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Testosterone therapy in men with Crohn's disease improves the clinical course of the disease: Data from long-term observational registry study

Authors:
  • Praxis Dr. Haider, Bremerhaven

Abstract and Figures

Crohn's disease is an inflammatory chronic bowel disease characterized by an imbalanced production of pro-inflammatory mediators (tumor necrosis factor-α) and an increased recruitment of leukocytes to the site of inflammation. Low serum testosterone is associated with an increase in inflammatory factors, while testosterone administration reduces them. There is evidence for an immunomodulatory effect of testosterone on differentiation of regulatory T cells. The research was carried out in clinics in Germany and Syria. The study was a cumulative, prospective, registry study with an increasing number of men over time receiving testosterone. While men diagnosed with Crohn's disease received appropriate treatment for Crohn's disease, they were tested for testosterone deficiency (cut-off point ≤12.1 nmol/L). In total, 92 men received parenteral testosterone undecanoate 1000 mg/12 weeks for up to 7 years. Fourteen men opted not to receive testosterone and served as a comparison group. In men receiving testosterone, the Crohn's Disease Activity Index declined from 239.36±36.96 to 71.67±3.26 at 84 months (p<0.0001 vs. baseline). C-reactive protein levels decreased from 12.89±8.64 to 1.78±1.37 mg/L at 84 months (p<0.0001 vs. baseline). Leukocyte count decreased from 11.93±2.85 to 6.21±1.01×109/L (p<0.0001 at 84 months vs. baseline). No changes were observed in the comparison group. There were no significant side effects of testosterone. Normalizing serum testosterone in hypogonadal men with Crohn's disease had a positive effect on the clinical course, also evidenced by biochemical parameters. Testosterone administration appeared safe.
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Horm Mol Biol Clin Invest 2015; 22(3): 111–117
*Corresponding author: Dr. Farid Saad, Bayer Pharma, Global
Medical Affairs Andrology, Muellerstrasse 178, 13353 Berlin,
Germany, Phone: +49-30-46815057, Fax: +49-30-46895057,
E-mail: farid.saad@bayer.com
Mahmoud Nasser: Department of Gastroenterology,
University of Aleppo, Aleppo, Syria
Ahmad Haider: Private Urology Practice, Bremerhaven, Germany
Winfried Kurtz: Department of Internal Medicine, Klinikum
Bremerhaven, Bremerhaven, Germany
Gheorghe Doros: Department of Epidemiology and Statistics,
Boston University School of Public Health, Boston, MA, USA
Monika Fijak: Department of Anatomy and Cell Biology,
Justus-Liebig University, Giessen, Germany
Linda Vignozzi: Sexual Medicine and Andrology Unit, Department
of Experimental and Clinical Biomedical Sciences, University of
Florence, Italy
Louis Gooren: VU medical Center, Department of Internal Medicine,
Endocrine Section, Amsterdam, The Netherlands
Mahmoud Nasser, Ahmad Haider, Farid Saad*, Winfried Kurtz, Gheorghe Doros, Monika Fijak,
Linda Vignozzi and Louis Gooren
Testosterone therapy in men with Crohn’s disease
improves the clinical course of the disease: data
from long-term observational registry study
Abstract
Background: Crohn’s disease is an inflammatory chronic
bowel disease characterized by an imbalanced production
of pro-inflammatory mediators (tumor necrosis factor-α)
and an increased recruitment of leukocytes to the site of
inflammation. Low serum testosterone is associated with
an increase in inflammatory factors, while testosterone
administration reduces them. There is evidence for an
immunomodulatory effect of testosterone on differentia-
tion of regulatory T cells.
Materials and methods: The research was carried out in
clinics in Germany and Syria. The study was a cumulative,
prospective, registry study with an increasing number of
men over time receiving testosterone. While men diagnosed
with Crohn’s disease received appropriate treatment for
Crohn’s disease, they were tested for testosterone deficiency
(cut-off point   12.1 nmol/L). In total, 92 men received paren-
teral testosterone undecanoate 1000 mg/12 weeks for up to
7 years. Fourteen men opted not to receive testosterone and
served as a comparison group.
Results: In men receiving testosterone, the Crohn’s Disease
Activity Index declined from 239.36±36.96 to 71.67±3.26 at
84 months (p < 0.0001 vs. baseline). C-reactive protein
levels decreased from 12.89±8.64 to 1.78±1.37 mg/L at
84 months (p < 0.0001 vs. baseline). Leukocyte count
decreased from 11.93±2.85 to 6.21±1.01 × 109/L (p < 0.0001 at
84months vs. baseline). No changes were observed in the
comparison group. There were no significant side effects
of testosterone.
Conclusions: Normalizing serum testosterone in hypogo-
nadal men with Crohn’s disease had a positive effect on
the clinical course, also evidenced by biochemical para-
meters. Testosterone administration appeared safe.
Keywords: Crohn’s disease; Crohn’s Disease Activity
Index; highly sensitive C-reactive protein; inflammation;
testosterone.
DOI 10.1515/hmbci-2015-0014
Received February 19, 2015; accepted April 22, 2015; previously
published online May 15, 2015
Introduction
Testosterone traditionally has been regarded as a hormone
serving male sexual and reproductive functions. Over
the last decades it has become clear that testosterone is
involved in a multitude of other biological processes, such
as the health of bone and muscle, numerous metabolic
processes and also the cardiovascular system. An even
more novel aspect of the physiology of testosterone is its
role in inflammation. Inflammatory processes play a sig-
nificant role in the etiology of cardiovascular disease, and
testosterone shows anti-inflammatory effects [1]. Several
studies have documented that low testosterone levels are
associated with an increase in inflammatory factors and
that administration reduces their levels (for review [2, 3]).
There is evidence showing an immunomodulatory and
protective effect of testosterone in a model of chronic tes-
ticular inflammation and testosterone as a new factor in
the differentiation of regulatory T cells [4].
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112     Nasser etal.: Crohn’s disease and testosterone
Inflammatory bowel disease is a chronic inflamma-
tory disorder that is comprised of both Crohn’s disease
and ulcerative colitis and is characterized by alternating
phases of clinical relapse and remission. Although their
etiologies are unknown, they are characterized by an
imbalance in production of pro-inflammatory mediators,
e.g., tumor necrosis factor (TNF)-α, as well as increased
recruitment of leukocytes to the site of inflammation [5, 6].
This contribution reports our observations in hypo-
gonadal men with Crohn’s disease receiving testosterone
treatment. While their hypogonadal status might be also
explained by a number of etiological factors, inflammatory
factors associated with Crohn’s disease might have contrib-
uted to their hypogonadism [7, 8]. This has been found to be
the case in not only elderly men but also younger men [9].
There is increasing evidence from both clinical and
experimental studies showing that testosterone has
marked anti-inflammatory effects. In a Russian rand-
omized, placebo-controlled trial in hypogonadal men
with metabolic syndrome (MetS), testosterone therapy
resulted in significant reductions in highly sensitive
C-reactive protein (hsCRP) (p < 0.001), TNF-α (p = 0.03)
and IL-1β (p = 0.008) [10]. In a controlled 2-year study
from Italy in hypogonadal men with MetS, reductions
of hsCRP (p < 0.001) and carotid intima media thickness
(CIMT) (p < 0.0001) were shown [11]. In another controlled
study by the same group of 3years duration in hypogo-
nadal men with MetS, hsCRP (p = 0.001) was significantly
reduced under testosterone treatment [12].
In a 12-month study in severely obese hypogonadal
men undergoing lifestyle intervention by diet and exercise
with or without addition of testosterone, there were signif-
icant reductions in hsCRP (p < 0.001) and CIMT (p < 0.0001)
in the testosterone but not in the control group [13]. In a
controlled 5-year study in hypogonadal men with MetS,
significant reductions in hsCRP (p = 0.001) and fibrinogen
(p = 0.0001) were observed [14].
In a wealth of studies, the anti-inflammatory effect of
testosterone has been demonstrated [8, 15–21].
Several preclinical studies have demonstrated that
androgens act as endogenous inhibitors of immune
responses in several autoimmune processes, including
those involved in non-alcoholic steatohepatitis (NASH)
[22], benign prostatic hyperplasia [23] and autoimmune
orchitis [4].
Moreover, the anti-inflammatory properties of
androgens were shown already in several experimental
animal models of autoimmune diseases such as experi-
mental autoimmune encephalomyelitis, myasthenia
gravis or diabetes [24–28]. At the cellular level, in vitro
testosterone treatment leads to the shift from Th1 to Th2
response by reduction of TNF-α or IL-6 secretion, inhibi-
tion of proliferation of T cells and apoptosis [26, 29–32]. As
shown recently, subphysiological levels of testosterone in
androgen-deficient male rats lead to decrease in IL-2, IL-6,
IL-10, IL-12 and IL-13, while testosterone supplementation
has an opposite effect [33].
Recently, activation of androgen receptor (AR) by
androgens has been demonstrated to reduce proliferation
of CD4+T clones and to markedly suppress the inflamma-
tory response of human non-professional antigen present-
ing cells culture – such as those present within the prostate
– to inflammatory stimuli [such as TNF-α and the lipopoly-
saccharide (LPS)] or to co-incubation with activated CD4+T
lymphocytes, therefore suggesting that androgens could
play a broad anti-inflammatory role in T cells. Interestingly,
supplementation of reduced serum testosterone levels in a
rat model of experimental autoimmune orchitis led in the
testis to reduction of disease severity, down- regulation of
TNF-α, IL-6 and MCP-1 mRNA expression, inhibition of mac-
rophages recruitment as well as increase in the number of
regulatory T cells – responsible for aggravation of autoim-
mune responses. In vitro, testosterone stimulated directly
the expression of regulatory T cell-specific transcription
factor Foxp3 in rat splenic T cells. Moreover, at the sys-
temic level significant decrease of pro- inflammatory Th1
cytokines IL-2 and IFN-γ secretion by mononuclear cells
from lymph nodes draining the testis was observed. Our
recent results show that testosterone administration is able
to inhibit LPS-induced TNF-α expression in testicular cells
(Sertoli and peritubular cells), and androgens secreted
directly by Leydig cells stimulate production of regulatory
cytokine IL-10 by T cells [34]. Similarly, human monocyte-
derived macrophages stimulated with oxidized low-den-
sity lipoproteins and subsequently treated with normal or
supraphysiological concentrations of testosterone showed
reduced expression and secretion of TNF-α and IL-1 beta;
however, the expression of IL-6 and C-reactive protein
(CRP) was not affected [35]. All these reports underline
immunoregulatory and protective properties of androgens
in immune tolerance.
Our previous study demonstrated the effects of 2years
of serum testosterone levels normalization in a small
group of men with Crohn’s disease [36]. Upon normaliza-
tion of plasma testosterone, the Crohn’s Disease Activity
Index (CDAI) and serum levels of CRP declined in hypo-
gonadal patients with Crohn’s disease. Immunosuppres-
sive effects of testosterone may have contributed to this
improvement of the disease.
The present study is a prospective, cumulative,
observational registry study of hypogonadal men with
Crohn’s disease who received treatment with testosterone.
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Nasser etal.: Crohn’s disease and testosterone     113
Untreated hypogonadal men with Crohn’s disease served
as comparison subjects.
Subjects and methods
The study was carried out in the Department of Internal Medicine,
Klinikum Bremerhaven, Germany, together with a private urology
practice in Bremerhaven, Germany, and the Department of Gas-
troenterology, University of Aleppo, Syria, between the years 2004
and 2013. In patients diagnosed with Crohn’s disease, serum testos-
terone was measured, and if below normal (see below) they were
referred to the urology practice for possible testosterone adminis-
tration. In Syria, if hypogonadal, they received testosterone treat-
ment in the Department of Gastroenterology, University of Aleppo.
The study was a cumulative, prospective, registry study of 92 men
with Crohn’s disease with testosterone levels     12.1 nmol/L. Patients
received standard treatment for Crohn’s disease by their internist/
gastroenterologist and also standard treatment for hypogonadism:
parenteral testosterone undecanoate (Nebido®, Bayer Pharma, Ber-
lin, Germany) 1000 mg/12 weeks following an initial 6-week interval
for up to 7 years. New patients were consecutively entered into the
study once they had completed 1 year of treatment. So, drop-outs in
this rst year of testosterone treatment have not been included in the
registry. In total, 92 men were treated for at least 12 months, 74 for at
least 24 months, 50 for at least 36 months, 30 for at least 48 months,
25 for at least 60 months, 17 for at least 72 months, and 12 for at least
84 months. The declining numbers do not reect drop-out rates but
are a result of the registry design. Fourteen hypogonadal men of simi-
lar age with Crohn’s disease in the Aleppo clinic who opted not to
receive testosterone were followed up for 30months and served as an
untreated comparison group.
The CDAI has been developed to assess the severity of the dis-
ease and to monitor the eects of interventions on the course of
the disease. The CDAI consists of eight factors, each summed aer
adjustment with a weighting factor. Index values of 150 and below
are associated with quiescent disease; values above that indicate
active disease, and values above 450 are seen with extremely severe
disease [37]. The severity of Crohn’s disease was assessed every
3months with the CDAI. In addition, hsCRP [38] and leukocyte count
were measured. Liver enzymes were determined since the liver is the
source of TNF-α [39].
The CDAI was assessed every 3months [40]. Anthropometric
parameters (waist circumference and weight), total testosterone,
fasting glucose, lipids (total cholesterol, LDL cholesterol, HDL cho-
lesterol and triglycerides), liver transaminases (aspartate and alanine
aminotransferase, AST and ALT), hemoglobin (Hb), hematocrit (Htc),
systolic and diastolic blood pressure, and heart rate were assessed
at each visit. T scores were obtained from those patients who had
osteoporosis. Prostate parameters [prostate volume, prostate-specic
antigen (PSA)] were measured at every other visit.
Exclusion criteria for testosterone administration included
previous treatment with androgens, prostate cancer or any suspi-
cion thereof: such as PSA levels  > 4 ng/mL, International Prostate
Symptom Score  > 19 points, breast cancer, a history of congestive
heart failure or recent angina, history of cerebral vascular accident
or severe untreated sleep apnea.
All initial serum testosterone samples had been obtained bet-
ween 7:00 and 11:00 a.m. Serum testosterone levels were measured
before testosterone administration, then before the second injection
at 6 weeks and subsequently before the next injection of testosterone
undecanoate was due, as a rule 12 weeks later. Serum testosterone
was measured by commercially available chemiluminescent radio-
immunoassays.
Ethical guidelines as formulated by the German “Ärztekam-
mer” (the German Medical Association) for observational studies in
patients receiving standard treatment were followed both in Germany
and Syria. Aer receiving an explanation regarding the nature and
the purpose of the study, all subjects consented to be included in the
research of their treatment protocol.
Statistical analysis
For continuous variables, the mean, median, standard deviation,
range, minimum, maximum and sample size for the overall sample and
various groups were reported at each time point. For categorical varia-
bles, the frequency distribution was reported. We tested the hypotheses
regarding change in outcome scores across the study period by tting a
linear mixed eects model to the data. Time (to indicate follow-up inter-
views) was included as xed eect in the model. A random eect was
included in the model for the intercept. Estimation and test of change
in scores were determined by computing the dierences in least square
means at baseline vs. the score at each follow-up interview. For the cor-
relation study, Pearson’s correlation was calculated between baseline
changes in outcomes at various time points. The signicance of each
correlation was tested using Fisher’s test.
Results
Serum testosterone
Testosterone levels at baseline were 9.68±1.09 nmol/L
in the testosterone group and 9.57±2.96 in the compari-
son group. During treatment, testosterone increased to
16.4±1.96 nmol/L within 24 months and then remained
stable. Serum testosterone slightly declined in the com-
parison group.
CDAI and inflammation parameters
In the testosterone group, the CDAI declined from
239.36±36.96 to 71.67±3.26 at 84 months (Figure 1).
This decrease was statistically significant vs. baseline
(p < 0.0001) at the end of each year and vs. previous year
for the first 3 years, after which levels stabilized. This
decline was not observed in the comparison group.
hsCRP levels decreased from 12.89±8.64 to 1.78±1.37
mg/L at 84months with statistical significance vs. base-
line (p < 0.0001) each year and vs. previous year for the
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114     Nasser etal.: Crohn’s disease and testosterone
first 4years in the testosterone group (Figure 2). There was
a tendency to increase in the comparison group.
Leukocyte count decreased from 11.93±2.85 to
6.21±1.01 × 109/L in the testosterone group (Figure 3). This
was statistically significant vs. baseline (p < 0.0001). Leu-
kocyte count remained unchanged in the comparison
group.
Liver transaminases (AST and ALT)
AST declined from 43.75±17.93 to 20.08±3.58 U/L (Figure 4),
ALT from 46.99±17.04 to 20.42±4.06 U/L in the testosterone
group (Figure 5). Changes for both were statistically sig-
nificant vs. baseline (p < 0.0001) each year and vs. previous
year for the first 3 years. Both enzymes showed a tendency
to increase in the comparison group. Twelve patients had
very high ( > 70 U/L) AST and 10 patients very high ( > 70U/L)
ALT levels at baseline, all in the testosterone group.
Hb: At baseline, Hb was 13.93±0.59 g/dL in the tes-
tosterone group and 14.43±0.23 in the control group
(p = 0.00269). Hb rose from 13.93±0.59 to 14.4±0.56 g/dL in
the testosterone group (p < 0.0001) with statistical signifi-
cance vs. previous year for the first 2 years. Hb remained
stable in the control group.
Htc: At baseline, Htc was 42.2±2.63% in the testoster-
one group and 45.5±1.61 in the control group (p = 0.000014).
Htc rose from 42.2±2.63 to 47.75±1.36% in the testosterone
group (p < 0.0001) with statistical significance vs. previ-
ous year for the first 4 years. Htc levels remained within
the normal range (minimum: 46%; maximum: 51%). Htc
showed a tendency to decrease in the control group.
ab
Leukocytes, 109/L
Figure 3: Effect of testosterone administration on leukocyte count
in 92 men receiving testosterone compared to 14 men receiving no
testosterone (mean±SEM). b vs. a, p = 0.0001.
ab c
Figure 4: Effect of testosterone administration on AST in 92 men
receiving testosterone compared to 14 men receiving no testoster-
one (mean±SEM). b vs. a, p = 0.001; c vs. b, p=0.02.
ab c d
Figure 1: Effect of testosterone administration on CDAI in 92 men
receiving testosterone compared to 14 men receiving no testoster-
one (mean±SEM). b vs. a, p = 0.001; c vs. b, p = 0.02; d vs. c, p < 0.05.
a b c d
Figure 2: Effect of testosterone administration on hsCRP in 92 men
receiving testosterone compared to 14 men receiving no testoster-
one (mean±SEM). b vs. a, p = 0.001; c vs. b, p = 0.02; d vs. c, p < 0.05.
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Nasser etal.: Crohn’s disease and testosterone     115
serum testosterone in elderly men will induce prostate
cancer can no longer be credited [44], nor that proper use
of testosterone induces cardiovascular disease [45].
However, our study design has a number of limita-
tions: it was not a double-blind placebo-controlled study.
Over 2years only the testosterone treatment group could
be compared to a smaller group of men who did not receive
testosterone treatment.
An abnormal immune response plays an important
role in the development and perpetuation of the inflam-
matory cascade in a variety of chronic inflammatory dis-
eases, including inflammatory bowel disease [46]. Under
most conditions, an immune competence of the gut would
be beneficial to the host. However, in some situations a per-
turbation of the fine balance in immune regulation with a
switch toward an effector Th1/Th17 phenotype might lead
to the development of chronic intestinal inflammation, as
observed in the pathogenesis of Crohn’s disease [46]. An
overt, or even a subclinical, bacterial or viral infection is
thought to cause intestinal inflammation (first hit) that
could be auto-sustained or exacerbated by the presence of
an altered and abnormal Th1 and Th17 immune response.
TNF-α plays an important role in the pathogenesis of
both Crohn and NASH, which indeed can be frequently
seen in the same patient [47].
An anti-inflammatory effect of testosterone in the liver
has previously been reported in preclinical [22] and clini-
cal papers [48–51]. Androgens inhibit Th1 differentiation
of CD4 T cells and are a factor for modulating actions of
androgens to mitigate CD4 responses in disorders of auto-
immunity [32]. Specifically, the importance of testosterone
in down-regulating the systemic immune response by cell
type specific effects in the context of immunological dis-
orders has been recently reviewed [52].
The mechanisms by which testosterone exerts its
anti-inflammatory effects are not completely understood.
We recently demonstrated that androgens inhibit both
TNF-α-induced NF-κB activation, a master transcription
factor in inflammation, and, as an additional mechanism,
TNF-α-induced overexpression of receptor for oxidized LDL
(oxLDL receptor, LOX-1) [53]. LOX-1 plays important roles
in pro-inflammatory signaling in several MetS-associated
chronic inflammatory diseases, including NASH [22].
Interestingly, activation of the AR by dihydrotestosterone
was demonstrated to blunt oxLDL-induced inflammatory
response by reducing the expression of LOX-1 in human non-
professional antigen presenting cells [53].
Our study contributes to the mounting evidence that
testosterone deficiency is associated with systemic inflam-
mation in an increasing number of diseases, such as car-
diovascular disease [41], rheumatoid arthritis [42] and
Discussion
Crohn’s disease is a chronic inflammatory bowel disease
characterized by a relapsing-remitting clinical course. The
disease is characterized by intestinal inflammation which
leads to progressive bowel damage, increasing disability
and a loss of quality of life, and the treatment is cumber-
some. In recent years, a significant role of testosterone as
an immune modulator [3] in a large number of disease
entities such as cardiovascular disease [41], rheumatoid
arthritis [42] or inflammatory processes of the central
nervous system [43] has become apparent.
In our previous pilot study investigating the effects of
normalization of serum testosterone in hypogonadal men
suffering from Crohn’s disease, we have shown a strong
significant reduction of the severity of Crohn’s disease as
measured by CDAI and a reduction of levels of CRP and
white blood cell count with an improvement of Hb levels
[35]. The present study includes a much larger group of
patients and contains also a comparison group without
testosterone treatment. The obtained results are in agree-
ment with our earlier study. The lack of changes in the
above mentioned parameters in the comparison group not
receiving testosterone confirms the importance of testos-
terone administration on the disease process.
The design of the study was a cumulative, prospective
registry, and 50 men had received testosterone treatment
for at least 36 months. The beneficial effects of normaliza-
tion of their serum testosterone levels had lasted for the
duration of 36 months; therefore, the effects of testoster-
one were not transient.
Hb levels and Htc increased significantly but remained
well within safe margins. Fears that normalization of
ab c
Figure 5: Effect of testosterone administration on ALT in 92 men
receiving testosterone compared to 14 men receiving no testoster-
one (mean±SEM). b vs. a, p = 0.001; c vs. b, p=0.02.
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116     Nasser etal.: Crohn’s disease and testosterone
the central nervous system [43]. Normalization of serum
testosterone can ameliorate this situation. So, it seems
mandatory that men with these conditions are tested for
testosterone deficiency. However, physicians treating
these conditions are often unfamiliar with the adminis-
tration of testosterone and are unduly apprehensive of
the side effects of testosterone administration which are
unfounded [44, 45].
Acknowledgments: Farid Saad, Louis Gooren and Gheorge
Doros contributed to the conception and design of the
study. Mahmoud Nasser, Ahmed Haider and Winfried
Kurtz were pivotal in data acquisition. Gheorge Doros,
Farid Saad, Louis Gooren, Monika Fijak and Linda Vig-
nozzi have analyzed and interpreted the data. All authors
have approved the final version for submission.
Funding: Dr. Haider received compensation for data entry
from Bayer Pharma. Dr. Doros received an honorarium
for statistical analyses from Bayer Pharma. Dr. Nasser
received free study medication from Bayer Pharma.
Conflicts of interest: Farid Saad is an employee of Bayer
Pharma AG, the manufacturer of testosterone unde-
canoate, the androgen used in this study. The other
authors declare no conflict of interests.
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... Disease activity was categorized into 3 groups based on a combination of clinical activity scores (HBI, pMCS) and biomarkers of disease for the purpose of deriving robust and objective endpoints, which has been absent from prior similar studies. 22,23 These composite outcomes have demonstrated high correlation with endoscopic activity in an international study. 24 The groups were the following: group A, raised disease activity scores (HBI ≥5 for CD or pMCS ≥2 for UC) and FC >100 µg/g; group B, raised disease activity scores and CRP >10 mg/L; and group C, raised disease activity scores with both CRP >10 mg/L and FC >100 µg/g. ...
... Nasser et al 23 showed in an uncontrolled prospective study of 92 hypogonadal males with IBD with T levels <12.1 ...
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Background An inverse relationship exists between inflammation and testosterone concentrations in non–inflammatory bowel disease (IBD) immune conditions but has not been objectively explored in the IBD male population. We aimed to characterize the distribution of testosterone concentrations in a cohort of males with IBD and identify any relationship between testosterone levels and disease activity. Methods We conducted a prospective cross-sectional study of male IBD patients. Demographics, disease characteristics, sex-hormone concentration, gonadotropins, C-reactive protein, fecal calprotectin, and patient-reported outcomes on quality of life and erectile function were collected. Relationships between disease activity, biomarkers, patient-reported outcome scores, and testosterone levels were analyzed using univariate and multivariate linear regression analyses. Results A total of 85 male IBD patients were included with a mean age 44 ± 14.1 years, of which 49.4% had Crohn’s disease. Mean testosterone concentration was 15.4 ± 5.2 nmol/L and 17.6% had a serum testosterone <10.4 nmol/L. Active disease was associated with lower testosterone concentrations in univariate analysis (β ± SE = −0.25 ± -1.99, P = .02) but not in multivariate analysis (β −0.18 ± 1.75, P = .06). Testosterone concentrations were independently associated with sex hormone–binding globulin levels (β ± SE = 0.45 ± 0.04, P < .0001) and a younger age (β ± SE = −0.32 ± 0.04, P <.0001). Erectile function scores (5-item International Index of Erectile Function) were lower in IBD patients with a longer duration of disease (β ± SE = −0.24 ± 0.006, P = .04). Conclusions Lower testosterone concentrations in men with IBD may reflect confounding from other factors and are not independently associated with disease activity. Greater awareness and screening for sexual dysfunction should occur in males with IBD, particularly in those with a longer disease duration.
... The copyright holder for this preprint (which this version posted https://doi.org/10.1101https://doi.org/10. /2024 Research suggests that hormone supplementation could potentially alleviate symptoms of IBD (Nasser et al., 2015;Rosen et al., 2015). However, the use of hormone supplementation in adolescents with IBD is contentious and can pose substantial risks due to potential side effects such as weight gain, mood changes, sleep disruption, and increased susceptibility to infections (Bishop et al., 2014). ...
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Despite recent advances in understanding the connection between the gut microbiota and the brain, there remains a wide knowledge gap in how gut inflammation impacts brain development. Microbiota-derived metabolite signaling from the gut to the brain is required for normal development of microglia, the brain’s resident immune cells. Disruption of the microbiota-brain communication has been linked to impaired behaviours and Autism Spectrum Disorder. We hypothesized that intestinal inflammation in early life would negatively affect neurodevelopment through dysregulation of microbiota communication to brain microglia. To test this hypothesis, we developed a novel pediatric model of Inflammatory Bowel Disease (IBD). IBD is an incurable condition affecting millions of people worldwide, characterized by chronic intestinal inflammation, and has comorbid symptoms of anxiety, depression and cognitive impairment. Significantly, 25% of IBD patients are diagnosed during childhood, and the effect of chronic inflammation during this critical period of development is largely unknown. We developed a chemical model of pediatric chronic IBD by repeatedly treating juvenile mice with dextran sodium sulfate (DSS) in drinking water. DSS-treated mice displayed increased intestinal inflammation, altered microbiota and changes in circulating metabolites. We also found that alterations in gut microbiota had long-term impacts on female microglia and male sex-specific behaviours and testosterone regulation, consistent with delayed puberty observed in male IBD patients. Our research expands our understanding of microbiota-microglia communication underlying development. The gut-brain axis is an exciting target for personalized medicine as microbiome manipulations could be feasible for early intervention to reverse deficits due to juvenile inflammation. Highlights Early life gut inflammation produces sex-specific i) microbiome, ii) sex hormone and iii) behavioural impacts Both sexes show disrupted gut bacterial members that regulate sex hormone levels Male mice demonstrate deficits in mate seeking, which may be mediated by reduced seminal vesicle mass and reduced androgen levels Female mice lack behavioural deficits, but demonstrate increased amoeboid microglia in the hippocampus
... In this study, we showed that an inverse relationship is present between testosterone and hsCRP levels in severe obesity, similar to what is observed in the aging male [26,27] . Recent evidence suggests the beneficial effects of testosterone supplementation on the inflammatory markers, and some studies demonstrated the anti-inflammatory potential of testosterone supplementation in hypogonadal subjects with metabolic syndrome [28] and chronic inflammatory diseases such as psoriasis and Crohn's disease [29,30] , thus promoting hormonal replacement therapy also in the cohort of male patients with obesity. ...
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Aim: In males, obesity is characterized by features resembling those observed during aging, such as hypogonadism and cytokines imbalance, yet at an early age. A direct connection between the low-grade inflammatory state and sex steroid abnormalities has been proposed to explain the development of these conditions in obesity. Methods: We evaluated the relationship between sex hormones plasma levels and metabolic and inflammatory parameters in a cohort of patients with grade III obesity (n = 24, BMI 43.4 ± 8.5 kg/m²) undergoing bariatric surgery. Furthermore, we assessed the in vitro effects of testosterone exposure on the expression of markers of adiposity such as FABP-4, PPARγ, leptin, and adiponectin in human-derived adipocytes. Results: A direct correlation was observed between BMI and hsCRP (P < 0.05), while testosterone plasma levels showed a statistically significant inverse correlation with hsCRP, but also with HOMA index, leptin, and von Willebrand factor concentrations (P < 0.05). In human-derived adipocytes, testosterone exposure promotes a reduction in the gene expression of adiposity markers, which is inhibited by co-exposure with the antiandrogen flutamide. Conclusion: Our study shows a relationship between testosterone plasma levels and markers of inflammation in severe obesity, with testosterone exposure affecting adiposity biomarkers expression in humans. In light of these results, hypogonadism should be promptly identified in male patients with obesity and timely treated to reduce the burden of the disease.
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There has been greater societal awareness of differences in gender identity and sexual orientation in recent years. The rates of identifying as transgender or gender non-conforming (TGNC) are increasing and are known to be higher in the younger population and will therefore be over-represented in the inflammatory bowel disease (IBD) subpopulation. However, despite this there is very little in the literature with regards to those who identify as TGNC and are diagnosed with IBD (TGNC-IBD). Many TGNC individuals have poor experiences when seeking healthcare and many physicians find it a challenging and daunting clinical situation to be faced with. We reviewed the available literature with regards to TGNC-IBD population demographics, physical, mental and sexual health considerations, medication interactions and implications for surgery in this heterogenous group. We have identified areas that need further research and suggested simple and practical steps that can be adopted in order to help healthcare providers improve the experience for TGNC individuals diagnosed with IBD and the quality of care they provide.
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Chapter
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ProblemPrevious studies demonstrated a strong association between low androgen levels and reduced capacity to mount an inflammatory response. However, the mechanisms underlying these observations are largely not understood.Methods of studyGeneration of CD4+CD25+Foxp3+ regulatory T cells in Leydig cell-conditioned media was determined by flow cytometry and ELISA. Influence of testosterone on cytokine response was measured in LPS-stimulated testicular macrophages, Sertoli and peritubular cells.ResultsLeydig cell-conditioned media dose-dependently stimulated expression of transcription factor Foxp3 and secretion of IL-10 in splenic CD4+ T cells, an effect abolished by addition of the anti-androgen flutamide. In isolated Sertoli and peritubular cells, testosterone pre-treatment suppressed the LPS-induced inflammatory response on TNF-α mRNA expression, while no effect was evident in testicular macrophages (TM).Conclusions Androgens can influence the immune system under normal conditions by the generation and functional differentiation of regulatory T cells and in testicular inflammation by direct effect on Sertoli and peritubular cells.
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Significance Testosterone has been implicated as a regulator of the immune response to viruses, vaccines, host tissue, and cancer. Despite this pleiotropic effect on the immune system, the mechanisms underlying this effect are not well understood. In this study, we investigated how testosterone altered gene expression and signaling mechanisms in CD4 T cells in mouse models and prostate cancer patients undergoing androgen deprivation therapy. We found that testosterone inhibited T-helper 1 differentiation by up-regulating the phosphatase, Ptpn1 , in both mice and humans. Additionally, the androgen receptor bound a highly conserved region of the Ptpn1 gene, suggesting an evolutionarily important purpose of this mechanism. This study provides a mechanism to explain recent discoveries regarding the role of testosterone-mediated inhibition of the immune response.
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Background: Androgen deficiency (AD) is associated with increased risk of atherosclerosis, cardiovascular, and peripheral arterial disease. Although the biochemical and molecular mechanisms underlying this risk remain unclear, higher testosterone (TST) levels correlate to significant immunoprotective molecular and cellular responses. Our group has previously demonstrated that female sex hormones influence vascular pathogenesis via inflammatory-modulated matrix metalloproteinase (MMP) regulation. Here we investigated the role of AD and androgen replacement therapy in the modulation of these hormonally responsive pathways that could be playing a role in the development of vascular pathogenesis. Methods: Aged orchiectomized male rats underwent TST supplementation per controlled release pellet implantation (0-150 mg). Young and aged intact groups served as controls. Serum was collected at 0-4 wk and analyzed by enzyme-linked immunosorbent assays, qualitative cytokine screening, and quantitative multiplex analyses. Human aortic smooth muscle cells were treated with 4,5α-dihydrotestosterone (DHT; 0-3000 nM) before or after interleukin 1β (IL-1β; 5 ng/mL) stimulation. Quantitative polymerase chain reaction and in-gel zymography was used to assay the effect on MMP expression and activity. Results: Subphysiological, physiological, and supraphysiological levels of TST were achieved with 0.5, 2.5, and 35 mg TST pellet implants in vivo, respectively. Inflammatory arrays indicated that interleukin cytokines, specifically IL-2, IL-6, IL-10, IL-12, and IL-13, were elevated at subphysiological level of TST, whereas TST supplementation decreased interleukins. Supraphysiological TST resulted in a significant increase in MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) in vivo. Pretreatment with IL-1β slightly increased membrane type 1-MMP (MT1-MMP) and MMP-2 expression at low to mid-level DHT exposure in vitro, although these trends were not statistically significant. Conclusions: Here we demonstrate AD is a proinflammatory modulator and indicate that MMP-independent mechanisms may play a role downstream of AD-induced inflammatory signaling in dysfunctional vascular remodeling. Future in vivo studies will examine AD and TST supplementation in acute inflammatory response to vascular injury and in MMP-modulated vascular disease.