Definition

The diagnosis of ectopic hormone production depends on a number of criteria, although it is seldom practicable or possible to confirm them all:

1. 1 There is an association of the tumour with an endocrine syndrome.

2. 2 Even though the endocrine syndrome may not be clinically florid, there is an elevated or inappropriately raised plasma level of the putative hormone.

3. 3 Removal or suppression of the tumour induces a regression of the endocrinopathy and a fall in the hormone level.

4. 4 The clinical picture and hormone levels are uninfluenced by removal of the gland that normally secretes the hormone.

5. 5 The hormone level is higher in venous blood draining the tumour than in the arterial blood supplying it.

6. 6 Extraction or immunohistochemical staining shows a higher concentration of the hormone in the tumour than in adjacent, noninvolved tissue.

7. 7 Demonstration can be made of tumour cell synthesis of identifiable hormones in vitro or of mRNA coding for the hormone.

Chemical structure

Most syndromes of ectopic hormone secretion are due to peptide hormones. It is rare for tumours to secrete steroid hormones because of the complexity of the enzyme cascade required for steroid biosynthesis. Tumours may, however, be associated with altered steroid metabolism—e.g. increased aromatase activity in hepatocellular carcinoma leads to feminization and gynaecomastia due to androgen conversion to oestrogens.

The precise amino acid sequences of hormones of ectopic origin are being increasingly defined. In general, they appear to resemble closely those of their normally occurring counterparts (except PTH and PTHrP). There is a tendency for a greater proportion of higher molecular weight precursors, prohormones, subunits, and fragments to be associated with an ectopic origin than with true endocrinopathies, but it is not always clear whether this is due to differences in biosynthesis or in intracellular or extracellular processing. Minor differences in molecular structure are sometimes reflected in disparities between bioassay and immunoassay.

Prevalence

Clinically evident syndromes are less common than biochemical or hormonal abnormalities. The prevalence of ectopic production of ACTH, corticotrophin-releasing hormone (CRH), PTHrP, calcitonin, human chorionic gonadotrophin (hCG), prolactin, or growth hormone (GH), without clinical manifestations, is high when extensive biochemical and hormonal assays are applied to patients with cancer. These assays bring closer the prospect of finding a diagnostic marker for tumours in general and, in particular, as is already the case with the monitoring of hCG or its subunits, to determine the response of tumours to treatment.

Hypercalcaemia in the absence of detectable bony metastases is the most common abnormality. It occurs in about 15% of patients with squamous cell carcinoma (usually of the bronchus), carcinoma of the kidney, ovary, or breast. Next most common in neoplastic diseases is the syndrome of inappropriate antidiuresis, usually associated with a small cell lung cancer and reported in 40% of such cases. Cushing’s syndrome due to ectopic ACTH or CRH secretion occurs in about 5% of patients with small cell lung cancer, and in association with other neoplasms. Biochemical accompaniments of Cushing’s syndrome in the absence of the clinical features are much more common, occurring in 50% of patients with small cell lung cancer.

Pathogenesis

As techniques for molecular analyses have evolved, it has become clear that every somatic cell is capable of synthesizing every polypeptide hormone. However, only under pathological circumstances is that capability ever likely to be expressed. A variety of hypotheses for ectopic hormone synthesis and secretion have been made. None explains all of the observed facts. Fundamentally, all cells inherit an identical complement of DNA. They are therefore totipotential and have all the coded information required for the synthesis of all proteins and peptides, including protein hormones. The normal inability of nonendocrine tissue to synthesize hormones is ascribed to repressors that mask specific segments of the DNA molecule. It seems possible that when a cell becomes malignant this normal repression becomes ineffective, allowing the unmasked DNA to synthesize proteins or peptides foreign to the cell concerned. Such a de-repression hypothesis does not explain why certain tumours are more prone to secrete certain ectopic hormones. Neuroendocrine cells, characterized by the presence of peptide hormone granules, are likely to be the origin of some tumours associated with hormone secretion, such as small cell lung cancer and bronchial carcinoids. Another hypothesis suggests that there are a small number of special proliferative cells in normal mature tissues that have fetal characteristics with the ability to produce peptide hormones—a process of dysdifferentiation rather than de-repression. There is currently no unifying mechanism with supportive experimental evidence to explain ectopic hormone production. Further information on the control of gene expression and hormone production, the role of oncogenes, and paracrine growth factors may provide further insight.

Treatment

Treatment of the clinical or biochemical abnormalities associated with endocrinopathies of nonendocrine origin is best directed at the primary disorder. In neoplastic disease, this may involve surgical excision, radiotherapy, or chemotherapy. Sometimes, the tumour secreting the ectopic hormone is extremely difficult to locate even with the use of sophisticated imaging techniques such as MRI, radiolabelled isotope scanning (e.g. indium-111 penetreotide imaging), or using selective venous catheterization.

More specific therapy may be necessary to contain the metabolic abnormality until such time as the fundamental disorder can be controlled. For example, immediate measures may be required to reduce hypercalcaemia with fluids and bisphosphonates, or steps taken (administration of metyrapone) to diminish corticosteroid secretion from adrenal glands stimulated by ectopic ACTH secretion.

Ectopic secretion of calciotropic hormones

Malignancy is the most common cause of hypercalcaemia in hospital inpatients and may be due to direct tumour spread to the bones or related to secreted calcium-releasing factors. Often several different mechanisms are involved in the same patient.

After its discovery in 1987, it was shown that PTHrP is responsible for hypercalcaemia in up to 70% of patients with this tumour-associated phenomenon. Most of these patients also have bone metastases. PTHrP shares amino acid homology with PTH between positions 2 and 13 of the 84 residues of PTH and acts via the PTH receptor, resulting in an elevation of extracellular calcium concentration. The PTHRP gene is located on the short arm of chromosome 12; that of PTH is on chromosome 11. The PTHRP gene may be activated by transactivation, hypomethylation (renal carcinomas), or the effect of growth factors and cytokines, including IGF-1 and epidermal growth factor, while glucocorticoids and vitamin D₃ suppress PTHrP levels. Unlike PTH-mediated hypercalcaemia, dihydroxycholecalciferol is suppressed in PTHrP-mediated hypercalcaemia. PTHrP is made by squamous carcinomas as well as renal, bladder, ovary, skin, pancreas, and breast carcinomas, and lymphomas.

Other factors can be involved in hypercalcaemia unassociated with osseous metastases. It is not uncommon for 1,25-dihydroxyvitamin D₃ to be made by lymphoproliferative tumours, which are either high grade or widely disseminated. Transforming growth factor-α (TGFα) which stimulates osteoclastic bone resorption, is also made by squamous carcinoma, and renal and breast carcinomas. Some tumours cosecrete both TGFα and PTHrP. Interleukin-1 (IL-1), which is a very powerful stimulator of osteoclastic bone resorption, is also made by squamous carcinomas as well as some haematological malignancies. Tumour necrosis factor (TNF) and lymphotoxin also stimulate osteoclastic bone resorption. These related cytokines cause hypercalcaemia in vivo; lymphotoxin is produced by cultured myeloma cells in vitro and accounts for the hypercalcaemia seen in this condition. Prostaglandins of the E series may also cause hypercalcaemia. Finally, vascular endothelial growth factor (VEGF) and IL-8 and IL-11 may be implicated in the development of hypercalcaemia of malignancy.

It is important to remember that primary hyperparathyroidism itself is common, particularly in older people; two diseases may coexist. For this reason, primary hyperparathyroidism should always be considered when hypercalcaemia occurs, even if it is in a patient within the setting of malignant disease. It is now possible to differentiate between these two conditions by using the PTH two-site radioimmunoassay.

Paraneoplastic hypercalcaemia may be either asymptomatic or dominate the clinical picture and be life-threatening as a consequence of dehydration and renal failure. The features of hypercalcaemia and its general management are discussed elsewhere (see Chapter 13.6).

Oncogenic osteomalacia, an acquired phenotype, is a rare syndrome characterized clinically by reduced mineralization of newly formed bone and the features of osteomalacia (including fractures, bone pain, and muscle weakness). It is usually associated with benign mesenchymal or mixed connective tissue tumours (particularly haemangiopericytomas) that have a propensity to arise in the head and neck. The use of imaging (including octreotide scintigraphy) is important in the localization of such tumours. Biochemical features of oncogenic osteomalacia include an excessive renal loss of phosphate that results in phosphaturia and hypophosphataemia. The serum calcium level is usually normal and serum alkaline phosphatase is usually elevated. Circulating levels of 1,25-dihydroxyvitamin D₃ are usually suppressed (despite ambient hypophosphataemia). Circulating levels of fibroblast growth factor 23 (FGF-23), a secretory product of tumours associated with oncogenic osteomalacia, are usually elevated. It is possible that FGF-23 plays an important role in renal phosphate wasting or impairs regulation of vitamin D metabolism, although there may be other unknown phosphaturic factors which also inhibit the 1α-hydroxylase enzyme. Removal of the causative tumour is the treatment of choice.

Syndrome of inappropriate antidiuresis (SIAD)

Syndrome of inappropriate antidiuresis is a disorder of sodium and water balance characterized by impaired water excretion, with resultant hyponatraemia, reduced plasma osmolality, and inappropriately high urine osmolality. A diagnosis of this syndrome requires the absence of hypovolaemia, hypotension, deficiency of cardiac, renal, thyroid or adrenal function, or any known stimulus for the secretion of AVP, an antidiuretic hormone. The syndrome is usually, but not invariably, associated with high levels of circulating AVP, although other, as yet unidentified antidiuretic substances are sometimes involved.

Inappropriate secretion of AVP can either be from an ectopic or eutopic (posterior pituitary) source. The most common ectopic source of AVP associated with a syndrome of inappropriate antidiuresis is bronchogenic carcinoma. Inappropriate eutopic secretion of AVP can be induced by a wide variety of diseases and drugs. Thus, although a syndrome of inappropriate antidiuresis in association with malignancy may be due to inappropriate ectopic secretion of AVP from the tumour itself, it may also result from inappropriate eutopic AVP secretion. The latter may be caused by treatment of the tumour (e.g. chemotherapy such as cyclophosphamide), an intercurrent illness such as pneumonia, a complication such as hydrocephalus or cerebrovascular accident, or even by the tumour itself (see Table 13.12.1). The treatment of this syndrome is often restriction of fluid intake (e.g. 500 ml/24 h). Occasionally, it may also be necessary to administer hypertonic saline. Use of aquaretic agents such as tolvaptan, which increase excretion of free water through antagonism of the V₂ receptor, thereby blocking the action of AVP within the distal nephron, is an important development in the management of SIAD and a useful addition to our treatment options for this condition.

Ectopic ACTH secretion

Pro-opiomelanocortin (POMC) is a 31-kDa precursor for both ACTH and β-lipotrophin as well as for other polypeptides derived from it, including γ-lipotrophin and β-endorphin. A variety of nonpituitary tumours are capable of secreting POMC-derived peptides, accounting for about 20% of patients with Cushing’s syndrome. Approximately 50% of ectopic ACTH-producing tumours are in the lung and the rest are present in a variety of other tissues (Table 13.12.2). Some tumours, particularly pancreatic islet cell tumours which are seldom (< 5%) associated with Cushing’s syndrome, can, in addition to ACTH, also secrete a number of other hormones, including insulin, gastrin, and glucagon (see Chapter 13.10). This accounts for the usefulness, when screening for ectopic ACTH, of measuring other hormones (e.g. calcitonin, hCG) which may be cosecreted, the presence of which raises the suspicion of an ectopic hormone-secreting tumour. Very rarely, CRH is secreted ectopically in association with ACTH.

Neuroendocrine tumours are the most common source of ectopically-derived ACTH. These include bronchial carcinoid tumours most frequently, but also include carcinoids at other sites including the foregut, pancreas, and thymus. Other endocrine and nonendocrine tumours that can secrete ectopic ACTH include small cell lung carcinoma, phaeochromocytoma, medullary carcinoma of the thyroid, mesothelioma, and small cell colorectal carcinoma (see Table 13.12.2).

The exact mechanism of synthesis of ectopic POMC-derived peptides is still debated. POMC mRNA can be found in the majority of tumours, but ACTH secretion is much less common, probably due to the lack of the signal sequence required for translocation. Changes in promoter usage and also in POMC processing may lead to ectopic secretion of ACTH. In addition, many tumours associated with ectopic ACTH secretion are of neuroendocrine morphology and may arise from progenitor cells associated with ACTH secretion. Differential gene expression profiles have been demonstrated in surgical tissue specimens taken from carcinoid tumours causing ectopic ACTH syndrome and pituitary tumours causing Cushing’s disease. These include more abundant mRNA expression in ectopic ACTH syndrome compared with Cushing’s disease from genes such as Ikaros family zinc finger protein 1 (IKZF1, a DNA-binding protein), proprotein convertase 2 (PC2) and somatostatin receptors 2 and 5 (SSTR-2 and -5). Enhanced SSTR-2 and -5 expression in tumours associated with ectopic ACTH syndrome has therapeutic implications for use of more selective somatostatin agonists in these patients.

Ectopic secretion of insulin-like growth factors

The insulin-like growth factors, IGF-1 and IGF-2, share some sequence homology and actions of insulin. IGF-2 is important in fetal growth, whereas IGF-1, synthesized in the liver, mediates most of the actions of GH. IGFs circulate bound to one of six binding proteins (IGFBPs). Of these, the most important is IGFBP3, which itself is GH-dependent and binds 75% of IGF-1 and IGF-2.

IGF-2 secretion from tumours may be associated with hypoglycaemia. Usually the tumour is large and of mesenchymal origin, arising in the abdomen or thorax. Symptoms are those of neuroglycopenia—sweating, tachycardia, disorientation, drowsiness, fits, and coma. Histology shows a mesothelioma, a fibrosarcoma, or other sarcoma such as a leiomyosarcoma. Other neoplasms associated with hypoglycaemia are haemangiopericytoma, hepatoma, adrenal carcinoma, lung carcinoma, Wilms’ tumour, and colonic carcinoma.

IGF-2 secretion leads to suppression of GH and insulin, and reduced production of IGFBP3, IGF-1, and acid-labile subunit (ALS), leading to reduced formation of the IGF–IGFBP3–ALS complex which protects the IGFs from degradation. IGF-2 circulates as a smaller complex which has enhanced tissue and receptor bioavailability, allowing access to the insulin receptor. There is also an increase in the large molecular weight molecules and the increased amounts of big IGF-2 not detected on radioimmunoassay. GH deficiency, decreased gluconeogenesis, and increased glucose metabolism by the tumour, which is usually large, may also contribute to hypoglycaemia. Treatment of these tumours is difficult. The hypoglycaemia is often not responsive to diazoxide, glucagon, octreotide, or corticosteroids. However, administration of GH may be effective—increasing IGFBP3 and IGF-1 and antagonizing the effect of excess IGF-2. The underlying tumour may be resistant to radiotherapy; surgery, although effective if possible, is not always feasible.

IGF-1 and IGF-2 may also play an important role in tumour progression. Studies of breast cancer cells have suggested that IGF-1 may have local mitogenic effects, and a role for IGF-2 has recently been proposed in hepatocellular, colorectal, and adrenocortical tumours.

Ectopic hCG secretion

hCG is a glycoprotein consisting of an α and a β subunit. The α subunit is species specific and is the same for all glycoprotein hormones—luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH). The β-subunit determines receptor interaction and specific hormone activity. The β subunit of hCG is very similar to that of LH and this can cause problems with cross-reaction in assays: the LH value may be spuriously elevated in the presence of increased hCG levels. Clinically silent, ectopic secretion of hCG, with or without its free α and β subunits, occurs in many patients (Table 13.12.4).

Patients with ectopic secretion of gonadotrophins usually present with abnormalities in the reproductive system. In the first decade of life, ectopic hCG production may cause isosexual precocious puberty in boys with hepatoblastoma or a germ cell tumour. hCG, through its LH-like action, causes Leydig cell stimulation in the testes. In turn, testosterone levels reach those of a normal adult, and secondary sexual characteristics develop together with premature skeletal maturity. The testes remain small because there is no seminiferous tubule growth as this is dependent on FSH. Precocious puberty is rare in girls.

Intracranial teratoma, choriocarcinoma, and pinealoma are associated with ectopic hCG secretion. In some patients, cosecretion of ectopic hCG with oestrogen may be associated with gynaecomastia in men, and with dysfunctional uterine bleeding in women. Hirsutism and amenorrhoea are also presenting features of women with ectopic hCG secretion. Other tumours associated with ectopic hCG secretion include dysgerminomas, testicular tumours, ovarian adenocarcinoma, and stomach, pancreatic, bronchogenic, hepatic, and renal cell carcinomas. Rarely, ectopic LH secretion has been described in adrenal tumours and pancreatic neuroendocrine tumours.

hCG is a useful tumour marker in gestational trophoblastic disease (choriocarcinoma) and in some men with testicular tumours, and provides an early warning of recurrent disease. However, it is important to measure other tumour markers, e.g. α-fetoprotein, which may also be secreted by nonseminomatous germ cell tumours. Discordance of marker levels and tumour progress may be seen. In central nervous system disease, cerebrospinal fluid/plasma ratios may help in the correct localization of tumours, as hCG does not cross the blood–brain barrier and levels in cerebrospinal fluid remain undetectable in pregnancy. Thus, cerebrospinal fluid concentrations higher than plasma suggest primary central nervous system disease.

In some patients, most commonly with choriocarcinoma and massive elevation of hCG, the latter, through its weak TSH activity, due to its biochemical similarity to TSH, may cause goitre and hyperthyroidism. This most frequently occurs in women, is not associated with eye signs, and is usually associated with modest biochemical abnormalities. Treatment of the tumour results in a resumption of a euthyroid state but, if this is not possible, carbimazole or propylthiouracil may be required.

Ectopic human placental lactogen

Human placental lactogen (hPL), also called human chorionic somatomammotropin (hCS), is a trophoblastic hormone which may be secreted ectopically in association with lung tumours, testicular tumours, and trophoblastic disease. It is usually associated with gynaecomastia in men, and these tumours may also be associated with increased levels of oestradiol and hCG.

Ectopic GHRH and GH secretion

Most patients with acromegaly (98%) have benign GH-producing pituitary adenomas. Less than 2% of patients with acromegaly have ectopic growth hormone-releasing hormone (GHRH) production which causes hyperstimulation of the somatotroph cells within the anterior pituitary, and consequently increased GH secretion. Indeed, the presence of anterior pituitary somatotroph hyperplasia differentiates histologically the minority of acromegalic patients with ectopic GHRH syndrome from those with GH-producing pituitary adenomas. A patient with a carcinoid tumour of the pancreas producing GHRH enabled the final elucidation of the structure of this important hypothalamic peptide. Ectopic GHRH syndrome is caused most frequently by carcinoid tumours, especially of the lung and gastrointestinal tract. Although many carcinoid tumours express immunoreactive GHRH, the development of acromegaly is uncommon (although many of these patients may display abnormal GH secretory dynamics). Other tumours reported to secrete GHRH ectopically include small cell lung cancer, adrenal adenomas, endometrial tumours, and phaeochromocytoma. GHRH can also be secreted by hypothalamic hamartomas which also result in anterior pituitary somatotroph hyperplasia. Determination of the cause of acromegaly (pituitary GH excess versus ectopic GHRH syndrome) is extremely important in the management of acromegaly. Ectopically GHRH-secreting tumours are usually clinically apparent and GHRH levels in the circulation are elevated. Surgical resection of such tumours is the logical approach to management. Long-acting somatostatin analogues can also be used in those patients with ectopic GHRH syndrome caused by disseminated or recurrent carcinoid tumours.

Ectopic GH secretion has been reported in patients with bronchial, pancreatic, and gastrointestinal carcinoma, and cells cultured from an undifferentiated lung cancer have been shown to synthesize GH in vitro. Breast carcinoma and ovarian tumours may also occasionally secrete GH but no clinical syndrome has been clearly identified as caused by ectopic GH.

Ectopic prolactin secretion

Prolactin may be secreted by bronchial carcinoma and renal cell carcinoma; the usual endocrine manifestation is galactorrhoea and there may be marked hyperprolactinaemia. These abnormalities are reversed if the tumour is controlled or removed. Difficulties in differential diagnosis may arise unless the underlying abnormality is clinically obvious or suspected, because in most instances the hyperprolactinaemia will be attributed to a prolactin-secreting adenoma. Suspicion of an ectopic source may only arise when the prolactin level is not lowered by treatment with dopamine agonists. An autocrine role for prolactin in breast and prostate cancer has recently been postulated.

Ectopic calcitonin secretion

Increased serum calcitonin levels are encountered in a variety of cancers apart from medullary carcinoma of the thyroid. The most common of these are small cell lung cancer, leukaemia, and neoplasms of the breast and pancreas. It is often produced as part of a multihormonal profile in conjunction with gastrin, ACTH, and somatostatin among others. Ectopic calcitonin may differ from the normal hormone in having more components of high molecular weight; it does not cause any apparent symptoms and does not produce hypocalcaemia.

Ectopic renin secretion

Although hypertension associated with hyper-reninism and increased aldosterone production is usually due to a renal lesion, ectopic secretion of renin has also been described in association with cancer of the lung, pancreas, ovary, and, rarely, testicle. The clinical picture is usually dominated by the underlying neoplasm but the patient has hypertension and the cause of this may be suspected from the associated hypokalaemia and its accompanying muscle weakness. Effective treatment of the primary lesion will reduce the increased renin and aldosterone levels and hence the raised blood pressure. When the underlying cause cannot be eradicated, the use of an angiotensin-converting enzyme (ACE) inhibitor will control the hypertension.

Ectopic aldosterone secretion

Hypertension and hypokalaemia related to ectopic secretion of aldosterone from a nonadrenal neoplasm have been described in patients with ovarian tumours. Its pathogenesis is different from the others described in this section. The aberrant production of a steroid, aldosterone, rather than a peptide, is presumably due to biochemical change in the ovarian steroidogenic cells. Attention is likely to be focused on a suspected lesion of the adrenal zona glomerulosa because the hyperaldosteronism is associated with low plasma renin activity. The ovarian lesion may initially be clinically silent and only revealed by pelvic imaging.

Disorders influencing hypothalamopituitary function

Anorexia nervosa is associated with complex changes in hypothalamopituitary function, with reduction in GnRH and gonadotrophin secretion leading to hypogonadotrophic hypogonadism, but increased GH secretion is associated with increased peripheral resistance to GH.

Iron overload due to haematological conditions such as β-thalassaemia major and to haemochromatosis may cause iron deposition in the anterior pituitary gland, and in particular in the gonadotrophs. This leads to hypogonadotrophic hypogonadism, which may be ameliorated to a degree by venesection and iron chelation therapy. Haemochromatosis may also lead to other hormonal changes due to pancreatic involvement causing diabetes mellitus, and cirrhosis associated with secondary hyperaldosteronism and hypogonadism.

Thyroid

Morning sickness in the first trimester of pregnancy may be associated with clinical and biochemical features of thyrotoxicosis, as the molecules hCG and TSH share very similar β subunits, allowing cross-reactivity when high levels of hCG occur.

Opportunistic infections of the thyroid gland may occur, in conditions associated with immunosuppression such as AIDS. Infections with cytomegalovirus, cryptococcus, and pneumocystis have been described. In addition, some patients with HIV infection have increased T₄ and T₃ due to increased thyroid binding globulin. As the disease progresses, T₄ and T₃ levels fall as patients develop biochemical features of sick euthyroidism.

Adrenal

Opportunistic infections (cytomegalovirus, atypical mycobacteria, cryptococci, toxoplasma, and pneumocystis), lymphoma, and Kaposi’s sarcoma may involve the adrenal glands in HIV and AIDS. The adrenal gland is the most commonly involved endocrine gland at autopsy. However, frank adrenal insufficiency is rare because this requires destruction of over 90% of the adrenal cortex.

Gonads

Chemotherapy and irradiation may be associated with gonadal failure due to hypothalamopituitary gonadotrophin deficiency, e.g. following cranial irradiation or due to testicular/ovarian damage following cytotoxic drug therapy such as cyclophosphamide, cisplatin, and busulfan.

Coeliac disease is associated with reversible male infertility due to androgen resistance, and improves on a gluten free diet. Alteration of gonadal steroid metabolism may occur in chronic liver disease, particularly if alcohol related. Elevated sex hormone binding globulin and oestradiol levels are associated with a reduction in bioavailable testosterone leading to testicular atrophy, gynaecomastia, and erectile impotence.

Gynaecomastia

Palpable breast glandular tissue is prevalent in population studies of men and boys. Subareolar glandular tissue of more than 2 cm in diameter is found in 35 to 60% of men. Gynaecomastia may occur as a result of different conditions (Table 13.12.6) as well as drug therapy, and results from an alteration in the ratio of oestrogen to androgen. Gynaecomastia has been found in association with testicular and adrenal neoplasms, Klinefelter’s syndrome, thyrotoxicosis, cirrhosis, primary hypogonadism, malnutrition, and ageing (see Table 13.12.6). An increase in free oestrogen, a decrease in free endogenous androgens, androgen receptor defects, and partially enhanced secretions of breast tissue may underlie these changes. Increased aromatization of oestrogen precursors occurs in patients with obesity, liver disease, and hyperthyroidism, and as a result of ageing.

Calcium

Hypercalcaemia in sarcoidosis is due to increased circulating 1,25-dihydroxyvitamin D₃. This is produced by alveolar macrophages in a dose-dependent fashion stimulated by γ-interferon, which is one factor responsible for the maintenance of the inflammatory process in sarcoidosis. Other granulomatous disorders (tuberculosis, histoplasmosis, coccidiomycosis, ruptured silicone breast implants) may rarely be associated with hypercalcaemia due to the same mechanism. Treatment with glucocorticoids or hydroxychloroquine are effective in lowering 1,25-dihydroxycholecalciferol and calcium.

HTLV1 infection may be associated with hypercalcaemia, due to transactivation of the PTHRP gene on chromosome 12.

Endocrine manifestations of obesity

Our understanding of adipose tissue has been transformed from a role of fat storage to one that incorporates a complex interplay of hormones with both endocrine and paracrine effects, and plays important roles in the regulation of appetite, energy expenditure, and body fat mass. A detailed description of the complexities of the endocrine manifestations of obesity is beyond the scope of this chapter (see Chapter 11.5), but the major endocrine manifestations are outlined. Leptin is an adipokine, levels of which increase with weight gain. Leptin has effects within the hypothalamus to suppress food intake and promote energy expenditure pathways. Leptin may also have direct effects on ovarian function in women, which may play a role in the link between menstrual cyclicity and fertility with optimum weight. Other adipokines such as visfatin and resistin play important roles in reducing insulin sensitivity and promoting a proinflammatory state in obesity. Levels of adiponectin (which has anti-inflammatory and immunoregulatory effects and improves insulin sensitivity) are reduced in obesity. Increased aromatase expression within the adipocyte in obesity may explain in part the association of male obesity with feminizing effects and, through suppression of the hypothalamo-pituitary regulation of the gonadal axis through oestradiol, the association of male obesity with hypogonadotropic hypogonadism. Finally, there has been much interest in the effects of obesity on steroid hormone regulation within the adipocyte, including the effects on the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that interconverts inactive cortisone and active cortisol. Inhibition of 11β-HSD1 remains an exciting therapeutic strategy for patients with obesity, to improve the associated dysmetabolic sequelae.

Thyroid

Adrenal cortex