Review Article

Gender dierences in thyroid system function:

relevance to bipolar disorder and its treatment
Bauer M, Glenn T, Pilhatsch M, Pfennig A, Whybrow PC. Gender
dierences in thyroid system function: relevance to bipolar disorder and
its treatment.
Bipolar Disord 2014: 16: 5871. 2013 John Wiley & Sons A/S.
Published by John Wiley & Sons Ltd.
Objectives: Thyroid hormones play a critical role in the functioning of
the adult brain, and thyroid diseases impair both mood and cognition.
This paper reviews gender dierences in thyroid system function that are
relevant to the diagnosis and treatment of bipolar disorder.
Methods: The study comprised a comprehensive literature review of
gender dierences in thyroid disease that are pertinent to mood
disorders.
Results: The prevalence of thyroid disease was found to be much higher
in females than males, and to increase with age. The most commonly
detected abnormality was subclinical hypothyroidism, which was found
to occur in up to 20% of postmenopausal women. Females also had
higher rates of thyroid autoimmunity. Individuals at risk for thyroid
disease, such as adult females, may have had less ability to compensate
for additional challenges to thyroid metabolism, including lithium
treatment. Thyroid abnormalities were associated with a poorer response
to standard treatments for mood disorders. Females with treatment-
resistant mood disorders may have responded better than males to
adjunctive therapy with thyroid hormones.
Conclusions: Disturbances of thyroid system function, which occur
commonly in females, may complicate the diagnosis and treatment of
mood disorders. In particular, this is clinically relevant during lithium
treatment because lithium may impair vital thyroid metabolic pathways
secondary to its anti-thyroid activity.
Michael Bauer
a
, Tasha Glenn
b
,
Maximilian Pilhatsch
a
, Andrea
Pfennig
a
and Peter C Whybrow
c
a
Department of Psychiatry and Psychotherapy,
University Hospital Carl Gustav Carus,
Technische Universit at Dresden, Dresden,
Germany,
b
ChronoRecord Association, Inc.,
Fullerton,
c
Department of Psychiatry and
Biobehavioral Sciences, The Semel Institute for
Neuroscience and Human Behavior, University
of California at Los Angeles, Los Angeles, CA,
USA
doi: 10.1111/bdi.12150
Key words: bipolar disorder depression
gender differences thyroid hormone thyroid
system
Received 2 August 2012, revised and accepted
for publication 1 July 2013
Corresponding author:
Michael Bauer, M.D., Ph.D.
Department of Psychiatry and Psychotherapy
University Hospital Carl Gustav Carus
Technische Universit at Dresden
Fetscherstrae 74
Dresden D-01307
Germany
Fax: +49-351-458-4324
E-mail: michael.bauer@uniklinikum-dresden.de
Thyroid diseases are common aictions, with a
prevalence that is much higher in females than in
males and which increases with age (13). Thyroid
hormones play an important role in the normal
functioning of the adult brain, although under-
standing of the underlying biology is just beginning
(4). Disturbances of thyroid metabolism, whether
resulting in inadequate (hypothyroidism) or exces-
sive (hyperthyroidism) hormone production, cause
mood and cognitive symptoms in patients without
underlying psychiatric disorders (5, 6). Some thy-
roid disorders also occur more frequently in
females, including those with unipolar depression
(7) and those suering bipolar disorder with persis-
tent rapid cycling (8, 9). In patients with mood dis-
orders, the added burden of abnormal thyroid
function may have signicant consequences that
impact the psychiatric symptoms presented, treat-
ment selection and response, and the clinical moni-
toring requirements. The present paper reviews
gender dierences in adult thyroid system function
that are particularly relevant to the diagnosis and
treatment of bipolar disorder.
Thyroid hormone actions in the brain
Thyroid hormone plays a critical role in the func-
tioning of the adult brain, as reviewed previously
(4, 10, 11). The synthesis and secretion of thyroxine
(T4) by the thyroid gland are regulated by a nega-
tive feedback loop that involves the hypothalamus,
pituitary, and thyroid gland (HPT axis). The rate
58
Bipolar Disorders 2014: 16: 5871
2013 John Wiley & Sons A/S
Published by John Wiley & Sons Ltd.
BIPOLAR DISORDERS
of secretion of T4 by the thyroid gland is stimu-
lated by pituitary thyrotropin-stimulating hor-
mone (TSH), which in turn is stimulated by
hypothalamic thyrotropin-releasing hormone
(TRH), with triiodothyronine (T3) and T4 as nega-
tive feedback regulators. T4 is circulated to periph-
eral tissues bound to protein, where it is converted
to the biologically active form T3 by deiodination.
T3 binds to thyroid hormone receptors with ten-
fold higher anity than does T4 (11).
Most T4 is transported into the brain by a car-
rier-mediated process, and most conversion from
T4 to T3 occurs locally within the brain. A com-
plex interplay of components, including thyroid
hormone transporters and deiodinases, maintains
the intracellular concentration of T3 at tightly con-
trolled levels (12). Biological actions are initiated
by the intracellular binding of T3 to nuclear thy-
roid hormone receptors, which are widely distrib-
uted throughout the adult brain. The binding of
the T3receptor complex results in the activation
of brain transcription machinery that may posi-
tively and negatively regulate the transcription of
target genes (11). The details of the mechanisms
that regulate intracellular T3 concentration, and
the biological actions of T3 within the adult brain
are not yet clear. Commonly proposed mechanisms
for the modulatory eects of thyroid hormone on
mood include interactions of thyroid hormone
with serotonin and norepinephrine neurotransmit-
ter systems (4, 10).
Thyroid diseases in adult life
The most frequently occurring thyroid diseases of
adult life are autoimmune disorders. Autoimmune
(Hashimotos) thyroiditis is the most frequent
cause of hypothyroidism in countries where there is
sucient iodine supply in the diet, and Graves dis-
ease is the most frequent cause of hyperthyroidism
(13, 14). Serum TSH is the most sensitive measure
for determining the presence of thyroid disease
(15). In overt hypothyroidism, serum thyrotropin-
stimulating hormone (TSH) is above the reference
range and serum free T4 (FT4) is below the refer-
ence range (13). In overt hyperthyroidism, serum
TSH is suppressed below the reference range and
most patients have increases in both serum FT4
and free T3 (FT3) (14). In subclinical thyroid dis-
ease, serum TSH is outside the reference range and
serum FT4 and FT3 are within the reference range.
Increased prevalence of thyroid disease in females
The detection of thyroid disease in a population
varies with many factors, including the distribution
of age and gender; the screening methodology,
such as ultrasound versus palpation to detect thy-
roid nodules; the diagnostic criteria, such as the
reference range for a laboratory test; and the expo-
sure to environmental conditions that interfere
with thyroid function, such as iodine deciency or
radiation. Despite such methodological dierences
and diverse populations, a higher prevalence of
hypothyroidism is reported in females, ranging
from two to seven times higher than in males
(Table 1). The most commonly detected thyroid
abnormality is subclinical hypothyroidism, or mild
thyroid disease, found in 410% of the population
in large studies (16). The prevalence increases with
age, so that as many as 20% of postmenopausal
women may have subclinical hypothyroidism (17).
There is also an increased prevalence of thyroid
autoimmunity in females. Three antibodies are
involved in thyroid autoimmunity: thyroglobulin
antibodies, thyroid peroxidase (TPO) antibodies,
and TSH-receptor antibodies. Clinically, testing
for TPO antibodies may be required to conrm an
autoimmune cause for thyroid disease (18). In
community studies, the prevalence of TPO
antibodies generally ranges from approximately
1020% (Table 2), in part varying with the sensi-
tivity and specicity of the assay system (15). The
prevalence of TPO antibodies is increased in
females, ranging from two to ve times higher than
in males. There are also signicant ethnic dier-
ences in the prevalence of thyroid antibodies. For
example, in the US National Health and Nutrition
Examination Survey (NHANES) of 16,000 indi-
viduals over the age of 12, the prevalence of TPO
antibodies is lower in African-Americans and His-
panics than in Caucasians, with the percentage in
females without thyroid disease being 6.4 0.5,
14.7 0.8, and 15.6 0.6, respectively (2).
The prevalence of hyperthyroidism is lower than
that of hypothyroidism, reported as about 0.5%
for overt disease and 1% for subclinical hyperthy-
roidism, dened as a serum TSH between 0.1 and
0.4 mIU/L (14). The prevalence is of hyperthyroid-
ism is higher in females than males, and higher in
iodine-decient areas for both males and females
(14).
Neuropsychiatric symptoms associated with
thyroid diseases
Disturbances of thyroid metabolism may pro-
foundly alter mental function in adults as both
hyperthyroidism and hypothyroidism are associ-
ated with changes in mood and cognition (5, 6, 19).
All patients receiving an initial diagnosis of depres-
sion or bipolar disorder should be assessed for
59
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60
Bauer et al.
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61
Thyroid gender dierences
thyroid disease (20). Psychiatric symptoms of hypo-
thyroidism include psychomotor retardation,
decreased appetite, fatigue, and lethargy, while
severe hypothyroidism can mimic dementia. The
memory decit associated with hypothyroidism
may be attributable to specic retrieval decits
rather than the broad executive diculties associ-
ated with major depression (21, 22). Older adults
may be more vulnerable to the cognitive changes
caused by thyroid failure (23). Psychiatric symp-
toms of hyperthyroidism include dysphoria, anxi-
ety, restlessness, emotional lability, and impaired
concentration, although elderly patients may expe-
rience apathy, lethargy, and pseudo-dementia. The
neurocognitive impairments accompanying thyroid
disease are usually reversed rapidly following return
to euthyroid hormone status, although if left
untreated, severe hypothyroidismmay result in irre-
versible dementia (24). There is some controversy as
to whether a subset of patients experience persistent
psychological impairment after recovery from overt
thyroid disease, especially hypothyroidism(25, 26).
In contrast to overt thyroid disease, studies of
the impact of subclinical thyroid disease on mood,
cognition, and quality of life have shown conict-
ing results, with most studies nding no impact or
changes of minimal severity (4). Several review
articles assessing the impact of subclinical hypo-
thyroidism and hyperthyroidism on mood and
cognitive impairment have reported no signicant
impact from subclinical hypothyroidism on mood,
cognition, and quality of life (16, 17). Contradic-
tory results were reported for the impact of sub-
clinical hyperthyroidism on symptoms of anxiety
and memory impairment, and further research is
indicated (16, 17).
Laboratory diagnosis of thyroid disease
The diagnosis and management of thyroid disease
is dependent on the laboratory reference range
used to determine whether an individuals serum
level falls within normal values. As many females
have abnormal or marginal TSH values, several
issues related to laboratory testing will be summa-
rized. The reference range for serum TSH is usu-
ally determined from a local population of at least
120 healthy individuals who do not have thyroid
disease (15). The distribution curve for serum TSH
is inuenced by age and race, with higher concen-
trations of serum TSH in Caucasians than African-
Americans of comparable age, and a large shift to
higher concentrations with aging in all races (2,
27). Although adjustment for gender is not
required for clinical practice (2), several research-
ers recommend that the reference range for TSH
should reect age and race (17, 27). The reference
range for TSH also varies with the location,
method used to dene euthyroid, healthy popula-
tion, and the analytical characteristics of the assay
system (28). The upper limit of the reference range
for serum TSH is critical to the diagnosis of sub-
clinical hypothyroidism, and in recent interna-
tional studies has varied from 2.12 to 4.70 (2, 29).
If an age-based upper limit of the reference range
for a third-generation serum TSH assay is not
available in an iodine-sucient area, an upper limit
of normal of 4.12 should be considered (20).
Each person has a genetically determined set-
point for serum TSH, although it is not practical to
measure this clinically (15, 30). The wide reference
range for serum TSH, generally about 0.454.50, is
due to this large population-based variance. By
contrast, individual variance in serum TSH around
a set-point is small, or about half the size of the ref-
erence range (31). Thus, the population reference
range for serum TSH may not be sensitive enough
to detect early thyroid changes within an individ-
ual, and a change in serum TSH that is clinically
signicant for an individual may still be within the
reference range (32). It is not known if mood disor-
ders have an impact on the set-point for serum
TSH or on individual variation in serum TSH,
FT3, or FT4. There are also large diurnal varia-
tions in serum TSH, which is generally lowest in
the late afternoon (31), and interpretation of
thyroid function tests must distinguish transient
from sustained abnormalities. Long-term monitoring
of serum TSH and FT4 levels is important for the
early detection of deterioration in thyroid function.
The target range for serum TSH for pregnant
women should be based on trimester-specic
ranges, and detailed guidelines for monitoring and
treating thyroid hormone during pregnancy are
available (20, 33).
A group of thyroid function test abnormalities,
including a suppressed TSH, are commonly
detected in hospitalized patients, including up to
one-third of those with psychiatric diagnoses (34,
35). Referred to as nonthyroidal illness, these
changes are thought to represent an adaptive
mechanism to critical illness rather than an endo-
crine disorder, and most resolve without treatment
(34). Thyroid function tests should only be per-
formed on hospitalized patients if thyroid dysfunc-
tion is suspected (20).
Progression of subclinical hypothyroidism to overt
hypothyroidism
Most patients with subclinical hypothyroidism do
not experience deterioration in thyroid function
62
Bauer et al.
for many years (32, 36, 37). The progression of
subclinical hypothyroidism to overt hypothyroid-
ism is about 58% per year (32), increasing in
females and with age. The primary factor indicat-
ing risk for the conversion to overt thyroid failure
is the degree of serum TSH elevation at baseline
(37, 38). Additionally, multiple studies have
reported an association between TPO antibodies,
which are more prevalent in females, and elevated
serum TSH (1, 2, 39, 40). In areas with sucient
iodine, mildly elevated TSH (510 mIU/L) is asso-
ciated with TPO antibodies in about 6080% of
patients (1). The presence of elevated TPO anti-
bodies is also associated with the conversion to
overt hypothyroidism (1, 36, 37). Some other risk
factors for developing overt hypothyroidism
include postpartum status, the presence of a goiter,
a family history of autoimmune disorders, previous
thyroid injury such as from radiotherapy or neck
surgery, and the use of drugs that impair thyroid
function (41).
Treatment of thyroid disease
Patients with overt thyroid disease, either hypothy-
roidism or hyperthyroidism, must receive appro-
priate treatment. Treatment for subclinical
hypothyroidism (serum TSH 4.510.0 mIU/L) is
not generally recommended in those without
behavioral symptoms (17). However, pregnant
women with subclinical hypothyroidism should be
treated with L-thyroxine (L-T4) replacement, and
individuals with an increased risk for progression
to overt hypothyroidism require further investiga-
tion and possible treatment (16). There is wide var-
iation in the clinical and biochemical symptoms
associated with serum TSH levels in hypothyroid-
ism (42, 43), and treatment should be tailored to
the individual patient (20). The treatment of sub-
clinical hyperthyroidism (serum TSH 0.10.5 mIU/
L) is recommended in older patients due to evi-
dence of an increased all-cause mortality and asso-
ciation with atrial brillation (4446). The most
common cause of subclinical hyperthyroidism is
unintentional excessive replacement therapy in
patients with hypothyroidism (16).
Thyroid hormone replacement therapy
The recommended treatment for overt hypothy-
roidism is L-T4 (20). The dose requirement for
L-T4 varies with age and body size (20), and
females may have a higher dose requirement (47).
A full replacement dose is about 1.6 lg/kg of L-T4
per day (20). Patients with subclinical hypothy-
roidism require a smaller dose of L-T4, typically
2575 lg/day (20). Adjustments to dosage are
guided by clinical response and follow-up labora-
tory values, and monitoring of L-T4 therapy
should selectively include serum FT4 as well as
TSH (20). Most incremental dosage changes are of
12.525.0 lg/day, and serum TSH should be mea-
sured 48 weeks after a dosage change (20). If sub-
clinical hypothyroidism is noted in patients
receiving L-T4 therapy, the dosage should be
adjusted to return serum TSH to the reference
range (17). After nding an adequate replacement
dose, monitoring at six-month or yearly increments
is recommended, with more frequent testing if
adherence is a problem (20). Blood should be
drawn before taking the daily L-T4 dose because
serum FT4 will transiently increase by up to 20%
after L-T4 administration (20). Patients may
require a dosage adjustment when changing L-T4
preparations (20).
A minority of patients prefer combination ther-
apy with T3 plus L-T4 for unclear reasons (48).
This may be related to genetic subtypes of type 2
deiodinase, but further research of this hypothesis
is required (49).
Serum TSH in patients taking thyroid medication
Without any consideration of psychiatric disease,
nonadherence with daily thyroid medication
remains an ongoing problem. In community stud-
ies of patients taking thyroid hormone replacement
therapy or antithyroid drugs, serum TSH levels
were outside the reference range in some 3040%
of patients in studies from Germany, the USA, and
the UK (2, 5052). A brief intervention with an
educational booklet did not improve adherence in
patients with stable hypothyroidism in the UK
(53). In addition to nonadherence issues, many fre-
quently prescribed drugs may interfere with the
absorption of L-T4, as discussed below (54).
Gender differences in bipolar disorder
Just as gender dierences are observed in thyroid
disease, the course and presentation of bipolar dis-
order dier between men and women. In addition
to more frequent thyroid comorbidity, women have
a higher prevalence of bipolar II disorder, and
experience more persistent rapid cycling, mixed epi-
sodes, and antidepressant-induced switches (55
60). Although the prevalence of alcoholism is
higher in men than women, the risk of alcoholism
for women with bipolar disorder is higher than for
women in the general population (61).
The changing levels of reproductive hormones
throughout menstruation, pregnancy, postpartum,
63
Thyroid gender dierences
perimenopause, and menopause may inuence sus-
ceptibility to aective disorders, as these hormones
may modulate neurohormonal, neurotransmitter,
and biologic clock mechanisms (62). The progres-
sion in female reproductive stages over a lifetime
may be associated with an exacerbation of bipolar
disorder and a decrease in mood elevation (63).
Treatment of bipolar disorder during pregnancy
and lactation is particularly challenging as mood
stabilizers may be a potential risk to the developing
fetus and infant, and there is a high risk of recur-
rence in the postpartum period (59, 60, 6466).
Thyroid disease in patients with mood disorders
Subclinical hypothyroidism
The behavioral and neuropsychiatric symptoms of
thyroid disease, especially the mood disturbances
of hypothyroidism, have long suggested a link
between thyroid hormone metabolism and mood
disorders. However, most patients with primary
mood disorders, including bipolar disorder, do not
have overt thyroid disease. Nevertheless, given the
high prevalence in the general population, subclini-
cal hypothyroidism is not uncommon in patients
with mood disorders, especially in older females,
and may predict a poor response to antidepres-
sants and mood stabilizers (3, 4, 67). Many subtle
alterations in thyroid function have also been
reported in patients with mood disorders, as
reviewed elsewhere (4, 68, 69). There is growing
evidence that thyroid hormone levels in the low-
normal range (i.e., thyroid hypofunction) can
result in a suboptimal treatment outcome. For
example, patients with bipolar disorder who have
TSH values at the higher end of the normal range
may be especially sensitive to variations in thyroid
hormone levels, and have a poor response to
antidepressants (70). Low-normal serum FT4 val-
ues are associated with a poor treatment response
to lithium in bipolar disorder (71). Furthermore,
the laboratory tests that are currently used to mon-
itor thyroid status may not provide an adequate
measure of thyroid hormone metabolism and
action within the brain itself (4).
Hypothyroidism in patients with persistent rapid cycling
Although most patients with bipolar disorder do
not have overt thyroid disease, one exception is
bipolar disorder with persistent rapid cycling (8).
Persistent, treatment-resistant rapid cycling occurs
predominantly in females (8), with about 58% of
those suering four to 11 episodes per year, and
100% with 12 or more episodes per year being
female (3). Many studies have noted an association
between hypothyroidism and bipolar disorder with
persistent rapid cycling, although some studies
have not found this association (e.g., 9). Some
patients with rapid cycling may have a latent dys-
function in the HPT axis that remains hidden until
challenged with an antithyroid stressor (8). Exam-
ples of stressors include drugs that interfere with
thyroid hormone metabolism, such as lithium. A
four-week lithium challenge test using a therapeu-
tic dose demonstrated latent hypothyroidism in
previously unmedicated patients with rapid cycling
and normal baseline thyroid levels (72). This sug-
gests that changes to thyroid homeostasis within
the brain of patients with hypothyroidism may
modify the phenotypic expression of bipolar disor-
der, resulting in a continuous cycling pattern that
is resistant to usual treatment (8).
Imaging studies of thyroid disease and mood
disorders
Advances in brain imaging techniques provide an
intriguing means to compare patients with thyroid
disease and mood disorders, although limited
research is currently available. Most patients with
mood disorders in these studies have unipolar
depression. As reviewed previously (4), the most
common nding in patients with hypothyroidism is
global, diuse hypoperfusion, with an inconsistent
reversibility when patients became euthyroid. The
most common nding in patients with depression is
frontal lobe hypoperfusion, with inconsistent
reversibility when patients become euthymic.
Direct comparison of the perfusion changes in
hypothyroidism and depression suggests that,
despite overlapping areas of hypoperfusion, dier-
ent circuits may be involved in the behavioral
symptoms for these diseases (73). Research from
both thyroid disease and mood disorders also sup-
ports a critical role for thyroid hormone in main-
taining euthymic mood. In a study of patients with
hypothyroidism, treatment with L-T4 restored glu-
cose metabolism to areas of the anterior cingulate
cortex that are integral to the regulation of mood
and cognition (74). In a study of patients with bipo-
lar depression who received supraphysiological
dosages of L-T4 (300 mg/day), mood improvement
was accompanied by normalization of perfusion in
frontal, limbic, and subcortical regions (75).
Thyroid hormones for treatment of mood disorders
Although thyroid hormone monotherapy is not an
adequate treatment of primary mood disorders,
most textbooks and treatment guidelines
64
Bauer et al.
recommend adjunctive treatment with thyroid hor-
mones for refractory mood disorders (76, 77).
However, the guidelines for adjunctive treatment
with thyroid hormone remain ambiguous, largely
due to missing pieces of research and inadequately
powered, small trials.
For more than 40 years, the therapeutic value of
adjunctive treatment with thyroid hormones in
mood disorders has been investigated in a series of
open and controlled clinical trials based on several
dierent paradigms. The acceleration of recovery
from depression, pioneered in the 1970s, simulta-
neously initiates therapy with an antidepressant
drug and thyroid hormone, with the goal of the
thyroid hormone speeding up the antidepressant
response. In these early studies, T3 was used as the
acceleration agent as L-T4 has a long half-life of
ve to seven days.
The augmentation approach adds thyroid hor-
mone only if a patient has a partial or nonresponse
to antidepressant monotherapy. Similarly, thyroid
hormones have been used to augment standard
prophylactic agents (mood stabilizers) in patients
with resistant recurrent mood disorders (adjunctive
prophylactic studies).
T3 acceleration and augmentation studies
Between 1969 and 1974, six double-blinded, ran-
domized, placebo-controlled trials investigated the
use of T3 to accelerate the response to a tricyclic
antidepressant (ve studies with imipramine and
one with amitriptyline) in subjects with unipolar
and bipolar disorder. A meta-analysis of these stud-
ies reported that T3 was signicantly more eective
than placebo in accelerating the antidepressant
response in ve of the six studies; that the pooled,
weighted eect size index was 0.58; and that the
eects of T3 acceleration were greater as the per-
centage of females participating in a study
increased (78). Two of the six studies in the meta-
analysis specically reported an earlier and more
favorable response in females (79, 80).
T3 has also been studied as an augmentation
agent for patients with treatment-resistant depres-
sion. Evidence from a meta-analysis suggests that
T3 may augment the response to tricyclic antide-
pressants in some patients, although results from
the eight studies were inconsistent (81). Gender
eects were not included in the latter meta-analy-
sis. In recent studies investigating T3 acceleration
or augmentation of selective serotonin reuptake
inhibitors (SSRI), gender eects were inconclusive
(8284) or not reported (85, 86). A strong gender
dierence was observed in an algorithm-based aug-
mentation study, where the addition of T3 to SSRI
nonresponders was eective in ten out of 16
women (62.5%), while none of the nine males
responded (82).
T4 adjunctive prophylactic studies
In both open-label and case studies, a supraphysio-
logical dose of L-T4 was an eective adjunctive ther-
apy for patients with bipolar disorder who did not
respond to standard maintenance treatments (87,
88), including those with rapid cycling (8992).
Adjunctive treatment with L-T4 may also have
immediate therapeutic value during a refractory
depression for patients with bipolar or unipolar dis-
order (75, 9396). At study entry, all patients in
these studies of L-T4 adjunctive treatment had not
responded to standard treatments, and did not have
overt thyroid disease (Table 3). Although only a few
of the studies of adjunctive L-T4 intentionally
excluded males (75, 95), the vast majority of patients
were females, and most patients showed a good
response (Table 3). The hypothesis that thyroid hyp-
ofunction plays a modulating role in the develop-
ment of rapid cycling is supported by the good
response to adjunctive supraphysiological doses of
L-T4 in patients with rapid cycling (93), and by the
emergence of thyroid hypofunction in patients with
rapid cycling after a lithium challenge (72).
There are safety concerns associated with the
prophylactic use of L-T4, and this treatment is
intended for patients with severe illness who do not
respond to standard measures. Although acceler-
ated bone loss was not found in most patients (97
99), regular assessment of bone mineral density is
needed, especially if other factors are present that
may potentiate bone loss, such as smoking, hyperp-
rolactinemia, dietary deciencies, and a small body
frame (100). Additionally, recent population-based
studies have conrmed that subclinical hyperthy-
roidism is associated with an increased risk of atrial
brillation and cardiac mortality (45, 46).
Challenges to thyroid function
Many drugs, as well as environmental and nutri-
tional factors, interfere with thyroid metabolism,
although compensatory mechanisms are generally
sucient to handle these challenges. However,
these agents may trigger overt thyroid disease in
patients who have mild thyroid disease or are at
risk for thyroid disease, such as older females.
Iodine
There is a complex relationship between iodine
intake and the prevalence of thyroid disease in
65
Thyroid gender dierences
adults, and thyroid abnormalities in areas of
high and low iodine intake develop in opposite
directions (101, 102). Mild-to-moderate iodine
deciency is associated with goiter and hyperthy-
roidism, whereas mild-to-moderate iodine excess is
associated more frequent with hypothyroidism (16,
102). The introduction of iodine supplementation
to a population may increase the incidence of
hypothyroidism (16). The optimal level of iodine
intake is a relatively small range around the recom-
mended daily intake of 150 lg (103), with a higher
requirement for women who are pregnant or
lactating.
Lithium
Lithium salts are a rst-line prophylactic treatment
for recurrent aective disorders, and they are also
widely prescribed for the treatment of resistant
depressive episodes. Lithium has multiple eects
on thyroid metabolism, and may impair vital
thyroid metabolic pathways during treatment. The
most clinically relevant action is that lithium
blocks the release of thyroid hormone from the
thyroid gland, which may lead to goiter and hypo-
thyroidism (104). The reported prevalence of hypo-
thyroidism in lithium-treated patients varies widely
with the methodology used to detect it, but is esti-
mated to be about 20% (104, 105). Up to 50% of
patients taking lithium may develop a goiter (104,
106). Regular monitoring of serum TSH and FT4
in all patients receiving lithium therapy is recom-
mended at intervals of 34 months for women over
the age of 45, and every 612 months for all others
(104, 107). In patients receiving L-T4 treatment for
hypothyroidism prior to starting lithium therapy,
serum TSH and FT4 should be measured within
48 weeks (20).
Lithium-induced hypothyroidism occurs more
frequently in those who are at higher risk for
autoimmune thyroid disease, including females
and older adults, with females about ve times
Table 3. Studies of levothyroxine (L-T4) as an adjunct to standard treatment in mood disorders
Study Sample N
Proportion of
female/male
subjects L-T4 dose, lg
Type of study;
duration of
treatment and
follow-up Outcome
Stancer and Persad,
1982 (89)
RC-BD 9 7/2 Supra (240400) Maintenance;
years
5 R and 2 PR in women;
NR in men
Leibow, 1983 (92) RC-BD 1 1/0 Supra (400) Maintenance;
months
Cessation of rapid
cycling
Bauer and Whybrow,
1990 (90)
RC-BD 11 10/1 Supra (150400) Maintenance;
years
9 R, 1 PR, 1 NR
Hurowitz and Liebowitz,
1993 (91)
RC-BD 3 2/1 Supra (200350) Maintenance;
months
2 R, 1 PR
Afelou et al.,
1997 (134)
RC-BD 6 4/2 50325 Maintenance;
years
2 R, 2 PR, 2 NR
Bauer et al., 1998 (93) Refractory bipolar
(n = 12) and unipolar
(n = 5) depression
17 16/1 Average 482
(300600)
Acute; 8 weeks 8 R, 2 PR, 7 NR
Rudas et al., 1999 (94) Refractory chronic
unipolar depression
and dysthymia
7 6/1 Average 235 Acute; 8 weeks 5 R, 1 PR, 1 NR
Bauer et al., 2002 (88) 20 16/4 Average 377
(200600)
Maintenance;
years
Signicant reduction of
mood episodes and
morbidity indexes; 52%
very much and 19%
much improved on CGI
Bauer et al., 2005 (75)
a
Refractory bipolar
depressed patients
10 10/0 Average 320 Acute; 7 weeks 7 R, 3 PR
Lojko and Rybakowski,
2007 (95)
a
Refractory unipolar and
bipolar depression
17 17/0 100 (xed dose) Acute; 4 weeks 11 R, 5 PR, 1 NR
Stamm et al., 2013 (96) Refractory bipolar
depression
62 32/30 300 (xed dose) Acute; 6 weeks Signicant decline of
depression score with
L-T4 in women, not in
men
CGI = Clinical Global Impression scale; NR = non response; PR = partial response; RC-BD = rapid cycling bipolar disorder;
R = response; Supra = supraphysiological dose.
a
In these studies, inclusion criteria for the study only allowed women to be enrolled.
66
Bauer et al.
more likely to develop hypothyroidism (104, 107).
A community study of adults over the age of 65
in Canada initiating lithium or valproate therapy
reported double the number of new prescriptions
for L-T4 for those receiving lithium (108). Lith-
ium may trigger an increase in thyroid antibody
titer in patients who have pre-existing autoim-
mune thyroid disease (104, 105). Recent guidelines
recommend measuring TPO antibodies for pre-
dicting the development of hypothyroidism in
patients receiving lithium therapy (20, 104),
although patients without antibodies are also at
risk. Although the presence of thyroid antibodies
was a strong risk factor for lithium-induced hypo-
thyroidism in a 15-year longitudinal study (annual
rate 6.4 versus 0.8) (109), another multiyear longi-
tudinal study did not nd this association (107).
Furthermore, there are ethnically dierent pat-
terns of thyroid antibodies (2), and high rates of
lithium-induced goiter and hypothyroidism were
reported in an Asian population with a low preva-
lence of thyroid antibodies (110). Iodine availabil-
ity may also contribute to the variation in
reported prevalence of lithium-induced hypothy-
roidism (111113). Lithium and iodine may have
synergistic eects such that lithium-induced hypo-
thyroidism will occur more frequently in areas of
iodine excess than in areas of iodine deciency
(111). Weight gain during the rst year of treat-
ment, despite normal thyroid laboratory test val-
ues, may also be predictive of hypothyroidism
(114).
Less commonly, lithium may also be associated
with hyperthyroidism. With a prevalence estimated
at about 1.72.5%, lithium-associated hyperthy-
roidism occurs most often after long-term use, and
is due to a heterogeneous mix of inammatory and
autoimmune etiologies (104, 115, 116). The inci-
dence of silent thyroiditis and thyrotoxicosis is
higher in those taking lithium (1.3 and 2.7 per
1,000, respectively) than in the general population
(0.030.28 and 0.80.12, respectively) (117). Thyro-
toxicosis may precipitate mania in lithium-treated
patients and contribute to lithium toxicity (118,
119).
Other psychotropic medications
Other medications prescribed for psychiatric disor-
ders may induce thyroid dysfunction. Drugs that
activate the cytochrome P450 system and/or uri-
dine diphosphate-glucuronosyltransferase (UGT)
enzymes may cause an increased clearance of thy-
roid hormone (54, 120), including carbamazepine,
oxcarbazepine, and barbiturates. Although the
thyroid axis can adapt and accommodate most of
these changes, patients with hypothyroidism who
receive these drugs may require an increased
replacement dose. Neither valproate nor lamotri-
gine appear to alter thyroid function (120, 121).
Quetiapine was associated with hypothyroidism in
several case reports and clinical trial results, and
future study is needed (122, 123).
Estrogen
Oral estrogen increases the amount of thyroxine-
binding globulin (TBG), the main transport for
thyroid hormones in the circulation, which in turn
may cause a transient drop in serum FT4 until a
new steady state is reached between serum-bound
and FT4 (124). By contrast, patients who are hypo-
thyroid may experience a persistent elevation of
serum TSH and decrease in serum FT4, and
require an increased replacement dose of L-T4.
Transdermal estrogen therapy does not have a clin-
ically signicant eect on TBG (54). Separate from
the eects on TBG, selective estrogen receptor
modulators may decrease the absorption of L-T4
(20).
Drugs for general medical conditions and food
Whereas the eects of drugs such as amiodarone
are long known, some of the newer immune modu-
lators used to treat infectious, autoimmune, and
neoplastic conditions may induce hypothyroidism
or hyperthyroidism, as reviewed elsewhere (54).
Glucocorticoids or dopaminergic agents may sup-
press TSH secretion (20). Many commonly pre-
scribed drugs may interfere with the absorption of
L-T4, including antacids, proton pump inhibitors,
H2 receptor antagonists, oral bisphosphonates,
calcium carbonate, ferrous sulfate, and multivita-
mins containing ferrous sulfate or calcium carbon-
ate (20). Food, dietary ber, and malabsorptive
disorders will also interfere with absorption of
L-T4 (20). Kelp supplements may contain large
quantities of iodine (20).
Environmental toxins
Females may also have increased susceptibility to
environmental toxins that impact thyroid metabo-
lism. An analysis of data from the NHANES study
found a signicant association between serum per-
uorooctanoic acid, a widely used industrial sur-
factant, and current thyroid disease that was
stronger in females than males (125). Additionally,
in a study of exposure to radioactive iodine fallout,
females experienced about three times the inci-
dence rate of thyroid disease than males, a ratio
67
Thyroid gender dierences
that persisted with increasing radiation dose expo-
sure (126).
Conclusions
Females are more likely to experience mood disor-
ders, including unipolar depression and bipolar
disorder with persistent rapid cycling. Females are
also more likely to suer from thyroid diseases and
to have thyroid autoimmunity. Thyroid hormones
play a critical role in the functioning of the adult
brain. In patients with thyroid disease, both an
excess and a deciency of thyroid hormones will
produce psychiatric symptoms. The most common
thyroid disease is subclinical hypothyroidism,
which occurs in up to 20% of postmenopausal
women and increases vulnerability to environmen-
tal or medication-induced challenges (e.g., by
lithium) to thyroid metabolism. Thyroid abnor-
malities are associated with a poorer response to
standard treatments for mood disorders. Females
with a mood disorder may respond better than
males to adjunctive treatment with thyroid hor-
mones. As specic knowledge regarding thyroid
homeostasis within the adult brain independent of
peripheral metabolism increases, understanding of
the complex inter-relation among thyroid hor-
mones and the mood disorders will evolve.
Disclosures
The authors of this paper do not have any commercial associa-
tions that might pose a conict of interest in connection with
this manuscript.
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