05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 51 Chapter 5 51 Neuroendocrine Complications of Cancer Therapy Wing Leung · Susan R. Rose · Thomas E. Merchant Contents 5.3 Detection and Screening . 67 5.1 Pathophysiology . 52 5.3.1 Signs and Symptoms Prompting 5.1.1 Normal Hypothalamic–Pituitary Axis . 52 Immediate Evaluation . 67 5.1.1.1 Growth Hormone . 53 5.3.2 Surveillance of Asymptomatic Patients . 67 5.1.1.2 Gonadotropins . 53 5.3.3 GH Deficiency . 67 5.1.1.3 Thyroid-Stimulating 5.3.4 LH or FSH Deficiency . 67 Hormone . 54 5.3.5 Precocious Puberty . 68 5.1.1.4 Adrenocorticotropin . 54 5.3.6 TSH Deficiency . 69 5.1.1.5 Prolactin . 54 5.3.7 ACTH Deficiency . 69 5.1.2 Injury of the Hypothalamic–Pituitary Axis 5.3.8 Hyperprolactinemia . 70 in Patients with Cancer . 56 5.3.9 Diabetes Insipidus . 70 5.1.3 Contribution of Radiation 5.3.10 Osteopenia . 70 to Hypothalamic–Pituitary Axis Injury . 56 5.3.11 Hypothalamic Obesity . 70 5.2 Clinical Manifestations . 60 5.4 Management of Established Problems . 71 5.2.1 GH Deficiency . 60 5.4.1 GH Deficiency . 71 5.2.2 LH or FSH Deficiency . 60 5.4.2 LH or FSH Deficiency . 73 5.2.3 Precocious 5.4.3 Precocious Puberty . 74 or Rapid Tempo Puberty . 63 5.4.4 Hypothyroidism . 74 5.2.4 TSH Deficiency . 64 5.4.5 ACTH Deficiency . 75 5.2.5 ACTH Deficiency . 66 5.4.6 Hyperprolactinemia . 76 5.2.6 Hyperprolactinemia . 66 5.4.7 Diabetes Insipidus . 76 5.2.7 Diabetes Insipidus . 66 5.4.8 Osteopenia . 76 5.2.8 Osteopenia . 66 5.4.9 Hypothalamic Obesity . 77 5.2.9 Hypothalamic Obesity . 66 References . 77 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 52 52 Chapter 5 W. Leung · S. R. Rose · T. E. Merchant Table 5.1. Anterior pituitary hormones and major hypothalamic regulatory factors Pituitary hormone Hypothalamic factor Effect Growth hormone Growth hormone-releasing hormone + Somatostatin – Prolactin Dopamine – Luteinizing hormone Gonadotropin-releasing hormone + Follicle-stimulating hormone Gonadotropin-releasing hormone + Thyroid-stimulating hormone Thyrotropin-releasing hormone + Somatostatin – Adrenocorticotropin Corticotropin-releasing hormone + Vasopressin + Effects on the hypothalamus are either stimulatory (+) or inhibitory (–) 5.1 Pathophysiology 5.1.1 Normal Hypothalamic–Pituitary Axis The hypothalamic–pituitary axis (HPA) is the pri- mary interface between the nervous system and the endocrine system.The actions and interactions of the endocrine and nervous systems constitute the major regulatory mechanisms for virtually all physiologic functions. The hypothalamus has extensive neural communications with other brain regions and regu- lates brain functions, including temperature, ap- petite, thirst, sexual behavior, and fear. The hypothal- amus also contains two types of neurosecretory cells (Fig. 5.1): (1) neurohypophysial neurons, which transverse the hypothalamic–pituitary stalk and re- lease vasopressin and oxytocin from their nerve end- ings in the posterior pituitary, and (2) hypophys- iotropic neurons, which release hormones into the portal hypophysial vessels to regulate the secretion of tropic hormones from the anterior pituitary. The six anterior pituitary hormones and their major hypo- Figure 5.1 thalamic regulatory factors are listed in Table 5.1. Diagrammatic representation of the hypothalamic– pituitary axis 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 53 Neuroendocrine Complications of Cancer Therapy Chapter 5 53 5.1.1.1 Growth Hormone Growth hormone (GH) is a 191-amino acid polypep- tide synthesized and secreted by the somatotrophs in the anterior pituitary gland in response to the hypo- thalamus releasing hormones, primarily GH-releas- ing hormone (GHRH) and somatostatin. GHRH se- cretion is usually steady, whereas somatostatin secre- tion is interrupted intermittently. Somatostatin con- tributes to the synthesis of GH in the pituitary but, paradoxically, inhibits GH release [45]. When so- matostatin concentrations decrease, the tonic con- centration of GHRH causes the release of GH into the systemic circulation. Factors such as neuropeptide Y, leptin, galanin, and ghrelin may also regulate GH secretion. In healthy children and adults, GH secre- tion is pulsatile,particularly during sleep,with two to a six pulses per night [50]. In adolescents, additional pulses occur during the day, and the pulses have higher peaks than those seen in children and adults (Fig. 5.2a). Circulating serum GH stimulates the production of insulin-like growth factor I (IGF-I) in all tissues. IGF-I mediates GH effects on growth, bone mineral- ization, and body composition (decreased fat deposi- tion, increased muscle mass) [71]. IGF-I is bound to IGF-binding proteins such as IGFBP3 and is trans- ported in the blood. IGF-I and IGFBP3 concentra- b tions are stable during the day and each reflects the integrated concentration of secreted GH. Figure 5.2 a,b a Changes with pubertal status in the normal daily pattern of growth hormone (GH), luteinizing hormone 5.1.1.2 Gonadotropins (LH), thyroid stimulating hormone (TSH), and adreno- corticotropin (ACTH) and cortisol secretion. b Normal Luteinizing hormone (LH) and follicle stimulating changes in LH and FSH levels from infancy to adoles- hormone (FSH) are glycoproteins both stored in the cence same cells in the anterior pituitary. Their overall pat- terns of secretion vary according to the age and gen- der of the person. The pituitary gland produces and secretes LH and FSH in a pulsatile manner in re- dren. In men, LH stimulates testosterone production sponse to a concordant episodic release of gonado- in the Leydig cells of the testes; normal spermatogen- tropin-releasing hormone (GnRH) from the hypo- esis requires both LH and FSH. In women, FSH stim- thalamus (Fig. 5.2a). The hypothalamic stimulus is ulates the production of estrogen and LH stimulates actively inhibited between 6 months of age and the the production of progesterone in the ovary. The LH onset of puberty (Fig. 5.2b). This inhibition can be surge near the end of the follicular phase of the men- disturbed by tumor mass, cranial surgery, or irradia- strual cycle is necessary to stimulate ovulation. De- tion, thereby resulting in precocious puberty in chil- velopment of the ovarian follicles is largely under 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 54 54 Chapter 5 W. Leung · S. R. Rose · T. E. Merchant FSH control, and the secretion of estrogen from the throughout the day; it peaks before the person awak- follicle is dependent on both FSH and LH (see section ens in the morning (Fig. 5.2a), increases with stress, 5.2.2 for information on the normal development of and is inhibited by glucocorticoids. Because cortisol the gonads). secretion is regulated by ACTH,cortisol secretion has characteristics similar to the secretion of ACTH. In 5.1.1.3 Thyroid-Stimulating Hormone addition to the negative feedback of glucocorticoids, ACTH inhibits its own secretion (short loop feed- Thyrotropin, also known as thyroid-stimulating hor- back). mone (TSH), is a glycoprotein synthesized in the an- terior pituitary.The secretion of TSH is stimulated by 5.1.1.5 Prolactin thyrotropin (or TSH)-releasing hormone (TRH) and inhibited by somatostatin and dopamine, secreted Prolactin (PRL) is a 198-amino acid polypeptide hor- from the hypothalamus. In persons older than 12 mone synthesized and secreted from the lactotrophs months of age,the TSH concentration is low in the af- of the anterior pituitary.A precursor molecule is also ternoon, rises dramatically (surges) after 1900 hours, secreted and can constitute as much as 10 %–20% of and reaches its highest concentrations between 2200 the PRL immunoreactivity in the plasma of healthy and 0400 hours (Fig. 5.2a) [51]. Thus, at least one persons.Hypothalamic control of PRL secretion (pri- third of the trophic influence of TSH on the thyroid marily through dopamine release) is different from gland occurs at night. TRH is necessary for TSH that of the other pituitary hormones in that the synthesis,post-translational glycosylation,and secre- hypothalamus inhibits, rather than stimulates, secre- tion of a fully bioactive TSH molecule from the pitu- tion of PRL. Thus, elevated PRL levels can be a use- itary [48]. Altered TSH glycosylation, resulting in ful marker of hypothalamic disorders that leave the altered bioactivity, is seen in mixed hypothyroidism pituitary intact. (central hypothyroidism with mild TSH elevation [5–15 mU/l]) [23, 49]. 5.1.2 Injury of the Hypothalamic–Pituitary Axis TSH stimulates the thyroid gland to produce in Patients with Cancer thyroxine (T4) and triiodothyronine (T3). T4 and T3 circulate in the blood stream bound to thyroxine- The hypothalamic–pituitary axis (HPA) is vulnerable binding globulin and albumin; only small amounts to damage by certain tumors, surgical trauma, irradi- are free or unbound. Free T4 undergoes intracellular ation, and chemotherapy [11, 60]. A summary of deiodination to form free T3,which interacts with the common risk factors for HPA disorders that develop DNA in a cell’s nucleus to influence cellular mRNA after cancer treatment is presented in Table 5.2. Pa- and protein synthesis. Free T4 also provides negative tients with tumors in the area of the HPA (e.g. cran- feedback to the hypothalamus and pituitary to mod- iopharyngioma or hypothalamic/chiasmatic tumor) ulate the secretion of TRH and TSH. are at particular risk for neuroendocrinopathy [15, 33]. Many HPA injuries are attributable to damage 5.1.1.4 Adrenocorticotropin caused by radiation therapy (see section 5.1.1.3). However, the incidence of pre-RT neuroendocrino- Adrenocorticotropin (ACTH) is a 39-amino acid pep- pathies in pediatric patients with brain tumors is tide hormone processed in the corticotrophs from a high. For example, out of 68 pediatric patients in one large precursor molecule, pro-opiomelanocortin. In study [32], 45 (66%) showed evidence of neuro- healthy individuals, hypothalamic corticotrophin-re- endocrinopathy before RT,including 15 of 32 patients leasing hormone and vasopressin are released in with tumors in the posterior fossa not adjacent to the two or three synchronous pulses per hour synergisti- HPA.