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Received: 16 March 2019    Revised: 2 May 2019    Accepted: 17 May 2019

DOI: 10.1111/jcpt.12987

ORIGINAL ARTICLE

The effect of testosterone on thyroid autoimmunity

in euthyroid men with Hashimoto's thyroiditis and low
testosterone levels

Robert Krysiak MD, PhD1  | Karolina Kowalcze MD2 | Bogusław Okopień MD, PhD1

1
Department of Internal Medicine and
Clinical Pharmacology, Medical University of Abstract
Silesia, Katowice, Poland What is known and objective: Thyroid autoimmune diseases occur much more
2
Department of Paediatrics in Bytom, School
frequently in women than men. Unfortunately, no previous study has determined
of Health Sciences in Katowice, Medical
University of Silesia, Katowice, Poland whether sex hormones produce any effect on thyroid antibody titres. The primary
study aim was to assess whether exogenous testosterone affects thyroid autoim‐
Correspondence
Robert Krysiak, Department of Internal munity in men with Hashimoto's thyroiditis and low testosterone levels.
Medicine and Clinical Pharmacology,
Methods: The study population consisted of 34 euthyroid men with autoimmune
Medical University of Silesia, Medyków 18,
40‐752 Katowice, Poland. thyroiditis and testosterone deficiency. On the basis of patient preference, these pa‐
Email: [email protected]
tients were either treated with oral testosterone undecanoate (120 mg daily; n = 16)
Funding information or remained untreated (n = 18). Circulating levels of thyrotropin, free thyroxine, free
The study was supported by the statutory
grant of the Medical University of Silesia triiodothyronine, prolactin and total testosterone, as well as serum titres of thyroid
(KNW‐1‐062/N/7/0). peroxidase and thyroglobulin antibodies, were measured at the beginning of the
study and 6 months later. The structure parameters of thyroid homeostasis (Jostel's
thyrotropin index, SPINA‐GT and SPINA‐GD) were also calculated. Moreover, semen
analyses were performed in eight patients in each group.
Results and discussion: In testosterone‐naïve men, serum hormone levels and anti‐
body titres remained at the similar levels throughout the study. Apart from increasing
serum testosterone levels, testosterone undecanoate reduced titres of thyroid per‐
oxidase and thyroglobulin antibodies and increased SPINA‐GT. The drug produced
a neutral effect on circulating levels of thyrotropin, free thyroid hormones, prolac‐
tin and testosterone, Jostel's thyrotropin index, SPINA‐GD and semen parameters.
Testosterone‐induced changes in antibody titres correlated with the effect of treat‐
ment on SPINA‐GT and with serum testosterone levels.
What is new and conclusion: This study is the first one to have shown that exog‐
enous testosterone may have a protective effect on thyroid autoimmunity in men
with Hashimoto's thyroiditis and testosterone deficiency.

KEYWORDS
hypothalamic‐pituitary‐thyroid axis, testosterone, thyroid autoimmunity, thyroid function
tests

J Clin Pharm Ther. 2019;00:1–8. © 2019 John Wiley & Sons Ltd |  1
wileyonlinelibrary.com/journal/jcpt  
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2       KRYSIAK et al.

1 |  W H AT I S K N OW N A N D O B J EC T I V E (thyrotropin between 0.4 and 4.5  mU/L, free thyroxine between
10.2 and 21.2  pmol/L and free triiodothyronine between 2.3 and
Hashimoto's or autoimmune thyroiditis is one of the most frequent 6.7  pmol/L). Assuming a power of 80% and a significance level of
human disorders, as well as by far the most common cause of thyroid 0.05, 15 or more men had to be included in each arm to detect a 20%
hypofunction in developed countries.1,2 The disease is characterized difference in thyroid antibody titres.
by replacement of follicular cells by lymphocytes and, at a later stage, Individuals were excluded if they met at least one of the follow‐
also by fibrous tissue.3,4 The biological hallmark of Hashimoto's thy‐ ing criteria: positive serum antibodies against thyrotropin receptor,
roiditis is the presence of antibodies directed against various anti‐ other autoimmune disorders, body mass index above 40  kg/m2,
gens of the thyroid gland, particularly thyroid peroxidase antibodies prostate cancer, severe lower urinary tract symptoms (the American
(TPOAb) and thyroglobulin antibodies (TgAb). 1,2 Urological Association International Prostate Symptom Score ex‐
Thyroid autoimmune disorders develop much more frequently ceeding 19), prostate‐specific antigen greater than 4 ng/mL (or pros‐
in women than men, 5 and this dimorphism may be at least in part tate‐specific antigen above 3 ng/mL in men at high risk of prostate
attributed to differences in the production of sex hormones. cancer), breast cancer, myocardial infarction, stroke or coronary
Surprisingly, very little is known about the role of testosterone in the revascularization procedure preceding the study, congestive heart
development of these disorders. Men with primary hypothyroidism, failure, haematocrit exceeding 50%, untreated obstructive sleep ap‐
62.5% of whom were diagnosed with autoimmune thyroiditis, were noea, diabetes mellitus, impaired renal or liver function, any treat‐
6
characterized by low levels of serum testosterone. Hashimoto's ment within 6 months before the beginning of the study and poor
thyroiditis was found to develop more frequently in men with high patient compliance.
than in men with low values of the estradiol:testosterone ratio.7 The study protocol was approved by the institutional review
Autoimmune thyroiditis occurs much more frequently in subjects board, and  all participants signed a written informed consent. The
with Klinefelter syndrome, the most common form of male hypo‐ principles of the Declaration of Helsinki were applied throughout
8
gonadism. The (CAG)n repeat polymorphism of the androgen re‐ the study.
ceptor gene influenced the age of onset of Hashimoto's thyroiditis.9
In the obese strain of chickens, testosterone prevented the devel‐
2.2 | Study design
opment of spontaneous autoimmune  thyroiditis.10,11 Moreover,
its administration to rats with autoimmune thyroiditis, by either At the beginning of the study, all participants were informed about
parenteral injection or implantation, resulted in disappearance of the benefits and possible adverse effects of testosterone therapy.
mononuclear cellular infiltration and reappearance of normal gland On the basis of patient preference, 16 men were then treated for
architecture. 12 6  months with exogenous testosterone, while the remaining pa‐
Despite the female preponderance, an increasing number of men tients (n = 18) did not receive any treatment and served as a control
are being diagnosed with Hashimoto's thyroiditis. 5 Unfortunately, group. The total daily dose of testosterone undecanoate (120  mg
to the best of our knowledge, no interventional study with the use orally) was divided into three equal doses and administered for
of exogenous testosterone has been conducted to date in humans. 6 months.
Therefore, the primary aim of the current research was to investi‐
gate whether testosterone undecanoate affects thyroid autoimmu‐
2.3 | Laboratory assays
nity in men with autoimmune thyroid disease and low testosterone
levels. Venous blood samples were obtained between 8.00 and 9.00  am,
12 hours after the last meal, in a quiet, temperature‐controlled room
(24‐25°C) at the beginning and at the end of the study (6  months
2 |  M E TH O DS later). Serum titres of TPOAb and TgAb, as well as serum levels of
thyrotropin, free thyroid hormones (free thyroxine and free triiodo‐
2.1 | Patients thyronine), prolactin and testosterone, were assayed by direct chemi‐
The participants of the study were selected among adult men luminescence using acridinium ester technology (ADVIA Centaur XP
(40‐70  years old) fulfilling the criteria of testosterone deficiency: Immunoassay System, Siemens Healthcare Diagnostics). All meas‐
serum levels of total testosterone less than 3.0  ng/mL on two urements were carried out in duplicate. The structure parameters
different occasions combined with reduced frequency of morn‐ of thyroid homeostasis were calculated using SPINA‐Thyr 4.0.1 for
ing erection, erectile dysfunction and/or decreased frequency of Windows software. Jostel's thyrotropin index was calculated as fol‐
sexual thoughts.13 We included 34 drug‐naïve men with recently lows: ln [thyrotropin]  +  0.1345  ×  free thyroxine.14 SPINA‐GT was
diagnosed autoimmune thyroiditis (defined as serum TPOAb titres calculated as follows: β T × (D T + thyrotropin) × (1 + K41 × standard
above 100  U/mL and the reduced echogenicity of the thyroid pa‐ concentration of thyroxine‐binding globulin + K42 × standard concen‐
renchyma on thyroid ultrasonography), in whom serum levels of thy‐ tration of transthyretin × free thyroxine)/(α T × thyrotropin).15 SPINA‐
rotropin and free thyroid hormone were within the reference range GD was calculated using the following formula: β 31  ×  (KM1  +  free
KRYSIAK et al. |
      3

thyroxine) (1  +  K30  ×  standard concentration of thyroxine‐binding 3 | R E S U LT S

16
globulin) × free triiodothyronine/(α 31 × free thyroxine). Constants
in the equations were as follows: β T = 1.1 × 10−6/s, D T = 2.75 mU/L, There were no significant differences between the study groups in
K41  =  2  ×  1010  L/mol, standard concentration of thyroxine‐bind‐ age, body mass index, smoking habits, thyroid antibody titres, serum
ing globulin  =  300  nmol/L, K42  =  2  ×  108  L/mol, standard concen‐ levels of thyrotropin, free thyroxine, free triiodothyronine, prolac‐
−6
tration of transthyretin = 4.5 mmol/L, α T = 0.1/L, β 31 = 8 × 10 /s, tin and testosterone, as well in values of the calculated parameters
KM1 = 5 × 10−7 mol/L, K30 = 2×109 L/mol and α 31 = 0.026/L.15,16 of thyroid homeostasis (Table 1). In testosterone‐naïve men, serum
hormone levels, antibody titres and values of all indices remained
at the similar levels throughout the study. In turn, testosterone un‐
2.4 | Semen analyses
decanoate reduced titres of thyroid peroxidase and thyroglobulin
Semen analyses were performed after 3‐5 days of sexual abstinence antibodies, increased SPINA‐GT and increased serum testosterone
in eight patients from each group at the beginning and at the end levels. The drug produced a neutral effect on circulating levels of
of the study (the remaining men did not agree on semen analyses). thyrotropin, free thyroid hormones, prolactin and testosterone, as
Each semen sample, collected in a sterile container and analysed well as on Jostel's thyrotropin index and SPINA‐GD. At the end of
within the first hour after collection, was evaluated for semen vol‐ the study, titres of TPOAb and TgAb were lower, while values of
ume, sperm concentration, total sperm count, total sperm motility, SPINA‐GT and levels of testosterone were higher in testosterone‐
progressive sperm motility and sperm normal morphology. treated than testosterone‐naïve men (Table 2).
Semen parameters did not differ between men belonging to both
subgroups and did not change throughout the study (Table 3).
2.5 | Statistical analysis
Baseline titres of TPOAb correlated with baseline titres of
All values were log‐transformed to meet the assumption of normally TgAb titres (r  =  0.59, P  <  0.001). There were also inverse correla‐
distributed data. Between‐ and within‐group comparisons were per‐ tions between baseline thyroid antibody titres and baseline SPINA‐
formed by Student's t tests for independent samples and Student's GT (TPOAb: r = −0.25, P < 0.05; TgAb: r = −0.28, P < 0.05). Sperm
paired t tests, respectively. The significance of the results was deter‐ concentration, total sperm count, total sperm motility, progressive
mined using a 95% confidence interval. A t statistic and two sample sperm motility and sperm normal morphology inversely correlated
means were used to generate an interval estimate of the difference with TPOAb titres (r values in the range between −0.24 [P < 0.05]
between two population means. Correlations were  assessed using and −0.35 [P < 0.01]), while sperm concentration, total sperm count,
Pearson's correlation coefficient (r). Differences were described as progressive sperm motility and sperm normal morphology posi‐
statistically significant if 95% confidence intervals did not include tively correlated with SPINA‐GT (r values in the range between
the null value and/or two‐tailed P values were below 0.05. 0.23 [P < 0.05] and 0.37 [P < 0.01]). Treatment‐induced changes in

TA B L E 1   Baseline characteristics of
Testosterone‐ Testosterone‐ Difference (95%
patients
Variable treated men naive men CI)

Number of patients 16 18
Age (years; mean [SD]) 58 (8) 57 (6) −1 [−6, 4]
Smokers (%) 31 28
Body mass index (kg/m2; mean [SD]) 28.8 (4.7) 28.4 (4.3) −0.4 [−3.5, 2.7]
TPOAb (IU/mL; mean [SD]) 882 (354) 902 (380) 20 [−238, 278]
TgAb (IU/mL; mean [SD]) 784 (305) 811 (364) 27 [−209, 263]
Thyrotropin (mIU/L; mean [SD]) 2.6 (1.2) 2.4 (1.1) −0.2 [−1.0, 0.6]
Free thyroxine (pmol/L; mean [SD]) 14.2 (2.0) 14.0 (1.9) −0.2 [−1.6, 1.2]
Free triiodothyronine (pmol/L; mean 3.4 (0.7) 3.5 (0.6) 0.1 [−0.4, 0.6]
[SD])
Jostel's thyrotropin index (mean [SD]) 2.9 (0.3) 2.8 (0.2) −0.1 [−0.3, 0.1]
SPINA‐GT index (pmol/s; mean [SD]) 2.22 (0.37) 2.28 (0.29) 0.06 [−0.17, 0.29]
SPINA‐GD index (nmol/s; mean [SD]) 22.14 (2.84) 23.12 (2.63) 0.98 [−0.93, 2.89]
Testosterone (ng/mL; mean [SD]) 2.2 (0.5) 2.3 (0.4) 0.1 [−0.2, 0.4]
Prolactin (ng/mL; mean [SD]) 11 (5) 10 (4) −1 [−4, 2]

Abbreviations: CI, confidence interval; IU, international unit; SD, standard deviation; SPINA, struc‐
ture parameter inference approach; TgAb, thyroglobulin antibodies; TPOAb, thyroid peroxidase
antibodies.
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4       KRYSIAK et al.

TA B L E 2   The effect of testosterone

Testosterone‐ Testosterone‐
undecanoate on thyroid antibody
Variable treated men naive men Difference (95% CI)
titres, hormones and thyroid function
TPOAb (IU/mL; mean [SD]) in euthyroid men with Hashimoto's
Baseline 882 (354) 902 (380) 20 [−238, 278] thyroiditis and low testosterone levels

After 6 mo 610 (283)b 878 (342) 268 [47, 489]a

Change −272 (134) −24 (103) 248 [165, 331]c
TgAb (IU/mL; mean [SD])
Baseline 784 (305) 811 (364) 27 [−209, 263]
b
After 6 mo 602 (211) 779 (281) 177 [2, 352]a
Change −182 (134) −32 (116) 150 [63, 237]c
Thyrotropin (mIU/L; mean [SD])
Baseline 2.6 (1.2) 2.4 (1.1) −0.2 [−1.0, 0.6]
After 6 mo 2.2 (1.2) 2.3 (1.0) 0.1 [−0.7, 0.9]
Change −0.4 (0.8) −0.1 (0.6) 0.3 [−0.2, 0.8]
Free thyroxine (pmol/L; mean [SD])
Baseline 14.2 (2.0) 14.0 (1.9) −0.2 [−1.6, 1.2]
After 6 mo 15.3 (2.4) 14.4 (2.2) −0.9 [−2.5, 0.7]
Change 1.1 (1.1) 0.4 (1.0) −0.7 [−1.5, 0.1]
Free triiodothyronine (pmol/L; mean [SD])
Baseline 3.4 (0.7) 3.5 (0.6) 0.1 [−0.4, 0.6]
After 6 mo 3.6 (0.8) 3.5 (0.6) −0.1 [−0.6, 0.4]
Change 0.2 (0.7) 0.0 (0.4) −0.2 [−0.6, 0.2]
Jostel's thyrotropin index (mean [SD])
Baseline 2.9 (0.3) 2.8 (0.2) −0.1 [−0.3, 0.1]
After 6 mo 2.8 (0.3) 2.8 (0.2) 0.0 [−0.2, 0.2]
Change −0.1 (0.2) 0.0 (0.2) 0.1 [−0.1, 0.3]
SPINA‐GT index (pmol/s; mean [SD])
Baseline 2.22 (0.37) 2.28 (0.29) 0.06 [−0.17, 0.29]
b
After 6 mo 2.61 (0.30) 2.40 (0.25) −0.21 [−0.40, −0.02]a
Change 0.39 (0.36) 0.12 (0.20) 0.27 [−0.48, −0.06]c
SPINA‐GD index (nmol/s; mean [SD])
Baseline 22.14 (2.84) 23.12 (2.63) 0.98 [−0.93, 2.89]
After 6 mo 21.76 (3.11) 22.47 (2.18) 0.71 [−1.15, 2.57]
Change −0.38 (0.40) −0.65 (0.52) −0.27 [−0.60, 0.06]
Testosterone (ng/mL; mean [SD])
Baseline 2.2 (0.5) 0.1 [−0.2, 0.4]
b
After 6 mo 5.9 (1.5) 2.5 (0.4) −3.4 [−4.1, −2.7]a
Change 3.7 (1.6) 0.2 (0.2) −3.5 [−4.3, −2.7]c
Prolactin (ng/mL; mean [SD])
Baseline 11 (5) 10 (4) −1 [−4, 2]
After 6 mo 12 (6) 12 (5) 0 [−4, 4]
Change 1 (4) 2 (3) 1 [−1, 3]

Abbreviations: CI, confidence interval; IU, international unit; SD, standard deviation; SPINA, struc‐
ture parameter inference approach; TgAb, thyroglobulin antibodies; TPOAb, thyroid peroxidase
antibodies.
a
Statistically significant difference between both groups.
b
Statistically significant difference between post‐treatment and baseline values in the same group.
c
Statistically significant difference between the changes in both groups.
KRYSIAK et al. |
      5

TA B L E 3   Seminal characteristics
Difference
of euthyroid men with Hashimoto's
Testosterone‐treated men Testosterone‐naive men (95% CI)
thyroiditis and low testosterone levelsa
Semen volume (mL; mean [SD])
Baseline 1.7 (0.7) 1.6 (0.6) −0.1 [−0.8, 0.6]
After 6 mo 1.6 (0.6) 1.5 (0.5) −0.1 [−0.7, 0.5]
Change −0.1 (0.2) −0.1 (0.1) 0.0 [−0.1, 0.1]
Sperm concentration (×106/mL; mean [SD])
Baseline 10.2 (4.0) 10.0 (3.6) −0.2 [−4.3, 3.9]
After 6 mo 9.6 (3.2) 9.2 (3.4) −0.4 [−4.0, 3.2]
Change −0.6 (0.3) −0.8 (0.4) −0.2 [−0.6, 0.2]
Total sperm count (×106; mean [SD])
Baseline 17.4 (7.6) 16.1 (7.5) −1.3 [−9.4, 6.8]
After 6 mo 15.4 (8.0) 13.9 (7.1) −1.5 [−9.6, 6.6]
Change −2.0 (1.2) −2.2 (1.4) −0.2 [−1.6, 1.2]
Total sperm motility (%; mean [SD])
Baseline 25.2 (10.2) 24.0 (12.8) −1.2 [−13.6,
11.2]
After 6 mo 23.4 (12.0) 21.5 (11.3) −1.9 [−13.4, 9.6]
Change −1.8 (1.0) −2.5 (1.5) −0.7 [−2.1, 0.7]
Progressive sperm motility (%; mean [SD])
Baseline 18.3 (7.4) 17.8 (6.9) −0.5 [−8.2, 7.2]
After 6 mo 17.7 (6.7) 16.8 (7.5) −0.9 [−8.5, 6.7]
Change −0.6 (0.5) −1.0 (0.8) −0.4 [−1.1, 0.3]
Sperm normal morphology (%; mean [SD])
Baseline 2.8 (1.2) 2.5 (1.5) −0.3 [−1.8, 1.2]
After 6 mo 3.0 (1.0) 2.6 (1.7) −0.4 [−1.9, 1.1]
Change 0.2 (0.4) 0.1 (0.3) −0.1 [−0.5, 0.3]
a
Data obtained from 8 men from each study group.

TPOAb correlated with the changes in TgAb (r  =  0.56, P  <  0.001). resolution of thyroid autoimmunity or to seasonal fluctuations
Testosterone‐induced changes in antibody titres inversely correlated in antibody titres. The study purposely included only men with
with baseline testosterone levels (TPOAb: r = −0.28, P < 0.05; TgAb: thyrotropin and free thyroid hormone levels within the reference
r = −0.31, P < 0.05) and positively correlated with baseline antibody range. Taking into account that patients with autoimmune hypo‐
titres (TPOAb: r = 0.57, P < 0.001; TgAb: r = 0.52, P < 0.001), base‐ thyroidism should receive thyroid hormone replacement,17 as well
line thyrotropin levels (TPOAb: r  =  0.29, P  <  0.05; TgAb: r  =  0.25, as that exogenous levothyroxine reduces thyroid antibody titres,18
P  <  0.05) and with the effect of treatment on SPINA‐GT (TPOAb: excluding men with thyroid hypofunction minimized the possibil‐
r  =  0.30, P  <  0.05; TgAb: r  =  0.27, P  <  0.05). Treatment‐induced ity that the alleviation of thyroid autoimmunity is a consequence
changes in SPINA‐GT correlated with baseline thyrotropin levels of the effect of levothyroxine (not testosterone) or is secondary
(r = 0.38, P < 0.001). The effect of treatment on TPOAb titres cor‐ to pharmacokinetic or pharmacodynamic interactions between
related with the impact of therapy on testosterone levels (r = 0.38, levothyroxine and testosterone. Because the study population
P < 0.001). No other correlations were found. consisted of only drug‐naïve subjects, the obtained results cannot
be also explained by a modulatory impact of testosterone on other
medications found to reduce thyroid antibody titres (vitamin D,
4 | D I S CU S S I O N selenium, myo‐inositol or statins).19-22
Interestingly, treatment‐induced improvement in thyroid autoim‐
This study is the first to have shown that testosterone replace‐ munity inversely correlated with baseline testosterone levels, while
ment therapy with oral testosterone preparations reduces thy‐ treatment‐induced changes in TPOAb correlated with an increase in
roid antibody titres in men with autoimmune thyroiditis. The lack testosterone levels. This finding suggests that, from a thyroid point of
of changes in TPOAb and TgAb in the control group indicates view, men with autoimmune thyroiditis co‐existing with severe forms
that testosterone action cannot be attributed to a spontaneous of hypogonadism may gain more benefits from testosterone treatment
 |
6       KRYSIAK et al.

than individuals with milder forms of testicular failure and individuals cells.29 However, this effect does not seem to be mediated by prolactin,
with the intact hypothalamic‐pituitary‐testicular axis. There are two stimulating immune cells and many immunological responses, as well
possible explanations for the lack of correlations between the changes as inducing the progression of numerous autoimmune disorders.30 We
in TgAb titres and serum testosterone levels. Firstly, measurements of think so because testosterone did not affect circulating levels of prolac‐
TgAb are characterized by lesser sensitivity and lesser specificity in the tin, as well as because, both at baseline and during treatment, prolactin
23
diagnosis of Hashimoto's thyroiditis than measurements of TPOAb. levels did not correlate with testosterone levels and thyroid antibody
Secondly, serum levels of testosterone do not seem to reflect well its titres. According to the alternative explanation, the inhibitory effect
tissue content in men receiving testosterone preparations.13 on thyroid immunity is a consequence of the improvement in thyroid
Because of the inclusion criteria baseline thyrotrope and thyroid secretory function. In line with this explanation, values of SPINA‐GT
cell function was only slightly impaired by the presence of autoim‐ correlated with antibody titres. Moreover, androgens receptors were
mune process and lymphocyte infiltration. This finding explains why, found in the thyroid gland,31 testosterone up‐regulated androgen re‐
despite reducing antibody titres, testosterone did not change thy‐ ceptors in rats32 and induced thyrocyte proliferation.33 Finally, exog‐
rotropin, free thyroxine and free triiodothyronine levels. However, enous levothyroxine reduced titres of TPOAb and TgAb in men with
the effect of oral testosterone on antibody titres was paralleled by a autoimmune thyroiditis.18 Therefore, it is also possible that increased
stimulatory effect on SPINA‐GT, estimating the maximum thyroidal endogenous thyroxine production induced by testosterone administra‐
capacity and being a more sensitive marker of thyroid cell function tion behaves similarly to exogenous levothyroxine.
than circulating levels of thyrotropin and free thyroid hormones.15,24 According to the protocol, the participants of the study were al‐
24
Hoermann et al observed lower values of this marker in euthyroid located to one of two groups based on their preference. Because
subjects with autoimmune thyroid disease than in healthy controls, the subjects under study were aware of their hormonal status and of
while Dietrich et al15,16 observed lower intra‐individual variation of group allocation, questionnaire analyses assessing sexual function‐
SPINA‐GT than of thyrotropin, free thyroxine and free triiodothy‐ ing would be highly questionable and therefore were not performed.
ronine. This may suggest that testosterone therapy improves secre‐ However, in the previous study of our research team,18 the benefi‐
tory function of the thyroid gland even in euthyroid patients. It is cial effect of levothyroxine on thyroid antibody titres in men with
likely that this effect is stronger in subjects with impaired activity of autoimmune hypothyroidism was accompanied by the improvement
the hypothalamic‐pituitary‐thyroid axis, because treatment‐induced in erectile function and, to a lesser extent also, by the improvement
changes in antibody titres and SPINA‐GT correlated with baseline in intercourse satisfaction, orgasmic function,  sexual  desire and
thyrotropin levels. Unlike SPINA‐GT, neither Jostel's index, quan‐ overall satisfaction. This may suggest that exogenous testosterone,
titatively assessing the thyrotropic function of the anterior lobe of apart from its well‐known direct effect on sexual functioning,34
14
the pituitary gland, nor SPINA‐GD, determining thyroid hormone may reverse sexual dysfunction in euthyroid men with autoimmune
15,16
conversion efficiency, changed during testosterone treatment. thyroiditis and low testosterone levels also indirectly by improving
Therefore, it seems that testosterone undecanoate does not affect thyroid autoimmunity and thyroid function. In line with this expla‐
hypothalamic‐pituitary‐thyroid axis activity at the level of thyro‐ nation, thyroid hormone receptors were identified in Sertoli, Leydig,
tropes and does not modulate global deiodinase activity. sperm and peritubular cells, while thyroid hormones were found to
The observational nature of our study allows us only to speculate stimulate proliferation and function of Leydig and Sertoli cells.35
about the molecular mechanisms underlying the obtained results. The Unlike positive effects on sexual functioning, exogenous testoster‐
reduction in antibody titres may be secondary either to alleviation of one therapy negatively affects fertility and therefore is used in male
immune processes or to a direct effect on thyrocytes. An argument contraception.36,37 By suppressing the pulsatile release of gonadotro‐
in favour of the first explanation is the above‐mentioned presence of pin‐releasing hormone, luteinizing hormone and follicle‐stimulating
correlations between baseline testosterone levels and antibody titres, hormone, testosterone preparations reduce testicular testosterone
as well as between treatment‐induced changes in titres of TPOAb and production and deprive developing sperm of the signals required for
the effect of testosterone on its serum levels. Hashimoto's thyroiditis normal maturation.36,37 Interestingly, testosterone produced a neu‐
develops as a consequence of a stimulatory effect of T and B cells in‐ tral effect on all semen parameters assessed in the subpopulation of
filtrating the thyroid gland on cell cytotoxicity, apoptosis and thyroid patients participating in the current study. It is possible that the unfa‐
antibody production.25 The proinflammatory state in Hashimoto's thy‐ vourable direct effect of testosterone on semen quality was counter‐
roiditis is partially mediated by proinflammatory cytokines, which seem balanced by an indirect beneficial effect associated with the reduction
to contribute to low‐grade systemic inflammation and gland destruc‐ in thyroid autoimmunity. This explanation is supported by the finding
tion.26 In turn, low testosterone levels were found to be associated with that semen quality was impaired in men with autoimmune hypothyroid‐
low‐grade systemic inflammation, while administration of exogenous ism.38 Moreover, in our study, sperm concentration, total sperm count,
testosterone inhibited the production of proinflammatory cytokines total sperm motility, progressive sperm motility and sperm normal mor‐
27,28
(interleukin‐1β, interleukin‐6, tumour necrosis factor‐α). It is pos‐ phology inversely correlated with TPOAb titres and, with the exception
sible that the increase in tissue testosterone content secondary to its of total sperm motility, positively correlated with SPINA‐GT.
oral administration suppresses thyroid autoimmunity via androgen re‐ Some limitations of the study should be pointed out. The main
ceptors expressed in primary lymphoid organs and peripheral immune limitation is a small number of participants and its non‐randomized
KRYSIAK et al. |
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design. Moreover, the Upper Silesia, where the study was carried 3. Brown RS. Autoimmune thyroid disease: unlocking a complex puz‐
out, is an area with low‐selenium status 39
and sufficient iodine sup‐ zle. Curr Opin Pediatr. 2009;21:523‐528.
4. Hiromatsu Y, Satoh H, Amino N. Hashimoto's thyroiditis: history
ply.40 It cannot be totally ruled out that the effect of testosterone
and future outlook. Hormones (Athens). 2013;12:12‐18.
is different in iodine‐deficient and/or selenium‐adequate areas. 5. Gessl A, Lemmens‐Gruber R, Kautzky‐Willer A. Thyroid disorders.
Furthermore, the study protocol does not allow us to verify whether Handb Exp Pharmacol. 2012;214:361‐386.
other forms of testosterone therapy: intramuscular preparations, 6. Wortsman J, Rosner W, Dufau ML. Abnormal testicular function in
men with primary hypothyroidism. Am J Med. 1987;82:207‐212.
topical gels, transdermal patches, buccal tablets, topical solutions or
7. Chen Y, Chen Y, Xia F, et al. A higher ratio of estradiol to testos‐
pellet implants, have the same impact on thyroid autoimmunity as terone is associated with autoimmune thyroid disease in males.
oral testosterone undecanoate. Finally, the question whether exoge‐ Thyroid. 2017;27:960‐966.
nous testosterone reduces thyroid antibody titres in eugonadal men 8. Rao A, Jain D, Aggarwal HK, Jain P. An enigmatic trio of Klinefelter's
syndrome, autoimmune hypothyroidism and nephrotic syndrome. J
requires further research.
R Coll Physicians Edinb. 2017;47:143‐145.
9. Doukas C, Saltiki K, Mantzou A, et al. Hormonal parameters and sex
hormone receptor gene polymorphisms in men with autoimmune
5 | W H AT I S N E W A N D CO N C LU S I O N diseases. Rheumatol Int. 2013;34:575‐582.
10. Fässler R, Dietrich H, Krömer G, Böck G, Brezinschek HP, Wick G.
The role of testosterone in spontaneous autoimmune thyroiditis of
In conclusion, oral testosterone administered for 6 months reduced
Obese strain (OS) chickens. J Autoimmun. 1988;1:97‐108.
thyroid antibody titres, which was paralleled by an increase in 11. Gause WC, Marsh JA. Effect of testosterone treatments for varying
SPINA‐GT in euthyroid men with autoimmune thyroiditis and low periods on autoimmune development and on specific infiltrating
testosterone levels, and these effects depended on both baseline leukocyte populations in the thyroid gland of obese strain chickens.
Clin Immunol Immunopathol. 1986;39:464‐478.
antibody titres and baseline testosterone levels. Our findings indi‐
12. Ansar Ahmed S, Young PR, Penhale WJ. Beneficial effect of testos‐
cate that testosterone therapy may reduce thyroid autoimmunity, terone in the treatment of chronic autoimmune thyroiditis in rats. J
at least in men with impaired activity of the hypothalamic‐pituitary‐ Immunol. 1986;136:143‐147.
testicular axis. Because of study limitations, the obtained results 13. Paduch DA, Brannigan RE, Fuchs EF, Kim ED, Marmar JL, Sandlow
JI. The laboratory diagnosis of testosterone deficiency. Urology.
should be verified in large clinical trials.
2014;83:980‐988.
14. Jostel A, Ryder WD, Shalet SM. The use of thyroid function tests
in the diagnosis of hypopituitarism: definition and evaluation of the
6 | I N S TIT U TI O N A L A PPROVA L TSH Index. Clin Endocrinol. 2009;71:529‐534.
15. Dietrich JW, Landgrafe‐Mende G, Wiora E, et al. Calculated param‐
eters of thyroid homeostasis: emerging tools for differential diag‐
The study was approved by the Bioethical Committee of the Medical nosis and clinical research. Front Endocrinol (Lausanne). 2016;7:57.
University of Silesia. 16. Dietrich JW, Müller P, Schiedat F, et al. Nonthyroidal illness syn‐
drome in cardiac illness involves elevated concentrations of 3,5‐
diiodothyronine and correlates with atrial remodeling. Eur Thyroid
C O N FL I C T O F I N T E R E S T J. 2015;4:129‐137.
17. Hennessey J. The emergence of levothyroxine as a treatment for
No conflicts of interest have been declared. hypothyroidism. Endocrine. 2017;55:6‐18.
18. Krysiak R, Szkróbka W, Okopień B. The effect of l‐thyroxine treat‐
ment on sexual function and depressive symptoms in men with au‐
E T H I C A L A P P R OVA L toimmune hypothyroidism. Pharmacol Rep. 2017;69:432‐437.
19. Krysiak R, Kowalcze K, Okopień B. The effect of vitamin D on thy‐
The study protocol was approved by the institutional review board roid autoimmunity in non‐lactating women with postpartum thy‐
by (the Bioethical Committee of the Medical University of Silesia), roiditis. Eur J Clin Nutr. 2016;70:637‐639.
and  all participants signed a written informed consent. The prin‐ 20. Wichman J, Winther KH, Bonnema SJ, Hegedüs L. Selenium sup‐
plementation significantly reduces thyroid autoantibody levels in
ciples of the Declaration of Helsinki were applied throughout the
patients with chronic autoimmune thyroiditis: a systematic review
study. and meta‐analysis. Thyroid. 2016;26:1681‐1699.
21. Fallahi P, Ferrari SM, Elia G, et al. Myo‐inositol in autoim‐
mune thyroiditis, and hypothyroidism. Rev Endocr Metab Disord.
ORCID 2018;19(4):349‐354.
22. Krysiak R, Szkróbka W, Okopień B. The relationship between statin
Robert Krysiak  https://orcid.org/0000-0001-5454-2620 action on thyroid autoimmunity and vitamin D status: a pilot study.
Exp Clin Endocrinol Diabetes. 2019;127:23‐28.
23. Muller AF, Drexhage HA, Berghout A. Postpartum thyroiditis and
REFERENCES autoimmune thyroiditis in women of childbearing age: recent in‐
sights and consequences for antenatal and postnatal care. Endocr
1. Caturegli P, Kimura H, Rocchi R, Rose NR. Autoimmune thyroid dis‐ Rev. 2001;22:605‐630.
eases. Curr Opin Rheumatol. 2007;19:44‐48. 24. Hoermann R, Midgley J, Larisch R, Dietrich JW. Relational stability
2. Lorini R, Gastaldi R, Traggiai C, Perucchin PP. Hashimoto's thyroid‐ of thyroid hormones in euthyroid subjects and patients with auto‐
itis. Pediatr Endocrinol Rev. 2003;1(Suppl. 2):205‐211. immune thyroid disease. Eur Thyroid J. 2016;5:171‐179.
 |
8       KRYSIAK et al.

25. Ajjan RA, Weetman AP. The pathogenesis of Hashimoto's thyroid‐ 36. Roth MY, Page ST, Bremner WJ. Male hormonal contraception:
itis: further developments in our understanding. Horm Metab Res. looking back and moving forward. Andrology. 2016;4:4‐12.
2015;47:702‐710. 37. Patel AS, Leong JY, Ramos L, Ramasamy R. Testosterone is a contra‐
26. Krysiak R, Okopień B. The effect of levothyroxine and sele‐ ceptive and should not be used in men who desire fertility. World J
nomethionine on lymphocyte and monocyte cytokine release Mens Health. 2019;37:45‐54.
in women with Hashimoto's thyroiditis. J Clin Endocrinol Metab. 38. La Vignera S, Vita R. Thyroid dysfunction and semen quality. Int J
2011;96:2206‐2215. Immunopathol Pharmacol. 2018;32:2058738418775241.
27. Bianchi VE. The anti‐inflammatory effects of testosterone. J Endocr 39. Kłapcińska B, Poprzecki S, Danch A, Sobczak A, Kempa K. Selenium
Soc. 2018;3:91‐107. levels in blood of Upper Silesian population: evidence of suboptimal
28. Gubbels Bupp MR, Jorgensen TN. Androgen‐induced immunosup‐ selenium status in a significant percentage of the population. Biol
pression. Front Immunol. 2018;9:794. Trace Elem Res. 2005;108:1‐15.
29. Tanriverdi F, Silveira LF, MacColl GS, Bouloux PM. The hypotha‐ 4 0. Szybiński Z. Polish council for control of iodine deficiency disor‐
lamic‐pituitary‐gonadal axis: immune function and autoimmunity. J ders. Work of the Polish council for control of iodine deficiency dis‐
Endocrinol. 2003;176:293‐304. orders, and the model of iodine prophylaxis in Poland. Endokrynol
3 0. De Bellis A, Bizzarro A, Pivonello R, Lombardi G, Bellastella A. Pol. 2012;63:156‐160.
Prolactin and autoimmunity. Pituitary. 2005;8:25‐30.
31. Pelletier G. Localization of androgen and estrogen receptors in rat
and primate tissues. Histol Histopathol. 2000;15:1261‐1270.
How to cite this article: Krysiak R, Kowalcze K, Okopień B.
32. Banu SK, Govindarajulu P, Aruldhas MM. Testosterone and estra‐
diol up‐regulate androgen and estrogen receptors in immature and
The effect of testosterone on thyroid autoimmunity in
adult rat thyroid glands in vivo. Steroids. 2002;67:1007‐1014. euthyroid men with Hashimoto's thyroiditis and low
33. Banu SK, Govindarajulu P, Aruldhas MM. Testosterone and estra‐ testosterone levels. J Clin Pharm Ther. 2019;00:1–8. https​://
diol differentially regulate TSH‐induced thyrocyte proliferation in doi.org/10.1111/jcpt.12987​
immature and adult rats. Steroids. 2002;67:573‐579.
3 4. Rastrelli G, Corona G, Maggi M. Testosterone and sexual function in
men. Maturitas. 2018;112:46‐52.
35. Maran RR. Thyroid hormones: their role in testicular steroidogene‐
sis. Arch Androl. 2003;49:375‐388.