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Endocrine late-effects of cancer treatment 3 Effect of cancer treatment on hypothalamic–pituitary function Elizabeth Crowne, Helena Gleeson, Helen Benghiat, Paul Sanghera, Andrew Toogood

The past 30 years have seen a great improvement in survival of children and young adults treated for cancer. Cancer treatment can put patients at risk of health problems that can develop many years later, most commonly affecting the endocrine system. Patients treated with cranial radiotherapy often develop dysfunction of the hypothalamic–pituitary axis. A characteristic pattern of hormone deficiencies develops over several years. Growth hormone is disrupted most often, followed by gonadal, adrenal, and thyroid hormones, leading to abnormal growth and puberty in children, and affecting general wellbeing and fertility in adults. The severity and rate of development of hypopituitarism is determined by the dose of radiotherapy delivered to the hypothalamic–pituitary axis. Individual growth hormone deficiencies can develop after a dose as low as 10 Gy, whereas multiple hormone deficiencies are common after 60 Gy. New techniques in radiotherapy aim to reduce the effect on the hypothalamic–pituitary axis by minimising the dose received. Patients taking cytotoxic drugs do not often develop overt hypopituitarism, although the effect of radiotherapy might be enhanced. The exception is adrenal insufficiency caused by glucocorticosteroids which, although transient, can be life-threatening. New biological drugs to treat cancer can cause autoimmune hypophysitis and hypopituitarism; therefore, oncologists and endocrinologists should be vigilant and work together to optimise patient outcomes.

Introduction Survivors of cancer face a range of long-term health issues primarily determined by the treatment received, the most frequent being endocrine dysfunction.1,2 An estimated 50% of survivors of childhood cancer will have an endocrinopathy, with most patients needing lifelong follow-up by an endocrinologist3–6 to minimise the effects on growth, pubertal development, bone health, and quality of life. Radiation is the mainstay of treatment for solid brain tumours in children and adults and can be used in combination with chemotherapy.7–9 In the past, CNS-directed radiotherapy was routinely used in children with acute lymphoblastic leukaemia, a practice that is now limited to patients with evidence of CNS disease.10 Radiation is also used to treat extracranial disease—eg, nasopharyngeal tumours—and for wholebody conditioning before stem-cell transplantation, which can affect the hypothalamic–pituitary axis.11 The primary lesion itself might be directly responsible for hypothalamic–pituitary dysfunction;12 indeed, the consequences of endocrinopathy might be the presenting feature. Patients who survive childhood cancer need systematic follow-up and management of treatment-related morbidity well into adult life.3,4 Radiation-induced anterior pituitary hormone deficiencies are among the most common long-term complications, requiring involvement of a multidisciplinary team spanning childhood, adolescence, and adulthood.13,14 As survival from primary brain tumours and head and neck cancers improves in adults, it is being recognised that a similar multidisciplinary approach is needed when the hypothalamic–pituitary axis is included in the radiation field.15 Advances in non-radiation treatments, such as biological drugs for extracranial tumours including

melanoma, have increased the number of patients developing hypopituitarism. In this Series paper, we discuss the effects and consequences of radiation on the hypothalamic–pituitary axis during childhood and adolescence, the stage of life from which much of the data are derived. However, the principles developed from these data form the basis of treatment of patients during adulthood, supported by an understanding of the behaviour of the hypothalamic–pituitary axis after treatment for benign lesions. We also review monitoring of pituitary function and management of endocrine deficiencies, new radiotherapy techniques designed to reduce the effect on the hypothalamic–pituitary axis, and the effect of new biological drugs on pituitary function and management of endocrine deficiencies.

Lancet Diabetes Endocrinol 2015 Published Online April 12, 2015 http://dx.doi.org/10.1016/ S2213-8587(15)00008-X See Online/Series http://dx.doi.org/10.1016/ S2213-8587(15)00039-X This is third in a Series of three papers about endocrine late-effects of cancer treatment Department of Paediatric Diabetes and Endocrinology, Bristol Royal Hospital for Children, Bristol, UK (E Crowne MD); and Department of Endocrinology (H Gleeson MD, A Toogood MD), Hall-Edwards Radiotherapy Research Group (H Benghiat FRCR, P Sanghera FRCR), Queen Elizabeth Hospital, University Hospitals Birmingham NHSFT, Birmingham, UK Correspondence to: Dr Andrew Toogood, Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham NHSFT, Edgbaston, Birmingham, B15 2TH, UK [email protected]

Effect of radiotherapy on hypothalamic–pituitary function Modifying factors Therapeutic cranial irradiation is used in doses up to 60 Gy in patients aged older than 2 years for a range of cancers including hypothalamic–pituitary axis tumours, non-pituitary brain tumours, and nasopharyngeal and skull base tumours for which the radiation fields can include the hypothalamic–pituitary axis. Lower doses are also used for other purposes: whole brain radiotherapy schedules (18–24 Gy) are used to treat children with acute lymphoblastic leukaemia, and total-body irradiation (10–14 Gy) is used as conditioning before bone-marrow transplantation for high-risk or relapsed childhood leukaemia. Therapeutic radiation is divided into several fractions delivered over several days or weeks. The development of radiation-induced hypopituitarism depends on the

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total dose, fraction size, and radiotherapy schedule.16–20 These variables determine the biological effective dose delivered to the hypothalamic–pituitary axis .21 As the biological effective dose increases, so does the risk of damage to the hypothalamic–pituitary axis and the speed at which it develops.21 The effect of radiation is cumulative, so, for example, a patient with acute leukaemia treated with 18 Gy of prophylactic cranial irradiation who then has stem-cell transplantation preceded by 14 Gy of total-body irradiation will have received a cumulative dose of 32 Gy to the hypothalamic–pituitary axis, which determines the consequent risk of pituitary dysfunction.22–25 Hypopituitarism is defined as the loss of one or more pituitary hormones. Anterior pituitary hormone deficiency follows a predictable pattern (figure). Growth hormone (GH) is the most commonly affected anterior pituitary hormone, followed by the gonadotropins, follicle-stimulating hormone (FSH), and luteinising hormone (LH). Loss of adrenocorticotropic hormone (ACTH) and thyroid-stimulating hormone (TSH) is less predictable.27 As the dose of radiation to the hypothalamic–pituitary axis increases, the time to develop hypopituitarism shortens and the risk of multiple pituitary hormone deficiencies increases. The fact that GH deficiency is the most common deficiency after low-dose radiation (18–24 Gy) suggests that the hypothalamus is more sensitive to radiation damage,28–32 whereas high doses (>30 Gy) are needed to damage the anterior pituitary and cause earlier, multiple pituitary hormone deficiencies.28,33 The evolution of anterior pituitary deficiencies with time and progressive accumulation of damage to the hypothalamic–pituitary axis suggest delayed effects of

Mean dose to hypothalamus

Time to development of GH deficiency

Effect on LH and FSH

TSH deficiency

ACTH deficiency

10–15 Gy

Unknown

15–20 Gy

60 months

Precocious puberty, in girls more than in boys

Rare

Rare

25–30 Gy

36 months

Precocious puberty, equally in girls and boys Possible

Possible in brain tumour survivors especially, or in patients with other pituitary hormone deficiencies

30 Gy

LH and FSH deficiency possible CRI doses >30 Gy

42–60 Gy

>60 Gy

12 months

Very likely

Figure: Effects of cranial irradiation on the hypothalamic–pituitary axis in children and adolescents Adapted from Late Effects of Treatment for Childhood Cancer 2014.26 The effect of cranial irradiation dose can be compounded by previous surgery or chemotherapy. GH=growth hormone. TSH=thyroid-stimulating hormone. LH=luteinising hormone. FSH=follicle-stimulating hormone. CRI=cranial irradiation. ACTH=adrenocorticotropic hormone.

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radiotherapy or the development of secondary pituitary atrophy after hypothalamic damage.19,21,34 Age at irradiation might also be a factor, although data are sparse. GH deficiency seems to be more common in children than in adults, although the clinical definition of GH deficiency differs between the two groups. ACTH deficiency is more common in adults than in children.13 The age at treatment also contributes to the effect of cranial irradiation; young prepubertal children might be more susceptible than older postpubertal children.35 Chemotherapy might have an additive effect on the damage to pituitary function caused by radiation.34,36,37

Effect of radiotherapy on individual pituitary hormones The development of GH deficiency depends on radiation dose and time elapsed since treatment. GH deficiency occurs rarely after radiation doses of 10 Gy,38,39 more commonly after CNS prophylaxis for acute lymphoblastic leukaemia (12–24 Gy),19,32,40,41 very likely within 3–5 years after doses of 30–50 Gy,19 and almost inevitably after high-dose brain tumour schedules (30–60 Gy).42 GH deficiency after cranial irradiation depends on the treatment schedule; radiation in a single fraction has a greater adverse effect on growth than does treatment delivered in multiple fractions.43 The prevalence of GH deficiency after total-body irradiation for bone-marrow transplantation is surprising in view of the low therapeutic dose to the hypothalamic–pituitary axis. GH deficiency is more common after single-fraction totalbody irradiation than after modern delivery of total-body irradiation in ten fractions.44,45 Some centres have reported a higher prevalence of GH deficiency after totalbody irradiation18,24,25,27,32 than have others.22,32,34,39,44–47 The prevalence of GH deficiency in adult survivors of bonemarrow transplantation during childhood needs further study, but there are reports of GH deficiency persisting and being diagnosed in adulthood.13,48,49 GH deficiency has not been reported in patients who received total-body irradiation in adulthood. The effect of cranial irradiation on gonadotropins is also dose dependent. Paradoxically, cranial irradiation can cause central precocious puberty, especially in girls treated with low doses (18–24 Gy), but equally in boys and girls treated with intermediate doses (25–50 Gy).50–52 The gender-specific effect at lower doses of cranial irradiation reflects gender differences inherent in the onset of puberty (girls go into normal and precocious puberty more easily), but is lost with higher exposures. Gonadotropin deficiency can subsequently occur even after low-dose irradiation in female survivors of acute lymphoblastic leukaemia after a mean of 20·8 years.53 Gonadotropin deficiency has been reported in 30% of children given high-dose cranial irradiation (>30 Gy), with increasing prevalence with time since irradiation.20,54,55 The hypothalamic–pituitary–adrenal axis is more resistant than are the GH and gonadotropin axes to

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radiation-induced damage in children, but dosedependent and time-dependent changes have been reported. Studies of high-dose brain tumour treatment schedules with less than 12 years of follow-up have shown only minor abnormalities,20,56–58 but the risk of abnormalities of the hypothalamic–pituitary–adrenal axis increases to 19% after 15 years.59 Investigation of the hypothalamic–pituitary axis at a mean of 8 years after low-dose cranial irradiation (18–24 Gy) for treatment of leukaemia has shown normal cortisol responses during an insulin tolerance test,60,61 and normal 24 h cortisol and ACTH profiles.62 Little data exist about the effects of totalbody irradiation on the hypothalamic–pituitary–adrenal axis, and any reported effects might be a result of chronic stress rather than radiation-induced damage. The hypothalamic–pituitary–thyroid axis is also resistant to radiation-induced damage, with 6% of recipients developing TSH deficiency.63 Dose and time since treatment affect the development of TSH deficiency.20,63 TSH deficiency and thyroid dysfunction have been described after both low-dose cranial irradiation and total-body irradiation in childhood.39,64 Hyperprolactinaemia has been reported in children after cranial irradiation for brain tumours but less commonly than in adults. It is not usually a clinical problem but could cause pubertal delay or arrest by inhibiting gonadotropin secretion.20,54 Until recently, the prognosis for adults with malignant brain tumours was poor, with few surviving long enough to develop hypopituitarism. Thus, few studies have assessed the effect of cranial irradiation on hypothalamic–pituitary function in adults treated for brain tumours. A systematic review15 identified 18 studies with a total of 813 patients who had mostly undergone radiotherapy when older than 18 years, including 608 (75%) patients treated for nasopharyngeal cancer and 205 (25%) for intracerebral tumours. The point prevalence of any degree of hypopituitarism was 66%. The prevalence of GH deficiency was 45%; of LH and FSH deficiency, 30%; of TSH deficiency, 25%; and of ACTH deficiency, 22%. The effects of radiotherapy did not differ between patients with nasopharyngeal and intracerebral tumours. Evidence of pituitary failure increased with time since radiotherapy, with GH deficiency occurring after a mean of 2·6 years, and TSH insufficiency after a mean of 11 years. Although diabetes insipidus might be a presenting feature of lesions (both benign and malignant) closely associated with the hypothalamic–pituitary axis, to date, no evidence suggests that cranial irradiation causes posterior pituitary dysfunction manifesting as diabetes insipidus in adults or children.

The effect of chemotherapy on hypothalamic– pituitary function Cytotoxic drugs are the mainstay of cancer treatment, either alone or in combination with radiotherapy. Most

are delivered intravenously, but in some circumstances they are delivered by the intrathecal route—eg, methotrexate for acute lymphoblastic leukaemia. Chemotherapy has been implicated as a cause of hypothalamic–pituitary dysfunction in survivors of childhood cancer, manifesting as deficiencies of individual hormones or in some cases multiple hormone deficiencies;65 however, the reported changes in pituitary function were subtle and remain controversial. Other studies have suggested that chemotherapy augments the effect of radiation on pituitary function, particularly in patients with medulloblastoma.37,66,67 Reports of individual patients who developed pituitary dysfunction after intrathecal methotrexate are anecdotal, but large cohort studies have failed to show any effect.68 Permanent disruption of posterior pituitary function has not been reported in patients who received either cranial radiotherapy or chemotherapy. Some chemotherapeutic drugs stimulate the release of antidiuretic hormone, resulting in symptomatic hyponatraemia. A case report has implicated temozolamide—used to treat primary brain tumours—in the development of diabetes insipidus that resolved when treatment was discontinued.69 Alkylating agents such as cyclophosphamide, lomustine, and procarbazine can affect pituitary hormone concentrations through their effects on gonadal tissue. These agents cause premature ovarian insufficiency or azoospermia, resulting in abnormal gonadotropin concentrations. In women, FSH and LH will be high and associated with oestrogen deficiency. In men, FSH blood concentration might be high, with an LH concentration in or just above the normal range and normal testosterone concentrations.70 Accepted opinion among endocrinologists is that these patterns of hormone secretion are not indicative of pituitary disease and do not require further investigation of the hypothalamic–pituitary axis. The effects of cancer treatment on gonadal function, including fertility, are reviewed in another paper in the Series.71 Glucocorticosteroids are often used to treat cancer, either in pulses in treatment regimens or to relieve sideeffects of chemotherapy, to reduce inflammation (particularly cerebral oedema associated with intracranial neoplasms), and for complications such as graftversus-host disease after stem-cell transplantation from an unrelated donor. Long-term use can result in suppression of the hypothalamic–pituitary–adrenal axis, resulting in ACTH deficiency and adrenal insufficiency that can persist even if steroids are gradually withdrawn. Up to 47% of patients who received steroids to treat acute lymphoblastic leukaemia have evidence of hypothalamic–pituitary–adrenal axis suppression, which can be short-lived or can take many months to recover from.72,73 If a patient has received long-term treatment with a glucocorticoid and reports fatigue or being generally

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unwell after it is withdrawn, suppression of the hypothalamic–pituitary–adrenal axis and hypoadrenalism should be considered. An appropriate test should be used to confirm the diagnosis and glucocorticoid replaced with hydrocortisone to avoid a potentially fatal Addisonian crisis.74 Steroid-induced hypoadrenalism is usually transient, but can take months and occasionally years to recover.

Immunotherapy Monoclonal antibodies (so-called immune checkpoint inhibitors) can be used to disrupt the immune system to generate an immune reaction against the tumour.75 Ipilimumab is directed against the CTLA4 receptor and enhances immunological anti-tumour activity by decreasing tumour immune tolerance. It has been used to treat metastatic melanoma, improving survival of patients with advanced disease; however, inhibition of CTLA4 results in several autoimmune side-effects including thyroiditis, adrenalitis, and hypophysitis.76 The development of hypophysitis with ipilimumab is dose dependent, affecting up to 17% of patients, and causes endocrinopathies ranging from isolated hormone deficiencies to panhypopituitarism.76 MRI findings include normal appearances, a thickened stalk, or the presence of a pituitary mass.76,77 Management includes suspending treatment, replacing affected hormones, and treatment with glucocorticoids such as dexamethasone.77 Pituitary function can return, but deficits are more likely to be permanent.77,78 Diabetes insipidus has not been described as a consequence of ipilimumab treatment. Tremelimumab, which has a similar mode of action, has been associated with hypophysitis in about 3% of patients.79 To date, these drugs have only been used in adults, but might be used in children in the future. We recommend that oncologists and endocrinologists should monitor patients taking immunotherapies for undiagnosed pituitary dysfunction and patients should be educated to report unusual symptoms of fatigue, amenorrhoea in premenopausal women, postural symptoms, and symptoms associated with hypothyroidism. Simple basal pituitary function tests should be done during treatment with these drugs. Assessment of GH is unlikely to be clinically relevant because its replacement is contraindicated in the presence of active malignancy, so patients do not need to have insulin tolerance or glucagon stimulation tests. Once hypopituitarism has been confirmed, a pituitary MRI should be done to establish the extent of the pituitary mass. Management of treatment-induced hypophysitis includes discontinuation of the drug responsible and replacing deficient hormones when appropriate.77 Highdose steroids are generally used, but whether they have a beneficial role is unclear. Pituitary dysfunction can resolve within 20 weeks, but persists in many cases.77 The appearances on MRI usually resolve rapdily. To 4

date, no cases of optic nerve compression have been reported. The situation might be firther complicated by adrenalitis—which will require assessment of the renin–aldosterone system and treatment with mineralocorticoid if present—or thyroiditis.76

Assessment of pituitary function The assessment of GH status at any age requires at least one dynamic function test to be done. Testing should only be undertaken in patients who are candidates for GH replacement treatment, as assessed by activity of the primary disease and time from treatment. In children, height and pubertal development must be monitored to identify abnormalities.4 Spinal radiotherapy is used in addition to cranial irradiation to treat medulloblastomas or germinomas. In these patients, spinal growth is reduced because of the effect of radiation on the vertebral growth plates, so growth is monitored by measuring leg length alone. Measurements should be recorded on the appropriate growth chart and considered in context of parental heights. Growth could be misinterpreted as adequate in a child thought to be prepubertal, rather than an inadequate pubertal growth spurt in a child with undiagnosed precocious puberty and GH deficiency. If growth is poor, accepted paediatric practice is that a dynamic test to determine GH status should be considered. In adults, GH status should only be investigated in those who are in a position to receive GH. It is usual to seek approval from the patient’s oncologist before proceeding with investigations. The insulin tolerance test is the gold standard to assess the GH and adrenal axes in children and adults aged up to 60 years,80 but is contraindicated in patients with a history of seizures or significant cardiac disease. Alternative tests include glucagon, arginine, or the combination of GH-releasing hormone and arginine testing. These tests provide similar GH responses to the insulin tolerance test in children;81 however, in adults, using either glucagon or arginine results in less vigorous GH responses than the insulin tolerance test.82 In adults, GH-releasing hormone and arginine testing provides the highest response,83 but has different diagnostic thresholds determined by a patient’s BMI.84 At all ages, GH status should be assessed by an endocrinologist with experience of diagnosing and managing GH deficiency.80 The diagnostic thresholds for confirming GH deficiency vary with age. In a poorly growing child, GH deficiency is confirmed if the GH response to a dynamic test is less than 7 μg/L. It is normal practice to reassess GH status once growth has been completed to establish whether GH treatment should be continued. A peak GH of 5 μg/L is the suggested threshold for continuing treatment with GH until the age of 25 years,85 but few data support this rationale. In adults, severe GH deficiency is defined as a GH peak of 3 μg/L or less.86

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Assessment of gonadotropin action in childhood and adolescence is essentially clinical. Signs of early puberty (breast development before age 8 years in girls, testicular development in boys before age 9 years) should prompt endocrine assessment by a paediatric endocrinologist. In boys who have received alkylating chemotherapy or testicular radiotherapy, testicular volume is unreliable, so evidence of virilisation should be investigated. Monitoring serum testosterone concentrations is not useful, because it is not detectable during daytime until puberty is well established. Breast development in girls can be difficult to assess in those with a degree of short spine or adiposity. Bone age provides useful information about skeletal maturity and growth potential. If puberty is delayed (no signs at 11 years in girls or 13·5 years in boys), baseline gonadotropin concentrations will rule out primary gonadal failure. In men, low testosterone, FSH, and LH concentrations suggest gonadotropin deficiency. In women with prolonged amenorrhoea and low oestradiol concentrations, low gonadotropin concentrations suggest pituitary damage. Fertility is important for young survivors of cancer and requires expert assessment and counselling. For those who receive cranial radiotherapy alone or in combination with drugs that are not gonadotoxic, the prospects for fertility are good, although treatment with exogenous gonadotropins might be needed. The limiting factor for other patients is exposure to gonadotoxic treatment, either direct radiotherapy or cytotoxic drugs that affect the gonads, which is reviewed in another paper in this Series.71 Assessment of the hypothalamic–pituitary–adrenal axis might be needed, especially if the child is symptomatic (fatigue is a common symptom) or if other anterior pituitary hormones are deficient. Clinicians should be aware of possible transient suppression of the hypothalamic–pituitary–adrenal axis from previous steroid treatment in the first months after treatment. The insulin tolerance test is again the gold standard, the glucagon response is less reliable for identification of ACTH deficiency. An alternative is the short synacthen test, which, though simple, can be difficult to interpret, especially in patients who have undergone surgery on the hypothalamus or pituitary within 6 weeks, or who might have developing ACTH deficiency after cranial irradiation.74 Because adults are more likely than children to develop ACTH deficiency, especially after high-dose radiotherapy, hypothalamic–pituitary–adrenal axis function should be assessed every year. TSH and free T4 concentrations should be measured to establish thyroid function in any patient who has received cranial irradiation, to avoid missing secondary hypothyroidism. Radiotherapy to the neck (spinal irradiation and total-body irradiation) can cause primary hypothyroidism. The frequency of assessment in children depends mainly on how often they are followed up for primary

disease, but should be at least every 6 months during adolescence. Because adults do not show any specific markers of pituitary dysfunction and the symptoms are vague, standard practice is for anterior pituitary function to be tested every year.

Endocrine treatment after cranial irradiation GH replacement is indicated in patients who have GH deficiency and whose cancer is in remission.44,45 It improves final height in children and is also needed for optimum body composition and for bone health, it also improves stamina, particularly in young adults who have completed growth.87 In adults, GH deficiency impairs quality of life, causes abnormal body composition (increased fat mass and reduced lean mass and bone mass), and increases adverse cardiovascular risk factors. GH replacement reverses many of the symptoms of GH deficiency syndrome, but it is mainly used to improve quality of life (particularly in the UK) and to improve the adverse cardiovascular risk profile.88 Initiation of GH treatment is usually delayed in children until 12 months after cancer treatment ends and is started after discussion between the multidisciplinary team and the family. In adults, starting GH replacement is usually delayed until 2 years after completion of cancer treatment, and is only started with the agreement of the patient’s oncologist. If the tumour grows while a patient is taking GH, discontinuation of treatment should be considered. Safety of GH treatment is paramount. Long-term follow-up data suggest that GH treatment is not associated with increased risk of relapse or development of new CNS malignancies or leukaemias.89–91 A possible increased prevalence of meningioma has been attributed to radiotherapy, not GH treatment.89 No data suggest that patients treated with GH are at risk of developing nonCNS malignancies. Further long-term follow-up studies are needed to establish whether GH affects risk of secondary cancer. Treatment with a LH-releasing hormone analogue should be considered for patients who develop precocious puberty, both to address the psychosocial issues associated with early puberty and to avoid further compromises to final height caused by premature skeletal maturation.92,93 Such treatment can improve final adult height although with some skeletal disproportion.92,93 Puberty can be delayed or arrested because of gonadotropin deficiency after high-dose cranial irradiation, or after chronic disease and in association with GH deficiency. It is not possible to definitively differentiate between delayed puberty and gonadotropin deficiency before puberty. If puberty is not progressing satisfactorily, gradual induction of puberty, starting with low doses of sex steroids, can be initiated at an appropriate age, individualised for each child, but usually around 11 years in girls and 12–13 years in boys.94

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Advantages

Disadvantages

Intensity-modulated radiotherapy

Suitable for complex irregular lesions Use of multiple photon beams shapes the treatment dose around the tumour, reducing the dose delivered to healthy tissue Widely available often combined with image guidance technology for more precise targeting

Low-dose radiation is spread over a wide volume of normal tissue Delivered in multiple daily fractions over several weeks

Stereotactic radiosurgery or radiotherapy

Uses multiple converging photon beams to produce sub-millimetre localisation Can be delivered during a single session (stereotactic radiosurgery) or several sessions (stereotactic radiotherapy) Use of multiple low-dose beams enables rapid dose fall and can protect against damage to the hypothalamic–pituitary axis

Suitable only for small, well-demarcated tumours Rarely used in children Availability is variable

Proton beam treatment

Energy deposited in a well-defined peak that can be localised to the tumour with minimal exit dose Particularly useful to reduce radiation explosure to large volumes of normal tissue in children—eg, craniospinal proton beam treatment for medulloblastoma reduces radiation dose to intra-abdominal and thoracic cavities minimising the risk of long-term organ damage and secondary malignancy in children

Available in few centres Expensive at present

Table: Advantages and disadvantages of different cranial irradiation treatments for cancer

Search strategy and selection criteria We searched PubMed and Google Scholar with the term “(((pituitary) AND cancer) AND hypopituitarism)” for studies published in English. We found 1638 reports of which 282 were published between Jan 1, 2010, and Nov 30, 2014. On the basis of search results and input from the authors, we selected studies of late effects of treatment for childhood cancer on the endocrine system.

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treatment to be focused on the area of interest while minimising exposure of normal tissue (table). It is hoped that these advances will reduce the risk of hypopituitarism after treatment. As more is understood about the molecular profiling and subsequent behaviour of several brain tumours in children, attempts to de-escalate radiation doses and treatment intensities in favourable subgroups could be a step forward to reduce toxic effects on the hypothalamic–pituitary axis in specific cohorts.

Standard clinical practice is that adults should receive appropriate sex steroid replacement, taking into account any history of thromboembolic disease in women. If fertility is desired then treatment is switched to exogenous gonadotropins to stimulate spermatogenesis in men and ovulation in women. Thyroid hormone replacement is used to correct central hypothyroidism, primary hypothyroidism, or a mixture of the two (which can occur after craniospinal irradiation or total-body irradiation). The therapeutic goal is a free T4 concentration in the upper part of the normal range. Patients with ACTH deficiency should receive hydrocortisone replacement in two or three doses throughout the day.74 A high dose is usually given in the morning to mimic diurnal variation of cortisol secretion. Counselling is needed to ensure that patients and parents increase the hydrocortisone dose during periods of illness or during surgical or dental treatment.74

Conclusion

Reducing the effect of cancer treatment on the hypothalamic–pituitary axis

Declaration of interests We declare no competing interests.

There has been a continuing effort to minimise the risk of long-term complications among survivors of childhood cancer. Perhaps the most obvious change was the removal of CNS-directed radiotherapy from the routine management of acute lymphoblastic leukaemia. Recent advances in radiotherapy techniques enable

References 1 Curry HL, Parkes SE, Powell JE, Mann JR. Caring for survivors of childhood cancers: the size of the problem. Eur J Cancer 2006; 42: 501–08. 2 Oeffinger KC, Mertens AC, Sklar CA, et al, and the Childhood Cancer Survivor Study. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006; 355: 1572–82.

Endocrine dysfunction is the most common long-term effect of cancer treatment. Pituitary dysfunction is common among patients treated for neoplasms of the brain or nasopharynx and can either be present at diagnosis as a result of surgical intervention or develop over many years after irradiation. The development of immunotherapy to treat cancer has led to the complication of autoimmune hypophysitis. Patients treated during childhood are especially vulnerable to the effect of radiotherapy on the hypothalamic–pituitary axis, which can affect growth, puberty, and the ability to function normally within adult society. Oncologists, surgeons, and endocrinologists should work together to monitor pituitary function and manage endocrine deficiencies for the best long-term outcomes. Contributors PS and HB wrote the report. EC and AT searched the published work and wrote the paper. HG searched the published work, and wrote and edited the paper.

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Landier W, Wallace WH, Hudson MM. Long-term follow-up of pediatric cancer survivors: education, surveillance, and screening. Pediatr Blood Cancer 2006; 46: 149–58. Skinner R, Wallace WH, Levitt G, eds. Therapy Based Long Term Follow Up: Practice Statement. 2nd edn; 2006. Wallace WH, Blacklay A, Eiser C, et al, and the Late Effects Committee of the United Kingdom Children’s Cancer Study Group (UKCCSG). Developing strategies for long term follow up of survivors of childhood cancer. BMJ 2001; 323: 271–74. Wallace WH, Thompson L, Anderson RA, and the Guideline Development Group. Long term follow-up of survivors of childhood cancer: summary of updated SIGN guidance. BMJ 2013; 346: f1190. Chintagumpala M, Gajjar A. Brain tumors. Pediatr Clin North Am 2015; 62: 167–78. Johnson DR, Galanis E. Medical management of high-grade astrocytoma: current and emerging therapies. Semin Oncol 2014; 41: 511–22. Michiels EM, Schouten-Van Meeteren AY, Doz F, Janssens GO, van Dalen EC. Chemotherapy for children with medulloblastoma. Cochrane Database Syst Rev 2015; 1: CD006678. Nathan PC, Wasilewski-Masker K, Janzen LA. Long-term outcomes in survivors of childhood acute lymphoblastic leukemia. Hematol Oncol Clin North Am 2009; 23: 1065–82, vi–vii. (vi–vii.). Lam KSL, Ho JHC, Lee AWM, et al. Symptomatic hypothalamicpituitary dysfunction in nasopharyngeal carcinoma patients following radiation therapy: a retrospective study. Int J Radiat Oncol Biol Phys 1987; 13: 1343–50. Toogood AA, Stewart PM. Hypopituitarism: clinical features, diagnosis, and management. Endocrinol Metab Clin North Am 2008; 37: 235–61. Darzy KH. Radiation-induced hypopituitarism after cancer therapy: who, how and when to test. Nat Clin Pract Endocrinol Metab 2009; 5: 88–99. Gleeson HK, Shalet SM. The impact of cancer therapy on the endocrine system in survivors of childhood brain tumours. Endocr Relat Cancer 2004; 11: 589–602. Appelman-Dijkstra NM, Malgo F, Neelis KJ, Coremans I, Biermasz NR, Pereira AM. Pituitary dysfunction in adult patients after cranial irradiation for head and nasopharyngeal tumours. Radiother Oncol 2014; 113: 102–07. Shalet SM, Beardwell CG, Pearson D, Morris PH. The effect of varying doses of cerebral irradiation on growth hormone production in childhood. Clin Endocrinol (Oxf) 1976; 5: 287–90. Duffner PK, Cohen ME, Voorhess ML, et al. Long-term effects of cranial irradiation on endocrine function in children with brain tumors. A prospective study. Cancer 1985; 56: 2189–93. Lam KSL, Tse VKC, Wang C, Yeung RTT, Ho JHC. Effects of cranial irradiation on hypothalamic-pituitary function—a 5-year longitudinal study in patients with nasopharyngeal carcinoma. Q J Med 1991; 78: 165–76. Clayton PE, Shalet SM. Dose dependency of time of onset of radiation-induced growth hormone deficiency. J Pediatr 1991; 118: 226–28. Constine LS, Woolf PD, Cann D, et al. Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med 1993; 328: 87–94. Schmiegelow M, Lassen S, Poulsen HS, et al. Cranial radiotherapy of childhood brain tumours: growth hormone deficiency and its relation to the biological effective dose of irradiation in a large population based study. Clin Endocrinol (Oxf) 2000; 53: 191–97. Cohen A, Duell T, Socié G, et al, and the European Group for Blood and Marrow Transplantation. Nutritional status and growth after bone marrow transplantation (BMT) during childhood: EBMT Late-Effects Working Party retrospective data. Bone Marrow Transplant 1999; 23: 1043–47. Shinagawa T, Tomita Y, Ishiguro H, et al. Final height and growth hormone secretion after bone marrow transplantation in children. Endocr J 2001; 48: 133–38. Huma Z, Boulad F, Black P, Heller G, Sklar C. Growth in children after bone marrow transplantation for acute leukemia. Blood 1995; 86: 819–24.

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Shalet SM, Brennan BM. Growth and growth hormone status after a bone marrow transplant. Horm Res 2002; 58 (suppl 1): 86–90. Late Effects of Treatment for Childhood Cancer 2014. http://www.cancer.gov/cancertopics/pdq/treatment/lateeffects/ HealthProfessional (accessed Feb 13, 2015). Littley MD, Shalet SM, Beardwell CG, Robinson EL, Sutton ML. Radiation-induced hypopituitarism is dose-dependent. Clin Endocrinol (Oxf) 1989; 31: 363–73. Samaan NA, Bakdash MM, Caderao JB, Cangir A, Jesse RH Jr, Ballantyne AJ. Hypopituitarism after external irradiation. Evidence for both hypothalamic and pituitary origin. Ann Intern Med 1975; 83: 771–77. Chrousos GP, Poplack D, Brown T, O’Neill D, Schwade J, Bercu BB. Effects of cranial radiation on hypothalamic-adenohypophyseal function: abnormal growth hormone secretory dynamics. J Clin Endocrinol Metab 1982; 54: 1135–39. Ahmed SR, Shalet SM, Beardwell CG. The effects of cranial irradiation on growth hormone secretion. Acta Paediatr Scand 1986; 75: 255–60. Lannering B, Albertsson-Wikland K. Growth hormone release in children after cranial irradiation. Horm Res 1987; 27: 13–22. Costin G. Effects of low-dose cranial radiation on growth hormone secretory dynamics and hypothalamic-pituitary function. Am J Dis Child 1988; 142: 847–52. Samaan NA, Vieto R, Schultz PN, et al. Hypothalamic, pituitary and thyroid dysfunction after radiotherapy to the head and neck. Int J Radiat Oncol Biol Phys 1982; 8: 1857–67. Spoudeas HA, Hindmarsh PC, Matthews DR, Brook CG. Evolution of growth hormone neurosecretory disturbance after cranial irradiation for childhood brain tumours: a prospective study. J Endocrinol 1996; 150: 329–42. Brauner R, Czernichow P, Rappaport R. Greater susceptibility to hypothalamopituitary irradiation in younger children with acute lymphoblastic leukemia. J Pediatr 1986; 108: 332. Achermann JC, Hindmarsh PC, Robinson IC, Matthews DR, Brook CG. The relative roles of continuous growth hormone-releasing hormone (GHRH(1-29)NH2) and intermittent somatostatin(1-14)(SS) in growth hormone (GH) pulse generation: studies in normal and post cranial irradiated individuals. Clin Endocrinol (Oxf) 1999; 51: 575–85. Gleeson HK, Gattamaneni HR, Smethurst L, Brennan BM, Shalet SM. Reassessment of growth hormone status is required at final height in children treated with growth hormone replacement after radiation therapy. J Clin Endocrinol Metab 2004; 89: 662–66. Brauner R, Fontoura M, Zucker JM, et al. Growth and growth hormone secretion after bone marrow transplantation. Arch Dis Child 1993; 68: 458–63. Ogilvy-Stuart AL, Clark DJ, Wallace WH, et al. Endocrine deficit after fractionated total body irradiation. Arch Dis Child 1992; 67: 1107–10. Adan L, Trivin C, Sainte-Rose C, Zucker JM, Hartmann O, Brauner R. GH deficiency caused by cranial irradiation during childhood: factors and markers in young adults. J Clin Endocrinol Metab 2001; 86: 5245–51. Crowne EC, Moore C, Wallace WH, et al. A novel variant of growth hormone (GH) insufficiency following low dose cranial irradiation. Clin Endocrinol (Oxf) 1992; 36: 59–68. Darzy KH, Pezzoli SS, Thorner MO, Shalet SM. The dynamics of growth hormone (GH) secretion in adult cancer survivors with severe GH deficiency acquired after brain irradiation in childhood for nonpituitary brain tumors: evidence for preserved pulsatility and diurnal variation with increased secretory disorderliness. J Clin Endocrinol Metab 2005; 90: 2794–803. Thomas BC, Stanhope R, Plowman PN, Leiper AD. Growth following single fraction and fractionated total body irradiation for bone marrow transplantation. Eur J Pediatr 1993; 152: 888–92. Giorgiani G, Bozzola M, Locatelli F, et al. Role of busulfan and total body irradiation on growth of prepubertal children receiving bone marrow transplantation and results of treatment with recombinant human growth hormone. Blood 1995; 86: 825–31. Frisk P, Arvidson J, Gustafsson J, Lönnerholm G. Pubertal development and final height after autologous bone marrow transplantation for acute lymphoblastic leukemia. Bone Marrow Transplant 2004; 33: 205–10.

www.thelancet.com/diabetes-endocrinology Published online April 12, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00008-X

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Sanders JE, Guthrie KA, Hoffmeister PA, Woolfrey AE, Carpenter PA, Appelbaum FR. Final adult height of patients who received hematopoietic cell transplantation in childhood. Blood 2005; 105: 1348–54. Bakker B, Massa GG, Oostdijk W, Van Weel-Sipman MH, Vossen JM, Wit JM. Pubertal development and growth after total-body irradiation and bone marrow transplantation for haematological malignancies. Eur J Pediatr 2000; 159: 31–37. Pasqualini T, Escobar ME, Domené H, Muriel FS, Pavlovsky S, Rivarola MA. Evaluation of gonadal function following long-term treatment for acute lymphoblastic leukemia in girls. Am J Pediatr Hematol Oncol 1987; 9: 15–22. Sanders JE, Buckner CD, Leonard JM, et al. Late effects on gonadal function of cyclophosphamide, total-body irradiation, and marrow transplantation. Transplantation 1983; 36: 252–55. Leiper AD, Stanhope R, Kitching P, Chessells JM. Precocious and premature puberty associated with treatment of acute lymphoblastic leukaemia. Arch Dis Child 1987; 62: 1107–12. Ogilvy-Stuart AL, Clayton PE, Shalet SM. Cranial irradiation and early puberty. J Clin Endocrinol Metab 1994; 78: 1282–86. Lannering B, Jansson C, Rosberg S, Albertsson-Wikland K. Increased LH and FSH secretion after cranial irradiation in boys. Med Pediatr Oncol 1997; 29: 280–87. Bath LE, Anderson RA, Critchley HO, Kelnar CJ, Wallace WH. Hypothalamic-pituitary-ovarian dysfunction after prepubertal chemotherapy and cranial irradiation for acute leukaemia. Hum Reprod 2001; 16: 1838–44. Rappaport R, Brauner R, Czernichow P, et al. Effect of hypothalamic and pituitary irradiation on pubertal development in children with cranial tumors. J Clin Endocrinol Metab 1982; 54: 1164–68. Schmiegelow M, Lassen S, Poulsen HS, et al. Gonadal status in male survivors following childhood brain tumors. J Clin Endocrinol Metab 2001; 86: 2446–52. Livesey EA, Hindmarsh PC, Brook CG, et al. Endocrine disorders following treatment of childhood brain tumours. Br J Cancer 1990; 61: 622–25. Spoudeas HA, Charmandari E, Brook CG. Hypothalamo-pituitaryadrenal axis integrity after cranial irradiation for childhood posterior fossa tumours. Med Pediatr Oncol 2003; 40: 224–29. Oberfield SE, Nirenberg A, Allen JC, et al. Hypothalamic-pituitaryadrenal function following cranial irradiation. Horm Res 1997; 47: 9–16. Schmiegelow M, Feldt-Rasmussen U, Rasmussen AK, Lange M, Poulsen HS, Müller J. Assessment of the hypothalamo-pituitaryadrenal axis in patients treated with radiotherapy and chemotherapy for childhood brain tumor. J Clin Endocrinol Metab 2003; 88: 3149–54. Drinnan CR, Miller JD, Guyda HJ, Esseltine DW, Chevalier LM, Freeman CR. Growth and development of long-term survivors of childhood acute lymphoblastic leukemia treated with and without prophylactic radiation of the central nervous system. Clin Invest Med 1985; 8: 307–14. Voorhess ML, Brecher ML, Glicksman AS, et al. Hypothalamicpituitary function of children with acute lymphocytic leukemia after three forms of central nervous system prophylaxis. A retrospective study. Cancer 1986; 57: 1287–91. Crowne EC, Wallace WHB, Gibson S, Moore CM, White A, Shalet SM. Adrenocorticotrophin and cortisol secretion in children after low dose cranial irradiation. Clin Endocrinol (Oxf) 1993; 39: 297–305. Schmiegelow M, Feldt-Rasmussen U, Rasmussen AK, Poulsen HS, Müller J. A population-based study of thyroid function after radiotherapy and chemotherapy for a childhood brain tumor. J Clin Endocrinol Metab 2003; 88: 136–40. Chow EJ, Friedman DL, Stovall M, et al. Risk of thyroid dysfunction and subsequent thyroid cancer among survivors of acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 2009; 53: 432–37. Rose SR, Schreiber RE, Kearney NS, et al. Hypothalamic dysfunction after chemotherapy. J Pediatr Endocrinol Metab 2004; 17: 55–66. Olshan JS, Gubernick J, Packer RJ, et al. The effects of adjuvant chemotherapy on growth in children with medulloblastoma. Cancer 1992; 70: 2013–17.

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80

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Ogilvy-Stuart AL, Shalet SM. Effect of chemotherapy on growth. Acta Paediatr Suppl 1995; 411: 52–56. Hasle H, Helgestad J, Christensen JK, Jacobsen BB, Kamper J. Prolonged intrathecal chemotherapy replacing cranial irradiation in high-risk acute lymphatic leukaemia: long-term follow up with cerebral computed tomography scans and endocrinological studies. Eur J Pediatr 1995; 154: 24–29. Faje AT, Nachtigall L, Wexler D, Miller KK, Klibanski A, Makimura H. Central diabetes insipidus: a previously unreported side effect of temozolomide. J Clin Endocrinol Metab 2013; 98: 3926–31. Wallace EM, Groome NP, Riley SC, Parker AC, Wu FC. Effects of chemotherapy-induced testicular damage on inhibin, gonadotropin, and testosterone secretion: a prospective longitudinal study. J Clin Endocrinol Metab 1997; 82: 3111–15. Anderson RA, Mitchell RT, Kelsey TW, Spears N, Telfer EE, Wallace WHB. Cancer treatment and gonadal function: experimental and established strategies for fertility preservation in children and young adults. Lancet Diabetes Endocrinol 2015; published online April 12. http://dx.doi.org/10.1016/S22138587(15)00039-X. Mahachoklertwattana P, Vilaiyuk S, Hongeng S, Okascharoen C. Suppression of adrenal function in children with acute lymphoblastic leukemia following induction therapy with corticosteroid and other cytotoxic agents. J Pediatr 2004; 144: 736–40. Rix M, Birkebaek NH, Rosthøj S, Clausen N. Clinical impact of corticosteroid-induced adrenal suppression during treatment for acute lymphoblastic leukemia in children: a prospective observational study using the low-dose adrenocorticotropin test. J Pediatr 2005; 147: 645–50. Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003; 361: 1881–93. Postow M, Callahan MK, Wolchok JD. Beyond cancer vaccines: a reason for future optimism with immunomodulatory therapy. Cancer J 2011; 17: 372–78. Corsello SM, Barnabei A, Marchetti P, De Vecchis L, Salvatori R, Torino F. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab 2013; 98: 1361–75. Faje AT, Sullivan R, Lawrence D, et al. Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J Clin Endocrinol Metab 2014; 99: 4078–85. Torino F, Barnabei A, De Vecchis L, Salvatori R, Corsello SM. Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte antigen 4: challenges from a new cause of a rare disease. Oncologist 2012; 17: 525–35. Ribas A, Camacho LH, Lopez-Berestein G, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol 2005; 23: 8968–77. Shalet SM, Toogood A, Rahim A, Brennan BM. The diagnosis of growth hormone deficiency in children and adults. Endocr Rev 1998; 19: 203–23. Ghigo E, Bellone J, Aimaretti G, et al. Reliability of provocative tests to assess growth hormone secretory status. Study in 472 normally growing children. J Clin Endocrinol Metab 1996; 81: 3323–27. Rahim A, Toogood AA, Shalet SM. The assessment of growth hormone status in normal young adult males using a variety of provocative agents. Clin Endocrinol (Oxf) 1996; 45: 557–62. Ghigo E, Goffi S, Nicolosi M, et al. Growth hormone (GH) responsiveness to combined administration of arginine and GH-releasing hormone does not vary with age in man. J Clin Endocrinol Metab 1990; 71: 1481–85. Corneli G, Di Somma C, Baldelli R, et al. The cut-off limits of the GH response to GH-releasing hormone-arginine test related to body mass index. Eur J Endocrinol 2005; 153: 257–64. Ho KK, and the 2007 GH Deficiency Consensus Workshop Participants. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. Eur J Endocrinol 2007; 157: 695–700.

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Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency. J Clin Endocrinol Metab 1998; 83: 379–81. Shalet SM, Shavrikova E, Cromer M, et al. Effect of growth hormone (GH) treatment on bone in postpubertal GH-deficient patients: a 2-year randomized, controlled, dose-ranging study. J Clin Endocrinol Metab 2003; 88: 4124–29. Höybye C, Christiansen JS. Growth hormone replacement in adults - current standards and new perspectives. Best Pract Res Clin Endocrinol Metab 2015; 29: 115–23. Patterson BC, Chen Y, Sklar CA, et al. Growth hormone exposure as a risk factor for the development of subsequent neoplasms of the central nervous system: a report from the childhood cancer survivor study. J Clin Endocrinol Metab 2014; 99: 2030–37. Wang ZF, Chen HL. Growth hormone treatment and risk of recurrence or development of secondary neoplasms in survivors of pediatric brain tumors. J Clin Neurosci 2014; 21: 2155–59.

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Chung TT, Drake WM, Evanson J, et al. Tumour surveillance imaging in patients with extrapituitary tumours receiving growth hormone replacement. Clin Endocrinol (Oxf) 2005; 63: 274–79. Adan L, Sainte-Rose C, Souberbielle JC, Zucker JM, Kalifa C, Brauner R. Adult height after growth hormone (GH) treatment for GH deficiency due to cranial irradiation. Med Pediatr Oncol 2000; 34: 14–19. Gleeson HK, Stoeter R, Ogilvy-Stuart AL, Gattamaneni HR, Brennan BM, Shalet SM. Improvements in final height over 25 years in growth hormone (GH)-deficient childhood survivors of brain tumors receiving GH replacement. J Clin Endocrinol Metab 2003; 88: 3682–89. Dunkel L, Quinton R. Transition in endocrinology: induction of puberty. Eur J Endocrinol 2014; 170: R229–39.

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