Key words Thyroid hormones - levothyroxine - liothyronine - combination therapy - bioavailability - hypothyroidism - questionnaire
Introduction
Hypothyroidism, either overt or subclinical, affects approximately 3% of the
European population [1 ]. Levothyroxine
(LT4) is the standard therapy for thyroid hormone (TH) substitution, and different
types of LT4 formulations are available, including tablets, liquid solutions, and
soft-gel capsules, in several European countries. Liquid solutions and soft-gel
capsules are relatively new LT4 formulations and were produced to overcome some of
the bioavailability issues with tablets [2 ]. Oral LT4 bioavailability may be reduced when tablets are administered
simultaneously with beverages, food, other types of medications (e. g.,
calcium carbonate, phosphate binders, proton-pump inhibitors, and iron supplements),
or in patients with concurrent gastrointestinal conditions (e. g., atrophic
gastritis, coeliac disease, Helicobacter pylori infection, and bariatric
surgery) [2 ]
[3 ].
Although all available LT4 formulations are regarded as effective in treating
hypothyroidism, pre-existing morbidity may be increased in hypothyroid individuals,
and post-diagnosis co-morbidity due to psychiatric [4 ] and somatic [5 ] disorders is higher than in euthyroid
controls. This is associated with a higher rate of disability pension, excess
mortality from natural and unnatural causes [6 ]
[7 ], and loss of labor
market income compared to the background population [8 ]. The aforementioned, together with the
fact that quality of life is not fully restored [9 ]
[10 ] in a significant proportion of patients, is one of several reasons
for a continued pursuit to optimize TH substitution in hypothyroid individuals.
Differences in bioavailability in favor of soft-gel capsules and liquid solution
compared to tablets have been suggested in both patients with and without impaired
absorption [3 ]. However liquid solution
and soft-gel capsules are more expensive than tablets, and the cost-effectiveness of
switching from tablets to the new formulations remains mostly based on limited size
and uncontrolled studies [11 ].
Before LT4 was synthesized, desiccated thyroid extract (DTE) was the standard therapy
for hypothyroidism. DTE is derived from the thyroid glands of animals, primarily
pigs, and contains both T4 and T3. Combination therapy can also be administered to
patients using the synthetic preparation of T3, liothyronine (LT3), and LT4. Thyroid
guidelines uniformly favor LT4 as standard therapy [12 ]; however, some patients with thyroid
failure have persistent symptoms despite adequate thyroid hormone replacement
therapy with LT4 [9 ]. According to
international guidelines and a recent European and American consensus document,
combination therapy with LT4 and LT3 may be considered in such individuals, mostly
as a short treatment trial [13 ]
[14 ].
Over the last decade, LT4 prescriptions have been increasing in several European
countries [15 ]
[16 ]. This can probably be explained by
changing clinical practices, particularly a decreasing thyroid stimulating hormone
(TSH) threshold for initiating treatment [17 ] and increasing the use of biochemical tests [18 ]
[19 ]. Furthermore, combination therapy with LT4+LT3 or DTE is also
gaining attention [17 ], mostly due to
growing demands from patients dissatisfied with the LT4 treatment [20 ]
[21 ]. However, prescribing T3-containing preparations is not without
risks. Side effects, including excess morbidity [22 ]
[23 ] and mortality [24 ], due to
possible factitious hyperthyroidism are a concern, and the broad evidence for
non-superiority of combination therapy over LT4 does not support this trend [12 ].
In Germany, where iodine fortification of table salt is voluntary, the iodine supply
improved in the early 2000s but declined later [25 ]. Germany is thus, again, a country with borderline iodine status and
about 30% of the adult population are iodine deficient [26 ]. The health insurance system in
Germany consists of a mixed, private and public sector. Most German patients with
hypothyroidism are treated by family doctors/general practitioners. Patients
referred to endocrinologists include cases with complicated hypothyroidism and those
with other concomitant endocrine disorders. LT4 tablets, LT3 tablets,
LT4+LT3 combination tablets, LT4-soft-gel capsules, and LT4 liquid solution
are commercially available in Germany, without prescribing restrictions. This survey
was part of an international initiative referred to as THESIS (T reatment of
H ypothyroidism in E urope by S pecialists: An
I nternational S urvey). We aimed to investigate the use of TH for
hypothyroid and euthyroid patients by German thyroidologists and hence asked members
of the thyroid section of the German Society for Endocrinology (DGE) for their
opinion and personal experience on this issue.
Materials and Methods
The questionnaire was developed to evaluate the attitude of European thyroidologists
regarding the treatment of hypothyroidism and the use of TH in euthyroid
individuals. The questionnaire was translated from English into German by a
bilingual physician and checked by a senior bilingual physician. An open-access
survey platform (link to the German version of SurveyMonkey:
https://de.surveymonkey.com/r/QZBDFLP) was used to
build and distribute the questionnaire, and a written introduction preceded the
survey. Eight questions about demographic data (section A) were followed by
twenty-three questions about the use of thyroid hormones for hypothyroid and
euthyroid patients (section B) (supplementary material 1).
An e-mail with an electronic link leading to the voluntary and anonymized
questionnaire was sent to all members of the Thyroid Section of the German Endocrine
Society (DGE) on 26th January 2021, followed by three reminders between
February and March 2021. Data were accessible to the authors only by password.
Repeat submissions from the same IP-address were automatically blocked;
confidentiality was preserved, and the study observed the rules on personal data
protection. Ethical approval was not necessary in view of the nature of the survey.
The thyroid section of the DGE is a thyroid expert group and comprises
endocrinologists, nuclear medicine specialists, endocrine surgeons, pathologists,
pediatricians, and basic researchers.
Statistical Analysis
Descriptive statistics were prepared for responses to all questions. Respondents
with incomplete demographic data were excluded. In all analyses, respondents who
did not know the answer to a question were pooled with respondents who did not
provide an answer. As not every respondent answered every question, the
percentage of respondents providing a given answer was calculated individually
for each question, using the number of respondents to that question as the
denominator. Pearson’s x2 -test was used to compare
frequencies between the categorical variables. Multiple logistic regression
analysis was performed to examine various predictor variables. A two-sided
p-value of<0.05 was considered statistically significant. All analyses
were conducted using IBM SPSS statistics software version 27 (SPSS Inc.,
Chicago, IL, USA). GraphPad Prism, version 5.02 (GraphPad Software Inc, La
Jolla, CA, USA), was used to prepare figures.
Results
Sample characteristics
Out of 206 members of the Thyroid Section of the German Endocrine Society (DGE),
163 (79.1%, 163/206) completed the survey, and their answers
were included in the study. The demographic data of the respondents are shown in
[Table 1 ]. Demographics
(questions “gender,” “years in medical
practice,” “accredited specialty”) were answered by all
respondents. Besides being members of DGE, nine respondents (4.9%) were
members of the American Thyroid Association (ATA), and 16 (8.7%) were
members of the European Thyroid Association (ETA).
Table 1 Characteristics of respondents
(n =163)
n
(
%
)
Gender
Female
81 (49.7)
Male
82 (50.3)
Age in years
20–30
5 (3.1)
31–40
15 (9.2)
41–50
52 (31.9)
51–60
58 (35.6)
61–70
21 (12.9)
70+
12 (7.4)
Years in medical practice
0–10
22 (13.5)
11–20
50 (30.7)
21–30
51 (31.3)
31–40
27 (16.6)
40+
13 (8.0)
Accredited Specialty*
Endocrinology#
138 (84.7)
Internal medicine
88 (54.0)
Pediatric endocrinology
7 (4.7)
Nuclear medicine
10 (6.1)
Surgery
3 (1.8)
Family Medicine
1 (0.6)
Gynecology
1 (0.6)
Others**
7 (4.3)
Place of employment*
University centre
44 (24.2)
Regional hospital
24 (13.2)
Private clinic
10 (5.5)
General practice
8 (4.4)
Basic researcher
1 (0.5)
Specialist practice („Facharztpraxis“)
95 (52.2)
Member of*
European Thyroid Association (ETA)
16 (8.7)
American Thyroid Association (ATA)
9 (4.9)
German Endocrine Society (DGE)
149 (81.0)
Others
10 (5.4)
Activity
Clinical active
151 (92.6)
*The sum of n exceeds n=163 because multiple
options may have been selected; percentage is given for respondents.
**other specialties (diabetology (n =4),
nephrology (n=1), gastroenterology (n =1),
andrology (n =1)). # Some of the respondents
(n =82) selected endocrinology as well as internal
medicine as specialization.
A total of 125 members (76.7%, 125/163) responded that they see
thyroid patients daily, while 35 (21.5%, 35/163) reported weekly
attendance to thyroid clinics. Of all responders, 119 (73%,
119/163) members treated>100 hypothyroid patients annually, 27
(16.6%, 27/163) managed 51–100 per year, 16
(9.8%, 16/163) cared for 10–50 annually.
Treating hypothyroid patients
One hundred and thirty-eight (98.6% 138/140) stated that they use
LT4 as the first-line treatment for patients with hypothyroidism. Twenty-three
individuals did not provide an answer to their first treatment of choice, but
none of the members suggested DTE as the initial substitution therapy. One
respondent (0.7%, 1/140) suggested monotherapy with LT3 or
LT4+LT3, as first choice for treatment of hypothyroid patients (LT4 vs.
LT3, p<0.001; LT4 vs. LT4+LT3, P<0.001).
Although combination therapy was not their first-line therapy, 45.4%
(74/163) of the respondents also prescribed LT4+LT3,
4.9% (8/163) DTE, and 23.3% (38/163) LT3 for
selected conditions in their daily clinical practice.
Using different LT4 formulations
Most of the respondents (80%, 112/140) indicated that they
decided the dispensed LT4 formulation, while only 10.7% (15/140)
indicated that they have no influence on this matter. Only 12 respondents
(8.6%, 12/140) answered that the type of dispensed LT4 was
mostly chosen by general practitioners (LT4 dispensed as prescribed vs. chosen
by general practitioners; p<0.001).
In the survey, five questions explored the use of different LT4 formulations in
specific situations ([Table 2 ]).
Most German thyroidologists preferred LT4 tablets to soft-gel capsules or liquid
LT4 for the treatment of hypothyroidism, and they did not expect any significant
difference when switching from one formulation to another. The same attitude
applied to situations with interfering drugs, intolerance to various foods,
unexplained poor biochemical control, or persistent symptoms despite reasonable
biochemical control. Only a minority of responding thyroid specialists use the
new LT4 formulations in situations with an expected lower absorption and reduced
bioavailability of LT4 tablets (prescribing tablets vs. “I expect no
major changes with the different formulations”; p<0.001, tablets
vs. soft-gel capsules; p=0.48, tablets vs. liquid solution;
p<0.001).
Table 2 Levothyroxine formulations preferred by the
members of the Thyroid Section of German Endocrine Society (DGE) in
different clinical situations
I expect no major changes with different formulations, n
(%)
Tablets/tablets from another manufacturer, n
(%)
Soft-gel capsules, n (%)
Liquid solutions, n (%)
Not sure/no answer, n (%)
B5 . Interfering drugs may influence the stability of
therapy. Which LT4 preparations, in your experience, are
least likely to be subject to variable absorption?
55 (33.7)
54 (33.1)
1 (0.6)
30 (18.4)
23 (14.2)
B6 . Which of the following preparations of LT4 would
you prescribe in case of the first diagnosis of
hypothyroidism when the patient self-reports intolerance to
various foods raising the possibility of celiac disease,
malabsorption, lactose intolerance, or intolerance to common
excipients?
31 (19.0)
67 (41.1)
3 (1.8)
39 (23.9)
23 (14.2)
B7 . Which of the following preparations of LT4 would
you prescribe for a patient established on LT4 who has
unexplained poor biochemical control of hypothyroidism?
37 (22.7)
61 (37.4)
4 (2.5)
38 (23.3)
23 (14.2)
B8 . Which of the following preparations of LT4 would
you prescribe for a patient with poor biochemical control
who is unable (due to a busy lifestyle) to take LT4 fasted
and separate from food/drink?
52 (31.9)
41 (25.2)
5 (3.1)
42 (25.8)
23 (14.2)
B9 . Which of the following preparations of LT4 would
you prescribe for a patient established on LT4 tablets who
have good biochemical control of hypothyroidism but
continues to have symptoms?
106 (65)
25 (15.3)
0 (0)
5 (31.0)
27 (16.6)
B# refers to the number of the question in the THESIS questionnaire,
LT 4 levothyroxine, n numbers
In a logistic regression analysis ([Table
3 ]), 3.2 times more female than male responders would switch to
tablets from another manufacturer when faced with biochemically euthyroid but
symptomatic patients, the other choices being “soft-gel
capsules,” “liquid LT4 solution,” or “no major
changes expected with different formulations” (Question #B9:
(p=0.021). Furthermore, female responders relate significantly to
switching LT4 tablets from another manufacturer (p=0.014). To the
question covering poor biochemical control of hypothyroidism, respondents
without membership of either ETA or ATA were not as likely (question #B7 in
[Table 2 ]) and question #B8 in
[Table 2 ]) to stick to
“tablets,” as compared to colleagues with a membership of one of
these associations.
Table 3 Multivariate logistic regression analysis
concerning question number B9 in the THESIS questionnaire
(Clinical scenario 4: Patient established on LT4 who has good
biochemical control of hypothyroidism but continues to have
symptoms) for the dependent variable ”Tablets from
another manufacturer ” and various independent
variables. LT4, levothyroxine
Regression coefficient B
P
Exp (B) (OR)
CI 95%
Gender (female)
1.185
0.021
3.271
1.2 – 8.918
Age (reference category: 20–30 years)
0.505
Age (31–40 years)
−1.455
0.256
0.233
0.019 – 2.877
Age (41–50 years)
−0.701
0.581
0.496
0.041 – 5.979
Age (51–60 years)
−0.018
0.989
0.982
0.067 – 14.396
Age (61–70 years)
0.898
0.563
2.454
0.117 – 51.552
Age (>70 years)
−18.046
0.999
0
Years in medical practice (reference category: 0–10
years)
0,726
Years in medical practice (11–20 years)
−1.08
0.204
0.34
0.064 – 1.798
Years in medical practice (21–30 years)
−0.531
0.564
0.588
0.097 – 3.567
Years in medical practice (31–40 years)
−0.948
0.411
0.387
0.04 – 3.723
Years in medical practice (>40 years)
−20.39
0.998
0
Member of (member of ETA or ATA)
−1.129
0.09
0.323
0.088 – 1.194
Number of patients with hypothyroidism treated (reference
category: 10–50/year)
0.833
Number of patients with hypothyroidism treated
(51–100/year)
−0.546
0.536
0.579
0.103 – 3.263
Number of patients with hypothyroidism treated
(>100/year)
−0.724
0.353
0.485
0.105 – 2.238
Number of patients with hypothyroidism treated (no,
rarely)
17.911
1
60091581.9
OR, odds ratio<; CI, confidence interval; ATA, American Thyroid
Association; ETA, European Thyroid Association
Monitoring thyroid hormone treatment
After initiating LT4 treatment (61.4% (86/140) members of the
Thyroid Section of the DGE would re-check serum TSH concentrations after
4–6 weeks, and 37.9% (53/140) after eight weeks. No
member would re-check after only two weeks, and 23 of the members did not
provide a definite answer (4–6 weeks vs. 8 weeks; p<0.001).
Most respondents would re-check serum TSH after 4–6 weeks (49.3%,
69/140) when switching to another formulation or changing to another
manufacturer, and 42.1% (59/140) would re-check after 8 weeks.
If the dosage was unchanged, six members (4.3%, 6/140) stated
that there is no need for TSH monitoring when switching from one preparation to
another, six members (4.3%, 6/140) relied on clinical
evaluation, and 23 members did not answer (4–6 weeks vs. 8 weeks;
p<0.001). The answers were not associated with any of the investigated
demographic variables of the respondents, such as gender, age, years in medical
practice, member of ETA/ETA, or the number of patients treated
annually.
Treating euthyroid patients with thyroid hormones
This section explored physicians’ attitudes towards prescribing TH to
euthyroid patients in specific clinical situations. A minority of the
respondents (26.4%, 37/140) stated that TH treatment in
euthyroid patients is never indicated (never indicated vs. others;
p<0.001; never indicated vs. “in patients with unexplained
fatigue”; p=0.015, never indicated vs. “in patients with
severe hypercholesterolemia, as a complementary treatment”;
p=0.007, never indicated vs. “in patients with simple
goiter”; p<0.001, never indicated vs. “in patients with
obesity resistant to lifestyle interventions”; p=0.143, never
indicated vs. “in patients with depression resistant to anti-depressant
medications,” p=0.09). The majority (62.9%,
88/140) indicated that TH treatment could be considered in infertile
females with high levels of thyroid antibodies (indicated in female infertility
vs. no indication; p<0.001), and a large number (57.1%,
80/140) would also consider TH therapy in patients with simple goiter
growing over time. Only a small number of respondents would consider TH
prescription in patients with treatment-resistant depression (6.4%,
9/140), unexplained fatigue (12.9%, 18/140), obesity
resistant to lifestyle interventions (5.0%, 7/140), or severe
hypercholesterolemia as a complementary treatment (7.1%, 10/140)
([Fig. 1 ]).
Fig. 1 Responses from 140 German thyroidologists concerning the
use of thyroid hormones in euthyroid individuals (Question B1:
“Thyroid hormones may be indicated in biochemically euthyroid
patients with: [check all that apply] “. Twenty-three
respondents did not answer this question. Total frequency
was>100% as more than one option was possible in the
questionnaire.
In a logistic regression analysis (Supplementary Table 1), 10.2 times more
responders with an experience of 21–50 years versus 0–10 years
in medical practice would consider TH therapy in female infertility with high
levels of thyroid antibodies (question #B1: “Thyroid hormones may be
indicated in biochemically euthyroid patients with:”). For the other
options (“unexplained fatigue”, “severe
hypercholesterolemia, as a complementary treatment,” “depression
resistant to antidepressant medications,” “simple goiter growing
over time” and “no, treatment is never indicated for these
patients,” respectively) to this question, demographic variables had no
impact on the stated answers.
Combination therapy with LT4 and LT3
A majority of respondents (94; 67.1%, 94/140) considered as appropriate
the switch from LT-4 to combination therapy for patients with normal serum TSH
and persistent symptoms suggestive of hypothyroidism. Only 24.3%
(34/140) of respondents would never use combination therapy due to the low
quality of evidence. No less than 5.7% (8/140) would recommend LT4-LT3
treatment also to patients with normal serum TSH and unexplained weight gain.
Four (2.9%, 4/140) respondents considered the use of combination therapy
in patients recovering from protracted hypothyroidism, and twenty-three members
did not provide an answer to this question (combination therapy vs.
“never use”; p<0.001). Thyroid specialists aged
51–60 years old considered combination therapy in patients with normal
serum TSH who still complain of symptoms suggestive of hypothyroidism 12 times
more often than younger members (20–30 years) (supplementary Table 2).
Other than age, demographic variables had no impact on the stated answers based
on multivariate analysis.
Persistent symptoms in LT4 treated patients
Twenty-nine respondents (20.7%, 29/140) estimated that up to 30%
of hypothyroid patients still experience persistent symptoms despite the
attainment of biochemical euthyroidism while on LT4 therapy, and 10
(7.1%, 10/140) claimed that>30% of the patients have
persistent symptoms despite normal TSH levels. The majority of the respondents,
however, estimated this fraction of patients to be as low as
6–10% (30.1%, 49/140) or less than 5%
(28.2%, 46/140); (≤10% vs.>10%,
p<0.001). Forty-eight thyroid specialists (34.3%, 48/140)
answered that this trend has increased over the past five years, 70
(50.0%, 70/140) did not observe a significant change, ten (7.1%,
10/140) declared that these cases are decreasing, twelve members (8.6%,
12/140) were not sure, and the rest of them (23/163) did not provide an answer
(more cases vs. fewer cases; p=0.041). Responders treating
51–100 patients with hypothyroidism/year were 4.4 times more certain
that patient benefit from TH therapy had “not changed” than
members treating only 10–50 hypothyroid patients/year (Supplementary
Table 3). The outcome of the rest of these questions did not depend on any of
the demographic variables stated above.
Regarding possible reasons for persistent hypothyroid symptoms, German thyroid
specialists were asked to comment on eight possible causes with five options
(strongly disagree, disagree, neutral, agree, strongly agree). While most
respondents selected the “neutral” option neutral, some
responders suggested that persistent symptoms could be due to psychological
factors, comorbidities, unrealistic expectations, chronic fatigue syndrome,
inflammation or autoimmunity, the burden of chronic disease, or the burden of
taking medication ([Fig. 2 ]). Only a
minority stated that symptom persistence might be due to LT4’s inability
to restore normal TH physiology ([Fig.
2 ]). Members of ETA or ATA strongly agreed with the statement that
“in most patients treated with levothyroxine who achieved normal serum
TSH, persistent symptoms are due to the inability of levothyroxine to restore
normal physiology” (Question #B16 in the questionnaire) 14.4 times more
than non-ETA or ATA members; no association, particularly with the age of
responders, was observed (Supplementary Table 4).
Fig. 2 The opinion of German thyroidologists on possible factors
explaining persistent symptoms of hypothyroidism despite biochemical
euthyroidism in patients treated with LT4.
Supplementation with selenium or iodine
Fifty-nine (42.1%, 59/140) experts answered that supplementation with
selenium or iodine could be used if requested by the patient (p<0.001),
while 22 (15.7%, 22/140) stated that such supplementation should never
be used (p<0.001). A total of 52 respondents (37.1%, 52/140)
answered that selenium or iodine may be used in patients with co-existing
autoimmune thyroiditis (p<0.001). Only seven respondents (5.0%,
7/140) recommended supplementation with selenium or iodine to patients with
subclinical hypothyroidism (p=0.241), while twenty-three did not provide
an answer. The outcome in questions regarding supplementations does depend on
some demographic variables. Thus, supplementation with selenium or iodine at the
patient’s request or as a complementary treatment was preferred 8.1
times more by non-members of ETA or ATA than ETA/ATA members (p=0.010)
(supplementary Table 5). Supplementation with selenium or iodine in coexisting
autoimmune thyroiditis was preferred 3.2 times more by members of ETA or ATA
than non-ETA or ATA members (p=0.032) (supplementary Table 6). Regarding
supplementation with selenium or iodine in subclinical hypothyroidism,
demographic variables had no impact on the stated answers on the basis of
multivariate analysis.
Endocrinologists with hypothyroidism
Twenty respondents (14.3%, 20/140) reported their own medical history of
hypothyroidism requiring treatment, 120 respondents (85.7%, 120/140) had
no history of hypothyroidism (p<0.001), 23 respondents did not respond.
Only four (22.2%, 4/18) respondents declared suffering from excessive
tiredness, whereas two (of 20 respondents with their medical history of
hypothyroidism) did not respond to this question. To the question #B20
(“Have you tried combination treatment with LT4 or LT3?”) as
well as the question #B21 (“Do you have tried thyroid treatment with
DTE?”, two (of 20 respondents with their medical history of
hypothyroidism) did not respond, six (33.3%, 6/18) respondents tried, 12
(66.7%, 12/18) did not try combination therapy. Two (11.1%,
2/18) respondents tried treatment with DTE and 16 (88.9%, 16/18) did not
try treatment with DTE (tried vs. not tried, p<0.001).
One-hundred-and-two respondents (75%, 102/136) would not consider
combination therapy with LT4 and LT3 or with DTE, and 34 (25%, 34/136)
might consider combination therapy in case they were to be affected by
hypothyroidism in the future (would consider vs. would not consider combination
therapy, p<0.001).
Discussion
Treatment with LT4
This survey among members of the Thyroid Section of the DGE confirmed that LT4 is
the treatment of choice for newly diagnosed hypothyroid patients in Germany
[27 ]. LT4 tablets, liquid
solution, and soft-gel preparations are commercially available in Germany.
However, only 3.6% (5/140) of respondents would consider
prescribing soft-gel capsules and 30% (42/140) liquid solution,
respectively, to patients for whom it is inconvenient to separate LT4 and food
intake. The reason for this attitude is unknown, but probably cost-effectiveness
and user aspects may be issues [2 ].
LT4 soft-gel capsules (Tirosint® 100 µg)
contain animal gelatin, which some patients may wish to avoid for personal
reasons. In Germany, LT4 soft-gel capsules (Tirosint®
100 µg) are three times more expensive than LT4 tablets
(e. g., L-Thyrox Hexal® 100 µg). LT4
as a liquid solution (in Germany, L-Thyroxine Henning Tropfen 30 mL,
100 µg/mL) is less convenient to use (drop counting) and
to store (cold storage). This is in line with the reports of the French [28 ], Bulgarian [29 ], Finnish [30 ], Swedish [31 ], and Polish [32 ] surveys, where the majority of the
respondents would also prefer LT4 tablets.
In contrast, 75% of respondents in the Italian survey [11 ] and 74% in the Romanian
survey [33 ] recommended soft-gel
capsules or liquid solutions to patients on LT4 therapy who have poor
biochemical control of their hypothyroidism. Interestingly, only 14.5%
of the Danish endocrinologists [34 ]
and only 30% (2.9% soft-gel, 27.1% liquid solution) of
the German thyroidologists agreed with this strategy. Soft-gel capsules have
been on the Italian market for a longer time than in Germany. Thus, Italian
endocrinologists are probably more familiar with other formulations of LT4 than
tablets. Other factors explaining why soft-capsules are more frequently
prescribed in Italy than in other countries could be differences in cost and
marketing and the fact that most studies on efficacy, safety, and
bioavailability of soft-gel capsules have so far been conducted in Italy.
Thyroid hormone therapy in euthyroid patients
In accordance with current guidelines [13 ]
[35 ], most responders
in the German survey agreed that TH therapy is not indicated in
treatment-naïve euthyroid patients. About 63% (88/140)
of German thyroidologists, however, would consider thyroid hormone
supplementation for infertile women with high levels of thyroid autoantibodies.
This is in agreement with reports from the Polish (63.4%) survey [32 ] but significantly higher than in
other countries in the THESIS survey, namely 48.5% of the Spanish [36 ], 36.4% of the Romanian
[33 ], 47.3% of the
Swedish [31 ], 42.1% of the
Danish [34 ], 31.7% of the
French [37 ], 30% of the
Finnish survey, and 17.5% of the Bulgarian [29 ] survey. These data were at least
partially in agreement with the 2012 ETA guidelines [13 ], stating that treatment with LT4
might be considered in some euthyroid thyroid peroxidase antibody
(TPOAb)-positive women undergoing fertility treatment, in whom plasma TSH is
within the upper normal reference range (i. e., 2.5–4.0
mIU/L). The rationale being to secure euthyroidism in case of pregnancy,
although LT4 treatment neither promotes conception nor reduces the risk of
pregnancy complications in such individuals [38 ]
[39 ]. Notably, the most recent 2021 ETA
guideline recommends that all women with subfertility should be screened for
TPOAb and suggests that in subfertile women, LT4 treatment should be started
promptly in case of overt hypothyroidism or when TSH levels are above 4.0
mIU/L or the upper limit of reference range [40 ].
Interestingly 57.1% (80/140) of responders in the German survey
agreed to treat euthyroid patients with a growing goiter with LT4. Our results
are in line with reports from the Bulgarian (35%) [29 ], the Romanian (39.4%)
[33 ], the French (40.2%)
[37 ], the Polish 40.3%)
[32 ], and the Finnish
(41%) surveys, but a lot higher than in the Danish (12.5%) [34 ], the Swedish 15.1% [31 ], the Italian (18.1%) [11 ], and the Spanish (21.1%)
[36 ] surveys. However, the
current guidelines discourage this approach, and action is needed to attain a
more appropriate management of these euthyroid patients, especially in
iodine-sufficient regions of Europe [41 ].
Combination therapy with LT4 and LT3 and supplementation with selenium or
iodine
According to ETA guidelines [13 ], the
LT4+LT3 combination may be used as an alternative to LT4 in patients
with persistent symptoms of hypothyroidism despite stable biochemical control
for at least six months, and after the exclusion of interfering conditions. If
improvement is not achieved after 3–6 months, the combination therapy
should be discontinued. This consideration was supported by 67.1%
(94/140) of the German thyroid specialists, and 52.9%
(74/140) reported to have prescribed combination therapy in clinical
practice. This is in agreement with reports from other countries in the THESIS
survey, where 78.5% of Swedish [31 ] and 71% of the Danish [34 ] respondents would prescribe
LT4+LT3 combination therapy in the presence of persistent symptoms
suggestive of hypothyroidism, but a lot higher than in the Finnish
(43%), Italian (40%) [11 ], Spanish (40%) [36 ], Romanian (35.9%) [33 ], Polish (32.2%) [32 ], French (26.0%) [37 ], and Bulgarian (24.2%) [29 ] surveys.
In the German survey, older physicians (51–60 years old) were 12 times
more likely to prescribe LT4+LT3, but they did not believe more than
younger physicians that “in most patients treated with LT4 who achieved
normal serum TSH, persistent symptoms are due to inability of LT4 to restore
normal physiology”. This apparent discrepancy may be consequent upon
patients exerting pressure on thyroid specialists to prescribe combination
treatment [42 ].
Finally, only very few German thyroid specialists considered the use of DTE,
which is characterized by a high content of T3 and has not been shown to result
in better outcomes compared to synthetic LT4 in a randomized controlled trial
[43 ].
Of note, almost one-third of German thyroid specialists would consider selenium
or iodine supplementation in patients with autoimmune thyroiditis, which,
however, is not recommended to patients with autoimmune thyroiditis according to
a recent ETA survey on the use of selenium supplementation in
Hashimoto’s thyroiditis, showing poor evidence for clinical efficacy of
selenium supplementation [44 ],
although an effect on TPO antibody levels was shown in a meta-analysis [45 ]. The results in the German survey
are in agreement with reports from other countries in the THESIS survey, where
29.6% of the Polish [32 ],
30% of the Finnish [30 ], and
56.8% of the Romanian [33 ]
respondents would prescribe selenium or iodine supplementation, but a lot higher
than in the Danish (6.6%) [34 ], Swedish (4.3%) [31 ], French (10.1%) [37 ], Spanish (14.1%), and Bulgarian (15%) [29 ] surveys.
Treatment of physicians with hypothyroidism
Most respondents declared that they would not consider TH combination therapy for
their treatment if they were to develop hypothyroidism, primarily based on a
lack of evidence. Those considering combination therapy would prefer
LT4+LT3, while DTE was rejected due to the non-physiologically high
T3:T4-ratio. Interestingly, 45.4% of the respondents would prescribe
combination therapy for their patients with hypothyroidism, but only 25%
would consider this treatment for themselves if they developed hypothyroidism.
This is in agreement with reports from other THESIS surveys, where 21.7%
of the Swedish [31 ] and 18.%
of the Danish [34 ] respondents would
consider a combination therapy with LT4+LT3 or DTE for themselves if
they developed hypothyroidism, but the values were a lot higher than in the
French (9.3%) [28 ], Polish
(11.8%) [32 ], Bulgarian
(15%) [29 ], and Spanish
(17.3%) [36 ] surveys. The
discrepancy in predisposition to use LT4+LT3 combination therapy for
patients compared to oneself among thyroid specialists suggests that factors
other than evidence influence clinical decisions, most likely related to the
ambiguity of professional guidelines and demands made by patients.
Strengths and limitations
The strength of this survey is the relatively high response rate, as compared to
similar THESIS surveys [11 ]
[28 ]
[30 ]
[31 ]
[32 ]
[33 ]
[34 ]
[36 ], with a response rate of
26.2% by the Spanish [36 ],
28.1% by the French [28 ],
28.2% by the Swedish [31 ],
30.0% by the Finnish [30 ],
31.2% by the Danish [34 ],
42.2% by the Romanian [33 ],
43.5% by the Italian [11 ],
and 59.5% by the Polish [32 ]
survey. By circulating the questionnaire to all 206 members of the Thyroid
Section of the DGE, we obtained 163 responses (79.1% response rate), and
more than 90% of thyroid specialists reported seeing hypothyroid
patients daily or at least weekly. Most DGE members who are clinically and
academically active within the thyroid field are organized within the Thyroid
Section of the DGE. In nearly all other THESIS surveys [11 ]
[28 ]
[30 ]
[31 ]
[32 ]
[33 ]
[34 ]
[36 ], the questionnaire was distributed
to all members of an Endocrine Society; limitations also include the virtual
patient cases with loss of nuances potentially interfering with the
interpretation. Another limitation is that treatment of hypothyroidism,
particularly LT4 prescription, in Germany is initiated mostly by family
doctors/general practitioners, who were not represented in this
survey.
In conclusion, in Germany, the treatment of choice for hypothyroidism is LT4
tablets, also when conditions possibly affecting LT4 bioavailability are
present. Combination therapy with LT4+LT3 is considered for patients
treated with LT4 with persistent symptoms and stable TSH within the reference
range, while only very few members of the Thyroid Section of the DGE prescribe
DTE. Notably, the outcome in questions regarding “the LT4+LT3
combination therapy”, “estimates on hypothyroid patients
experience persistent symptoms despite biochemical euthyroidism while on LT4
therapy”, and “supplementation with selenium and iodine”
depend on the demographic variables of the respondents.
L-T4 treatment of infertile euthyroid women harboring thyroid antibodies, which
is not evidence-based, is considered by about 63% of German thyroid
specialists. German thyroid specialists differ from other national survey
respondents in their selenium and iodine supplementation recommendations, which
warrants further study.
