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Cranial irradiation and central hypothyroidism Susan R. Rose Cranial irradiation causes thyrotropin (TSH)-releasing hormone (TRH) secretory abnormalities. TRH deficiency leads to abnormal glycosylation of TSH α and β subunits and loss of the normal circadian pattern of TSH secretion (low in the afternoon, a surge in the evening, higher at night). This disruption results in either mixed hypothyroidism (raised TSH with abnormal secretory kinetics) or central hypothyroidism (abnormal secretory kinetics without raised TSH). Although primary hypothyroidism is more common in the general population and cancer survivors, the cumulative incidence of central and mixed hypothyroidism is high during the ten years after cranial irradiation. Monitoring for decline in free thyroxine (FT4) and rise in serum TSH, and early recognition using TSH surge and TRH tests, are clinically valuable. Early thyroid hormone replacement therapy to achieve serum FT4 in the upper half of the normal range is crucial for maintaining optimal health and growth in cancer survivors.

Susan R. Rose Children’s Hospital Medical Center, Division of Endocrinology, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA. e-mail: [email protected]

Cranial irradiation is a component of curative therapy for brain tumors and leukemia, and is part of preparatory total body irradiation for bone marrow transplantation. Childhood survivors of such cancers might be at risk for hypothalamic–pituitary disorders caused by a combination of the effects of tumor, surgery and cranial irradiation1–9. Cranial irradiation, even at doses as low as 18 Gy, reduces growth velocity10–12. In addition, slow growth velocity might be secondary to additional factors: neuraxis or mantle irradiation, chemotherapy, decreased nutritional intake or intercurrent illness. An important and well-documented cause of poor growth in childhood cancer survivors is altered growth hormone (GH) secretion. The hypothalamic regulation of secretory bursts of GH is often altered after cranial irradiation4–6,13–15. However, even with GH therapy, some childhood cancer survivors do not grow as well as expected, suggesting that other factors, such as thyroid hormone deficiency, might be interfering with normal health. Primary hypothyroidism occurs fairly commonly after radiation therapy, whereas central (hypothalamic or pituitary) hypothyroidism is considered less common and a consequence of higher doses of irradiation (>30 Gy). The first synthetic hypothalamic-releasing hormone available for clinical testing was thyrotropin (TSH)-releasing hormone (TRH)16. The first report (in 1975) of TRH testing in children after radiotherapy suggested that hypopituitarism was more common than had been previously suspected17. The first use of TSH surge studies in leukemia survivors (in 1991) showed that five of ten patients had primary hypothyroidism and one of ten had central hypothyroidism9. It was not until 1999 that central hypothyroidism was

recognized in as many as 65% of patients after brain tumor or nasopharyngeal tumor, in more than 35% after bone marrow transplantation, and in as many as 15% after leukemia, suggesting that central hypothyroidism (hypothalamic–pituitary–thyroid dysregulation) might be common in cancer survivors (Fig. 1)18. This review discusses the effects of cranial irradiation on regulatory cells of the hypothalamus and secretory cells of the pituitary gland. It then summarizes the characteristics of mild hypothyroidism (primary, central and mixed) resulting from radiation therapy, discusses diagnostic methods and recommends guidelines for the treatment of central hypothyroidism. Radiation

Radiation therapy has been an integral component of combined modality therapy for childhood cancer for more than 40 years. For adults, radiation therapy has been used in various forms for more than 100 years. Typically, the administration of radiation therapy is conducted with the use of a linear accelerator – otherwise known as external beam radiation therapy (EBRT). EBRT is usually delivered in daily doses of 150–200 centigray (cGy), depending on the tumor type. The amount received by the hypothalamus, pituitary or thyroid gland depends on the dosimetry of the treatment and the proximity of these crucial structures to the targeted region. Ionizing radiation induces DNA damage and apoptosis through cellular mechanisms that are under investigation but not yet fully understood19–23. Radiation affects stromal cells of particular organs and might also affect the vascular supply through effects on the endothelium. It is not fully known why normal tissues exposed to radiation can continue to function for several years after irradiation and then gradually lose their function24,25. However, the late development of endocrinopathies (from months to ten or 20 years after radiation therapy) might be a consequence of both a direct effect on the hypothalamus and an effect on the vascular supply. Cell-cycle dependence of radiation effects are well recognized26,27. Recent advances suggest that conformal radiation therapy (involving a spectrum of three-dimensional radiation therapy customized to an individual tumor) might reduce the fractional (daily) and total dose received by crucial structures, such as the

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Fig. 1. Cumulative incidence of types of hypothyroidism according to specific tumor diagnosis. (a) Central hypothyroidism, (b) mixed hypothyroidism, and (c) mild primary hypothyroidism. Leuk + BMT refers to patients diagnosed with leukemia who were treated with bone marrow transplantation. (Reproduced, with permission, from Ref. 18.)

hypothalamus (Ref. 28; T.E. Merchant et al., unpublished). This and other new advances in the delivery of radiation therapy might help to reduce the deleterious effects of radiation therapy on hypothalamic function. The hypothalamus is thought to be even more sensitive to radiation damage than the pituitary itself 29–31, and might be more vulnerable in children than in adults32. When judging the extent of the effect of irradiation on the hypothalamic–pituitary axis, it is necessary to recognize that surgery, or the tumor itself, might have already had effects on endocrine function before the administration of radiation therapy (T.E. Merchant et al., unpublished). The subsequent risk for the development of central hypothyroidism is clearly related to radiation dose. Higher total doses of cranial or craniospinal radiation are associated with earlier development of hypothyroidism and a higher long-term probability of abnormal thyroid function18. Because intracranial solid tumors are treated with higher total doses of radiation, the incidence of central hypothyroidism is also related to the type of tumor. Thyroid axis regulation

TSH is synthesized in pituitary cells in response to TRH, which is secreted from the hypothalamus and transported to the pituitary via the hypothalamic–pituitary portal system. Dopamine and somatostatin, which inhibit TSH release, are also transported from the hypothalamus to the pituitary via the portal system. In adults, children and infants as young as six months of age, TSH secretion normally occurs in a circadian pattern with lower concentrations in the afternoon, a nocturnal surge beginning after 1900 h, and higher concentrations http://tem.trends.com

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Fig. 2. Assessment of the nocturnal thyrotropin (TSH) surge. The circles indicate the mean serum TSH (±2 SEM) in 96 normal children; arrows indicate sampling times. The nadir TSH was the mean of the three consecutive lowest TSH values in the afternoon. The peak TSH was the mean of the three consecutive highest TSH values in the night. TSH surge (%) = 100 × (peak − nadir)/nadir. (Reproduced, with permission, from Ref. 51.)

between 2200 h and 0400 h (Fig. 2)33,34. Thus, much of the tropic influence of TSH on the thyroid gland occurs during the hours of sleep. The circadian pattern of TSH secretion appears to be dependent on TRH, although levels are modulated by glucocorticoids, dopamine, somatostatin and feeding (the last of which might be mediated by leptin levels). TSH is composed of an α subunit (identical to that of luteinizing hormone, follicle-stimulating hormone and human chorionic gonadotropin) and a unique β subunit. Both of these subunits undergo posttranslational glycosylation, which itself influences the bioactivity of the TSH molecule. The importance of the glycosylation pattern on bioactivity has recently been highlighted35. TRH is necessary for TSH synthesis, post-translational glycosylation and the secretion of a fully bioactive TSH molecule35. There are two oligosaccharide chains on the α subunit and one on the β subunit. Patterns of glycosylation of the TSH subunits affect their bioactivity – endogenous TSH β subunits have oligosaccharides with sialic acid and galactose, or sulfate and N-acetyl-galactosamine. Highly sialated chains (as in recombinant TSH) have decreased bioactivity, decreased hepatic clearance and a longer half-life. Moreover, altered TSH glycosylation resulting in altered bioactivity35–40 is seen in mixed hypothyroidism (central hypothyroidism with raised TSH), in which the increase of mannose in the oligosaccharide chains decreases TSH bioactivity.

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Fig. 3. Growth velocity shown in standard deviation units (SD) from the mean for age during six months at baseline (light-blue bars), six months of treatment with levothyroxine (pink bars) and six months of follow-up on no therapy (dark-blue bars) in three groups of children: idiopathic short stature (ISS) with free thyroxine (FT4) in the upper twothirds of the normal range (ISS, higher FT4), ISS with FT4 in the lowest third of the normal range (ISS, lower FT4), and isolated central hypothyroidism (TSH-D). Bars show mean ±SE. *P <0.05 compared with baseline growth velocity. (Reproduced, with permission, from Ref. 51.)

For TSH to act, both the α and β subunits must interact with the G-protein-coupled TSH receptor35 to generate cAMP within the cell. TSH stimulates the production of thyroxine (T4) and triiodothyronine (T3), and influences the uptake of iodine. Plasma T4 and T3 circulate bound to thyroxine-binding globulin and albumin, with only small amounts free or unbound (FT4 and FT3). FT4 undergoes intracellular deiodination to FT3, which then interacts with nuclear DNA to influence mRNA and protein synthesis. Both T4 and T3 provide negative feedback at the hypothalamus and pituitary to modulate TRH and TSH secretion. Primary hypothyroidism

Primary hypothyroidism (reduced function of the thyroid gland itself) is the most common form of hypothyroidism, both in the general population and in cancer survivors. It is most likely to occur in patients who have received mantle irradiation for Hodgkin’s disease41, craniospinal irradiation for medulloblastoma or total body irradiation before bone marrow transplantation (BMT) (Fig. 1). Primary hypothroidism is rarely isolated in cancer survivors; only 18% of patients with mild primary hypothyroidism had mild TSH elevation alone; the remainder also had hypothalamic–pituitary hormone deficiencies as well18. In children, most previous studies of thyroid function after treatment for brain tumors8,42 have emphasized the identification of raised TSH concentrations, and most patients with such a condition have been considered to have ‘compensated hypothyroidism’. There has been controversy regarding whether http://tem.trends.com

The clinical significance of mild primary hypothyroidism (‘compensated’ or ‘subclinical’) has been controversial. Such mild hypothyroidism is characterized by slight rises in TSH values and T4 values that, as in central hypothyroidism, are in the low part of the normal range. Several studies have found significant clinical differences between adults with normal thyroid function and those with mild hypothyroidism43–45. The treatment of mild hypothyroidism has also been shown capable of producing meaningful clinical benefit46–49. At the 2000 meeting of The Endocrine Society, in a symposium on ‘Why treat mild thyroid failure anyway?’, it was emphasized that normal euthyroid individuals (without a history of cranial irradiation) have an average serum TSH concentration of 1.0 mU l−1, with a range of 0.7–1.5 mU l−1, clearly not in the upper part of the usual stated assay range of about 0.5–5 mU l−1. Thus, if TSH is 5–20 mU l−1, even with a normal FT4, the intact thyroid axis is recognizing inadequate circulating thyroid hormone. The condition might be ‘subclinical’ or minimally symptomatic. There is reason to expect benefits, including relief of symptoms, improvement in lipid profiles and cardiovascular risk, and prevention of progression to overt hypothyroidism, from the initiation of replacement therapy with levothyroxine50. Thus, mild primary hypothyroidism is clinically relevant: children with mildly elevated TSH and T4 levels within normal limits typically grow less well than do other children. Thyroid replacement therapy in mild hypothyroidism improves growth velocity (Fig. 3)51. Even mild TSH rises might be a sign of possible thyroid dysfunction and should not be ignored. Indeed, if ignored during slowed growth in childhood, the opportunity to improve the growth rate will be missed. Central hypothyroidism

Normal individuals generally maintain a fairly stable FT4 at an optimal ‘set point’ for thyroid function. If the FT4 production from an injured thyroid gland declines (as in mild primary hypothyroidism), the intact pituitary secretes more TSH. Conversely, in central hypothyroidism, FT4 declines because of impaired hypothalamic–pituitary release of TSH (Fig. 4); the patient is just as hypothyroidic but the TSH concentration is not usually raised. It is important to note that daytime serum TSH is not usually low in central hypothyroidism. Instead, a proportion of the usual nocturnal TSH secretion is absent (Fig. 5). In central hypothyroidism, FT4 and T4 values are similar to those seen in mild primary hypothyroidism. However, the ability to increase TSH secretion is impaired, so the ‘red flag’ of an elevated TSH

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Fig. 4. Overlap of the distribution of free thyroxine values (ng dl−1) between a normal population (light-blue line) and patients with central hypothyroidism (dark-blue line). The pink, shaded area represents patients with central hypothyroidism incorrectly diagnosed as normal. (Reproduced, with permission, from Ref. 52.)

concentration is absent. A blunted or absent nocturnal TSH surge is a characteristic of central hypothyroidism, suggesting a loss of the normal circadian variation in TRH release. The TSH surge each night provides approximately one-third to onehalf of the daily tropic stimulus to the thyroid gland. In central hypothyroidism, FT4 is low or in the lowest third of the normal range (Fig. 4), with a normal daytime TSH (Refs 51,52). GH deficiency has been reported to be the first hypothalamic–pituitary deficiency to emerge, followed by deficiencies in gonadotropin, adrenocorticotropin (ACTH) and TSH (Refs 7,29,53). However, TSH secretory alterations might have been recognized last in these studies because only relatively insensitive tests, such as single measures of TSH and T4, or the TSH response to TRH, were used. Detailed reviews of previous studies suggest that TSH secretory dysregulation after irradiation might precede other endocrine disorders in some patients. For example, 90% of patients receiving cranial irradiation for nasopharyngeal carcinoma had a delayed peak TSH response to TRH (suggestive of central hypothyroidism) by one year after therapy. Subsequently, at five years after radiation therapy, 64% had GH deficiency, 31% had gonadotropin deficiency and 27% had ACTH deficiency53. In seven children with brain tumors, studied prospectively after >30 Gy cranial irradiation, the TSH surge became blunted before the onset of reduced GH levels (H.A. Spoudeas et al., unpublished). Thirty-four percent of patients diagnosed with central hypothyroidism had dysregulation of TSH secretion before the development of GH deficiency18. If TSH secretion is not tested until GH deficiency becomes apparent, the diagnosis of hypothyroidism might be delayed in a third of the patients. Although such a delay might be acceptable in a minimally symptomatic adult, in children the lost growth opportunities and potential functional implications of hypothyroidism indicate the need for early intervention51. http://tem.trends.com

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Fig. 5. Normal individuals (b) have a 50–300% rise in thyrotropin (TSH) concentrations during the night compared with the afternoon. By contrast, patients with central hypothyroidism (a) have a blunted or absent TSH surge. The normal individuals were selected as having TSH values, at 1500 h, that matched those of the patients. (Reproduced, with permission, from Ref. 35.)

The dose of cranial irradiation affects the risk for development of hypothyroidism. In adults who had received cranial irradiation five years previously, central hypothyroidism was diagnosed in 9% of patients after a total dose of 20 Gy, in 22% after 30–37 Gy, in 35% after 40 Gy and in 52% after 42–45 Gy (Ref. 54). Similarly, in children, central hypothyroidism was most often associated with total radiation doses >40 Gy to the hypothalamic–pituitary region55. Chemotherapy, especially the regimens used for BMT, might exacerbate the effects of irradiation on hypothalamic–pituitary–thyroid function42. Patients who had been treated with a BMT preparatory regimen (total body irradiation and chemotherapy) were as likely to have central hypothyroidism as were those who had received more than 30 Gy of cranial irradiation18. Mixed hypothyroidism

Mixed hypothyroidism is a newly named syndrome consisting of central hypothyroidism associated with TSH elevation. Some TSH levels are raised and TSH secretory dynamics are abnormal. This is in contrast to primary hypothyroidism in which the TSH surge and timing of response to TRH are normal (Fig. 6). Mixed hypothyroidism has been described in survivors of childhood cancer18 and in women with Sheehan’s syndrome (postpartum pituitary necrosis)56. With reduced TRH release from the hypothalamus, TSH might be abnormally glycosylated and of lower biological activity35.

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Fig. 6. Typical thyrotropin (TSH) response to TSHreleasing hormone (TRH) infusion (7 µg kg−1 body weight up to maximum dose of 200 µg, intravenously) in primary hypothyroidism (dark-blue), mixed hypothyroidism (magenta) and central hypothyroidism (green), compared to the response in normal controls (lightblue lines). The two lines representing the control response reflect upper and lower 95% confidence limits.

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Thus, mild elevation of serum TSH (5–15 mU l−1) might be seen in the form of central hypothyroidism called mixed hypothyroidism; the differentiation from primary hypothyroidism can be made by documentation of a blunted or absent TSH surge16,36,37, or by the observation of a delayed peak response (occurring after 45 min) to TRH (Fig. 6)37,38. ‘Mixed’ hypothyroidism refers to mild TSH elevation combined with either a blunted TSH surge or a TSH peak after TRH that was delayed in onset or rate of decline. Mixed hypothyroidism might reflect either separate injuries to the thyroid gland and to the hypothalamus (such as radiation injury of both structures) or central hypothyroidism in which the biological activity of the secreted TSH is reduced. A bioinactive TSH molecule has been described in some patients with central hypothyroidism and mild TSH elevation without a history of radiation therapy or chemotherapy36–38. Irradiation of the hypothalamus has been proposed to reduce the biological activity of the TSH molecule secreted from the pituitary39,42. Mixed hypothyroidism could be consistent with hypothalamic injury causing decreased TRH secretion, in view of the recently recognized importance of TRH in stimulating normal patterns of glycosylation of the TSH subunits35. Mixed hypothyroidism was most prevalent in patients who had received either total cranial or craniospinal radiation doses >30 Gy, or a BMT preparatory regimen18. Mixed hypothyroidism was not always associated with raised basal TSH; thus, both the TSH surge test and the TRH test were required for diagnosis. Diagnosing central or mixed hypothyroidism Single measures of thyroid function

Many studies in the past have used only raised TSH levels to identify hypothyroidism8,11,42,53,57–61. However, TSH levels are often normal in central hypothyroidism. It is only the failure of night-time http://tem.trends.com

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TSH values to rise significantly when compared with daytime values that is indicative of central hypothyroidism. Thus, the use of raised daytime TSH values as the sole criterion for hypothyroidism will miss most cases of central hypothyroidism. If serum TSH is >15 mU l−1, then the patient clearly has primary hypothyroidism. If the TSH is 5–15 mU l−1, the patient might have mixed hypothyroidism, primary hypothyroidism or non-thyroidal illness (NTI) (Ref. 62). T4 remains a good measurement of thyroid function; however, its levels are influenced by serum protein binding. Thyroxine-binding globulin decreases with age and male puberty, increases with estrogen and pregnancy, and is altered during malnutrition and illness. Thus, a ‘low’ T4 can be normal, and a ‘high’ T4 might delay the recognition of a deficiency. FT4 is more stable throughout these conditions. The absolute thyroid hormone values observed are dependent upon the assay used, especially for FT4. In general, automated assays for FT4 are thought to be less reliable than FT4 measured by equilibrium dialysis. However, specific comparison of FT4 assays show that certain automated FT4 assays correlate well with the equilibrium dialysis method, with few false positives or negatives63,64. FT4 assays involving two step immunoextraction or labeled antibody with T3 solid phase are affected less by thyroid autoantibodies than are one step assays65. The FT4 index tends to overestimate FT4 in both hypothyroidism and NTI (Ref. 66). Of course, NTI alters thyroid hormone levels, with increased illness severity correlating with greater depression of T3, FT3, T4 and FT4 levels, and elevation of reverse T3 with both peripheral thyroid metabolism and hypothalamic function impaired. Thyroid metabolic alterations in NTI include altered type I iodothyronine deiodinase in the liver, confounders of the FT4 assay, biological stress responses including glucocorticoid elevation, and effects of medications such as dopamine and dobutamine62. During NTI, there is decreased hypothalamic mRNA for TRH, decreased pituitary TSH and immature TSH glycosylation. Transient central hypothyroidism during NTI is the result of multiple factors, including stress, starvation, glucocorticoids and cytokines [such as interleukin (IL) 1, IL-6 and tumor necrosis factor α]. Despite these problems, along with serum TSH, FT4 is currently the best measure of thyroid status. FT4 below the normal range without TSH elevation is clearly suggestive of central hypothyroidism. However, the FT4 concentration can also be within normal limits in such patients, albeit in the lowest third of the range (Fig. 4)18,37,51. The higher frequency with which central hypothyroidism was identified in childhood cancer survivors by Rose et al.18, when compared with rates in other reports, reflected the necessity to maintain a high index of suspicion and recognize that FT4 values in the lowest third of the

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normal range are compatible with thyroid dysfunction. Central hypothyroidism can be difficult to diagnose because of this subtle presentation. A decline in FT4 over time (years) after radiation therapy can be the most important observation; however, baseline (before radiation therapy) measurements of FT4 are not always available for comparison. As a result, diagnosis and treatment might be delayed until impaired growth or constitutional symptoms become overt51. TRH test in diagnosis

As the first clinically useful dynamic endocrine test, the TSH response to TRH has historically been the standard test used to identify central hypothyroidism. However, 30–90% of patients with central hypothyroidism can have a normal response to TRH (a normal amplitude TSH peak, normally timed)36,37,50,51. If the response to TRH is abnormal in central or mixed hypothyroidism, it is usually abnormally late in time of peak TSH (after 45 min) or in rate of decline after the peak (TSH value remains above 75% of the peak value at 1 h after the peak, or exceeds three times the basal TSH at 3 h after TRH administration) (Fig. 6). The TRH-induced TSH rise is lower after prolonged starvation (such as in NTI) than after an overnight fast35. In central hypothyroidism after cranial irradiation, the TRH test identifies 60% of cases. Measurement of the nocturnal TSH surge (identifying 71% of cases) is also required to ascertain all cases of central hypothyroidism18. TSH surge in diagnosis

The nocturnal TSH surge (Fig. 2) is a demonstrably more sensitive indicator (than the TRH test) of idiopathic or isolated central hypothyroidism37,51. Both children and adults normally experience a nocturnal surge in TSH of 50–300% as a normal circadian event33,34. The TSH surge is frequently blunted or absent in patients with central hypothyroidism, despite normal basal TSH values. Blunting of the TSH surge reduces the daily total production of TSH by approximately one-third, causing a subtle decrease in thyroid hormone production that is sufficient to slow the growth of some children51. A TSH surge ≤50% is diagnostic for central hypothyroidism. A TSH surge >300% also indicates hypothalamic injury; however, although the child requires close follow up, thyroid hormone therapy is not needed unless FT4 levels are in the lowest third of the normal range. Most previous studies of thyroid function after radiation therapy have used only single TSH and T4 assays, or TRH tests, to identify TSH disorders. Neither approach is as sensitive as the additional use of the TSH surge test for identifying central hypothyroidism37. Used in combination with the TRH test, the TSH surge provides maximal sensitivity for confirmation of central hypothyroidism, permitting http://tem.trends.com

the identification of central hypothyroidism when it is milder or earlier in development18. An unexpectedly high number of cancer survivors with slow growth rate (43%) had abnormal TSH regulation (34% with central hypothyroidism, 9% with mixed hypothyroidism). Using baseline FT4 and TSH alone, 92% of those with central hypothyroidism and 27% of those with mixed hypothyroidism would have been missed by standard laboratory screening. The TRH test identified 60% of the patients with central hypothyroidism and the TSH surge test identified 71%. Both tests were necessary for the identification of all cases of central or mixed hypothyroidism. Treatment of central hypothyroidism

Yearly measurement of TSH and FT4 levels and growth surveillance are recommended in childhood cancer survivors. Improved diagnosis of mild hypothyroidism will enable treatment that enhances patients’ growth velocities (Fig. 3) and sense of wellbeing. Criteria for starting thyroid hormone therapy without further diagnostic testing include: (1) TSH values above 4 µU l−1 at 0800 or 0900 h, or above 3 µU l−1 between 1000 h and 2000 h (regardless of the FT4 value), or (2) FT4 values at or below the lower limits of the normal range, for the assay (regardless of the TSH value). If the FT4 value is in the upper twothirds of the normal range and TSH does not meet the above criteria, no thyroid therapy is needed. Thyroid hormone status and growth should be reviewed in one year. If the FT4 value is in the lowest third of the normal range (Fig. 4), without a rise in TSH, both the TRH test and the TSH surge should be performed. Because slowed growth rate is not available as a sign, central hypothyroidism can be difficult to recognize in adults. Symptoms of central hypothyroidism (e.g. asthenia, edema, drowsiness, adynamia, skin dryness) might be of gradual onset and can go unrecognized until treatment is begun and the patient subsequently feels better67. Therapy with T4 rapidly suppresses TSH before the resolution of clinical symptoms, so TSH is not a useful measure during replacement therapy, unless TSH levels were initially raised. Ferretti et al. monitored FT4 and FT3 during therapy, adjusting the dose to achieve FT4 in the mid-normal range without FT3 elevation and without symptoms of hypo- or hyperthyroidism67. I recommend adjusting thyroid hormone therapy in patients with central hypothyroidism to keep their FT4 values at 1.4–1.6 ng dl−1 (Abbott IMX assay normal range, 0.78–1.85 ng dl−1). In conclusion, the cause of poor growth in childhood cancer survivors cannot always be identified. Although often caused by toxic effects of chemotherapy, radiation effects on bone growth centers or GH deficiency, poor growth can, in many cases, be caused by undiagnosed central hypothyroidism. Central hypothyroidism is much more common after radiation therapy for childhood cancer than has generally been recognized. Early

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Acknowledgements I appreciate the critical review and comments by my colleagues, Thomas Merchant and Jane Silva.

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identification and treatment of hypothyroidism can improve the quality of life and optimize the final adult height of these patients. Similar hormone alterations most probably occur in adults who are cancer survivors, but are less clinically evident without the marker of slowed growth velocity. It is probable that adults with central hypothyroidism would also benefit from early identification and therapy by experiencing improved energy and quality of life. The use of FT4 screening and of confirmatory testing that combines the TSH surge test with the TRH test should improve the sensitivity with which central hypothyroidism is diagnosed. The TSH surge

References 1 Shalet, S.M. et al. (1988) Growth and pituitary function in children treated for brain tumours or acute lymphoblastic leukaemia. Horm. Res. 30, 53–61 2 Leiper, A.D. et al. (1988) Precocious or early puberty and growth failure in girls treated for acute lymphoblastic leukaemia. Horm. Res. 30, 72–76 3 Rapaport, R. and Brauner, R. (1989) Growth and endocrine disorders secondary to cranial irradiation. Pediatr. Res. 25, 561–567 4 Blatt, J. et al. (1984) Reduced pulsatile growth hormone secretion in children after therapy for acute lymphoblastic leukemia. J. Pediatr. 104, 182–186 5 Romshe, C.A. et al. (1984) Evaluation of growth hormone release and human growth hormone treatment in children with cranial irradiationassociated short stature. J. Pediatr. 104, 177–181 6 Darendeliler, F. et al. (1990) Growth and growth hormone secretion in children following treatment of brain tumors with radiotherapy. Acta Paediatr. Scand. 79, 950–956 7 Littley, M.D. et al. (1989) Hypopituitarism following external radiotherapy for pituitary tumors in adults. Q. J. Med. 70, 145–160 8 Livesey, E.A. and Brook, C.G. (1989) Thyroid dysfunction after radiotherapy and chemotherapy of brain tumours. Arch. Dis. Child. 64, 593–595 9 Pasqualini, T. et al. (1991) Subtle primary hypothyroidism in patients treated for acute lymphoblastic leukemia. Acta Endocrinol. 124, 375–380 10 Starceski, P.J. et al. (1987) Comparable effects of 1800- and 2400-rad (18- and 24-Gy) cranial irradiation on height and weight in children treated for acute lymphocytic leukemia. Am. J. Dis. Child. 141, 550–552 11 Oberfield, S.E. et al. (1986) Long-term endocrine sequelae after treatment of medulloblastoma: prospective study of growth and thyroid function. J. Pediatr. 108, 219–223 12 Schriock, E.A. et al. (1991) Abnormal growth patterns and adult short stature in 115 long-term survivors of childhood leukemia. J. Clin. Oncol. 9, 400–405 13 Toogood, A.A. et al. (1995) The evolution of radiation-induced growth hormone deficiency in adults is determined by the baseline growth hormone status. Clin. Endocrinol. 43, 97–103 14 Lannering, B. et al. (1995) Reduced growth hormone secretion with maintained periodicity following cranial irradiation in children with acute lymphoblastic leukemia. Clin. Endocrinol. 42, 153–159

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and TRH tests should be used to assess thyroid status in cancer survivors whose FT4 value is in the lowest third of the normal range, whose basal TSH concentration is normal and whose growth rate is slowed. Other hypothalamic–pituitary axes should be evaluated concurrently as clinically indicated. Future research should permit the evaluation of metabolic markers, enabling earlier detection of mild hypothyroidism and optimization of treatment. Awareness of the potential for the development of subtle endocrine alterations might permit the development of treatment methods that reduce the frequency of endocrine deficiencies.

15 Lannering, B. et al. (1998) Growth hormone secretion and response to growth hormone therapy after treatment for brain tumour. Acta Paediatr. Scand. Suppl. 343, 146–151 16 Foley, T.P., Jr et al. (1972) Serum thyrotropin responses to synthetic thyrotropin-releasing hormone in normal children and hypopituitary patients. A new test to distinguish primary releasing hormone deficiency from primary pituitary hormone deficiency. J. Clin. Invest. 51, 431–437 17 Samaan, N.A. et al. (1975) Hypopituitarism after external irradiation. Evidence for both hypothalamic and pituitary origin. Ann. Intern. Med. 83, 771–777 18 Rose, S.R. et al. (1999) Diagnosis of hidden central hypothyroidism in survivors of childhood cancer. J. Clin. Endocrinol. Metab. 84, 4472–4479 19 Macklis, R.M. et al. (1993) Cell cycle alterations, apoptosis, and response to low-dose-rate radioimmunotherapy in lymphoma cells. Int. J. Radiat. Oncol. Biol. Phys. 27, 643–650 20 Guo, M. et al. (1997) Characterization of radiation-induced apoptosis in rodent cell lines. Radiat. Res. 147, 295–303 21 Zhivotovsky, B.M. et al. (1999) Tumor radiosensitivity and apoptosis. Exp. Cell Res. 248, 10–17 22 Verheij, M. et al. (1998) Radiation-induced apoptosis – the ceramide SAPK signalling pathway and clinical aspects. Acta Oncol. 37, 575–581 23 Bold, R.J. et al. (1997) Apoptosis, cancer and cancer therapy. Surg. Oncol. 6, 133–142 24 Liu, S.Z. (1989) Radiation hormesis. A new concept in radiological science. Chin. Med. J. 102, 750–755 25 Isakov, A.V. et al. (1988) Effect of proton irradiation of the hypophysis on its gonadotropic and thyrotropic functions in patients with prolactinoma. Probl. Endokrinol. (Mosk) 34, 28–32 26 Rosen, E.M. et al. (2000) Biological basis of radiation sensitivity. Part 1: factors governing radiation tolerance. Oncology 14, 543–550 27 Rosen, E.M. et al. (2000) Biological basis of radiation sensitivity. Part 21: cellular and molecular determinants of radiosensitivity. Oncology 14, 741–765 28 Schmiegelow, M. et al. (1999) Dosimetry and growth hormone deficiency following cranial irradiation of childhood brain tumors. Med. Pediatr. Oncol. 33, 564–571 29 Littley, M.D. et al. (1990) Radiation and hypothalamic–pituitary function. Baillieres Clin. Endocrinol. Metab. 4, 147–175

30 Jambart, S. et al. (1980) Panhypopituitarism secondary to head trauma: evidence for a hypothalamic origin of the deficit. Acta Endocrinol. 93, 264–270 31 Lustig, R.H. et al. (1985) Effect of growth hormone-releasing factor on growth hormone release in children with radiation-induced growth hormone deficiency. Pediatrics 76, 274–279 32 Shalet, S.M. et al. (1995) Growth and endocrine function after bone marrow transplantation. Clin. Endocrinol. 42, 333–339 33 Rose, S.R. and Nisula, B.C. (1989) Circadian variation of thyrotropin in childhood. J. Clin. Endocrinol. Metab. 68, 1086–1090 34 Azukizawa, M. et al. (1976) Plasma thyrotropin, thyroxine, and triiodothyronine relationships in man. J. Clin. Endocrinol. Metab. 43, 533–542 35 Rose, S.R. (2000) Disorders of thyrotropin synthesis, secretion, and function. Curr. Opin. Pediatr. 12, 375–381 36 Manasco, P.K. et al. (1994) Thyrotropin abnormalities in central hypothyroidism. In Glycoprotein Hormones: Structure, Function and Clinical Implications (Serono Symposia) (Lustbader, J.W. et al., eds), pp. 343–348, Springer-Verlag 37 Rose, S.R. et al. (1990) Hypothyroidism and deficiency of the nocturnal thyrotropin surge in children with hypothalamic–pituitary disorders. J. Clin. Endocrinol. Metab. 70, 1750–1755 38 Faglia, G. et al. (1979) Thyrotropin secretion in patients with central hypothyroidism: evidence for reduced biological activity of immunoreactive thyrotropin. J. Clin. Endocrinol. Metab. 48, 989–998 39 Lee, K.O. et al. (1995) Thyrotropin with decreased biological activity, a delayed consequence of cranial irradiation for nasopharyngeal carcinoma. J. Endocrinol. Invest. 18, 800–805 40 Patel, Y.C. and Burger, H.G. (1973) Serum thyrotropin (TSH) in pituitary and/or hypothalamic hypothyroidism: normal or elevated basal levels and paradoxical responses to thyrotropin-releasing hormone. J. Clin. Endocrinol. Metab. 37, 190–196 41 Sklar, C. et al. (1999) Thyroid dysfunction in survivors of Hodgkin’s disease: data from the Childhood Cancer Survivor Study (CCSS). Pediatr. Res. 45, 98A, abstr. 566 42 Ogilvy-Stuart, A.L. et al. (1991) Thyroid function after treatment of brain tumors in children. J. Pediatr. 119, 733–737 43 Monzani, F. et al. (1997) Clinical and biochemical features of muscle dysfunction in subclinical hypothyroidism. J. Clin. Endocrinol. Metab. 82, 3315–3318

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44 Kung, A.W. et al. (1995) Elevated serum lipoprotein(a) in subclinical hypothyroidism. Clin. Endocrinol. 43, 445–449 45 Hickie, I. et al. (1996) Clinical and subclinical hypothyroidism in patients with chronic and treatment-resistant depression. Aust. New Zealand J. Psychiatry 30, 246–252 46 Baldini, I.M. et al. (1997) Psychopathological and cognitive features in subclinical hypothyroidism. Prog. Neuropsychopharmacol. Biol. Psychiatry 21, 925–935 47 Jaeschke, R. et al. (1996) Does treatment with L-thyroxine influence health status in middleaged and older adults with subclinical hypothyroidism? J. Gen. Intern. Med. 11, 744–749 48 Yildirimkaya, M. et al. (1996) Lipoprotein (a) concentration in subclinical hypothyroidism before and after levo-thyroxine therapy. Endocr. J. 43, 731–736 49 Tanis, B.C. et al. (1996) Effect of thyroid substitution on hypercholesterolaemia in patients with subclinical hypothyroidism: a reanalysis of intervention studies. Clin. Endocrinol. 44, 643–649 50 Ayala, A.R. and Wartofsky, L. (1997) Minimally symptomatic (subclinical) hypothyroidism. The Endocrinologist 7, 44–50 51 Rose, S.R. (1995) Isolated central hypothyroidism in short stature. Pediatr. Res. 38, 967–973 52 Pitukcheewanont, P. and Rose, S.R. (1997) Nocturnal TSH surge: a sensitive diagnostic test

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55

56

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for central hypothyroidism in children. The Endocrinologist 7, 226–232 Lam, K.S. et al. (1991) Effects of cranial irradiation on hypothalamic–pituitary function – a 5-year longitudinal study in patients with nasopharyngeal carcinoma. Q. J. Med. 78, 165–176 Littley, M.D. et al. (1989) Radiation-induced hypopituitarism is dose-dependent. Clin. Endocrinol. 31, 363–373 Sklar, C.A. and Constine, L.S. (1995) Chronic neuroendocrinological sequelae of radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 31, 1113–1121 Maccagnan, P. et al. (1999) Abnormal circadian rhythm and increased non-pulsatile secretion of thyrotrophin in Sheehan’s syndrome. Clin. Endocrinol. 51, 439–447 Devney, R.B. et al. (1984) Serial thyroid function measurements in children with Hodgkin disease. J. Pediatr. 105, 223–227 Ogilvy-Stuart, A.L. et al. (1992) Endocrine deficit after fractionated total body irradiation. Arch. Dis. Child. 67, 1107–1110 Chen, M.S. et al. (1989) Prospective hormone study of hypothalamic–pituitary function in patients with nasopharyngeal carcinoma after high dose irradiation. Jpn. J. Clin. Oncol. 19, 265–270 Tell, R. et al. (1997) Hypothyroidism after external radiotherapy for head and neck

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62

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cancer. Int. Radiat. Oncol. Biol. Phys. 39, 303–308 Michel, G. et al. (1997) Late effects of allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: the impact of conditioning regimen without total-body irradiation – a report from the Socié té Française de Greffe de Moelle. J. Clin. Oncol. 15, 2238–2246 DeGroot, L.J. (1999) Dangerous dogmas in medicine: the nonthyroidal illness syndrome. J. Clin. Endocrinol. Metab. 84, 151–164 Van Blerk, M. et al. (1996) Four radioisotopic immunoassays of free thyroxine compared. Ann. Clin. Biochem. 33, 335–343 Christenson, R.H. et al. (1995) Thyroid function testing evaluated on three immunoassay systems. J. Clin. Lab. Anal. 9, 178–183 Sapin, R. et al. (1996) Familial dysalbuminemic hyperthyroxinemia and thyroid hormone autoantibodies: interference in current free thyroid hormone assays. Horm. Res. 45, 139–141 Faix, J.D. et al. (1995) Indirect estimation of thyroid hormone-binding proteins to calculate free thyroxine index: comparison of nonisotopic methods that use labeled thyroxine (‘T-uptake’). Clin. Chem. 41, 41–47 Ferretti, E. et al. (1999) Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J. Clin. Endocrinol. Metab. 84, 924–929

Apparent mineralocorticoid excess Robert C. Wilson, Saroj Nimkarn and Maria I. New Apparent mineralocorticoid excess (AME) is a potentially fatal genetic disorder causing severe juvenile hypertension, pre- and postnatal growth failure, hypokalemia and low to undetectable levels of renin and aldosterone. It is caused by autosomal recessive mutations in the HSD11B2 gene, which result in β-hydroxysteroid dehydrogenase type 2 (11β β-HSD2). The a deficiency of 11β β-HSD2 enzyme is responsible for the conversion of cortisol to the inactive 11β metabolite cortisone and, therefore, protects the mineralocorticoid receptors from cortisol intoxication. In 1998, a mild form of this disease was reported, which might represent an important cause of low-renin hypertension. Early and vigilant treatment might prevent or improve the morbidity and mortality of end-organ damage.

Robert C. Wilson Saroj Nimkarn Maria I. New* Pediatric Endocrinology, New York-Presbyterian Hospital and the Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021, USA. *e-mail: minew@ mail.med.cornell.edu

Apparent mineralocorticoid excess (AME) is a genetic disorder that typically causes severe hypertension in children, pre- and postnatal growth failure, hypokalemic metabolic alkalosis and low to undetectable levels of renin and aldosterone. This potentially fatal disease is the result of autosomal recessive mutations in the HSD11B2 gene, which cause a deficiency of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2. Investigations into the cause of this disease have shown that the activity of aldosterone in mineralocorticoid-responsive cells depends on the function of a metabolic enzyme rather

than on the specificity of aldosterone for the mineralocorticoid receptor (MR). AME also has broader significance because of the possible link between 11β-HSD activity and common essential hypertension, as well as a clearer understanding of human hormone action. Historical background

Although Werder et al.1 described a patient with similar clinical features to AME in 1974, the first biochemical description of this disease was in a threeyear-old Native American child from the Zuni tribe2. Detailed clinical and endocrine evaluations of this child established the presence of features that could not be explained by a known syndrome. Aldosterone regulates electrolyte excretion and intravascular volume by stimulating increased resorption of Na+ from the urine. It is the most potent endogenous mineralocorticoid; yet, despite strong evidence of mineralocorticoid excess and hyperaldosteronism, aldosterone was undetectable in both the prismatic case and similar cases that were subsequently identified. Thus, it was initially thought that the condition was caused by an unknown

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