Answers

Short answers

1 Sheehan’s syndrome: hypopituitarism resulting from infarction of the enlarged pituitary gland after hypotension caused by blood loss in the peripartum period.

2 Baseline pituitary function testing showed hypopituitarism (9 am cortisol <30 nmol/l, adrenocorticotrophic hormone <5 ng/l, thyroid stimulating hormone 0.88 mU/l, free T4 9.1 pmol/l, luteinising hormone <0.5, follicle stimulating hormone 1.0, oestradiol <70 pmol/l, prolactin 375 mU/l), and magnetic resonance imaging of the pituitary gland showed a central pituitary infarction.

3 Hypocortisolism manifested as hyponatraemia.

Long answers
1 Diagnosis
Sheehan’s syndrome was first described by H L Sheehan in 1937.¹ It is the syndrome of panhypopituitarism that is caused by ischaemic damage to the pituitary gland or hypothalamic-pituitary stalk in association with vascular collapse during the peripartum period.² The pituitary gland is particularly susceptible to vascular compromise during pregnancy because high levels of placental oestrogens stimulate the gland to enlarge through lactotroph hyperplasia and proliferation. The mechanism for pituitary ischaemia is unclear, but hypotension and vasospasm of the hypophysial arteries is thought to compromise arterial supply to the gland. The pituitary gland has a portal blood supply (with capillaries at both ends) to collect the hypothalamic factors needed to release pituitary hormones. The blood supply to the pituitary gland is unable to increase proportionally with gland hyperplasia. Pituitary ischaemia may be seen rarely without major haemorrhage, or even after a normal delivery.²

Sheehan’s syndrome is one of the most common causes of hypopituitarism in developing countries.³ It is less common in women who deliver in countries with more modern obstetric care,⁴ in whom lymphocytic hypophysitis is more likely to occur. As in hypopituitarism resulting from other causes, hormonal deficiency varies from a single hormonal deficiency to panhypopituitarism. Clinical features arise secondary to sodium and water disturbances, hypocortisolism, hypothyroidism, hypogonadism, hypoprolactinaemia, and growth hormone deficiency.⁵ Patients may present immediately post partum in severe cases, but in milder cases may not be recognised for several decades.^{5 6} Severe hyponatraemia is a common presenting complaint⁶ and clinical suspicion should be aroused by a history of failed lactation (agalactia) or a failure to resume normal menstrual periods after parturition.^{5 7}

2 Tests
Pituitary function testing—The patient became severely hyponatraemic (serum sodium less than 125 mmol/l) immediately postpartum. She had a low serum osmolality with inappropriately concentrated urine and high urine sodium. It is always important to exclude glucocorticoid deficiency before making a diagnosis of "syndrome of inappropriate antidiuretic hormone secretion." Hypopituitarism should be tested for with baseline hormonal tests of pituitary function, but patients with less severe disease may require dynamic pituitary function testing—for example, an insulin tolerance test. Hypopituitarism in a hyponatraemic patient should be suspected if the early morning cortisol level is less than 440 nmol/l.⁸ A proportion of patients with levels below this range may have normal dynamic testing after recovery from hyponatraemia. Glucocorticoid treatment in these patients will rarely be harmful, whereas failing to treat a patient who has hypopituitarism can be fatal. This woman had low 9 am cortisol, and hypogonadotrophic hypogonadism with a relative hypoprolactinaemia for the immediate postpartum period (table).

View larger version (156K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1 T2 Weighted magnetic resonance image of the pituitary gland showing (A) a central pituitary infarction (arrow) and (B) an atrophic anterior pituitary gland.

3 Hypocortisolism manifested as hyponatraemia
Severe hyponatraemia caused by hypopituitarism can be life threatening, but it is an often overlooked cause of low serum sodium.⁸ Hypocortisolaemia must be considered early because prompt treatment with steroids is extremely effective and potentially life saving. The hyponatraemia is the result of an inability to excrete a water load appropriately in the absence of glucocorticoid. This could be caused by a failure to suppress vasopressin (an antidiuretic hormone) secretion from the posterior pituitary gland despite low osmolality,^{8 9} and an increased expression of aquaporin-2 water channels in the renal collecting ducts.¹⁰ Both these mechanisms promote water reabsorption. An increase in water reabsorption and subsequent volume expansion may lead to suppression of renin and aldosterone and secretion of atrial natriuretic peptide, which further exacerbates hyponatraemia by promoting natriuresis. In hypopituitarism, secondary hypothyroidism may also contribute to hyponatraemia, but glucocorticoid deficiency is probably the most important contributing factor. This is because the hypo-osmolality recovers rapidly when cortisol is replaced before thyroxine treatment has been given.⁸ It is important that hydrocortisone is replaced before thyroxine to avoid worsening hypocortisolism. After hydrocortisone replacement this patient’s serum sodium improved to 122 mmol/l and her urine sodium fell to 38 mmol/l with complete resolution of her neurological deficit within 48 hours. An important clinical difference exists between a failure of free water clearance (euvolaemic) and salt wasting (volume deplete). In Sheehan’s syndrome (in contrast to adrenal failure) mineralocorticoid action is preserved so that salt wasting and volume depletion are less common features. Volume depletion should be managed with intravenous saline and once normovolaemic normalisation of sodium can then be considered with fluid restriction if the cause is syndrome of inappropriate antidiuretic hormone secretion.

References

Cite this as: BMJ 2008;337:a2377