Hypothyroidism is a common disease, occurring 5 to 10 times more frequently in women than in men. The global prevalence of overt hypothyroidism in the general population ranges between 0.2% and 5.3% in Europe and 0.3% and 3.7% in the USA (Table 1) [10]. The prevalence figures from the USA originate from population-based surveys and a statewide health fair [11,12]. The European figures are derived from two meta-analyses of published population studies [13,14] and a national survey in Spain [15]. The Japanese data were obtained at a general health check-up [16], and the Korean data come from the sixth Korea National Health and Nutrition Examination Survey [17,18].

Is there any evidence for increasing prevalence over the last decades? Epidemiological studies in this respect are limited. Most are based on data obtained from drug prescription and hospital discharge databases. The Thyroid Epidemiology Audit and Research Study (TEARS) study from Scotland reported an increase of 63% in the prevalence of treated hypothyroidism in the period 1994–2001 from 3.1% to 5.1% for women and from 0.5% to 0.9% for men; the year-on-year increase was 7.5% [19]. The National Health and Nutrition Examination Surveys in the USA have described an increase in the use of LT4 from 5.1% in the period 1999–2000 to 6.4% in the period 2011–2012 (P= 0.007 for trend) [20]. The prevalence of treated hypothyroidism in the Italian region of Piedmont was 3.11% (0.23% for iatrogenic hypothyroidism) in 2012, and in Spain it was 4.2% in 2009 to 2010 [15,21]. In the UK, the prevalence of treated hypothyroidism, based on LT4 prescriptions in a national-level database covering 99% of general practitioner (GP) practices, increased by 57% from 2.3% (1.43 million) in 2005 to 3.5% (2.24 million) in 2014; the year-on-year increase was significant (P= 0.03) [22]. Growth in population size or prolonged lifespan in the period under investigation only partially explained the observed increase. In multivariate analysis, the prevalence of treated hypothyroidism was positively associated with female sex, white ethnicity and obesity, and negatively with smoking. It was forecasted the prevalence of treated hypothyroidism in 2025 would increase to 4.65% (3.23 million persons) [22]. These data are in accordance with a prevalence of 3.6% for treated hypothyroidism in north-east England in 2016 [23]. A similar trend was observed in the USA, where the proportion of the population reporting thyroid hormone use increased from 4.1% in 1997 to 8.0% in 2016 (P<0.01) [24]. This increase occurred predominantly in individuals over age 65. LT4 became the most prescribed drug in the USA in 2014 and was the second most dispensed drug in the UK in 2020 [25,26]. A community-based study in the UK found that the median TSH level at initiation of LT4 therapy fell from 8.7 to 7.9 mU/L between 2001 and 2009 [27]. A Danish study in a primary care population demonstrated a considerable fall in the median serum TSH at LT4 initiation from 10 mU/L in 2001 to 6.8 mU/L in 2015 [28].

The proportion of thyroid hormone users in the Dutch population increased from 1.87% in 2005 to 2.79% in 2011, an increase of 49% [29]. In the same period, the Dutch population size increased only by 2.1%. With regard to the various thyroid hormone preparations, the proportion of only T4 users gradually but consistently decreased from 99.05% in 2005 to 98.98% in 2011. The opposite trend was observed in T4+T3 users, the proportion of which slowly but steadily increased from 0.82% in 2005 to 0.90% in 2011; in absolute numbers, the increase was from 2,499 to 4,179 persons (67%). The proportion of only T3 users remained the same (0.13% and 0.12%). About two-thirds of prescriptions are from GPs and one-third from specialists. In a questionnaire survey among T4+T3 users in Denmark, GPs prescribed the medicine in 44% and specialists in 41% of cases, and 4% of patients bought the drugs through the internet [30]. The serum TSH level at diagnosis was <4, 4–10, 10–20, and >20 mU/L in 21%, 25%, 7%, and 14%, respectively; 32% did not remember. The number of applications for reimbursement of T4+T3 therapy was used as a surrogate for the number of new patients starting T4+T3 therapy. A 3.8-fold increase was observed from 2012 to 2014, obviously induced by the publication of a book describing experience of patients with hypothyroidism and its treatment. A United States survey in 2013 reported that overt hypothyroidism would be treated with LT4 by 99.2% of respondents and that 0.8% would use T4+T3 combination therapy [31]. Persistent hypothyroid symptoms despite achieving a target TSH on LT4 would prompt 3.6% of respondents to use T4+T3 combination therapy. In contrast, a follow-up United States survey in 2017 demonstrated that as many as 18% to 41% of physicians were willing to prescribe T4+T3 combination therapy, depending on the specific scenario [32]. Physicians from North America were found to be more likely to prescribe T4+T3 combination than physicians from outside North America (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.2 to 2.9). A questionnaire survey called Treatment of Hypothyroidism in Europe by Specialists: an International Survey (THESIS) was done recently among members of national endocrine societies in five European countries [33–37]. Although LT4 remained the drug of choice for initiating treatment of hypothyroidism, 1% to 1.5% of respondents already used combined T4+T3 at the initiation of thyroid hormone therapy. Furthermore, 24% to 59% of respondents considered using combination therapy in patients who experience persistent hypothyroid symptoms despite a normal TSH while receiving LT4 (Table 2). Interestingly, this proportion is directly related to a given country’s economic health expressed as per capita gross domestic product (GDP): the higher the GDP, the higher the willingness to use T4+T3 combination therapy (Fig. 1).

The prevalence of persistent symptoms has increased according to most respondents of the THESIS survey (Table 3). High prevalence figures are found in countries with a high GDP, whereas the figures are much lower in countries with a low GDP. Approximately one-third of respondents stated that the prevalence of persistent symptoms increased in the last 5 years (Table 4).

The nature of hypothyroid symptoms tends to be non-specific and difficult to distinguish from other conditions or general suboptimal health [38]. This was nicely illustrated by a study in patients with newly diagnosed overt autoimmune hypothyroidism using a population-based case-control design [39]. Among 34 symptoms investigated, 13 symptoms were overrepresented in patients with hypothyroidism. Hypothyroid patients suffered mostly from tiredness (81%), dry skin (63%), and shortness of breath (51%). None of the individual symptoms of hypothyroidism had high likelihood ratios or diagnostic ORs [39]. The authors concluded that neither the presence nor absence of any individual hypothyroid symptom had sufficient accuracy for establishing the diagnosis of hypothyroidism.

A Danish internet-based questionnaire study inquired about persistent symptoms on LT4 therapy before the initiation of T4+T3 combination therapy [30]. The median number of symptoms per participant was 7 (interquartile range [IQR], 5 to 8); as many as 69% of patients had ≥6 different symptoms. The frequency of these symptoms is listed in Table 5. An online survey of hypothyroid patients, posted on the American Thyroid Association website, asked the question. If you are not satisfied, indicate relevant areas you feel are affected by your thyroid treatment with LT4? [40]. The four most prevalent answers among 6,949 respondents were fatigue or energy levels (80%), weight management (70%), memory (60%), and mood (49%). These prevalence figures are in good agreement with those from the Danish online survey (Table 5) [30]. The issue of body weight might be relevant, as the preference for T4+T3 combination therapy in some of the early randomized controlled trials (RCTs) could be linked to greater weight loss [8]. In an open-label cohort study, 23 hypothyroid patients referred because of persistent symptoms despite adequate LT4 monotherapy were switched to T4+T3 combination therapy at a dose ratio of !7:1 [41]. Quality of life (QoL) assessed by the Thypro-39 composite score improved (from a baseline value of 54 towards 15 and 20 after 3 and 12 months, respectively), but there was no change in body weight. In a meta-analysis of seven blinded RCTs, the pooled prevalence rate for preference of combination therapy was 46.2% [42]. Sensitivity analysis explained the preference for T4+T3 combination in part by treatment effects on serum TSH, mood and symptoms, but not on QoL or body weight. There existed a positive association between the total daily liothyronine (LT3) dose and treatment preference [42].

Prominent dissatisfaction among 12,146 treated hypothyroid patients, measured on a scale from 1 (not satisfied) to 10 (very satisfied), was observed in a United States online survey done in 2017 [40]. Satisfaction was lowest in the LT4 group (median score 5; IQR, 3 to 7), intermediate in the T4+T3 group (median score 6; IQR, 3 to 8), and highest in the desiccated thyroid extract (DTE) group (median score 7; IQR, 5 to 9). Respondents taking DTE compared to those taking T4 or T4+T3 were less likely to report problems with fatigue/energy levels (−10% and −9%, respectively), weight management (−5% and −7%), mood (−11% and −11%), and memory (−8% and −11%) (all P values <0.0001). It should be emphasized that this online survey among treated hypothyroid patients was based on responses from a self-selected sample, unlikely to represent the whole United States population of hypothyroid patients, and therefore liable to multiple biases [40]. The online survey captured predominantly women, half of the respondents had changed their physician twice or more, and two-thirds believed that stress or physical comorbidities other than hypothyroidism might have caused at least part of the symptoms [40]. Similar restrictions apply to another online survey of people with treated hypothyroidism in the UK in 2019 [43]. Immediately after posting the questionnaire on the website, there was a surge of responses and the maximum number of responses allowed by the license (n=1,014) was reached within 24 hours. The sample thus represented about 0.04% of all hypothyroid patients in the UK, and was liable to bias. Satisfaction with treatment and care was recorded as a binary response (satisfied or not satisfied), and QoL was recorded on a scale of 0 to 100 (0 being worst and 100 being best) [43]. The proportion of dissatisfaction in patients treated with DTE (n=123), LT4 (n=677), and T4+T3 (n=124) was 83%, 78%, and 69%, respectively; the mean corresponding QoL was 54, 46, and 56. Multivariate analysis showed significant positive correlations between satisfaction and age, male gender, currently being under the care of a thyroid specialist, GP-prescribed DTE or T4+T3, and being fully informed by one’s GP; significant negative correlations existed between satisfaction and expectation for more support from one’s GP, negative experiences with LT4, the expectation that LT4 would resolve all symptoms, and the expectation to be referred to a specialist. QoL was positively correlated with male gender and duration of hypothyroidism, and was negatively correlated with age, ≥3 visits to a GP with symptoms of hypothyroidism before diagnosis, obtaining treatment with DTE, T4+T3, or T3 without the GP’s help, experiencing difficulties with LT4, the expectation that LT4 would resolve all symptoms, and the expectation for more support from GP. It is surprising to find that the level of satisfaction and QoL were not substantially different between users of LT4, T4+T3, and DTE, suggesting that other determinants than the thyroid hormone preparation must play a role. The authors conclude that focusing on enhancing the patient experience and clarifying expectations at diagnosis may improve satisfaction and QoL [43].

The inability of LT4 to restore thyroid hormone physiology is aptly called the “low tissue T3 hypothesis” by Perros et al. [44]. The name directly refers to the basic research by Escobar-Morreale et al. [1,2], demonstrating in experimental animals that tissue T3 content could be normalized only by the combined administration of T4 and T3, not by T4 alone. There is extensive circumstantial evidence supporting this hypothesis. Hypothyroid patients replaced with LT4 require somewhat higher serum free thyroxine (FT4) levels in order to normalize serum TSH, whereas their serum free triiodothyronine (FT3) levels are somewhat lower than in euthyroid controls. Actually, 7.2% of hypothyroid patients on LT4 have FT4 levels above the upper normal limit, and 15.2% of patients have FT3 levels below the lower normal limit [45]. To compensate for the reduced thyroidal secretion of T3 (normally responsible for 20% of the daily T3 production), more T3 must be generated in extrathyroidal tissues from exogenous T4. Some tissues depend largely on serum T3 for their T3 content, whereas other tissues are capable of producing T3 themselves by deiodination of local T4. Three types of deiodinases regulate the conversion of T4 into T3 and the inactivation of T4 and T3. The expression of these enzymes varies between tissues, and it has been suggested that a polymorphism in the deiodinase 2 gene (Thr92Ala) may cause slight changes in deiodinase activity but important changes in thyroid hormone bioavailability [38]. Indeed, carriers of the Thr92Ala polymorphism demonstrate a hypothyroid-like state in the brain [46]. The co-existence of polymorphisms in the iodothyronine deiodinase 2 (DIO2) gene (rs225014=Thr92Ala) and the thyroid hormone transporter gene monocarboxylate transporter 10 (MCT10; rs17606253) significantly enhanced the preference for T4+T3 combination therapy (the preferences in patients with 0, 1, or 2 polymorphisms were 42%, 63%, and 100% respectively) [47]. In a study evaluating tissue function tests before total thyroidectomy and at 1 year postoperatively when using LT4, it was found that peripheral tissue function tests indicated mild hyperthyroidism at TSH <0.03 mU/L and mild hypothyroidism at TSH 0.3 to 5.0 mU/L; the tissues were closest to euthyroidism at TSH 0.03 to 0.3 mU/L [48]. A normal serum TSH level consequently does not necessarily indicate a euthyroid state at the tissue level [49]. In accordance, a systematic review found that clinical parameters are associated with FT4 or FT3 significantly more often than with TSH levels (50% and 23% respectively, P<0.0001) [50]. The scientific basis of the “low tissue T3 hypothesis” is thus sound, and individualized therapy for hypothyroidism could be indicated, as LT4 monotherapy may provide dissatisfaction in a subset of patients [7].

The most remarkable finding in the questionnaire survey is that the majority of respondents disagreed that the “low tissue T3 hypothesis” plays a major causal role in persistent complaints. My feeling is that 10 years ago, it was the opposite and most specialists supported this hypothesis as a reasonable explanation of persistent symptoms. If so, what changed the perception of doctors that other factors must be involved? The very idea that there existed an alternative for T4 monotherapy became well known among hypothyroid patients, thanks to information by active thyroid patient associations in many countries and improved counseling by physicians, boosted by ongoing scientific reports that apparently strengthened the rationale for combination treatment. T4+T3 therapy became thus rather popular, and attractive to dissatisfied patients. It is against this background that the observed direct relationship between the use of T4+T3 and the per capita GDP should be considered. People in richer countries have more time and resources at their disposal to deal with their health problems, and can afford to buy the pills required for the T4+T3 combination treatment, which are not always available or reimbursed by insurance companies.

The persistence of symptoms despite ‘adequate’ LT4 monotherapy may generate dissatisfaction in patients; these patients could have great expectations about the outcomes, and could be inclined to believe it will resolve all their symptoms [43]. Epidemiological data (summarized above) demonstrate most patients treated with LT4 in the last two decades had subclinical hypothyroidism (their median TSH before treatment was 6.8 to 7.9 mU/L). A large placebo-controlled trial among patients with subclinical hypothyroidism at least 65 years of age demonstrated no apparent benefits of LT4 treatment [51]. A meta-analysis among nonpregnant adults with subclinical hypothyroidism showed the use of thyroid hormone therapy was not associated with improvements in general QoL or thyroid-related symptoms [52]. Later studies among adults aged 80 years and older with subclinical hypothyroidism confirmed that LT4 treatment, compared to placebo, was not significantly associated with improvement in hypothyroid symptoms, fatigue, or depressive symptoms [53,54]. A guideline panel including patients, clinicians, and methodologists issued in 2019 a strong recommendation against thyroid hormones in adults with subclinical hypothyroidism (which may not apply to pregnant women, patients with TSH >20 mU/L, patients with severe symptoms, or young adults ≤30 years of age) [55]. Furthermore, 36% of patients with treated subclinical hypothyroidism remain euthyroid after thyroid hormone discontinuation [56]. It is thus likely that most patients who were dissatisfied with the outcome of LT4 treatment had received LT4 because of subclinical hypothyroidism, a condition that by itself poorly responds to LT4.

Associated autoimmune diseases occur in 14% of patients with Hashimoto’s disease and in 10% of patients with Graves’ disease [57]. Therefore the 2012 ETA guidelines already recommended excluding these comorbidities before embarking on T4+T3 combination therapy [4]. Symptoms resembling those of hypothyroidism also occur in medical conditions like chronic fatigue, anemia, stress, and changes in body weight [38]. It would be prudent to check for such conditions unrelated to the thyroid gland itself. The issue of body weight deserves special attention, as the responses to the THESIS survey disclose the use of LT4 in obese patients [33–37]. Serum TSH is significantly higher in obese patients than in normal weight controls; subclinical hypothyroidism is recorded in 13.7% of obese patients, but thyroid autoimmunity is not a major cause [58–60]. Longitudinal studies suggest that changes in the hypothalamus-pituitary-thyroid axis are side effects of increasing body weight rather than its cause, and are reduced after weight loss obtained by caloric restriction [61]. The increase in serum TSH in the absence of thyroid antibodies is likely an adaptive response. Recent European Society of Endocrinology guidelines recommend testing all patients with obesity for hypothyroidism, based on TSH; if TSH is elevated (using the same reference range as for non-obese), FT4 and thyroid peroxidase antibody (TPO-Ab) should be measured [62]. The guidelines recommend against the use of thyroid hormones to treat obesity in case of normal thyroid function; they also recommend that hyperthyrotropinemia (elevated TSH and normal FT4) should not be treated in obesity with the aim of reducing body weight.

The awareness of having a chronic disease and lifelong dependency on thyroid medication could make patients unhappy and less healthy [4,9]. Patients with persistent symptoms despite a normal serum TSH level frequently feel that their normal TSH presents a barrier to further evaluation. GPs and nurses often have inadequate knowledge of medication interactions and LT4 pharmacokinetics; information exchange is usually restricted by time and often centered on symptoms rather than patient education [63]. Positive correlations were noticed between satisfaction and being well-informed about hypothyroidism, whereas negative correlations were observed between satisfaction and expectations for more support from one’s GP [43]. Improvement of the interactions between physicians and patients could reduce barriers to optimal thyroid replacement [9].

Up to 85% of respondents in the THESIS survey thought that psychosocial factors and chronic fatigue syndrome can play a causal role in persistent symptoms. These patients may have somatic symptom and related disorders (SSRD) as proposed by Perros et al. [44]. SSRD is a diagnostic classification with specific criteria described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [64,65]. It refers to persistent bodily symptoms associated with significant functional impairment, psychological distress, and high healthcare costs. The distress can concern bodily symptoms in the context of a chronic medical condition, such as hypothyroidism, or medically unexplained symptoms. It can be accompanied by anxiety or depressive disorders [44]. An individual with SSRD has a maladaptive reaction to a somatic symptom [66]. Perros et al. [44] elegantly describe the sequence of affairs: “Patients with SSRD have multiple medical consultations and inevitably thyroid function tests are ordered.” “Approximately 10% of SSRD patients may also have thyroid dysfunction, usually subclinical hypothyroidism. If patient and doctor assume the symptoms are due to hypothyroidism, LT4 is prescribed but will not be followed by symptom resolution if the actual diagnosis is SSRD. Any benefits tend to be minor and transient, leading to escalation of the dose of LT4, without consistent symptomatic improvement.” “LT4 is declared ineffective by the patient who, having consulted blogs and patient forums, may then seek treatment with T4+T3 or DTE. The patient may encounter resistance from the doctor to prescribe these treatments leading to consultations with several specialists or alternative practitioners or purchasing LT3 or DTE online. The difficulty that patients experience accessing their ‘desired’ treatment may also increase the perception of a benefit of treatment when they receive it, although symptoms usually persist. Frustration and dissatisfaction ensue and are perpetuated by the absence of effective treatment directed at the underlying cause of the symptoms.”

A cross-sectional study among patients with autoimmune hypothyroidism observed that TPO-Ab levels (but not TSH, FT4, or FT3) are related to goiter symptoms, depressivity, and anxiety [67]. A meta-analysis observed an association between autoimmune thyroiditis and depression (OR, 3.56; 95% CI, 2.14 to 5.94) or anxiety (OR, 2.32; 95% CI, 1.40 to 3.85) [68]. LT4-treated patients with persistent symptoms despite a normal TSH and high TPO-Ab were randomized to receive total thyroidectomy or continuation of LT4 treatment; QoL and fatigue improved after total thyroidectomy. After 1.5 years, median TPO-Ab values were reduced from 2,232 to 152 kU/L in the surgical group, and from 2,052 to 1,300 kU/L in the medical group [69]. The autoimmune neuroinflammation hypothesis is the only cause of persistent symptoms shown in Table 5, for which there existed a complete overlap between respondents agreeing or not agreeing with this particular cause (Table 5). Obviously, respondents felt quite uncertain about this cause. However, the hypothesis remains plausible, as strengthened by a recent systematic review [70].

Can the occurrence of persistent symptoms on LT4 treatment be avoided? Probably so, at least to a certain extent, especially in patients who had unrealistic expectations about the outcome of LT4 treatment. We have seen an increase in the prevalence of treated hypothyroidism in the last decades, mostly due to an increase in the prevalence of treated subclinical hypothyroidism [27,28]. More recently, it has become clear from placebo-controlled RCTs that the use of thyroid hormone in subclinical hypothyroidism is not associated with improvements in QoL or thyroid-related symptoms [52]. Better counseling of patients and more information on what might be expected from treatment before initiating LT4, might reduce unrealistic expectations and the chance of persisting symptoms.

Persistent symptoms are sometimes caused by associated autoimmune diseases, which in view of their high prevalence in Hashimoto’s thyroiditis (13.7%) should be given more attention [57]. The rising worldwide prevalence of obesity is of concern in this context, because 14% of obese patients have subclinical hypothyroidism, often without thyroid antibodies [58–60]. Recent guidelines recommend not to treat isolated hyperthyrotropinemia in obese patients with thyroid hormone if the goal of treatment is reduction of body weight [62]. This advice will prevent dissatisfaction with the outcome of LT4 treatment, as a recent meta-analysis showed that treatment of subclinical hypothyroidism does not improve clinical symptoms such as overweight [52].

Many studies report that dissatisfaction with LT4 outcomes in hypothyroid patients is related to previous negative experiences with health care workers [32,38,40,43,44]. For instance, dissatisfied patients had often paid ≥3 visits to their GP with symptoms before the diagnosis of hypothyroidism was made, had changed their GP ≥2 times, were not fully informed or had expected more support from their doctor. Doctors are instrumental in helping patients to cope with the burden of having a chronic disease and the burden of taking daily medication. Focusing on enhancing the patient experience and clarifying expectations at diagnosis may improve satisfaction and QoL [43].

Hypothyroid women on LT4 (score <60 on the SF36 QoL questionnaire) were randomized to cognitive behavioral therapy (CBT) (8 weekly sessions each lasting 90 minutes, in a group of 12) or no specific intervention; CBT improved scores for emotional health, energy, and general health to a greater extent than in controls [71]. CBT might be feasible as treatment for somatic symptom disorder [72], and recommendations have been published for core outcome domains in clinical trials on somatic symptom disorder [73]. A collaborative care model combining training with psychiatric consultation in the general practice setting could also be an effective intervention in the treatment of persistent medically unexplained symptoms [74]. It is obvious that much has to be learned about this approach to persistent symptoms in LT4-treated hypothyroid patients.

To validate the “low tissue T3” hypothesis, more and better-designed RCTs should be done. The RCTs carried out so far did not provide conclusive answers, as most if not all studies could be criticized for the following reasons: (1) heterogeneous patient population including hypothyroid patients due to Hashimoto’s disease or thyroidectomy/¹³¹I therapy (for thyroid cancer, multinodular goiter, or Graves’ disease); (2) inclusion of patients irrespective of persistent symptoms; (3) too small a sample size; (4) wide variation in T4+T3 dosages in combination treatment; and (5) different primary and secondary outcomes [8,9]. To promote discussions about an optimal study design, the American, European and British thyroid associations have recently published a consensus document, which is very helpful [75]. My own recommendations for a new RCT comparing T4 monotherapy versus T4+T3 combination therapy would be: