Hair Cortisol Concentrations From Hydrocortisone Replacement
Hair Cortisol Concentrations From Hydrocortisone Replacement
To our knowledge, this is the first study reporting hair cortisol concentrations in children on GC replacement therapy. In patients with adrenal insufficiency at the age of 4–18 years receiving GC replacement therapy, hair cortisol concentrations were found to be significantly higher than in healthy controls. Additionally, waist circumference and BMI SDS were significantly increased in hydrocortisone-treated patients, which can partially be explained by increased HCC. These finding probably correlated with inadequate chronic serum cortisol levels, which was revealed by high HCC. This suggests that adrenal insufficiency patients are on average overtreated with hydrocortisone, resulting in the hallmark sequelae of hypercortisolism such as increased BMI and central adiposity. All patients in this study are treated according to national GC replacement guidelines, still effects of GC overtreatment were observed and long-term cortisol exposure, measured as hair cortisol, was significantly higher than in healthy controls. This is in line with previous studies showing increased serum cortisol concentrations in AI patients after GC ingestion, compared with healthy individuals. HCC in AI patients are partially overlapping with concentrations in healthy controls, the extreme values in AI patients are the most informative results which may indicate glucocorticoid overreplacement. Hydrocortisone overdosing is difficult to identify, as treatment adequacy in AI patients is primarily evaluated through the administered GC dose and clinical assessment of the symptoms of over- and undertreatment. Serum cortisol and urinary free cortisol (UFC) measurements are not useful in treatment adjustment. Clinical symptoms indicating overtreatment are, amongst others, weight-gain, increased waist circumference, metabolic syndrome, sleep disturbances and skin changes such as acne. These are nonspecific symptoms which are often slow to develop. Filipsson et al. demonstrated overdosing of GC, defined as an hydrocortisone equivalent dose of at least 20 mg per day, to be related to an adverse metabolic profile, including increased BMI and serum triglycerides and total cholesterol, in a large cohort of 2424 patients with hypopituitarism, with and without GC treatment. These observations have been replicated in patients with Addison's disease. Moreover, patients with Addison's disease treated with GCs were shown to have a two-fold mortality rate, mainly due to an increase in cardiovascular disease, infectious diseases and cancer, and the authors speculated that this was, at least in part, attributable to GC overtreatment.
Medicinal therapy is influenced by absorption, distribution, metabolism and excretion. These factors vary between individuals, complicating prediction of the treatment effect in general. This is particularly true during childhood and adolescence, as absorption and excretion change over age, distribution is influenced by changes in body composition and metabolism is affected by changing hepatic enzyme activity and clearance. This is even further complicated in cortisol pharmacokinetics, which undergo marked changes during puberty. Hence, the lack of a correlation between the hydrocortisone dose and HCC was not surprising. This is also represented by the large range of salivary cortisol concentrations after GC ingestion. In a study on HCC in patients with adrenal insufficiency, Gow et al. did report a correlation between HCC and hydrocortisone dose. However, the patients studied by Gow et al. received a large range of hydrocortisone doses from 10 to 60 mg per day and were all adults. Hydrocortisone dose in these patients was not adjusted for BSA or body weight, which may further increase the difference of cortisol exposure between patients.
Objectively measuring long-term systemic cortisol exposure may improve current GC dosing regimens. Our results suggest measurement of hair cortisol concentration may be a novel method for identifying patients receiving supraphysiological hydrocortisone doses. Measurement of HCC has been shown to be of value in diagnosing and follow-up of Cushing's syndrome and cyclic Cushing's disease. Moreover, elevated cortisol exposure within physiological ranges, as identified through HCC measurement, has been associated with increased risk for cardiovascular disease and the metabolic syndrome. In adult AI patients on GC replacement therapy, Gow et al. reported increased HCC in patients compared with healthy controls similar to our results. No difference in HCC was found between 10 patients treated with cortisone acetate and patients treated with hydrocortisone, implicating this method can be applied in cortisone acetate treated patients as well.
One of the strengths of the current study is the sample size of hydrocortisone-treated paediatric patients with adrenal insufficiency, with a large age range from 4 to 18 years, and the comparison with age- and gender-matched healthy controls. This study has a wide scope of adrenal insufficiency aetiologies. Moreover, as this study has an observational and cross-sectional design, no causal relation between hydrocortisone overdosing, HCC and anthropometric effect can be demonstrated. Longitudinal intervention studies focused on a more homogeneous patient population are required for this, and may be a subject for future research. The current study is limited to the analysis of anthropometric data as metabolic data on aspects such as glucose and lipid metabolism were not routinely available. Application of the described method to children under 4 years of age receiving GC treatment has not been studied. Previous studies have shown higher HCC and a larger range in healthy children at the age of 1 and 3 years. For this age-group, a separate study should be conducted. Also for use of glucocorticoid treatment with other aims than replacement, for example, anti-inflammatory treatment, additional studies are required. In another study on HCC in children performed by Karlén et al., comparable ranges in HCC were found in children at the age of 8. Due to the nonphysiologic administration of GC in adrenal insufficiency patients, HCC equal to those of healthy controls may prove unachievable, which is especially true for CAH patients, where GC treatment is not only focused on replacement, but also on decreasing ACTH secretion and resulting androgen excess. This does not decrease the validity of measuring cortisol in hair in GC-treated patients, but it may require the establishment of reference ranges in well-controlled AI patients. One limitation of hair cortisol measurement is that it provides no direct information on systemic cortisol peak exposure directly after ingestion, as the maximal resolution of cortisol exposure is approximately 1 month. Additional measurement of for instance salivary cortisol day curves after GC ingestion may yield more information on short term peak cortisol exposure and nadir concentrations. Furthermore, the potential influence of GC stress dosing on HCC has not been assessed in the current or previous studies, and warrants further research.
Measurement of cortisol concentrations in scalp hair provides clinicians with a long-term reflection of systemic cortisol exposure. The method is relatively simple, easily implemented and noninvasive, making it especially suitable in the paediatric clinical practice. Measurement of cortisol concentrations in scalp hair reflecting long-term systemic cortisol exposure at the tissue level may provide a new method for identifying hydrocortisone overtreatment in patients with adrenal insufficiency. This may improve current glucocorticoid replacement quality, limiting long-term negative health effects of previously unobserved overtreatment.
Discussion
To our knowledge, this is the first study reporting hair cortisol concentrations in children on GC replacement therapy. In patients with adrenal insufficiency at the age of 4–18 years receiving GC replacement therapy, hair cortisol concentrations were found to be significantly higher than in healthy controls. Additionally, waist circumference and BMI SDS were significantly increased in hydrocortisone-treated patients, which can partially be explained by increased HCC. These finding probably correlated with inadequate chronic serum cortisol levels, which was revealed by high HCC. This suggests that adrenal insufficiency patients are on average overtreated with hydrocortisone, resulting in the hallmark sequelae of hypercortisolism such as increased BMI and central adiposity. All patients in this study are treated according to national GC replacement guidelines, still effects of GC overtreatment were observed and long-term cortisol exposure, measured as hair cortisol, was significantly higher than in healthy controls. This is in line with previous studies showing increased serum cortisol concentrations in AI patients after GC ingestion, compared with healthy individuals. HCC in AI patients are partially overlapping with concentrations in healthy controls, the extreme values in AI patients are the most informative results which may indicate glucocorticoid overreplacement. Hydrocortisone overdosing is difficult to identify, as treatment adequacy in AI patients is primarily evaluated through the administered GC dose and clinical assessment of the symptoms of over- and undertreatment. Serum cortisol and urinary free cortisol (UFC) measurements are not useful in treatment adjustment. Clinical symptoms indicating overtreatment are, amongst others, weight-gain, increased waist circumference, metabolic syndrome, sleep disturbances and skin changes such as acne. These are nonspecific symptoms which are often slow to develop. Filipsson et al. demonstrated overdosing of GC, defined as an hydrocortisone equivalent dose of at least 20 mg per day, to be related to an adverse metabolic profile, including increased BMI and serum triglycerides and total cholesterol, in a large cohort of 2424 patients with hypopituitarism, with and without GC treatment. These observations have been replicated in patients with Addison's disease. Moreover, patients with Addison's disease treated with GCs were shown to have a two-fold mortality rate, mainly due to an increase in cardiovascular disease, infectious diseases and cancer, and the authors speculated that this was, at least in part, attributable to GC overtreatment.
Medicinal therapy is influenced by absorption, distribution, metabolism and excretion. These factors vary between individuals, complicating prediction of the treatment effect in general. This is particularly true during childhood and adolescence, as absorption and excretion change over age, distribution is influenced by changes in body composition and metabolism is affected by changing hepatic enzyme activity and clearance. This is even further complicated in cortisol pharmacokinetics, which undergo marked changes during puberty. Hence, the lack of a correlation between the hydrocortisone dose and HCC was not surprising. This is also represented by the large range of salivary cortisol concentrations after GC ingestion. In a study on HCC in patients with adrenal insufficiency, Gow et al. did report a correlation between HCC and hydrocortisone dose. However, the patients studied by Gow et al. received a large range of hydrocortisone doses from 10 to 60 mg per day and were all adults. Hydrocortisone dose in these patients was not adjusted for BSA or body weight, which may further increase the difference of cortisol exposure between patients.
Objectively measuring long-term systemic cortisol exposure may improve current GC dosing regimens. Our results suggest measurement of hair cortisol concentration may be a novel method for identifying patients receiving supraphysiological hydrocortisone doses. Measurement of HCC has been shown to be of value in diagnosing and follow-up of Cushing's syndrome and cyclic Cushing's disease. Moreover, elevated cortisol exposure within physiological ranges, as identified through HCC measurement, has been associated with increased risk for cardiovascular disease and the metabolic syndrome. In adult AI patients on GC replacement therapy, Gow et al. reported increased HCC in patients compared with healthy controls similar to our results. No difference in HCC was found between 10 patients treated with cortisone acetate and patients treated with hydrocortisone, implicating this method can be applied in cortisone acetate treated patients as well.
One of the strengths of the current study is the sample size of hydrocortisone-treated paediatric patients with adrenal insufficiency, with a large age range from 4 to 18 years, and the comparison with age- and gender-matched healthy controls. This study has a wide scope of adrenal insufficiency aetiologies. Moreover, as this study has an observational and cross-sectional design, no causal relation between hydrocortisone overdosing, HCC and anthropometric effect can be demonstrated. Longitudinal intervention studies focused on a more homogeneous patient population are required for this, and may be a subject for future research. The current study is limited to the analysis of anthropometric data as metabolic data on aspects such as glucose and lipid metabolism were not routinely available. Application of the described method to children under 4 years of age receiving GC treatment has not been studied. Previous studies have shown higher HCC and a larger range in healthy children at the age of 1 and 3 years. For this age-group, a separate study should be conducted. Also for use of glucocorticoid treatment with other aims than replacement, for example, anti-inflammatory treatment, additional studies are required. In another study on HCC in children performed by Karlén et al., comparable ranges in HCC were found in children at the age of 8. Due to the nonphysiologic administration of GC in adrenal insufficiency patients, HCC equal to those of healthy controls may prove unachievable, which is especially true for CAH patients, where GC treatment is not only focused on replacement, but also on decreasing ACTH secretion and resulting androgen excess. This does not decrease the validity of measuring cortisol in hair in GC-treated patients, but it may require the establishment of reference ranges in well-controlled AI patients. One limitation of hair cortisol measurement is that it provides no direct information on systemic cortisol peak exposure directly after ingestion, as the maximal resolution of cortisol exposure is approximately 1 month. Additional measurement of for instance salivary cortisol day curves after GC ingestion may yield more information on short term peak cortisol exposure and nadir concentrations. Furthermore, the potential influence of GC stress dosing on HCC has not been assessed in the current or previous studies, and warrants further research.
Measurement of cortisol concentrations in scalp hair provides clinicians with a long-term reflection of systemic cortisol exposure. The method is relatively simple, easily implemented and noninvasive, making it especially suitable in the paediatric clinical practice. Measurement of cortisol concentrations in scalp hair reflecting long-term systemic cortisol exposure at the tissue level may provide a new method for identifying hydrocortisone overtreatment in patients with adrenal insufficiency. This may improve current glucocorticoid replacement quality, limiting long-term negative health effects of previously unobserved overtreatment.
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