH),
growth hormone (GH), and prolactin—in patients with
SLE. These anterior pituitary hormones are peptides of
various molecular weights that bind to surface receptors
and stimulate a variety of actions (6,7). They can affect
the immune system directly (11) or indirectly through
their effects on the synthesis of sex steroids with immunomodulatory capacity (1–4). Moreover, manipulation of
serum pituitary hormones has been shown to be immunoregulatory, especially in animal models (11–15). In
order to better understand the associations between
SLE, sex, and pituitary hormones, clinical studies measuring serum concentrations of FSH, LH, ACTH, TSH,
and GH (as well as prolactin) in nonpregnant adult
women and men with SLE were identified by a comput-
Introduction
Systemic lupus erythematosus (SLE) is known for
its predominant occurrence in women and for its peak
incidence during the reproductive years. The increased
ratio of female to male SLE patients implies that
sex-associated genetic and/or endocrine factors modulate disease proclivity and development. While chromosome differences or sex-associated metabolic or environmental factors may underlie the predominant
occurrence of SLE in women, no relationship with the
disease has proven stronger than those of female sex and
female/male differences in sex hormones. This concept
has been supported not only by epidemiologic studies,
but also by substantial evidence of the immunoregulatory actions of 17␤-estradiol (estradiol), testosterone,
progesterone, dehydroepiandrosterone (DHEA)/
DHEA sulfate, and prolactin (1–4).
A recent review and meta-analysis of data examining sex hormone abnormalities in SLE patients revealed that female SLE patients had significantly depressed concentrations of androgens and elevated
concentrations of estradiol compared not only with their
male counterparts with SLE but also with healthy controls (5). In addition, both female and male SLE patients
had abnormally elevated serum prolactin concentrations, and in male SLE patients, elevation of serum
prolactin concentrations was the only sex hormone aberration clearly identified in meta-analyses (5). Elevated
prolactin concentrations in SLE patients (4,5), regulation of sex steroids by pituitary gonadotropins (6,7),
interdependence of neuroendocrine and immune systems (8), and effects of inflammatory cytokines on
Supported by the Mississippi Lupus Association.
Jing Li, MD, Warren May, PhD, Robert W. McMurray, MD:
University of Mississippi Medical Center, Jackson.
Address correspondence and reprint requests to Robert W.
McMurray, MD, Division of Rheumatology and Molecular Immunology, L525 Clinical Sciences Building, University of Mississippi Medical
Center, 2500 North State Street, Jackson, MS 39216. E-mail:
Robert.McMurray@medicine.umsmed.edu.
Submitted for publication March 9, 2005; accepted in revised
form August 25, 2005.
3701
3702
LI ET AL
Table 1. Controlled studies of serum concentrations of follicle-stimulating hormone (FSH) in patients with systemic lupus erythematosus (SLE)
No. of subjects
Author, year (ref.)
Female-only studies
Yozai, 1976 (23)
Lavalle et al, 1984 (24)
SLE
patients Controls
Age, mean ⫾ SD or range years
SLE
patients
7
8
10
6
18–26
18–38
26
140
14
21
20
20
21–34
14–40
16–37
Redlich et al, 2000 (28)
Koeller et al, 2004 (29)
Male-only studies
Lavalle et al, 1987 (30)
Mackworth-Young et al,
1983 (31)
Stahl and Decker, 1978 (32)
Wen and Li, 1993 (26)
30
8
39
7
18–26
34 ⫾ 5
8
9
11
11
8
19
31
7
23–60
14–40
Sequiera et al, 1993 (33)
14
17
22–67
Munoz et al, 1994 (27)
Vilarinho and Costallat,
1998 (34)
5
7
7
10
22–57
26 ⫾ 7
Chang et al, 1999 (35)
16
20
19–46
Mok and Lau, 2000 (36)
35
33
17–71
Koeller et al, 2004 (29)
3
2
34 ⫾ 5
Arnalich et al, 1992 (25)
Wen and Li, 1993 (26)
Munoz et al, 1994 (27)
Controls
Conclusions
Matched (not shown) No significant difference
22–30
No significant difference; patients had active
and inactive disease
20–32
No significant difference; quiescent lupus
20–36
FSH higher in SLE patients
Matched (not shown) FSH higher only during follicular phase; no
association with disease activity
Matched (not shown) FSH higher in SLE patients
38 ⫾ 4
No difference reported
19–39
25–40
No significant difference
Matched (not shown) Matched (not shown) No significant difference
erized search of the medical literature and are classified
for presentation, analysis, and discussion below.
SLE, sex influences, and the pituitary–cytokine axis
The strongest risk factor for the development of
SLE is female sex. The female:male ratio in SLE rises to
9:1 during the peak reproductive years, with a gradual
decline after menopause. The age at SLE onset is more
evenly distributed in males (16). There is evidence to
support the concept that correlations exist between
disease severity and the pituitary–gonadal axis; however,
scattered studies have shown direct or inverse, simultaneous or temporal relationships between hormone concentrations or concentration changes and SLE disease
activity indices. Serum gonadal and pituitary hormone
concentrations in SLE patients are not typically outside
of physiologic ranges (see ref. 5 and data below), although mean concentrations are statistically different
from those in healthy controls. Bias in ascribing sex
differences in SLE disease incidence to pituitary or
gonadal hormones may be introduced by physiologic
Matched (not shown) No significant difference
20–36
FSH higher in SLE patients; all patients
newly diagnosed and untreated
27–40
FSH higher in SLE patients; 21% of SLE
patients had abnormally elevated FSH
compared with 0% of controls
Matched (not shown) FSH higher in SLE patients
Matched (not shown) FSH higher in SLE patients; 29% of SLE
patients had abnormally elevated FSH
compared with 0% of controls
Matched (not shown) FSH higher in SLE patients; all patients
newly diagnosed and untreated
19–71
FSH higher in SLE patients; 54% of SLE
patients had abnormally high FSH
compared with 18% of controls
38 ⫾ 4
FSH higher in SLE patients (P value or SD
not reported)
reality: females differ from males in their hypothalamic,
adenohypophyseal, and gonadal/adrenal functions (6,7).
Nevertheless, a finding of significant differences in pituitary hormones between female or male lupus patients
or between lupus patients and their healthy controls
would identify immunoendocrine regulatory loops that
may be important in the modulation of SLE disease
development and disease activity and that may provide
new targets for therapeutic intervention.
Observational data suggesting that pituitary–
gonadal axis–related hormones may modulate SLE disease incidence or severity include reports of lupus flares
caused by oral contraceptives, estrogen administration,
and ovulation induction regimens (1–5). Preliminary
reports of the SELENA (Safety of Estrogens in Lupus
Erythematosus: National Assessment) trial found no
increase in severe flares associated with hormone replacement therapy (HRT) in postmenopausal women,
although total flares were increased by 30% (statistically
significant) in the HRT arm of the study. In contrast,
combination oral contraceptives did not exacerbate lu-
HORMONES IN SLE
pus in premenopausal women (17), suggesting a differential effect of estrogenic compounds as well as different
autoimmune disease response in pre- and postmenopausal women. Although there was no effect of oral
contraceptive pills on lupus disease activity in premenopausal women, results of their effects on the pituitary–
gonadal/adrenal axes, if any, are not yet available.
In animal models, an LH antagonist suppressed
autoimmune disease activity without a direct effect on
serum prolactin concentrations (12,13). Cyproterone, an
antigonadotropic agent, suppressed SLE disease activity
by lowering the estradiol:testosterone ratio (18). Similarly, bromocriptine, a dopamine agonist and suppressor
of prolactin, inhibited autoimmune disease in murine
lupus (15) and in patients with SLE (19). These observations have an underlying complexity based on the
interactions of the pituitary and immune systems, in that
inflammatory cytokines, especially interleukin-1 (IL-1),
tumor necrosis factor ␣, and IL-6, stimulate the release
of pituitary polypeptide hormones (9,10). Similarly, cytokines directly affect the target organs of FSH and LH,
primarily inhibiting the production of steroid hormones
(20,21). Completing the “endocrine” loop, pituitary hormones have direct effects on cytokine production and
lymphocytes (11). While the focus of investigation has
been on differences in steroid hormone immunoregulation, pituitary hormones may also play a critical role in
the modulation of SLE.
FSH
FSH is a 240–amino acid ␣,␤-chain peptide released from the anterior pituitary gland under hypothalamic pulse generator release control of gonadotropinreleasing hormone (GnRH), with feedback inhibition
from steroid hormones, especially estradiol. Responsible
primarily for gametogenesis (and ovulation) and stimulation of P450 aromatase enzyme activity, FSH in
women normally drives the production of estradiol from
testosterone in the ovary. Aromatase activity can occur
in other tissues, especially adipose tissues, and can
convert testosterone to estradiol in an FSH-independent
manner. In men, FSH primarily drives gametogenesis in
the testes (6,7).
To analyze associations between FSH and SLE,
we used a meta-analysis format in which all studies
identified by electronic medical literature search and
secondary reference reviews were collected and examined for the following inclusion criteria: enrollment of
nonpregnant female or male patients meeting the American College of Rheumatology 1982 revised criteria for
the classification of SLE (22), comparison of serum
3703
concentrations of the specified hormone using conventional measurement techniques, and inclusion of ageand sex-matched controls. Studies were excluded from
the meta-analysis if they did not measure serum hormone concentrations in a healthy control population, did
not provide clear data on statistical variation, or used
unconventional techniques of hormone assessment. We
sought to calculate a weighted common estimator based
on within-study variances. Calculation of Hedges common estimator (see Appendix A) is a basic statistical
analysis that facilitates comparison of multiple studies
that, individually, may not reach a definitive conclusion
regarding association or effect (5).
Several studies have assessed serum FSH concentrations in adult patients with SLE (23–36); those using
healthy age-matched controls and providing accessible
data for variation analyses were analyzed. In adult
patients with SLE, higher serum FSH concentrations
were found in 10 of 17 SLE patient/healthy control
groups, while FSH concentrations did not differ in 7
comparisons (Table 1 and Figure 1). Reporting of FSH
concentrations in SLE patients was relatively uniform,
and as expected, FSH concentrations were markedly
increased in postmenopausal SLE patients and healthy
controls, but did not differ significantly between controls
and patients (27).
To formulate general conclusions regarding serum pituitary hormone concentrations in adult SLE
patients, Hedges common estimator, a meta-analytic
measure of effect size (see ref. 5 and Appendix A), was
determined for SLE studies of females only and for SLE
studies of males only (Table 2). Additionally, 95%
confidence intervals (95% CIs) for overall effect were
calculated such that CIs that did not include zero
indicated a statistically significant difference. Since there
was not homogeneity of variances across all studies (one
of the confounders in interpreting SLE hormone data),
the Hedges common estimator results we report should
be interpreted with caution until more large-scale definitive and appropriately powered results are available.
Initial analysis of studies revealed considerable
heterogeneity between studies of FSH with respect to
mean differences and variation; therefore, a combined
estimator across all studies was not warranted. In the
initial statistical analysis of FSH, it was noted that 2
outlier studies (of females and males by Wen and Li [26]
and the midcycle study by Munoz et al [27]) contributed
the most to heterogeneity and an extremely large
Hedges effect for both female and male comparison
groups. Analysis of data without elimination of heterogeneous studies (which we do not believe is warranted)
unduly inflated Hedges gu (a measure of effect size) to
3704
LI ET AL
positive association was indicated between elevated FSH
levels and male SLE (Table 2).
While this analysis is not conclusive, it suggests
that FSH is not a persistent driving stimulus for the
increased estradiol concentrations reported in female
SLE patients (5). Possible explanations for the finding of
normal FSH levels with increased estradiol in women
with SLE include an FSH-independent increased aromatic hydroxylase activity or increased “throughput” of
steroid hormones driven by LH. Although to our knowledge, genetic polymorphisms of aromatase in SLE patients have not been analyzed, Folomeev et al have
reported increased aromatic hydroxylase activity in SLE
patients, even though this activity was inversely related
to SLE disease activity (37). Abnormal estrogen and
testosterone metabolism have also been reported in SLE
Table 2.
in SLE*
Hedges common estimator of studies of pituitary hormones
Pituitary hormone,
SLE patient group†
Figure 1. Controlled studies of serum concentrations of folliclestimulating hormone (FSH) in female and male patients with systemic
lupus erythematosus (SLE). Horizontal lines represent upper and
lower limits of normal (7). Values are the mean and SD. For the study
by Munoz et al (27), separate hormonal determination subsets are
indicated as follows: Munoz-1 ⫽ follicular phase; Munoz-2 ⫽ midcycle; Munoz-3 ⫽ luteal phase. Data from the study by Koeller et al
(29) were not included in the meta-analysis due to the absence of
values from the published report. # ⫽ P ⬍ 0.05 versus healthy
controls.
0.59 (95% CI 0.41, 0.77), indicating a strong association
between elevated FSH levels and SLE. Eliminating
outlier studies (2 studies of females only [1 with a
positive effect and 1 with a negative effect] and 1 study
of males only [with a positive effect]) produced, in our
estimation, a more valid assessment of the effect size for
the remaining studies. Additionally, the recent report by
Koeller et al (29) did not include data on variation at
baseline and was not included in the meta-analysis.
For female-only SLE patients, Hedges gu was
0.24 (95% CI ⫺0.02, 0.49), a value indicating no significant difference in FSH concentrations between female
SLE patients and female healthy controls. In male-only
SLE patients, the Hedges gu was 0.59 (95% CI 0.32,
0.85); since this CI did not include zero, a significant
FSH
Females only
Males only
LH
Females only
Males only
ACTH
All SLE patients
Females only
Males only
Prolactin
Females only
Males only
Hedges gu
(95% CI)‡
0.24 (⫺0.02, 0.49)
0.59 (0.32, 0.85)§
0.36 (0.10, 0.63)§
0.59 (0.32, 0.85)§
⫺0.27 (⫺0.61, 0.08)
ND
ND
0.30 (0.10, 0.50)§
1.20 (0.76, 1.65)§
* For meta-analysis, studies were included if they enrolled nonpregnant female or male systemic lupus erythematosus (SLE) patients who
met the American College of Rheumatology 1982 revised classification
criteria, compared serum concentrations of the specified hormone
using conventional measurement techniques, and had matched controls. Studies were excluded from the meta-analysis if they did not
measure serum hormone concentrations in a healthy control population, did not provide clear data on statistical variation, or used
unconventional techniques for hormone assessment. Some studies
examined female SLE patients in various hormonal states (i.e., follicular phase, luteal phase, postmenopausal) or included male SLE
patients in a separate analysis and were subclassified by first author
name and a numeric designation for separate hormonal determination
subsets (e.g., Munoz-1, Munoz-2, etc.). These data were treated as
individual assessments of hormonal status. Hedges common estimator
and 95% confidence interval (95% CI) were calculated according to
standard statistical methods (5). Data from the study by Koeller et al
(29) were not included due to the absence of SD data from the
published report. FSH ⫽ follicle-stimulating hormone; LH ⫽ luteinizing hormone; ACTH ⫽ adrenocorticotropic hormone; ND ⫽ not
determined.
† The common estimator compared SLE patients with their respective
controls for all SLE patients, female-only SLE patients, and male-only
SLE patients for the pituitary hormones listed.
‡ Hedges gu is a measure of effect size.
§ Statistically significant 95% CIs do not include zero.
HORMONES IN SLE
3705
Table 3. Controlled studies of serum concentrations of luteinizing hormone (LH) in patients with systemic lupus erythematosus (SLE)
No. of subjects
Age, mean ⫾ SD or range years
Author, year (ref.)
SLE
patients
Controls
SLE
patients
Controls
Conclusions
Female-only studies
Yozai, 1976 (23)
Lavalle et al, 1984 (24)
Arnalich et al, 1992 (25)
Wen and Li, 1993 (26)
Munoz et al, 1994 (27)
7
8
26
140
14
10
6
21
20
20
18–26
18–38
21–34
14–40
16–37
Matched (not shown)
22–30
20–32
20–36
Matched (not shown)
Redlich et al, 2000 (28)
Koeller et al, 2004 (29)
Male-only studies
Lavalle et al, 1987 (30)
Mackworth-Young et al,
1983 (31)
Stahl and Decker, 1978
(32)
Wen and Li, 1993 (26)
30
8
39
7
18–26
34 ⫾ 5
Matched (not shown)
38 ⫾ 4
LH higher in SLE patients
LH higher in SLE patients
No difference in LH
No difference in LH
LH higher in SLE patients during follicular
phase and luteal phase, but not during
midcycle; no correlation with disease
activity
LH higher in SLE patients
No difference reported
8
9
11
11
19–39
Matched (not shown)
25–40
Matched (not shown)
LH higher in SLE patients
No difference in LH
8
31
23–60
Matched (not shown)
No difference in LH
19
7
14–40
20–36
Sequiera et al, 1993 (33)
14
17
22–67
27–40
Munoz et al, 1994 (27)
Vilarinho and Costallat,
1998 (34)
5
7
7
10
22–57
26 ⫾ 7
Matched (not shown)
Matched (not shown)
Chang et al, 1999 (35)
16
20
19–46
Matched (not shown)
Mok and Lau, 2000 (36)
35
33
17–71
19–71
Koeller et al, 2004 (29)
3
2
34 ⫾ 5
38 ⫾ 4
patients (38,39), and other metabolic enzyme differences exist between healthy females and males (2).
While cytokines can affect ovarian steroid synthesis and
aromatase activity, IL-1 and IL-6 generally suppress
estradiol synthesis (20,21). Lupus patients have an increased 16␣:2␣ hydroxylated estrogen metabolite ratio,
producing more “feminizing” estrogens, and female SLE
patients have increased oxidation of testosterone
(38,39), but the relationship of these metabolic abnormalities to FSH secretion in lupus has not been elucidated.
In contrast to female SLE patients, the finding
of increased FSH in male SLE patients suggests that
hypothalamic–pituitary–gonadal (HPG) axis abnormalities exist. It should be noted that male SLE
patients are devoid of menstrual cyclicity and may
reflect a more constant baseline status of the HPG
axis. Significantly increased FSH levels in male SLE
patients in the setting of normal androgen and estradiol levels (5) implies that a central hypothalamic or
LH higher in SLE patients; all patients
were newly diagnosed and untreated
No difference in LH; abnormally high LH
in 21% of SLE patients compared with
0% of controls
LH higher in SLE patients
No difference in LH; abnormally high LH
in 14% of SLE patients compared with
0% of controls
LH higher in SLE patients; all patients
were newly diagnosed and untreated
LH higher in SLE patients; abnormally
high LH in 34% of SLE patients
compared with 9% of controls; no
correlation with active disease
LH higher in SLE patients (P value or SD
not reported)
hypophyseal disorder may exist in men with lupus. In
a small study (29), FSH release in response to GnRH
in male lupus patients was found to be higher than
that in healthy controls. Generally speaking, in
healthy men, neither androgens nor estrogens markedly affect FSH secretion frequency, and they only
modestly affect amplitude (6,7). Alternatively, the
increased FSH levels in male SLE patients may reflect
cytokine-stimulated release from the pituitary gland
(9,10). The abnormal FSH concentrations in only
male SLE patients, in combination with the previously
reported abnormal prolactin concentrations (5), imply
a primary pituitary abnormality associated with SLE
but absent from healthy controls.
LH
Closely resembling FSH, LH is also a 240–amino
acid ␣,␤-chain polypeptide hormone that is released
3706
from the anterior pituitary gland under the direct frequency and amplitude control of the rhythmic LHreleasing hormone (LHRH) oscillator. Under regulatory feedback control of androgens and estrogens, LH is
primarily responsible for the stimulation of the enzyme
P450 side-chain–cleavage enzyme that converts cholesterol to pregnenolone. LH drives initial steps in the
steroid synthesis pathway leading to DHEA, androstenedione, testosterone, and, eventually, estradiol after
aromatization. Several studies have assessed serum LH
concentrations in adult patients with SLE (23–36). Studies that included healthy age-matched controls and
provided accessible data for variation analysis are shown
in Table 3 and Figure 2. Similar to the case with FSH in
adult patients with SLE, there were higher serum concentrations of LH in 10 of 17 SLE patient/healthy
control groups, while there was no difference in 7
comparisons (Table 3). Reporting of LH concentrations
in SLE patients was relatively uniform, and, as expected,
LH was markedly increased in postmenopausal SLE
patients and in healthy controls (27).
Using Hedges common estimator, we formulated
general conclusions regarding serum LH concentrations
in adult female and male SLE patients compared with
healthy controls for SLE studies of females only and for
SLE studies of males only (Table 2 and Figure 2).
Meta-analysis again revealed considerable heterogeneity
of the Hedges common estimator (see Appendix A)
among these studies; therefore, a combined estimator
across all studies was not warranted. It was noted that 2
studies (of females and males by Wen and Li [26] and
the midcycle study by Munoz et al [27]) contributed the
most to heterogeneity and an extremely large Hedges
effect for both female and male comparison groups;
additionally, the recent report by Koeller et al (29) did
not include data on variation at baseline and was not
included in the meta-analysis. Eliminating the outlier
studies (1 with a positive effect and 1 with a negative
effect) produced a combined estimator for the remaining studies (Hedges gu) of 0.47 (95% CI 0.28, 0.66).
Analysis showed that for female SLE patients
only, Hedges gu was 0.36 (95% CI 0.10, 0.63), a value
that indicated significantly increased LH concentrations
in female lupus patients compared with healthy controls.
Similarly, for SLE studies of males only, the Hedges gu
was 0.59 (95% CI 0.32, 0.85); since this CI did not
include zero, a significant, positive, strong association
was indicated between elevated LH levels and SLE in
males. LH release in male SLE patients in response to
GnRH has recently been reported to be higher than LH
release in healthy controls (29).
LI ET AL
Figure 2. Controlled studies of serum concentrations of luteinizing
hormone (LH) in female and male patients with systemic lupus
erythematosus (SLE). Horizontal lines represent upper and lower
limits of normal (7). Values are the mean and SD. For the study by
Munoz et al (27), separate hormonal determination subsets are
indicated as follows: Munoz-1 ⫽ follicular phase; Munoz-2 ⫽ midcycle; Munoz-3 ⫽ luteal phase; Munoz-4 ⫽ postmenopausal. Data
from the study by Koeller et al (29) were not included in the
meta-analysis due to the absence of values from the published report.
# ⫽ P ⬍ 0.05 versus healthy controls.
Increased serum LH levels in SLE patients is
consistent with the findings of several individual studies
and a previous analysis showing that androgen levels,
specifically, DHEA and testosterone, are lower in SLE
patients (5), leading to a loss of feedback inhibition of
LH secretion (6,7). A plausible explanation would be a
hyperactive P450 aromatization enzyme that lowers testosterone concentrations, increases LH secretion via loss
of negative feedback from androgens, and leads to
increased estradiol concentrations. Increased aromatase
activity may possibly be independent of pituitary regulation or suppression from prolactin (6,7). Clinical manifestations of disease caused by chromosomal transloca-
HORMONES IN SLE
3707
Table 4. Controlled studies of serum concentrations of adrenocorticotropic hormone (ACTH) in female and male patients with systemic lupus
erythematosus (SLE)
No. of subjects
Age, mean ⫾ SD or range years
Author, year (ref.)
SLE
patients
Controls
SLE
patients
Controls
Conclusions
Schurmeyer et al, 1985 (46)
14
19
16–68
Matched (not shown)
Iushchishin et al, 1989 (47)
25
25
Matched (not shown)
Matched (not shown)
7
10
20–53
Matched (not shown)
Zietz et al, 2000 (49)
12
12
Matched (not shown)
Matched (not shown)
Jiang et al, 2001 (50)
39
15
14–56
Matched (not shown)
Martins et al, 2002 (51)
10
10
44 ⫾ 13
25 ⫾ 4
No difference in ACTH; receiving
steroid treatment
Lower ACTH in SLE patients;
treatment status unknown
Higher ACTH in SLE patients;
active, untreated SLE
No difference in ACTH; receiving
steroid treatment
No difference in ACTH; active,
untreated SLE
Lower ACTH in SLE patients;
active, untreated SLE
Gutierrez et al, 1998 (48)
tion of the P450 aromatase enzyme locus to the
constitutive promoter (40,41) have been described which
have led to excessive feminization due to estradiol
synthesis. Increased aromatase activity has been reported in SLE patients (37), and an aromatase inhibitor
suppresses murine lupus disease activity (42), suggesting
that this may be a primary hormonal aberration in lupus
patients.
It must be further considered that LH has direct
immunomodulatory effects on lymphocyte proliferation
(11) and cytokine production (43). Peripheral production of pituitary peptides by mononuclear cells has been
suggested (44,45). Conversely, LHRH antagonists suppress murine lupus disease activity in castrated animals,
and LH immunomodulation may occur in a sexdependent pattern (12,13). Therefore, the increased LH
levels in SLE patients that were observed across several
studies may not only be a marker for the disordered
HPG axis in lupus patients, but it may also contribute
directly to lupus disease expression.
ACTH
ACTH, a 128–amino acid hormone released from
the anterior pituitary gland, stimulates adrenal cortisol
production. Its release is normally under direct regulatory feedback control from cortisol as well as from
innervation of the sympathetic nervous system (6,7).
Surprisingly, few studies have directly evaluated the
hypothalamic–pituitary–adrenal (HPA) axis in SLE patients compared with healthy controls (46–51). Studies
of ACTH in SLE patients that included healthy agematched controls and provided accessible data for analysis are shown in Table 4. In contrast to the gonadotro-
pins FSH and LH, there were no clear trends toward an
association of serum ACTH levels with SLE: 1 study
showed higher levels, 2 studies showed lower levels, and
3 studies showed the same levels in SLE patients compared with healthy controls. The Hedges gu across all
studies was –0.27 (95% CI –0.61, 0.08), a small effect
size that failed to reach statistical significance. Because
of the small number of studies and the small number of
patients enrolled in each study, the results must be
considered with caution. Moreover, several of these
studies were confounded by the use of corticosteroids in
the treatment of SLE. The largest study of serum ACTH
levels in untreated SLE patients with active disease (50)
showed no difference between SLE patients and healthy
controls. Similarly, there are very few studies of cortisol
that clarify the function of the HPA axis in SLE patients
(5).
TSH and GH
TSH, a small polypeptide, is known to have
immunoregulatory functions (52); however, essentially
no studies have investigated the relationship between
serum concentrations of TSH and the development or
severity of SLE in a case–control manner. Clearly,
several studies have established that the development of
thyroid autoantibodies and thyroid autoimmunity can be
associated with SLE (53–56) and hyperprolactinemia. A
preliminary study (29) has suggested that SLE patients
have increased TSH release in response to provocation
as compared with healthy controls. However, the baseline TSH concentrations were not different in SLE
patients and healthy controls, and the significance of this
preliminary finding is unknown. This finding adds to the
3708
implication that abnormalities of several pituitary hormones exist in SLE patients and may contribute to the
development or activity of SLE.
Similarly, even though GH has been implicated
to play a variety of immunomodulatory roles (57,58),
GH abnormalities in SLE patients are virtually unreported. Available studies (29,59) have not identified
marked abnormalities in GH physiology in patients with
SLE; however, there is a single case report (60), similar
to that for prolactin in rheumatoid arthritis (61), in
which GH administration was temporally associated
with the development of SLE. While GH appears to be
immunomodulatory, the paucity of current data precludes conclusions regarding the potential role of GH in
SLE. Similar to the case with TSH and GH, there are no
remarkable studies reported that have assessed the
posterior pituitary hormones—antidiuretic hormone or
oxytocin—in SLE patients and healthy controls.
Prolactin
The association between SLE and abnormalities
of prolactin (as a sex hormone) has been recently
reviewed in detail (4,5); however, due to the duality of
prolactin as a pituitary hormone and as a sex hormone,
we include a brief discussion of this association for
completeness. Prolactin is a polypeptide pituitary sex
hormone with different concentrations between sexes
(6,7) as well as a broad array of immunoregulatory
properties (4,5). Estradiol stimulates prolactin secretion,
and prolactin typically suppresses the stimulatory effect
of gonadotropins on gonadal steroid synthesis, leading
to amenorrhea (6,7). A recent analysis (5) found increased prolactin concentrations across all SLE patients
as well as in female-only and male-only groups of SLE
patients (Table 2). Moreover, the prevalence of hyperprolactinemia (prolactin ⬎20 ng/ml) in SLE patients was
20% across several studies compared with 3% in healthy
controls. This prevalence in SLE patients was markedly
higher than the 1–2% prevalence reported for general
populations and was also significantly higher than that in
healthy controls (for review, see ref. 5).
Prolactin probably stimulates lupus disease activity, and serum prolactin concentrations have been positively correlated with disease activity. Abnormally high
prolactin levels during pregnancy in SLE patients also
correlate with disease activity; however, in pregnancy,
this appears to occur in the setting of abnormally low
estrogen concentrations, again implying an underlying
primary pituitary abnormality or one perpetuated by
autoimmune inflammatory changes (for review, see refs.
LI ET AL
4 and 5). Two double-blind, placebo-controlled studies
in humans have shown that suppression of prolactin with
bromocriptine reduces SLE disease activity (19,62).
Conclusion
Possible associations between the sexual dichotomy in SLE and endocrinologic abnormalities extend
beyond estrogens and androgens. Lower than normal
levels of androgens and/or higher than normal levels of
estradiol/prolactin in SLE patients appear to constitute
immunostimulatory hormone environments in this disease (3–5). However, traditional immunoendocrine concepts of manipulating just estrogens or androgens for a
directed, desired effect may be too simplistic. The
presence of pituitary hormone abnormalities suggests
that predisposing or even modulatory relationships exist
between lupus or lupus disease activity and LH, prolactin, and, possibly, FSH. In fact, in the perceivably less
complex male pituitary–gonadal axis, strong associations
exist between FSH, LH, and prolactin and SLE without
well-established evidence for estradiol or testosterone
(suppressed androgen) abnormalities in men with lupus
(5). It is not known whether male SLE patients with
abnormal levels of FSH, LH, and prolactin had more
severe disease, since disease severity indices were not
provided in the majority of studies reviewed. While age
has a significant influence on SLE incidence (16) and
serum hormone concentrations (17), in the majority of
studies included in our analyses, patients and controls
appeared to be relatively well matched, and age is
therefore unlikely to account for the significant differences observed between lupus patients and healthy
controls.
Chronobiologic variability of menses and hormone administration as well as the heterogeneity of
results in some studies further confound the conclusions,
especially in female patients. The possibility of a reporting bias also exists, but is somewhat mitigated by the fact
that investigators in several studies included in this
review (see Tables 1, 3, and 4) reported “no difference”
in the results for the pituitary hormones. Finally, treatment with nonsteroidal antiinflammatory drugs, corticosteroids, hydroxychloroquine, and cytotoxic drugs may
affect the pituitary–gonadal axis, thereby confounding
the interpretation of the results. However, the effects of
various immunosuppressive treatments on pituitary hormone concentrations in SLE patients in relation to
disease activity are essentially unknown. While studies
(e.g., assessing long-term cytotoxic drug administration)
have shown significant effects on gonadal function,
HORMONES IN SLE
virtually none have assessed the relationship with disease activity or pituitary hormone release.
Corticosteroids, perhaps the most widely administered treatment in the studies reviewed, have generally
been reported to suppress the release of pituitary hormones (FSH, LH, ACTH, prolactin) in healthy individuals (6,7). These results are in clear contrast to the
findings of elevated FSH, LH, and prolactin levels in the
present study, which imply that corticosteroid suppression of pituitary hormones was not a significant influence across our analysis. In a subset analysis of SLE
patients, Munoz et al (27) found that corticosteroids
suppressed prolactin concentrations; in contrast, Mok
and Lau (36) did not find a significant difference in the
effect of corticosteroids on pituitary hormone concentrations between male SLE patients and controls. Prolonged treatment with cytotoxic drugs may induce hypogonadism and thereby elevate FSH and LH levels (6,7).
A few patients in 4 studies of males (27,33,34,36) and in
1 study of females (27) were treated with azathioprine,
but this was unlikely to markedly influence the results. In
a subset analysis of SLE patients, Mok and Lau (36) did
not find significant effects of azathioprine or hydroxychloroquine treatment on serum pituitary hormone levels in male SLE patients. Therefore, the meta-analysis
results, which must be interpreted with caution, cannot
be explained by an effect of SLE treatment, especially in
relation to cytotoxic drugs.
While associations do not equal causality, this
Hedges analysis leads to the conclusion that in addition
to the well-described gonadal hormone abnormalities
(5), SLE patients also have an altered pituitary hormonal milieu, best described as abnormally elevated
FSH, LH, and prolactin concentrations compared with
those in healthy matched controls. These findings complicate a simple and clear understanding or explanation
of SLE predisposition and modulation of disease activity
by hormones; they highlight the fact that pituitary
hormone abnormalities occur both in women and in men
with SLE, while sex steroid hormone abnormalities
appear to segregate to women with SLE (5). Since levels
of estrogens, androgens, FSH, LH, and prolactin normally differ between healthy women and men, the
current study emphasizes the differences in pituitary
hormones between SLE patients and controls. It remains to be proven whether these changes predispose to
disease development, modulate or perpetuate autoimmunity, or result from the autoimmune process. However, results of clinical studies manipulating pituitary
hormones, via either the antigonadotropin cyproterone
(18) or the prolactin-suppressive drug bromocriptine
3709
(19,62), imply that pituitary peptide hormones directly
or indirectly (through gonadal steroids) modulate autoimmune disease manifestations.
Virtually no studies have examined the relationship between changes in pituitary hormone levels and
SLE disease activity over time, with the exception of
small studies of the effects of cyproterone (18) and
bromocriptine-induced effects (19,62). Changes in gonadal steroids via the HPG axis (cyproterone induced)
(18) or prolactin (bromocriptine induced) (19,62) were
associated with decreased SLE activity over time. Lower
than normal levels of androgens, as previously reviewed
(5), and/or higher than normal levels of estradiol/
prolactin also appear to constitute immunostimulatory
hormone environments in SLE (3–5). Missing information focusing on the etiology of elevated LH levels and
the role of aromatase activity in SLE may be of critical
importance. The findings of FSH, LH, and prolactin
abnormalities in male-only groups with SLE (with comparatively normal estradiol/testosterone; see ref. 5) suggest that male lupus patients may have a primary
pituitary abnormality that predisposes to or modulates
lupus disease activity. These results in adult SLE patients are similar to those reported by Athreya et al (63)
in pediatric SLE patients. In that study, FSH and LH
levels were higher in postpubertal boys and girls with
SLE than in healthy individuals. This trend did not reach
statistical significance, but there was a significantly
higher percentage of pediatric female SLE patients with
abnormal serum levels of FSH, LH, and prolactin (63).
The most accurate and feasible method by which
to determine conclusively the role of pituitary hormones
in human SLE appears elusive. A large prospective study
of hormonal abnormalities in a population at high risk of
developing SLE (as described for rheumatoid arthritis
below) is not clearly feasible for SLE due to the lower
incidence of the disease. Conversely, a longitudinal case
study correlating hormone concentrations with disease
activity in untreated SLE and/or with treatment with
hormone agonists or antagonists is unlikely to be acceptable or precise due to high variability and confounding
factors, such as age, concomitant hormone administration, and various treatment regimens.
Nevertheless, findings of hormonal aberrations in
rheumatoid arthritis prior to the onset of disease (64)
have implied that endocrine abnormalities may predispose to autoimmune disease development and are not
the result of inflammation. The current results disclose
the extended range of endocrine abnormalities in SLE
and call for further analyses and investigation that would
lead to novel and improved understanding of the factors
3710
LI ET AL
that predispose to SLE development and would provide
for more effective application of hormonal immunotherapy.
19.
ACKNOWLEDGMENT
Dr. McMurray would like to thank Dr. Sara Walker for
her support and mentorship.
20.
21.
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APPENDIX A: HEDGES COMMON ESTIMATOR
CALCULATION
The Hedges formulation is based on the usual T statistic
approach to testing for differences between the experimental (E) and
control (C) group means. The pooled estimator of the SD, sp, is used
for Hedges gu, as:
sp ⫽
冑
共nE ⫺ 1兲sE2 ⫹ 共nC ⫺ 1兲s2C
nE ⫹ nC ⫺ 2
where sE and sC are the SDs from the experimental and control groups,
respectively. Find this estimator for each of the i studies in the
meta-analysis.
The Hedges estimator (gu) of the effect for the ith study is
determined as:
gi ⫽
៮ Ei ⫺ Y
៮ Ci
Y
s Pi
៮ E and Y
៮ C are the sample means for the experimental and
where Y
control groups. In a sense, gi represents the standardized estimate of
increase (decrease) in mean response over that of normal controls.
The variance of gi is determined as:
Var共gi兲 ⫽
n Eu ⫹ n Cu
gi2
⫹
n Ein Ci
2共nEuI ⫹ nCi ⫺ 2兲
The above formulas give gi and Var(gi) for the ith study. To
find a combined estimator of the effect size, calculate the above
(simple enough to program in a spreadsheet) and sum over all studies
using the following formula:
冘
冘
k
w ig i
␦ˆ ⫽
i⫽1
k
i⫽1
wi
3712
LI ET AL
where the weight, wi, is the inverse of the variance:
wi ⫽
1
Var共gi兲
The square root of the variance is the standard error, so a
100(1 ⫺ ␣)% confidence interval is easy to compute:
␦ˆ ⫾
The variance of the combined Hedges g estimator is:
Var共 ␦ˆ 兲 ⫽
1
冘
DOI 10.1002/art.21614
k
wi
i⫽1
k
i⫽1
冑冘
Za/2
wi
Thus, the Hedges common estimator provides a statistical measurement of effect size over a number of studies that, in and of themselves,
do not arrive at a consistent conclusion (5).
Clinical Images: Dysphagia after testicular cancer
The patient, a 34-year-old man, developed progressive muscle weakness and dysphagia 3 months after surgery for testicular cancer.
On examination, the patient’s proximal muscle strength was diminished, and an erythematous, scaly, and plaque-like rash with a
predilection for extensor surfaces was observed. His serum creatine kinase level was 3,549 units/liter (normal ⬍325). Magnetic
resonance imaging (MRI) of the shoulder and neck revealed multifocal areas of inflammation. Increased STIR signal was apparent
at the shoulder muscles, most prominent in the infraspinatus (arrow in A) and deltoid (arrowhead in A) muscles. Increased T2 signal
was identified in the tongue (curved arrow in B), masticator (arrowhead in B), pharyngeal (thick arrow in B), and paravertebral
(thin arrow in B) muscles. Laboratory testing and skeletal muscle biopsy confirmed a diagnosis of malignancy-associated
dermatomyositis. The clinical symptoms improved with immunosuppressive treatment. MRI is a useful tool for identifying
inflammation in areas that are otherwise difficult to visualize.
Rodolfo V. Curiel, MD
Kathleen A. Brindle, MD
George Washington University Medical Center
Washington, DC
Bruce R. Kressel, MD
Washington Oncology Hematology Center
Washington, DC
James D. Katz, MD
George Washington University Medical Center
Washington, DC
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