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Cited by 185Thyroid Disorders and TreatmentsAdipokines, Inflammation, and Metabolic DiseasesOvarian function and disorders

European Society of Endocrinology Clinical Practice Guideline: Endocrine work-up in obesity

Open access
Pasquali, R, Casanueva, F, Haluzik, M, van Hulsteijn, L, Ledoux, S, Monteiro, M P, Salvador, J, Santini, F +2 more·2020·European Journal of Endocrinology
DOI 10.1530/eje-19-0893
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Abstract

Obesity is an emerging condition, with a prevalence of ~20%. Although the simple measurement of BMI is likely a simplistic approach to obesity, BMI is easily calculated, and there are currently no data showing that more sophisticated methods are more useful to guide the endocrine work-up in obesity. An increased BMI leads to a number of hormonal changes. Additionally, concomitant hormonal diseases can be present in obesity and have to be properly diagnosed - which in turn might be more difficult due to alterations caused by body fatness itself. The present European Society of Endocrinology Clinical Guideline on the Endocrine Work-up in Obesity acknowledges the increased prevalence of many endocrine conditions in obesity. It is recommended to test all patients with obesity for thyroid function, given the high prevalence of hypothyroidism in obesity. For hypercortisolism, male hypogonadism and female gonadal dysfunction, hormonal testing is only recommended if case of clinical suspicion of an underlying endocrine disorder. The guideline underlines that weight loss in obesity should be emphasized as key to restoration of hormonal imbalances and that treatment and that the effect of treating endocrine disorders on weight loss is only modest.

Integrity signals

Registry

Crossref · 10.1530/eje-19-0893

Cites

125 of 125 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 230 cited sources checked · 0 supported · 0 flagged

  • Findingcitation
    § Reasoning:

    Treatment of overt hypothyroidism produces only a modest weight loss (usually of less than 10%).

    “treatment of overt hypothyroidism produces only a modest weight loss (usually of less than 10%) (29, 30, 31)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [29]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [30]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [31]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Findingcitation
    § 4. Summary of results from the systematic review

    The prevalence of hypothyroidism in obesity was 14.0% (95% CI 9.7-18.9), based on 19 studies.

    “the prevalence of hypothyroidism in obesity was 14.0% (95% CI: 9.7-18.9), based on 19 studies”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Findingnone given
    § Abstract

    There are currently no data showing that more sophisticated methods than BMI are more useful to guide the endocrine work-up in obesity.

    “there are currently no data showing that more sophisticated methods are more useful to guide the endocrine work-up in obesity.”
    • Also stated in: § 2. Obesity - a short introduction · plain
      “there are currently no data showing that more sophisticated methods are more useful to guide the endocrine work-up in obesity.”
    Quote in the paperNot a substantial claim
  • Findingnone given
    § 3.4. Summary of methods used for guideline development

    No studies comparing diagnostic strategies with respect to clinical effectiveness and harms have been performed in obesity.

    “Such studies have not been performed in obesity.”
    • Also stated in: § 3.5. Clinical questions, eligibility criteria and endpoint definition · hedged
      “to the knowledge of the panel no such trials in obesity were published.”
    Quote in the paperSubstantial claim
  • Findingnone given
    § Abstract

    The effect of treating endocrine disorders on weight loss is only modest.

    “the effect of treating endocrine disorders on weight loss is only modest.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 31
  • May combine two claims. 62

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data
    § 3.6. Description of search and selection of literature

    Overall, 3819 potentially relevant papers were considered and 68 were included.

    “Overall, 3819 potentially relevant papers were considered; 68 were included”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation
    § Reasoning:

    The prevalence of undiagnosed hypothyroidism in Europe was estimated around 5%.

    “the prevalence of undiagnosed hypothyroidism in Europe was estimated around 5% (22)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § 4. Summary of results from the systematic review

    The reported prevalence of male hypogonadism in the 11 included papers ranged from 16 to 52%, suggesting underlying heterogeneity.

    “the reported prevalence in the 11 included papers ranged from 16 to 52%, also suggesting underlying heterogeneity”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation
    § Reasoning:

    In Europe, the prevalence of overt hypothyroidism varies between 0.2 and 5.3%.

    “In Europe, the prevalence of overt hypothyroidism varies between 0.2 and 5.3% (20)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation
    § 3.6. Description of search and selection of literature

    Two studies assessed both hypothyroidism and hypercortisolism.

    “(two studies assessed both hypothyroidism and hypercortisolism (16)).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation
    § Reasoning:

    In Europe, the prevalence of subclinical hypothyroidism varies between 4 and 10%.

    “that of subclinical hypothyroidism between 4 and 10% (21)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Findingcitation
    § Reasoning:

    The evidence is currently too weak to recommend testing for thyroglobulin antibodies.

    “the evidence is currently too weak to recommend testing for thyroglobulin antibodies (50)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Reasoning:

    L-thyroxine is the hormone of choice; no additional benefits have been demonstrated of L-thyroxine and L-triodothyronine combination.

    “L-thyroxine is the hormone of choice; no additional benefits have been demonstrated of L-thyroxine and L-triodothyronine combination (56).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Reasoning: Thyroid hormone preparations and their derivatives have been extensively employed in the past century as antiobesity drugs (the first clinical reports on the weightlowering effect of sheep-derived thyroid extracts date from the 1890s) and sometimes are still inappropriately prescribed, despite specific recommendations against their use in euthyroid obese subjects (45). The rationale for this misuse stems from the well-known link between thyroid hormones and resting energy expenditure, which in popular fallacy is often translated into a link between hypothyroidism and obesity. Furthermore, the reduction in FT3 levels during caloric deprivation has been advocated as a possible cause for failure of hypocaloric diets. Several studies have been performed to investigate the ability of thyroid hormone or their analogues to favour weight loss, without producing adverse effects due to iatrogenic thyrotoxicosis (58, 59, 60). Overall, these studies have demonstrated only minor effects in terms of efficacy, while increased urinary nitrogen excretion has been observed, indicating loss of fat-free tissue beside the occurrence of adverse effects on bone metabolism and affective status. Furthermore, excessive thyroid hormone in patients with obesity already at risk for cardiovascular disease may facilitate the onset of cardiac arrhythmia, heart failure or ischemic events (61). Apart from decreasing body weight, thyroid hormone also improves hepatic lipid metabolism, which was also used as an argument for use in obesity. The development of TR β -selective agonist supposed to improve metabolic parameters without affecting heart rate did not have a conclusive outcome and the combined peptides that deliver FT3 specifically in the liver are not yet developed (62). R.2.7. We recommend that hyperthyrotropinaemia (elevated TSH and normal FT4) should not be treated in obesity with the aim at reducing body weight (++00).

    The development of TRβ-selective agonist supposed to improve metabolic parameters without affecting heart rate did not have a conclusive outcome and the combined peptides that deliver FT3 specifically in the liver are not yet developed.

    “The development of TR β -selective agonist supposed to improve metabolic parameters without affecting heart rate did not have a conclusive outcome and the combined peptides that deliver FT3 specifically in the liver are not yet developed (62).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation
    § Reasoning:

    Raised concentrations of thyroid antibodies are detected in about 11% of the general population.

    “Raised concentrations of thyroid antibodies are detected in about 11% of the general population (47)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Reasoning:

    FT3 has been described to be higher in obesity than in lean people, this being mainly related to the nutritional status.

    “FT3 has been described to be higher in obesity than in lean people, this being mainly related to the nutritional status (53).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Reasoning:

    The Whickham survey estimated that annual progression of subclinical hypothyroidism to overt hypothyroidism occurs in 2-5% and the rate may be lower in obesity.

    “The Whickham survey estimated that annual progression of subclinical hypothyroidism to overt hypothyroidism occurs in 2-5% (63) and the rate may be lower in obesity (64).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [63]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [64]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Reasoning:

    The relation of BMI with FT3 and FT4 is inconsistent, but a negative relation between BMI and FT4 and a positive relation between BMI and FT3 with a decrease FT4/FT3 ratio have been described.

    “The relation of BMI with FT3 and FT4 is inconsistent, but a negative relation between BMI and FT4 and a positive relation between BMI and FT3 with a decrease FT4/FT3 ratio have been described (48, 53).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [53]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Reasoning:

    Obesity is associated with modifications of thyroid parameters: TSH levels are usually higher than in normal-weight, age- and gender-matched individuals and are correlated with BMI.

    “Obesity is associated with modifications of thyroid parameters: TSH levels are usually higher than in normal-weight, age- and gender-matched individuals and are correlated with BMI (48).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Reasoning: Thyroid hormone preparations and their derivatives have been extensively employed in the past century as antiobesity drugs (the first clinical reports on the weightlowering effect of sheep-derived thyroid extracts date from the 1890s) and sometimes are still inappropriately prescribed, despite specific recommendations against their use in euthyroid obese subjects (45). The rationale for this misuse stems from the well-known link between thyroid hormones and resting energy expenditure, which in popular fallacy is often translated into a link between hypothyroidism and obesity. Furthermore, the reduction in FT3 levels during caloric deprivation has been advocated as a possible cause for failure of hypocaloric diets. Several studies have been performed to investigate the ability of thyroid hormone or their analogues to favour weight loss, without producing adverse effects due to iatrogenic thyrotoxicosis (58, 59, 60). Overall, these studies have demonstrated only minor effects in terms of efficacy, while increased urinary nitrogen excretion has been observed, indicating loss of fat-free tissue beside the occurrence of adverse effects on bone metabolism and affective status. Furthermore, excessive thyroid hormone in patients with obesity already at risk for cardiovascular disease may facilitate the onset of cardiac arrhythmia, heart failure or ischemic events (61). Apart from decreasing body weight, thyroid hormone also improves hepatic lipid metabolism, which was also used as an argument for use in obesity. The development of TR β -selective agonist supposed to improve metabolic parameters without affecting heart rate did not have a conclusive outcome and the combined peptides that deliver FT3 specifically in the liver are not yet developed (62). R.2.7. We recommend that hyperthyrotropinaemia (elevated TSH and normal FT4) should not be treated in obesity with the aim at reducing body weight (++00).

    Overall, these studies have demonstrated only minor effects in terms of efficacy, while increased urinary nitrogen excretion has been observed, indicating loss of fat-free tissue beside the occurrence of adverse effects on bone metabolism and affective status.

    “Overall, these studies have demonstrated only minor effects in terms of efficacy, while increased urinary nitrogen excretion has been observed, indicating loss of fat-free tissue beside the occurrence of adverse effects on bone metabolism and affective status.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [58]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [59]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [60]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Reasoning:

    There are very few data on the incidence of non-thyroidal illness in the obese population but one publication suggested that inflammation may increase non-thyroidal illness in obesity.

    “There are very few data on the incidence of non-thyroidal illness in the obese population but one publication suggested that inflammation may increase non-thyroidal illness in obesity (52).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Reasoning:

    In obesity, treatment of hypothyroidism is followed by a mild increase in resting energy expenditure but only a modest weight loss is achieved, mainly determined by excretion of excess body water.

    “In obesity, treatment of hypothyroidism is followed by a mild increase in resting energy expenditure (34) but only a modest weight loss is achieved (29), mainly determined by excretion of excess body water.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [29]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Reasoning:

    Despite a previous study has shown a prevalence of CS of 9.3% among a series of 150 patients with obesity, in most series the diagnosis of CS in obesity has been very uncommon, ranging from 0 to 0.7%, though patients with severe obesity have been included.

    “Despite a previous study has shown a prevalence of CS of 9.3% among a series of 150 patients with obesity (80), in most series the diagnosis of CS in obesity has been very uncommon, ranging from 0 to 0.7%, though patients with severe obesity have been included (81, 82).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [80]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [81]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [82]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Reasoning:

    Some experimental and clinical data points to a dysregulation in the activity of HPA axis in some patients with abdominal obesity, including excessive cortisol response to physical and psychological stimuli, reduced glucocorticoid feedback sensitivity and increased activity of 11-beta hydroxysteroid dehydrogenase in adipose tissue.

    “Some experimental and clinical data points to a dysregulation in the activity of HPA axis in some patients with abdominal obesity, including excessive cortisol response to physical and psychological stimuli, reduced glucocorticoid feedback sensitivity and increased activity of 11-beta hydroxysteroid dehydrogenase in adipose tissue (94).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingreasoning
    § Reasoning:

    Other features that may increase the probability of CS are nephrolithiasis, frequent infections and hypokalaemia, though are less specific than catabolic manifestations.

    “Other features that may increase the probability of CS are nephrolithiasis, frequent infections and hypokalaemia, though are less specific than catabolic manifestations (Table 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation
    § Reasoning:

    Each 5-unit increase in BMI was associated with 30% greater risk of thyroid cancer and both general and abdominal adiposity increased the risk.

    “Each 5-unit increase in BMI was associated with 30% greater risk of thyroid cancer and both general and abdominal adiposity increased the risk.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Reasoning:

    Subclinical CS has been reported to be more common in patients with obesity than in the general population, though its diagnostic criteria and treatment program have not been well established yet.

    “Moreover, subclinical CS has been reported to be more common in patients with obesity than in the general population (86), though its diagnostic criteria and treatment program have not been well established yet.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingreasoning
    § Reasoning:

    Harms of treatment were poorly studied and sparsely reported, and low TSH values are frequently found in patients treated with l-thyroxine potentially causing side effects.

    “Harms of treatment were poorly studied and sparsely reported, and low TSH values are frequently found in patients treated with l -thyroxine potentially causing side effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation
    § Reasoning:

    Obesity was positively related to papillary, follicular and anaplastic thyroid cancers, but negatively with medullary thyroid cancer.

    “Obesity was positively related to papillary, follicular and anaplastic thyroid cancers, but negatively with medullary thyroid cancer (75).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Reasoning: A more pronounced elevation of TSH is related to higher risk of developing hypothyroidism (67). Although there is a general agreement that hypothyroidism with TSH levels above 10 mIU/L should be treated (45), whether and which patients with TSH levels of 4.5-10 mIU/L benefit is less certain. For the decision on starting treatment of mild hypothyroidism other considerations should be taken into account. The presence of thyroid autoimmunity (see 5.2.2), or coexistence of other causes of primary hypothyroidism (e.g. previous radioiodine treatment for hyperthyroidism or a history of destructive thyroiditis), particularly in a young subject or in a woman in fertile age should prompt l -thyroxine treatment. By contrast, older age ( > 70 years) particularly in the presence of concurrent (cardiovascular) diseases, should direct the decision toward a follow-up strategy (45). l -thyroxine replacement therapy is recommended for older patients in good health status with TSH > 10 mIU/L (68). The link between mild hypothyroidism and coronary heart disease is generally observed in the youngest population only and on the contrary, cohort studies have demonstrated that extreme longevity is associated with higher TSH levels (68). In addition, in the 'Trust Thyroid Trial', levothyroxine provided no apparent benefits on clinical symptoms in older persons with subclinical hypothyroidism (69), but no specific trial was performed in old obese persons. Among women of reproductive age, subclinical hypothyroidism has been associated with infertility, an increased risk of adverse pregnancy and neonatal outcomes, and possibly with an increased risk of neurocognitive deficits in offspring. There is evidence that T-thyroxine therapy decreases the risk for pregnancy loss and preterm delivery in pregnant women with TSH > 4.0 mIU/L (70). The ATA recommendations propose to treat women of childbearing age who are pregnant or planning a pregnancy, if they have positive levels of serum TPOAb and their TSH is > 2.5 mIU/L (45). During pregnancy, the target range for TSH should be based on trimester-specific ranges (around 2.5 mIU/L, 3 mIU/L and 3.5 mIU/L at the first, second and third trimester, respectively). However, no study was specifically conducted in obese women to ensure that the same targets are to be achieved.

    The link between mild hypothyroidism and coronary heart disease is generally observed in the youngest population only and on the contrary, cohort studies have demonstrated that extreme longevity is associated with higher TSH levels.

    “The link between mild hypothyroidism and coronary heart disease is generally observed in the youngest population only and on the contrary, cohort studies have demonstrated that extreme longevity is associated with higher TSH levels (68).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Reasoning:

    In addition to biochemical changes, structural changes of the thyroid have also been associated with obesity. These include increases in thyroid volume and hypoechogenicity as well as thyroid nodules, which may be due to increased TSH stimulation or increase in inflammatory mediators produced by the adipose tissue.

    “In addition to biochemical changes, structural changes of the thyroid have also been associated with obesity. These include increases in thyroid volume and hypoechogenicity as well as thyroid nodules (27, 73), which may be due to increased TSH stimulation or increase in inflammatory mediators produced by the adipose tissue (27).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [73]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Reasoning:

    Although the prevalence of CS in patients with severe obesity is generally low, a study of 16 patients operated of bariatric surgery has shown that CS diagnosis, persistence or recurrence was unrecognised, suggesting that CS may be responsible for less than expected improvement in hypertension and diabetes control as well as intense weight regain after bariatric surgery.

    “Although the prevalence of CS in patients with severe obesity is generally low (81, 82, 91), a study of 16 patients operated of bariatric surgery has shown that CS diagnosis, persistence or recurrence was unrecognised, suggesting that CS may be responsible for less than expected improvement in hypertension and diabetes control as well as intense weight regain after bariatric surgery (92).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [81]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [82]

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    • cites [91]

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    • cites [92]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Findingcitation
    § Reasoning:

    The impact of obesity on thyroid cancer aggressiveness has still to be defined.

    “The impact of obesity on thyroid cancer aggressiveness has still to be defined (76).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Reasoning:

    Between 10 and 33% of individuals on l-thyroxine therapy have TSH values below normal and approximately one third to one half of these TSH levels are less than 0.1 mIU/L.

    “Indeed, between 10 and 33% of individuals on l -thyroxine therapy have TSH values below normal and approximately one third to one half of these TSH levels are less than 0.1 mIU/L (66).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given
    § 2. Obesity - a short introduction

    Increased body fatness leads to a number of hormonal changes, the most obvious example being insulin resistance.

    “Increased body fatness leads to a number of hormonal changes, the most obvious example being insulin resistance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given
    § 3.4. Summary of methods used for guideline development

    The guideline used GRADE as a methodological base.

    “the guideline used GRADE (Grading of Recommendations Assessment, Development and Evaluation) as a methodological base.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Reasoning:

    Thyroid hormones have an important role in energy metabolism.

    “thyroid hormones have an important role in energy metabolism”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [27]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Premisecitation
    § Reasoning:

    Screening of the general population for hypothyroidism is mostly not recommended.

    “Screening of the general population is mostly not recommended (24)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given
    § 3.7. Review process and endorsement of other societies

    A draft of the guideline was reviewed by experts in the field and submitted for comments by ESE members; all comments and suggestions were discussed and implemented as appropriate by the panel.

    “A draft of the guideline was reviewed by the experts in the field; it was also submitted for comments by ESE members. All comments and suggestions were then discussed and implemented as appropriate by the panel.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § 2. Obesity - a short introduction

    Concomitant hormonal diseases can be present in obesity.

    “Additionally, concomitant hormonal diseases can be present and have to be properly diagnosed”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning
    § Reasoning:

    Thyroid function is commonly assessed, independently of obesity, because hypothyroidism is one of the most common endocrine diseases.

    “Thyroid function is commonly assessed, independently of obesity, because hypothyroidism is one of the most common endocrine diseases.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Reasoning:

    BMI is considered an adequate indicator of obesity and sufficient as first diagnostic measure.

    “thus BMI is considered an adequate indicator of obesity and sufficient as first diagnostic measure”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Reasoning:

    Symptoms of hypothyroidism (such as fatigue, depression, cramps, menstrual disturbance or weight gain) are nonspecific and can be confused with those of obesity.

    “Symptoms of hypothyroidism (such as fatigue, depression, cramps, menstrual disturbance or weight gain) are nonspecific (23) and can be confused with those of obesity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § 2. Obesity - a short introduction

    Obesity is an emerging condition and plays a central role in the development of non-communicable diseases such as diabetes, hyperlipidaemia, hypertension, cardiovascular disease and cancer.

    “Obesity is an emerging condition and plays a central role in the development of non-communicable diseases like diabetes, hyperlipidaemia, hypertension, cardiovascular disease and cancer (1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Premisecitation
    § 3.4. Summary of methods used for guideline development

    The presence of a reference standard is crucial when formally grading studies on diagnostics.

    “the presence of such reference standard is crucial when formally grading studies on diagnostics (12).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning
    § Reasoning:

    This interpretation is in line with lower FT4 levels in obesity, together with the need for higher doses of substitutive l-thyroxine in hypothyroid patients with obesity.

    “This interpretation is in line with lower FT4 levels in obesity, together with the need for higher doses of substitutive l -thyroxine in hypothyroid patients with obesity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation
    § Reasoning:

    The TSH elevation could reflect decrease in thyroid hormones concentrations, explained by an increased plasmatic volume or increased rate of thyroid hormone disposal in obesity, causing in turn a compensatory activation of the pituitary-thyroid axis.

    “The TSH elevation could reflect decrease in thyroid hormones concentrations, explained by an increased plasmatic volume or increased rate of thyroid hormone disposal in obesity, causing in turn a compensatory activation of the pituitary-thyroid axis (54).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning:

    According to American guidelines, TSH is the best screening test for thyroid dysfunction for the vast majority of clinical situations, in which normal TSH is enough to rule out primary hypothyroidism.

    “According to American guidelines (45), TSH is the best screening test for thyroid dysfunction for the vast majority of clinical situations, in which normal TSH is enough to rule out primary hypothyroidism.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation
    § Reasoning:

    Hypothyroidism contributes to an unfavorable lipid profile, and thus, potentially increases vascular risk.

    “Hypothyroidism contributes to an unfavorable lipid profile, and thus, potentially increases vascular risk (43, 44).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [44]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Reasoning:

    Other mechanisms proposed to explain these modifications include increases in leptin and insulin.

    “Other mechanisms proposed to explain these modifications include increases in leptin and insulin (27).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given
    § Reasoning:

    Candidates to bariatric surgery commonly present with obesity-related comorbidities such as hypertension, metabolic syndrome and type 2 diabetes, which are also frequent in CS.

    “Candidates to bariatric surgery commonly present with obesity-related comorbidities such as hypertension, metabolic syndrome and type 2 diabetes, which are also frequent in CS.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Reasoning:

    Obesity is commonly listed among the different entities of so-called pseudo-Cushing states.

    “Obesity is commonly listed among the different entities of so-called pseudo-Cushing states (77, 78).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [77]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [78]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning:

    Despite that subjects with abdominal obesity may display less cortisol suppression in some cases, the vast majority of authors consider that this test shows an acceptable performance to rule out CS.

    “Despite that subjects with abdominal obesity may display less cortisol suppression in some cases, the vast majority of authors consider that this test shows an acceptable performance to rule out CS (78, 87, 95).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [78]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [87]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [95]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § Reasoning:

    Patients with obesity often complain of symptoms suggestive of hypothyroidism that may prompt the practitioner to introduce thyroid hormone treatment.

    “Patients with obesity often complain of symptoms suggestive of hypothyroidism that may prompt the practitioner to introduce thyroid hormone treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Reasoning:

    The presence of uncontrolled hypertension and/or type 2 diabetes despite conventional therapy in young patients with abdominal obesity may also raise the possibility of CS and justify the screening for detection of hypercortisolism.

    “The presence of uncontrolled hypertension and/or type 2 diabetes despite conventional therapy in young patients with abdominal obesity may also raise the possibility of CS and justify the screening for detection of hypercortisolism (78).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Premisereasoning
    § Reasoning:

    Guidelines recommend investigating whether patients are on glucocorticoid treatment before starting evaluation for potential endogenous CS.

    “Guidelines recommend investigating whether patients are on glucocorticoid treatment before starting evaluation for potential endogenous CS (78, 87, 95).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [78]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [87]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [95]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation
    § Reasoning:

    Despite CS being a very rare disease, eventually some candidates to bariatric surgery may have endogenous hypercortisolism that could lead to severe adverse effects after surgery if undiagnosed.

    “Despite CS being a very rare disease, eventually some candidates to bariatric surgery may have endogenous hypercortisolism that could lead to severe adverse effects after surgery if undiagnosed (89).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning:

    Other factors such as chronic stress may also be involved and hair cortisol measurement, when available, may offer a better reflection of chronic cortisol exposure than plasma or salivary samples.

    “However, other factors such as chronic stress may also be involved and hair cortisol measurement, when available, may offer a better reflection of chronic cortisol exposure than plasma or salivary samples (95).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation
    § Reasoning:

    Factors such as hypercoagulability, catabolic state and increased cardiovascular risk may be responsible for severe postoperative complications, making this scenario especially sensible for CS detection.

    “Factors such as hypercoagulability, catabolic state and increased cardiovascular risk may be responsible for severe postoperative complications, making this scenario especially sensible for CS detection (90).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning:

    Obesity is associated with an increased prevalence of hypogonadism, and no adjustments for BMI are used to confirm the biochemical diagnosis of hypogonadism.

    “Although obesity is associated with an increased prevalence of hypogonadism, no adjustments for BMI are used to confirm the biochemical diagnosis of hypogonadism (107).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning:

    Equilibrium dialysis is the gold standard procedure to measure free testosterone but is not widely available.

    “However, since the gold standard procedure to measure free testosterone (equilibrium dialysis) is not widely available, it may be preferable to calculate bioavailable testosterone by using testosterone, sex hormonebinding globulin (SHBG) and albumin concentrations (111, 123).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [111]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [123]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning:

    Testosterone measurements are affected by chronic diseases, medications, genetics, lifestyle, and intra-individual variations.

    “Moreover, testosterone measurements are affected by chronic diseases, medications, genetics, lifestyle, and intra-individual variations (126).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning: Male obesity-secondary hypogonadism (low plasma testosterone concentrations) has been reported in up to 45% of patients with moderate-to-severe obesity (107); in our review, we found a pooled prevalence of hypogonadism based on free testosterone measurements of 32.7% (95% CI: 23.1-43.0) (16). Moreover, obesity impairs sperm concentration, motility and morphology (108). Patients with obesity and associated comorbidities such as metabolic syndrome or type 2 diabetes exhibit a higher prevalence of hypogonadism (109). In fact, 75% of patients with class III obesity waiting for bariatric surgery have hypogonadism on the basis of a testosterone value lower than 12.1 nM/L (110). Accordingly, severe obesity is listed as a cause of functional secondary hypogonadism (111). Other terms such as late-onset hypogonadism and dysmetabolic hypogonadotrophic hypogonadism may also apply to this condition reflecting the participation of several metabolic factors such as obesity, visceral fat excess, insulin resistance, inflammation, oxidative stress and type 2 diabetes in its pathophysiology (107, 108, 111, 112, 113, 114, 115). There are multilateral relationships between obesity, hypogonadism, type 2 diabetes and metabolic syndrome. Thus, obesity-associated comorbidities are commonly accompanied by low testosterone values and, on the other hand, low testosterone plasma values are associated with obesity, metabolic syndrome and type 2 diabetes (116). The increase in aromatase activity in adipose tissue, responsible for converting testosterone into oestradiol, may also contribute to inhibit LH secretion and reduce testosterone (117), as well as oestradiol blood levels (109). A dysregulation of the hypothalamic-pituitary-adrenal axis inducing functional hypercortisolism in obesity may also play a role in gonadotrophin inhibition and, consequently, reduced testosterone levels (94). As for the general population (111), a routine hormonal screening for male hypogonadism is not recommended in patients with obesity, and testing should be considered when clinical features create the need for investigating hypogonadism (Table 5). Therefore, we recommend investigating routinely key clinical symptoms/signs of hypogonadism in all men with obesity, including proper testicular size assessment. In line, we suggest that obese patients with metabolic syndrome and/or insulin resistance and/or type 2 diabetes are tested for the presence of hypogonadism especially if the clinical picture is suspicious of hypogonadism (113, 118).

    Increased aromatase activity in adipose tissue, responsible for converting testosterone into oestradiol, may contribute to inhibit LH secretion and reduce testosterone and oestradiol blood levels.

    “The increase in aromatase activity in adipose tissue, responsible for converting testosterone into oestradiol, may also contribute to inhibit LH secretion and reduce testosterone (117), as well as oestradiol blood levels (109).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [117]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [109]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning: Male obesity-secondary hypogonadism (low plasma testosterone concentrations) has been reported in up to 45% of patients with moderate-to-severe obesity (107); in our review, we found a pooled prevalence of hypogonadism based on free testosterone measurements of 32.7% (95% CI: 23.1-43.0) (16). Moreover, obesity impairs sperm concentration, motility and morphology (108). Patients with obesity and associated comorbidities such as metabolic syndrome or type 2 diabetes exhibit a higher prevalence of hypogonadism (109). In fact, 75% of patients with class III obesity waiting for bariatric surgery have hypogonadism on the basis of a testosterone value lower than 12.1 nM/L (110). Accordingly, severe obesity is listed as a cause of functional secondary hypogonadism (111). Other terms such as late-onset hypogonadism and dysmetabolic hypogonadotrophic hypogonadism may also apply to this condition reflecting the participation of several metabolic factors such as obesity, visceral fat excess, insulin resistance, inflammation, oxidative stress and type 2 diabetes in its pathophysiology (107, 108, 111, 112, 113, 114, 115). There are multilateral relationships between obesity, hypogonadism, type 2 diabetes and metabolic syndrome. Thus, obesity-associated comorbidities are commonly accompanied by low testosterone values and, on the other hand, low testosterone plasma values are associated with obesity, metabolic syndrome and type 2 diabetes (116). The increase in aromatase activity in adipose tissue, responsible for converting testosterone into oestradiol, may also contribute to inhibit LH secretion and reduce testosterone (117), as well as oestradiol blood levels (109). A dysregulation of the hypothalamic-pituitary-adrenal axis inducing functional hypercortisolism in obesity may also play a role in gonadotrophin inhibition and, consequently, reduced testosterone levels (94). As for the general population (111), a routine hormonal screening for male hypogonadism is not recommended in patients with obesity, and testing should be considered when clinical features create the need for investigating hypogonadism (Table 5). Therefore, we recommend investigating routinely key clinical symptoms/signs of hypogonadism in all men with obesity, including proper testicular size assessment. In line, we suggest that obese patients with metabolic syndrome and/or insulin resistance and/or type 2 diabetes are tested for the presence of hypogonadism especially if the clinical picture is suspicious of hypogonadism (113, 118).

    Obesity impairs sperm concentration, motility, and morphology.

    “Moreover, obesity impairs sperm concentration, motility and morphology (108).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Reasoning:

    Male testosterone levels decrease with age, though the magnitude of testosterone reduction seems to be lower than previously thought.

    “Male testosterone levels decrease with age, though recent reports suggest that the magnitude of testosterone reduction seems to be lower than previously thought (124, 125).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [124]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [125]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning:

    Male obesity-secondary hypogonadism is associated with low plasma gonadotrophin concentrations, and in some cases with predominance of FSH over LH, in contrast with primary hypogonadism, where gonadotrophins are elevated.

    “Male obesity-secondary hypogonadism is associated with low plasma gonadotrophin concentrations, and in some cases with predominance of FSH over LH (107), in contrast with primary hypogonadism, where gonadotrophins are elevated.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning:

    Body fat excess and insulin resistance are commonly associated with low SHBG circulating values, complicating the interpretation of testosterone concentrations.

    “This suggestion applies especially to obesity, since body fat excess and insulin resistance are commonly associated with low SHBG circulating values (111, 116), complicating the interpretation of testosterone concentrations.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [111]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [116]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Reasoning:

    The 1 mg overnight dexamethasone suppression test is used in the majority of previous studies.

    “A 1 mg overnight dexamethasone suppression test is simple, well standardized and used in the majority of previous studies (79).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning:

    Both leptin- and leptin-receptor gene mutations are associated with growth hormone deficiency (in some patients).

    “growth hormone deficiency (in some patients)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [186]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [187]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [189]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning:

    Both leptin- and leptin-receptor gene mutations are associated with lack of normal pubertal development (in majority of patients).

    “and lack of normal pubertal development (in majority of patients) (186, 187, 189).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [186]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [187]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [189]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning:

    In severely obese patients, bariatric surgery is a very effective means of increasing testosterone levels and recovery of the hypothalamic-pituitary gonadal axis function besides achieving significant and sustained weight loss.

    “In severely obese patients, bariatric surgery is a very effective means of increasing testosterone levels and recovery of the hypothalamic -pituitary gonadal axis function besides achieving significant and sustained weight loss (134, 135).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [134]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [135]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning:

    Obesity is associated with reductions in total and free 25OHD but unchanged vitamin-D binding proteins.

    “obesity is associated with reductions in total and free 25OHD but unchanged vitamin-D binding proteins”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [181]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [182]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning:

    There is a vicious cycle where obesity can lead to functional male hypogonadism, while male hypogonadism can further promote adiposity.

    “There is compelling evidence highlighting the potential of a vicious cycle where obesity can lead to functional male hypogonadism, while male hypogonadism can further promote adiposity. Indeed, increased fat mass and reduced fat free mass is a common feature among men with androgen deficiency (129), although rarely having a significant impact on BMI (130).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [129]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [130]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationnone given
    § Reasoning:

    The ideal vitamin D replacement therapy and target 25OHD concentrations in the obese or bariatric populations are unknown.

    “However, the ideal vitamin D replacement therapy and target 25OHD concentrations in the obese or bariatric populations are unknown.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Reasoning:

    Serum leptin concentration correlates with BMI and body fat content.

    “and correlates with BMI and body fat content (185).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [185]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning:

    Both leptin- and leptin-receptor gene mutations are associated with hypothalamic hypothyroidism (low FT4 and TSH levels).

    “Both leptin- and leptinreceptor gene mutations are associated with hypothalamic hypothyroidism (low FT4 and TSH levels)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [186]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [187]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [189]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning:

    Patients with Prader-Willi syndrome typically present with significant weight gain in childhood, significantly increased appetite, GH deficiency, hypogonadism, sleep disturbances and other abnormalities.

    “These patients typically present with significant weight gain in childhood, significantly increased appetite, GH deficiency, hypogonadism, sleep disturbances and other abnormalities.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Reasoning:

    Vitamin D deficiency elicits a compensatory rise in parathyroid hormone (PTH), which increases bone turnover and calcium mobilization from the skeleton, leading to a decrease in bone mineral density and increase in the risk of osteopenia and osteoporosis.

    “Vitamin D deficiency elicits a compensatory rise in parathyroid hormone (PTH), which increases bone turnover and calcium mobilization from the skeleton, leading to a decrease in bone mineral density and increase in the risk of osteopenia and osteoporosis (177).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [177]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Reasoning:

    Vitamin-D binding proteins are among the most polymorphic proteins known and different alleles can have substantial impact on their biologic functions.

    “which are among the most polymorphic proteins known and different alleles can have substantial impact on its biologic functions (181, 182).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [181]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [182]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § 5.7.1. Pregnancy

    No specific data is available in the literature concerning the impact of obesity on PTH regulation during pregnancy.

    “No specific data is available in the literature concerning the impact of obesity on PTH regulation during pregnancy”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § 5.7.2. The elderly

    No study has specifically studied the hormonal modification induced by age in obese people.

    “Unfortunately, no study has specifically studied the hormonal modification induced by age in obese people.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Ageing is associated with alterations of hormonal secretions with variable amplitude for each endocrine system.
    • Rests on an assumption: The symptoms of endocrine disease change with aging and are often less pronounced, which can lead to missing of the diagnosis.
    • Rests on an assumption: The consequences of endocrine diseases can change in elderly with greater health risks (notably for muscle mass and cardiovascular functions).
    • Rests on an assumption: The indication to treat is different in elderly because the benefit to risk ratio may be less favourable.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given
    § 5.7.1. Pregnancy

    Few studies have reported the effects of interactions between obesity and pregnancy on endocrine functions.

    “However, few studies have reported the effects of interactions between obesity and pregnancy on endocrine functions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 5.7.1. Pregnancy

    In men, testosterone secretion and bioavailability decrease with age.

    “In men: Decreased testosterone secretion (208 ) and bioavailability”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [208]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § 5.7.1. Pregnancy

    Decreased ghrelin occurs with age.

    “Decreased ghrelin (208 )”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [208]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § 5.7.1. Pregnancy

    During pregnancy, urine and plasma aldosterone increase.

    “Because, during pregnancy, urine and plasma aldosterone increase”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [197]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § 5.7.1. Pregnancy

    The increase in CBG results in a two to threefold increase of plasma cortisol levels and a lesser increase in free cortisol.

    “The increase in CBG (200), result in a two to threefold increase of plasma cortisol levels and a lesser increase in free cortisol (197).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [200]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [197]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § 5.7.2. The elderly

    Obesity may alter the consequences of age-related hormonal changes.

    “Obesity may alter the consequences of age-related hormonal changes.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Ageing is associated with alterations of hormonal secretions with variable amplitude for each endocrine system.
    • Rests on an assumption: The symptoms of endocrine disease change with aging and are often less pronounced, which can lead to missing of the diagnosis.
    • Rests on an assumption: The consequences of endocrine diseases can change in elderly with greater health risks (notably for muscle mass and cardiovascular functions).
    • Rests on an assumption: The indication to treat is different in elderly because the benefit to risk ratio may be less favourable.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given
    § 5.7.1. Pregnancy

    Obesity can further decrease GH, but the consequences are not known.

    “Obesity can further decrease GH, but the consequences are not known.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Pregnancy induces profound changes in endocrine functions that affect the gonadotropic axis, hormones of lactation, placental hormones, and other endocrine glands such as the adrenal and thyroid glands.

  • May combine two claims.

    Premisecitation
    § 5.7.1. Pregnancy

    GH decreases during pregnancy but IGF1 increases because of placental growth hormone production.

    “GH decreases during pregnancy but IGF1 increases because of placental growth hormone production (197).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

84 of 84

  • The paper relies on this without support.

    Weight loss restores hormonal imbalances in obesity.

    “weight loss in obesity should be emphasized as key to restoration of hormonal imbalances”

  • The paper relies on this without support.

    For obese patients, the same normal thyroid hormonal values apply as for non-obese patients.

    “We suggest that for obese patients the same normal hormonal values are applied as for non-obese (+000).”

  • The paper relies on this without support.

    For patients with obesity, the same normal values for hypercortisolism testing apply as for non-obese patients.

    “We suggest that for patients with obesity the same normal values are applied as for non-obese (+000).”

  • The paper relies on this without support.

    Obesity is not a rare condition.

    “as obesity is not a rare condition”

  • The paper relies on this without support.

    BMI is easily calculated in clinical practice.

    “BMI is easily calculated in clinical practice”

  • The paper relies on this without support.

    In most cases, obesity is not caused by other endocrine diseases or hormonal disturbances.

    “In most cases, despite obesity being a condition of endocrine and metabolic imbalance, obesity is not caused by other endocrine diseases or hormonal disturbances.”

  • The paper relies on this without support.

    The prevalence of obesity is such that standard referral to an endocrinologist would not be compatible with available resources in most countries.

    “Furthermore, the prevalence of obesity is such that standard referral to an endocrinologist would not be compatible with available resources in most countries.”

  • The paper relies on this without support.

    The prevalence of endocrine disturbances is related to obesity severity.

    “because the prevalence of endocrine disturbances is related to obesity severity”

  • The paper relies on this without support.

    Clinical signs and symptoms of endocrine conditions can be difficult to distinguish from obesity.

    “because clinical signs and symptoms of endocrine conditions can be difficult to distinguish from obesity”

  • The paper relies on this without support.

    For most hormones (TSH, cortisol, testosterone), the proper equilibrium is usually restored following weight reduction, irrespective of therapeutic strategy.

    “For most hormones (TSH, cortisol. testosterone), the proper equilibrium is usually restored following weight reduction, irrespective of therapeutic strategy”

  • The paper relies on this without support.

    Several dietary supplements are commonly taken by patients with obesity, with the aim of facilitating weight loss or well-being, controlling glucose metabolism or preventing cardiovascular events.

    “several dietary supplements are commonly taken by patients with obesity, with the aim of facilitating weight loss or well-being, controlling glucose metabolism or preventing cardiovascular events.”

  • The paper relies on this without support.

    Hypothyroidism can be easily diagnosed by blood tests.

    “Hypothyroidism can be easily diagnosed by blood tests.”

  • The paper relies on this without support.

    Untreated hypothyroidism could blight the attempts at loosing body weight.

    “Finally, untreated hypothyroidism could blight the attempts at loosing body weight.”

  • The paper relies on this without support.

    The most common cause of hypothyroidism is chronic autoimmune thyroiditis.

    “The most common cause of hypothyroidism is chronic autoimmune thyroiditis.”

  • The paper relies on this without support.

    Thyroid antibody profiles are helpful to diagnose autoimmune hypothyroidism and to determine patients at risk of developing hypothyroidism.

    “Thyroid antibody profiles are helpful to diagnose autoimmune hypothyroidism and to determine patients at risk of developing hypothyroidism.”

  • The paper relies on this without support.

    Among women of reproductive age, subclinical hypothyroidism has been associated with infertility, an increased risk of adverse pregnancy and neonatal outcomes, and possibly with an increased risk of neurocognitive deficits in offspring.

    “Among women of reproductive age, subclinical hypothyroidism has been associated with infertility, an increased risk of adverse pregnancy and neonatal outcomes, and possibly with an increased risk of neurocognitive deficits in offspring.”

  • The paper relies on this without support.

    Autoimmune thyroiditis is often characterized by a hypoechogenic pattern on thyroid ultrasonography.

    “Autoimmune thyroiditis is often characterized by a hypoechogenic pattern on thyroid ultrasonography.”

  • The authors state this as an assumption.

    Obesity has epidemic proportions.

    “Assuming the epidemic proportions of obesity”

  • The authors state this as an assumption.

    Obesity has a multifactorial origin.

    “its multifactorial origin”

  • The paper relies on this without support.

    Adjustment of the dexamethasone dose to body weight does not substantially improve the sensitivity of the dexamethasone suppression test in individuals with obesity, particularly when near-maximal doses are administered.

    “In line, a study has shown that adjustment of the dexamethasone dose to body weight does not seem to substantially improve the sensitivity of the test, even in individuals with obesity, particularly when near-maximal doses are administered.”

  • The paper relies on this without support.

    The ability to sustain male gonadal benefits after weight loss achieved through conservative interventions is relatively small, as weight regain is also very common.

    “Besides, the ability to sustain the male gonadal benefits after weight loss achieved through conservative interventions is relatively small, as weight regain is also very common.”

  • The paper relies on this without support.

    Testosterone results depend on the assay technique used.

    “Testosterone results also depend on the assay technique used.”

  • The paper relies on this without support.

    Most available testosterone assays are immunoassays (RIA, enzyme immunoassay or fluoroimmunoassay), which are rapid, simple, and inexpensive.

    “Most available testosterone assays are immunoassays (RIA, enzyme immunoassay or fluoroimmunoassay), which are rapid, simple and inexpensive.”

  • The paper relies on this without support.

    Most reference ranges have been established using immunoassays.

    “Moreover, most reference ranges have been established using immunoassays.”

  • The paper relies on this without support.

    The accuracy of immunoassays is lower than that obtained by mass spectrometry, which is more expensive and requires regular calibration.

    “However, their accuracy is lower than that obtained by mass spectrometry, which is more expensive and requires regular calibration.”

  • The paper relies on this without support.

    Equilibrium dialysis represents the gold standard method to measure free testosterone but is expensive and technically challenging.

    “Equilibrium dialysis represents the gold standard method to measure free testosterone but is expensive and technically challenging.”

  • The paper relies on this without support.

    Most guidelines recommend direct measurements or calculation of free testosterone by a formula.

    “For practical reasons, most guidelines recommend direct measurements or calculation of free testosterone by a formula.”

  • The paper relies on this without support.

    The injectable preparation of testosterone undecanoate (1000 mg every 12 weeks) is widely used as treatment of hypogonadism because it leads to steady testosterone plasma levels.

    “The injectable preparation of testosterone undecanoate (1000 mg every 12 weeks) is widely used as treatment of hypogonadism because it leads to steady testosterone plasma levels.”

  • The paper relies on this without support.

    Testosterone replacement therapy given to men with hypogonadism is associated with weight loss and body composition improvement, but no evidence of this beneficial effect is observed in eugonadal subjects.

    “Although TRT given to men with hypogonadism is associated with weight loss and body composition improvement, no evidence of this beneficial effect is observed in eugonadal subjects.”

  • The paper relies on this without support.

    Vitamin D is essential for bone-mineral health and calcium homeostasis.

    “Vitamin D is essential for bone-mineral health and calcium homeostasis.”

  • The paper relies on this without support.

    The diagnosis of Prader-Willi syndrome can be established based on clinical features, hormonal abnormalities and genetic testing.

    “The diagnosis of this syndrome can be established based on clinical features, hormonal abnormalities and genetic testing.”

  • The paper relies on this without support.

    Hypothyroidism can be accompanied by both obesity and hypertension.

    “Hypothyroidism can be accompanied by both obesity and hypertension”

  • The paper relies on this without support.

    None of these conditions (obesity and hypertension in hypothyroidism) is usually severe.

    “although none of these conditions is usually severe.”

  • The paper relies on this without support.

    Other causes of endocrine hypertension can be present in obesity.

    “Other causes of endocrine hypertension can be present in obesity”

  • The paper relies on this without support.

    Other causes of endocrine hypertension are not characterized by increased prevalence of obesity.

    “nevertheless, these are not characterized by increased prevalence of obesity.”

  • The paper relies on this without support.

    Pregnancy induces profound changes in endocrine functions that affect the gonadotropic axis, hormones of lactation, placental hormones, and other endocrine glands such as the adrenal and thyroid glands.

    “Pregnancy induces profound changes in endocrine functions that affect not only the gonadotropic axis (increase in oestrogens, progesterone and androgens), hormones of lactation (increase in oxytocin and prolactin) and placental hormones (notably human chorionic gonadotropin: HCG), but also other endocrine glands such as the adrenal and thyroid glands.”

  • The paper relies on this without support.

    During the 1st trimester, HCG induces a transient increase in free thyroid hormones levels and a decrease in TSH.

    “during the 1st trimester, HCG induces a transient increase in free thyroid hormones levels and a decrease in TSH.”

  • The paper relies on this without support.

    Later in pregnancy, serum free hormones concentrations decrease of approximately 10-15%, and TSH returns to normal.

    “Later, serum free hormones concentrations decrease of approximately 10-15%, and TSH returns to normal.”

  • The paper relies on this without support.

    Most scientific societies recommend specific reference ranges for free thyroid hormones and TSH throughout pregnancy.

    “Thus, most scientific societies recommend specific reference ranges for free thyroid hormones and TSH throughout pregnancy.”

  • The paper relies on this without support.

    Glucocorticoids are vital for normal foetal growth.

    “Glucocorticoids are vital for normal foetal growth.”

  • The paper relies on this without support.

    During pregnancy, a number of endocrine changes induce activation in maternal hypothalamic-pituitary-adrenal (HPA) axis.

    “During pregnancy, a number of endocrine changes induce activation in maternal hypothalamic-pituitaryadrenal (HPA) axis.”

  • The paper relies on this without support.

    The foeto-placental unit produces large amounts of steroid and peptide hormones including CRH.

    “The foeto-placental unit produces large amounts of steroid and peptide hormones including CRH.”

  • The paper relies on this without support.

    Renin-angiotensin-aldosterone (RAA) axis is activated during pregnancy to compensate vasodilation and to increase extracellular fluid volume.

    “Renin-angiotensin-aldosterone (RAA) axis is activated during pregnancy to compensate vasodilation and to increase extracellular fluid volume.”

  • The paper relies on this without support.

    Alterations of RAA axis have been incriminated in the pathophysiology of preeclampsia.

    “Alterations of RAA axis have been incriminated in the pathophysiology of preeclampsia”

  • The paper relies on this without support.

    Preeclampsia is more prevalent in obese pregnant women.

    “that is more prevalent in obese pregnant women.”

  • The paper relies on this without support.

    Around 30 g of calcium is transferred to the foetus, especially in the last trimester of pregnancy, needed for bone mineralization.

    “Around 30 g of calcium is transferred to the foetus, especially in the last trimester of pregnancy, needed for bone mineralization.”

  • The paper relies on this without support.

    Ageing is associated with alterations of hormonal secretions with variable amplitude for each endocrine system.

    “Ageing is associated with alterations of hormonal secretions with variable amplitude for each endocrine system.”

  • The paper relies on this without support.

    The symptoms of endocrine disease change with aging and are often less pronounced, which can lead to missing of the diagnosis.

    “Furthermore, the symptoms of endocrine disease change with aging and are often less pronounced, which can lead to missing of the diagnosis.”

  • The paper relies on this without support.

    The consequences of endocrine diseases can change in elderly with greater health risks (notably for muscle mass and cardiovascular functions).

    “The consequences of endocrine diseases can also change in elderly with greater health risks (notably for muscle mass and cardiovascular functions).”

  • The paper relies on this without support.

    The indication to treat is different in elderly because the benefit to risk ratio may be less favourable.

    “Finally, the indication to treat is also different, because the benefit to risk ratio may be less favourable.”
50 of 50

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Subclinical hypothyroidism confidence interval has two lower bounds

    Minor

    The review summary gives 9.2% as the lower bound of the 95% confidence interval, while the later account of the same meta-analysis gives 9.4%.

1 of 1

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Authors
Pasquali, R., Casanueva, F., Haluzik, M., van Hulsteijn, L., Ledoux, S., Monteiro, M. P., Salvador, J., Santini, F., Toplak, H., & Dekkers, O. M.
Affiliations
  • University of Bologna (IT)
  • Complejo Hospitalario Universitario de Santiago (ES)
  • 3Diabetes Centre and Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine and Institute of Endocrinology, Prague, Czech Republic
  • 4Department of Clinical Endocrinology and Metabolism, University Medical Centre Groningen, Groningen, the Netherlands
  • Hôpital Louis-Mourier (FR)
  • Universidade do Porto (PT)
  • Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (ES)
  • Azienda Ospedaliera Universitaria Pisana (IT)
  • Medical University of Graz (AT)
  • Leiden University (NL)
ORCID
Venue
European Journal of Endocrinology
Publisher
Oxford University Press (OUP)
Published
2020-01
Volume
182
Issue
1
Pages
G1-G32
ISSN
  • 0804-4643 (ISSN-L)
  • 1479-683X
DOI
10.1530/eje-19-0893
OpenAlex
W2994986481
Semantic Scholar
305b19ef98c1ddb882ff636c4548d296e5feed93
Cited by
180
References
126
Citations by year
2026: 15 · 2025: 29 · 2024: 41 · 2023: 26 · 2022: 26 · 2021: 31 · 2020: 12
FWCI
15.23
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • European Journal of Endocrinology (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, other-oa)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by)
Funders
European Society of Endocrinology
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
Keywords
obesity, thyroid function tests, hypothyroidism, hypercortisolism, male hypogonadism, body mass index, weight loss, hormonal imbalance
MeSH terms
Endocrinology, Humans, Hypothyroidism, Obesity, Thyroid Function Tests, Comorbidity, Body Mass Index, Prevalence

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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