Endocrine problems are important in the general practice setting, for a range of reasons. First, they are common enough to occur regularly, either as new cases or in patients managing a chronic illness. Secondly, they can cause serious and life-threatening complications if not diagnosed and treated. Thirdly, they often present a challenging diagnostic problem because of their often slow onset and their capacity to produce non-specific symptoms such as weakness, tiredness or weight change, particularly in the early stages.
This chapter explores the endocrinological disorders that are important for a GP to know about and to manage. The common model of managing endocrine problems is as a shared-care model with an endocrinologist.
The pituitary normally sits in the sella turcica at the base of the middle cranial fossa (Fig 29.1). It is covered by a dural layer known as the diaphragma sella. The pituitary is joined to the hypothalamus by the infundibulum or pituitary stalk, in front of which sits the optic chiasm. The sella turcica is bounded laterally by the cavernous sinuses and their contents, and the sphenoid sinus antero-inferiorly. The anterior pituitary is embryologically derived from the posterior pharynx and secretes prolactin follicle-stimulating hormone (FSH), luteinising hormone (LH), growth hormone (GH), thyrotropin-stimulating hormone (TSH) and adrenocorticotrophic hormone (ACTH) in response to trophic-releasing hormones from the hypothalamus via a portal blood flow system. The posterior pituitary secretes oxytocin and vasopressin under neural control from the hypothalamus.
Tumours in the pituitary are common and have been found to occur in around 10% of people in autopsy studies.1 Various series have reported rates of up to 24%. With the high background rate of pituitary masses seen on MRI, clinical questions about how to proceed are likely to occur. Unless the brain is imaged for another reason, it is more prudent to have a clinical diagnosis and confirmatory tests of a pituitary disorder before requesting a CT or MRI of the pituitary.
Adenomas may be functioning or non-functioning. Physiological effects may be excess autonomous secretion of hormones or trophic hormones, loss of normal pituitary function or mass effects that include compression of nearby structures such as the optic chiasm.
Tumours smaller than 10 mm in size are called microadenomas, and those bigger than 10 mm, macroadenomas. Compressive effects of a pituitary tumour normally occur when the adenoma grows to > 10 mm and enlarges beyond the pituitary fossa. Common symptoms of a mass effect are headaches and loss of peripheral vision that correlates with a bitemporal hemianopia as the optic chiasm is compressed.
As an adenoma grows, there may be loss of function of the normal anterior pituitary in a typical order. The mnemonic: ‘Go Looking For That Adenoma’ is a good aide memoire for the order of loss of pituitary function:
Simple developmental cysts account for around 40% of pituitary tumours. Around 20% are adenomas, of which the majority are prolactin-secreting tumours known as prolactinomas. The ACTH-secreting tumours of Cushing’s disease or the GH-secreting tumours of acromegaly and gigantism are much rarer. Non-functioning adenomas are also quite common, and may still impair normal anterior pituitary function.
It is thought that somatic mutations in cell signal pathways are the cause of primary pituitary tumours, with growth of monoclonal cells. The minority of tumours have a germline mutation aetiology, such as in the case of multiple endocrine neoplasia (MEN-1) and Carney complex.
The most important thing is that the diagnosis of a pituitary hormone-stimulated excess or deficiency is made, or at least suspected, and then the pituitary may be imaged. Tumours are sometimes found when a CT head or MRI brain is performed for another reason. In this case, careful history and examination needs to be done, and then testing for any anterior pituitary hormone deficiencies or excesses may be done.
Tumours are defined by their size and secretion of hormones. Tumours do not tend to invoke a mass-related loss of function of other anterior pituitary hormones until they tend toward macroadenomas. The exception to this is a prolactinoma, which will suppress the gonadotrophs in a normal physiological way even when it is a microprolactinoma.
Prolactinomas tend to produce prolactin in a linear relation to their size. Macroadenomas therefore tend to produce levels of prolactin greater than 10 times the upper limit of the reference range. Microadenomas tend to produce levels of prolactin from 1–10 times the upper limit of normal. Other causes of prolactin in this range include medications with a dopamine antagonistic effect, such as antipsychotics and antiemetics. Stress may cause a transient increase in prolactin, as will physical causes such as nipple stimulation and lesions that affect the T4 dermatome, including Varicella zoster. Masses that result in compression or loss of function of the pituitary stalk also limit the inhibitory signals from the hypothalamus and result in microadenoma-level hyperprolactinaemia.
Cushing’s disease and TSH-omas tend to present with microadenomas, while acromegaly tumours are more often macroadenomas than they are microadenomas. Prolactinomas can be either, and tend to present as microadenomas in women, due to the objective problems of loss of regular periods.
Apart from pressing on the optic chiasm, prolactinomas may invade laterally into the bones and cavernous sinuses, as they may produce enzymes that erode the bones of the sella. These large tumours therefore may produce mass effects of headaches and visual field losses as well as the symptoms of hormone excesses and losses as noted above.
A family history can be helpful, especially in younger patients, due to the fact that pituitary tumours run together with the almost ubiquitous primary hyperparathyroidism, and also pancreatic endocrine tumours such as insulinomas. This is an autosomal-dominant condition.
Target the examination to the symptoms and manifestations of hormone excesses or deficiencies as outlined in Table 29.1. Check for galactorrhoea as well as back and skin lesions in patients suspected with hyperprolactinaemia. Galactorrhoea from one breast in the absence of hyperprolactinaemia requires careful examination to ensure that there is no local breast pathology. Always check visual fields to confrontation.
In a pituitary mass, checking paired trophic hormones and their target hormones is essential for proper interpretation. Check ACTH and cortisol at around 8–9 am, together with FSH, LH and testosterone (oestrogen in females), which also has a diurnal variation, with higher levels in the morning, TSH and thyroxine (T4), prolactin (with dilution in macroadenomas), GH and insulin-like growth factor 1 (IGF-1). Non-functioning adenomas tend to produce higher levels of alpha-1 glycoprotein subunit, which may be requested on a sample of serum. Be aware that ACTH in particular degrades quickly, and so informing the laboratory beforehand of an impending test can help ensure it is put on ice and sent to the central laboratory quickly.
If there are any concerns, dynamic tests may be ordered, although these are often ordered by a specialist and/or in a hospital environment. Of the dynamic test, the oral glucose tolerance test (OGTT) to suppress GH to < 1.0 ng/mL is the only one that is reliable and may safely be done as an outpatient. Twenty-four hour urinary free cortisol and 1 mg overnight dexamethasone suppression tests may also be performed as an outpatient, to help with the investigation of cortisol excess. If an excess is confirmed, then a high-dose dexamethasone suppression test will help delineate whether the problem is Cushing’s disease or ectopic ACTH production.
In microadenomas that have been confirmed to be both non-functioning and not affecting normal pituitary function, it may be appropriate to watch at intervals, monitoring for signs of growth or endocrine disturbances.
Prolactinomas are usually medically treated, even if they exhibit mass effects. Dopamine agonists such as cabergoline and bromocriptine can be used to suppress the production of prolactin and to shrink the tumour.
Acromegaly, Cushing’s disease and the rare TSH-omas should be considered for surgical treatment in the first instance by an experienced neurosurgeon, although there have been some advances in medical technology with new drugs such as pasireotide, which have a better blockade of the somatostatin 5 and 3 receptors. These receptors are more commonly expressed in acromegaly, and Cushing’s/non-functioning adenomas respectively.
In surgically and medically refractory conditions, radiotherapy may be used to try to control mass and growth, and function of pituitary tumours. The effect is more gradual and also tends to result in panhypopituitarism at a rate of around 5–8% per year. Often, maximal medical therapy needs to be continued while awaiting the radiotherapy effects.
If control cannot be achieved, blocking the production of the target hormone, or blocking its effects, may be an option. Ketaconazole and metyrapone have been used to block the production of cortisol in surgical and medically refractive Cushing’s disease. This may also be done in acromegaly with pegvisomant, although with the loss of feedback of IGF-1 on the pituitary, there is the potential for growth of the pituitary tumour.
Testosterone and gonadotrophs, and the hypothalamic-pituitary-thyroid axis, are the two axes that may be affected most by patient conditions and stressors. If the tests don’t make sense, seek endocrinological clarification.
GH is normally secreted in a diurnal and metabolic fashion, with pulsatile release that is highest during sleep. Amino acids and ghrelin from the gut are also stimuli to its release via the hypothalamus.
GH stimulates the production of IGF-1 and IGFBP-3 (insulin-like growth factor binding protein-3) on binding to the receptors in the liver. There are some direct effects on the cartilage but, other than that, the majority of the physiological effects of GH are mediated via IGF-1. The liver’s ability to produce IGF-1 in response to GH is blunted in liver disease, hypothyroidism and poorly controlled diabetes mellitus. Interestingly, malnutrition reduces IGF-1 production, and obesity inhibits GH pulses from the pituitary.
There are several somatic mutations that confer autonomous monoclonal cell signal proliferation, or loss of apoptosis that may result in somatotroph growth in the person with other genetic predispositions. The growth is a benign monoclonal expansion that results in the excess secretion of GH, in a non-physiological, non-pulsatile fashion.
If excess GH is produced before the closing of the epiphyses, gigantism occurs and the diagnosis is made relatively quickly with overt clinical signs. In adults the diagnosis may be delayed, due to slow insidious changes in appearance and the overlap with the common primary conditions of diabetes, weight gain, obstructive sleep apnoea and osteoarthritis.
If the clinical diagnosis is suspected on clinical grounds, then testing the visual fields to confrontation and measurement of a static GH and IGF-1 should be done. If the levels are normal but the clinical suspicion is high, then an OGTT suppression test should be performed, to confirm that the GH can suppress to < 1 ng/mL. This is a very sensitive test, with about 85% specificity if > 2 ng/mL after 2 hours.
The patient’s preference may be to not have surgery at the time. Acromegaly has been shown to confer an increased mortality, which may limit lifespan by approximately 10 years. This is mainly due to increased cardiovascular morbidity and mortality, and cancer-related mortality.
The metabolic manifestations such as diabetes, hypertension, diastolic heart failure, arrhythmias and hyperhidrosis are all improved with treatment, but patients should be warned that much of the soft tissue growth will not regress, but neither will it progress further. Obstructive sleep apnoea may improve but is often not cured. The longer the patient waits, the more soft tissue will grow.
Surgical management is the currently accepted primary treatment for the majority of acromegalic adenomas. Macroadenomas have a lower cure rate and higher complication rate than microadenomas, on the whole. Complications include diabetes insipidus or syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH), and hypopituitarism, including panhypopituitarism. Immediate surgical risks include bleeding and CSF leaks.
While surgical management is still thought to be the primary option for acromegaly, there are some data indicating that long-acting octreotide, in the form of octreotide LAR, shrinks acromegalic adenomas without complete regression. This takes several months of treatment and the effects are modest. At this stage there are no outcome data indicating that this improves surgical outcomes when used in this neo-adjuvant way. Microadenomas do have a higher surgical cure rate and lower complication rate than do macroadenomas.
Somatostatin analogues or SRIFs (somatomedin-releasing inhibitory factors) currently on the market are octreotide, octreotide LAR and lanreotide. These three tend to be more active against the SST-2 receptors expressed in lower levels on acromegalic tumours, and less active at blocking the SST-5 receptors, which are more prevalent. Pasireotide has a stronger effect at blocking SST-5 receptors and less effect at SST-2, so as it becomes available, medical therapy may become more successful at controlling acromegaly. Octreotide or lanreotide ± D2 agonist is the current medical treatment. The somatostatin analogues may be given as injections once a month and should be started at the lowest dose, warning the patient of diarrhoea, nausea and cholecystitis as possible complications of therapy. Dopamine agonists (DA) may produce nausea and peripheral vasodilatation, resulting in postural hypotension on the days it is given.
Given that the majority of acromegalic tumours are macroadenomas at the time of diagnosis, complete surgical cure is not a certainty. Confirmation of cure should be carried out with a measurement of GH in the perioperative period together with confirmation of pituitary reserve.
Cure and return to background-for-age mortality risk occurs when an OGTT is able to suppress GH to a level of < 1 ng/mL. Yearly MRI is prudent for a few years, to ensure no recurrence of the tumour, together with biochemical testing as required.
For those with improved but not cured acromegaly, medical management should be aimed at the same GH target. The interval for re-imaging the pituitary with contrast will be patient specific, depending on the size and location of residual tumour and symptomatology, but should be at least yearly as a default. The neurosurgeons or endocrinologists will provide guidance if different from this.
The prognosis depends on whether the GH levels return to normal. If so, the mortality, which is mainly due to cardiovascular disease, returns to the background for non-acromegalic patients. There may be some residual medical morbidity associated with the irreversible issues of joint pains and osteoarthritis, OSA and cosmetic changes.
Congenital problems are many and rare, and such things as PIT-1 gene mutations cause a loss of lactotrophs (prolactin), thyrotrophs (TSH) and somatotrophs (GH). Others, such as Kallmann’s syndrome, result in loss of the gonadotrophs and a normal male phenotype but hypogonadotrophic hypogonadism and a degree of olfactory deficit.
Acquired hypopituitarism may occur due to problems such as trauma affecting the pituitary stalk (infundibulum), apoplexy or infarction in Sheehan’s syndrome. Other issues such as lymphocytic hypophysitis are being increasingly recognised with higher-teslar MRI machines. Infections and inflammatory lesions such as sarcoid and histiocytosis may affect the pituitary, as well as intra- and extrasellar masses.
or those with:
or those who have had pituitary surgery or cranial radiation.
Many of the deficiencies of the hypothalamic-pituitary axis are life threatening. Replacement of glucocorticoids, if these are thought to be deficient, should be done prior to thyroxine replacement and would generally be instigated by an endocrinologist and in hospital. If a patient is in a critical condition, then 200 mg of IV hydrocortisone should be given. Otherwise 100 mg of IV hydrocortisone with 50 mg q6h can be started and blood tests awaited. Maintenance doses of glucocorticoids are not fully elucidated but hydrocortisone equivalent 20–30 mg given in 2–3 divided doses, or cortisone acetate at 25–37.5 mg per day in two divided doses for adults, is a good place to start. The goal is to very slowly and carefully titrate down to the lowest dose that keeps the patient well. Thyroxine may then be replaced if necessary at a dose of 1.6 μg/kg.
Central diabetes insipidus may be treated by dDAVP® (desmopressin) administration via oral tablet or nasal spray. Starting dose should be 50 μg per day for the tablet and 10 μg a day for the nasal spray.
If a mass is blocking normal pituitary function, neurosurgical opinion may be sought as to whether pituitary surgery may help. Normally, 90% of the pituitary mass has to be lost, to render the patient panhyopituitary.
Discussion about a Medicalert bracelet, and teaching the patient and carer how to administer intramuscular glucocorticoids, are critical. Teaching the patient about sick-day management is also very important. A minor illness such as a respiratory virus would require a doubling of the dose for at least 3 days and then decreasing to normal dose. In an illness significant enough to make the patient bed-bound, a tripling of the dose for at least 3 days, or for as long as the condition remains, is advisable. A vomiting illness preventing the patient from taking their glucocorticoids requires administration of IM glucocorticoids and attendance at a hospital.
While the reason is not known, there is an increase in the mortality in panhypopituitary patients after pituitary surgery of about double that of the normal population. This is even after replacement therapy was instituted. Further information and evidence is still being gathered on adult replacement of growth hormone, and the physiological replacement doses of glucocorticoids.
Located generally behind the thyroid gland are the four parathyroid glands, which have the role of producing parathyroid hormone (PTH). PTH is the main controller of calcium levels within the blood and bones, and this of course has important implications for neuromuscular function.
Extracellular calcium is a tightly controlled electrolyte. Significant symptoms, including life-threatening conditions, occur when control is lost and the levels of calcium in the body go outside the tightly controlled range. The largest store of calcium within the body is in the bones, but calcium is stored within skeletal and cardiac muscle, and within the neuronal signalling and neuromuscular junctions.
The most common symptoms of hypercalcaemia are the classic ‘stones, bones, moans and groans’ of kidney stones, bone pains, mood changes including depressive symptoms and abdominal pains including constipation. Polyuria and dehydration can occur secondary to high serum calcium. The most common cause for congenital hypercalcaemia is familial hypocalciuric hypercalcaemia. The most common acquired causes of hypercalcaemia are hyperparathyroidism and malignancy. A useful thought map to think about acquired hypercalcaemia is to think about PTH-dependent and PTH-independent causes of hypercalcaemia (see Fig 29.3).
Extracellular calcium is normally controlled very tightly by two interrelated hormones, namely parathyroid hormone (PTH) and vitamin D. There is a sigmoidal inverse relationship between serum calcium levels and PTH levels, such that a decrease in serum calcium results in increased PTH and vice versa.
Familial hypocalciuric hypercalcaemia is a congenital variation in the sensitivity of the calcium-sensing receptor, with a reduced sensitivity to serum calcium and so a higher set point of serum calcium at which the PTH is turned down. Serum calcium is high, as is PTH, but urine 24-hour calcium excretion is low.
Milk–alkali syndrome is less common now that histamine receptor antagonists and proton pump inhibitors are the mainstay treatment of hyperacidity syndromes of the stomach. The use of antacids together with the ingestion of milk products results in increased absorption and mild hypercalcaemia. While there has been a reduction in the presentation of milk–alkali syndrome from these less-used drugs, there have been a number of case reports of similar presentations in those using large doses of calcium carbonate, which provides both calcium and alkali. High calcium level together with high bicarbonate and perhaps some renal impairment should prompt the GP to ask about calcium carbonate intake.
PTH-dependent hypercalcaemia can be due to primary hyperparathyroidism, less commonly secondary hyperparathyroidism, or tertiary hyperparathyroidism. Secondary hyperparathyroidism often does not result in hypercalcaemia alone, as it is an appropriate response to maintain calcium levels. This occurs in the situation of vitamin D deficiency, where high parathyroid levels maintain serum calcium when vitamin D levels are insufficient to provide enough gut and renal absorption to do so. Primary hyperparathyroidism may be due to a parathyroid adenoma, or adenomas on their own or in the setting of MEN1 syndrome of pituitary tumours, hyperparathyroidism and pancreatic tumours, or MEN2 with medullary thyroid cancer and phaeochromocytoma. Parathyroid adenomas are most commonly sporadic and not part of another syndrome, and are mostly single-gland adenomas. Less commonly, PTH-secreting thymus tumours can produce the parathyroid hormone excess. Tertiary hyperparathyroidism is thought to occur through long-standing secondary hyperparathyroidism, which then causes irreversible parathyroid gland hyperplasia and autonomous function.
PTH-independent causes of hypercalcaemia are usually due to excesses in active vitamin D, or lytic lesions of the bone. The far less common production of PTHrp (PTH-related protein) is usually associated with squamous cell carcinomas, or renal, bladder, breast or ovarian cancers. The conditions that result in excess active vitamin D (1,25-dihydroxy vitamin D) are excess intake of calcitriol, or granulomatous diseases such as sarcoid, tuberculosis and lymphoma, both non-Hodgkins and Hodgkins. In these conditions the macrophages in the granulomata convert the inactive vitamin D to active vitamin D without the need for PTH, which normally carries this out by stimulating the 1-alpha-hydroxylase enzyme in the kidneys.
Other causes such as multiple myeloma and breast cancer are the two more common malignancies that can lead to lytic bone lesions and uncontrolled release of calcium into the extracellular fluid, independently of a suppressed PTH level.
The first thing to do is to try to ameliorate the symptoms and effects of the hypercalcaemia. In many cases there is a degree of dehydration from polyuria. Correction of the volume status will often correct some of the hypercalcaemia.
Thinking of the causes, checking the PTH together with 25 OH vitamin D, calcium and phosphate, electrolytes and liver function tests, and a full blood count, is a good place to start. If the PTH is normal or high with a high calcium, think of familial hypocalciuric hypercalcaemia (FHH) or hyperparathyroidism, whether it be primary or tertiary. Hyperparathyroidism will have a high 24-hour urinary calcium, whereas FHH will not, and so this is the next test.
If PTH is low, the cause is high calcium with an appropriately suppressed PTH. Check active vitamin D (1,25 dihydroxycholecalciferol), PTHrp, selenoprotein P (sEPP), ask for a chest X-ray and, if the sEPP shows a monoclonal protein band, a skeletal survey for lytic lesions. These tests are best done stepwise, to avoid unnecessary tests and costs, although the patient’s condition and preference may dictate otherwise.