Introduction

Hypopituitarism entails reduced secretion of anterior pituitary hormones.

Which hormones go first?
Anterior pituitary hormones are affected in the following order:

  • GH >> muscle and bone
  • FSH >> ovary
  • LH >> testes
  • Polactin >> breast
  • TSH >> thyroid
  • ACTH >> kidney and adrenal gland

N.B.
Rather than prolactin deficiency, hyperprolactinaemia occurs relatively early because of loss of tonic inhibitory control by dopamine.

Which hormones go when?

  • Deficiency of hypothalamic-releasing hormones or pituitary hormones may be either selective or multiple.
  • Multiple deficiencies usually result from tumour growth or other destructive lesions.
  • Panhypopituitarism is deficiency of all anterior hormones, usually caused by irradiation, surgery, or pituitary tumour.
  • Vasopressin and oxytocin secretion will only be affected if the hypothalamus is involved by either hypothalamic tumour or by extension of a pituitary lesion.

 

Aetiology

The commonest cause of hypopituitarism is a pituitary or hypothalamic tumour, or treatment of a tumour by surgical removal or radiotherapy.

Causes are at 3 levels:
1.     Hypothalamus: Kallman’s syndrome, tumour, inflammation, infection (meningitis, TB), ischaemia.
2.     Pituitary stalk: trauma, surgery, mass lesion (craniopharyngioma), meningioma, carotid artery aneurysm.
3.     Pituitary: tumour, irradiation, inflammation, autoimmunity, infiltration (haemochromatosis, amyloid, metastases), ischaemia (pituitary apoplexy, DIC – snake bite common cause in India, Sheehan’s syndrome – pituitary necrosis after postpartum haemorrhage).

Autoimmune Hypophysitis

  • Inflamed pituitary
  • Mimics pituitary adenoma
  • May be triggered by pregnancy or immunotherapy blocking CTLA-4.
  • No pituitary autoantigen is yet used diagnostically.

Classification of different causes:

Neoplastic Primary tumour of pituitary or hypothalamus
Secondary deposits, especially breast
Lymphoma
Infective Basal meningitis, e.g. tuberculsosis
Encephalitis
Syphilis
Vascular Pituitary apoplexy
Sheehan’s syndrome
Carotid artery aneurysms
Trauma Skull fracture
Surgery
Infiltrations Sarcoidosis
Haemochromatosis
Immunological Pituitary antibodies
Congenital Kalmann’s syndrome
Functional Anorexia
Starvation
Emotional deprivation
Others Radiation damage
Chemotherapy
Empty sella syndrome

 

Some Specific Syndromes

  • Kallmann’s Syndrome: congenital deficiency of gonadotrophin-releasing hormone (GnRH).
  • Sheehan’s Syndrome: pituitary infarction following severe postpartum haemorrhage. Rare in developed countries.
  • Pituitary Apoplexy: rapid enlargement of pituitary tumour due to infarction or haemorrhage. There is severe haemorrhage and sudden severe visual loss, sometimes followed by acute, life-threatening hypopituitarism.
  • Empty Sella Syndrome: Radiologically the sella turcica (the bony structure that surrounds the pituitary) appears devoid of pituitary tissue. In some cases, the pituitary is actually placed eccentrically and function is usually normal. In others, there is pituitary atrophy (after injury, surgery or radiotherapy) and associated hypopituitarism.

Clinical Features

These depend on the extent of hypothalamic-pituitary differences. They result from either hormone deficiency or mass effect from a tumour.

Hormone insufficiencies

GH insufficiency

  • Central obesity
  • Atherosclerosis
  • Dry wrinkly skin
  • Reduced strength
  • Reduced balance
  • Reduced wellbeing
  • Reduced exercise ability
  • Low CO
  • Osteoporosis
  • Hypoglycaemia

Gonadotropin (FSH; LH) insufficiency

Females

  • Few, scant or no menses (oligomenorrhoea or amenorrhoea)
  • Reduced fertility
  • Reduced libido
  • Osteoporosis
  • Breast atrophy
  • Dyspareunia

Men

  • Erectile dysfunction
  • Low libido
  • Low muscle bulk
  • Hypogonadism (low air, all over, small testes, ejaculate volume reduced, low spermatogenesis).

Thyroid Insufficiency

Corticotropin insufficiency

Signs of adrenal insufficiency, e.g.:

  • Lean
  • Tanned
  • Tired
  • Tearful
  • Weakness
  • Anorexia
  • Dizzy
  • Giants
  • Flu-like myalgias/arthralgias
  • Depression/ psychosis/ low self-esteem
  • N&V, abdominal pain, diarrhoea/constipation
  • No skin pigmentation as low ACTH – usually adrenal insufficiency e.g. with steroid withdrawal presents with pigmented palmar creases and buccal mucosa (as high ACTH cross-reacts with melanin receptors)
  • Postural hypotension
  • Vitiligo
  • Shock (low BP, tachycardia)
  • High temperature and possibly coma

Prolactin insufficiency

  • Rare
  • Absent lactation

 

Cause of Hypopituitarism

Pituitary tumour causing mass effect or hormone secretion with reduced secretion of other hormones, e.g. prolactinoma, acromegaly, rarely Cushing’s.

 

Investigations

Each axis of the hypothalamo-pituitary system requires separate investigation. The presence of normal gonadal function (ovulatory menstruation or normal libido/ erections) suggests that multiple defects of the anterior pituitary are unlikely. Tests range from measurement of basal hormone levels to stimulatory tests of the pituitary and tests of feedback for the hypothalamus.

The triple stimulation test is now rarely done.

Basal Tests

  • LH & FSH (low or normal)
  • Testosterone or oestradiol low
  • TSH low or normal
  • T4 low
  • Prolactin may be high from loss of hypothalamic domapine that normally inhibits its release
  • IGF-1 low – used as a measure of GH axis.
  • Cortisol low.
  • U&E: low Na+ from dilution.
  • Low Hb with normochromic normocytic anaemia.

 

Dynamic Tests

  • Short Synacthen test to assess adrenal axis.
  • Insulin Tolerance Test: done in specialist centres to assess the adrenal and GH axes. CI: epilepsy, heart disease, adrenal failure. Consult lab first. It involves IV insulin to induce hypoglucaemia, causing stress to increase cortisol and GI secretion, It is done in the morning (water only taken from 22:00 the night before). Have 50% glucose and hydrocortisone to hand and IV access. Glucose must fall below 2.2mmol/L and the patient should become symptomatic when cortisol and GH are taken. Normal GH >20mu/L, and peak cortisol >550nmol/L.
  • Arginine and growth hormone releasing hormone test.
  • Glucagon stimulation test alternative when ITT is contraindicated.

Investigate cause: MRI scan to look for a hypothalamic or pituitary lesion.

Treatment

Principle of treatment: hormone replacement and treatment of underlying cause.

Steroid and thyroid hormones are essential for life and are given as oral replacement drugs. Androgens and oestrogens are replaced for symptomatic control. If fertility is desired, LH and FSH analogues are used. GH therapy given to growing children, and may be considered in adults to improve work capacity and psychological well-being.

Management

Hydrocortisone for secondary adrenal failure.
Thyroxine if hypothyroid but TSH is useless for monitoring.
Hypogonadism (for symptoms and to prevent osteoporosis):

  • Males: options include testosterone enanthate 250mg IM every 3 weeks, daily topical gels or buccal mucoadhesive tablets. Patches and gels are also used.  Testogel is applied in a thin film. Avoid skin contact with gel sites to prevent testosterone transfer to others, especially pregnant women and children.
  • Women: if premenopausal give oestrogen via transdermal oestradiol patches. Oestradiol implants or contraceptive pill (exceeds replacement needs) +/- testosterone or dehydroepiandrosterone (DHEA, in hypoandrogenic women; a small amount may improve wellbeing and sexual function and help bone mineral density and lean body mass).

Gonadotropin therapy is needed to induce fertility in both men and women.
GH:

  • Somatropin addresses problems of increased fat mass, reduced bone mass, reduced lean body mass (muscle bulk), reduced exercise capacity and problems with heat intolerance.
  • Increased abdominal fat results in reduced insulin sensitivity and dyslipidaemia.
  • Somatropin uses DNA technology to mimic human GH. It can be used in known GH deficiency, e.g. peak GH response of <9mu/L during TT – if there is impaired quality of life and treatment for other pituitary deficiencies is under way.
  • Refer to endocrinologist for insulin tolerance testing.
  • Self injection of 0.15-0.3mg/d; needs lessen with age. Dose titration (1st 3 months of therapy) is done by an endocrinologist.
  • SE: oedema, carpal tunnel syndrome, myalgia, CCF, HTN, high ICT (rare).
  • IGF-1 levels rise with GH replacement. High IGF-1 is linked with increased risk of neoplasia.
  • CI: malignancy, pregnancy, renal transplant.
  • Somatropin can be stopped after 9 months if quality of life scores do not improve by 7 points or more.

 

Warnings for therapy

  • Thyroid replacement should not commence until normal glucocorticoid function has been demonstrated or replacement steroid therapy initiated, as an adrenal crisis may otherwise be precipitated.
  • Glucocorticoid deficiency masks impaired urine concentrating ability. Diabetes insipidus is apparent after steroid replacement, the steroids being necessary for excretion of water load.

Related entries