Flashcards in Endocrinology - Pituitary and Hypothalamus Deck (67):
Where is the hypothalamus located?
The hypothalamus is part of the diencephalon (together with the thalamus) and forms the floor of the third ventricle.
What structures form the hypothalamus?
From front to back, the hypothalamus includes the optic chiasma, the tuber cinereum, the infundibular stalk (leading down to the posterior part of the pituitary), the mammillary bodies and the posterior perforated substance.
In each of these there is a small number of cell masses or nuclei.
What connects the hypothalamus with the midbrain posteriorly and the basal forebrain areas anteriorly?
The medial forebrain bundle runs through the length of the hypothalamus.
What is the main function of the hypothalamus?
The hypothalamus is responsible for autonomic activity and can be divided into a posteromedial sympathetic area and an anterolateral area for parasympathetic activity.
What is different about hypothalamic control of the posterior and anterior pituitary?
The hypothalamus is linked to the anterior pituitary by the hypothalamic-hypophyseal portal system, which transmits hypothalamic releasing or inhibitory factors to the cells of the anterior pituitary.
The hormones oxytoxin and vasopressin are produced by neurones in the hypothalamus and released at their axon terminals in the posterior pituitary.
What are the effects of hypothalamic lesions?
Lesions of the hypothalamus may result in a variety of autonomic disturbances - e.g. somnolence, disturbances in temperature, obesity as well as many endocrine abnormalities such as hypothyroidism and hypogonadism.
What area of the hypothalamus, if damaged, causes diabetes insipidus?
Diabetes insipidus is an unresponsivness to circulating levels of ADH or a lack of ADH production that is synthesised by the supraoptic and paraventricular nuclei. Thus, damage to the supraoptic area or infundibular stalk leads to diabetes insipidus.
Describe the structure of the pituitary gland? How is it connected to the hypothalamus?
The pituitary gland is composed of 2 parts - a larger anterior part and a small posterior part. The latter is connected by a hollow infundibulum (pituitary stalk) to the tuber cinereum in the floor of the 3rd ventricle. The two lobes are connected by a narrow zone called the pars intermedia.
Where is the pituitary gland located? What are the important anatomic relations of the pituitary?
The pituitary gland lies in the cavity called the pituitary fossa (part of the sphenoid bone called the sella turcica) and covered by the diaphragma sellae, which is a fold of dura mater. This fold has a central hole through which the infundibulum passes through. Below is the body of the sphenoid (sella turcica), laterally lies the cavernous sinus and its contents separated by the dura mater, with intracavernous sinuses communicating in front, behind and below. The optic chiasma is above immediately in front of the infundibulum.
Describe the structure of the pituitary gland
The anterior lobe is extremely cellular and consists of chromophobe, eosinophilic and basophilic cells. The pars intermedia contains large colloid vesicles reminiscent of the thyroid gland. The posterior lobe is made up of nerve fibres whose cell stations lie in the hypothalamus.
Outline the development of the pituitary gland?
The posterior and anterior pituitary develop as separate parts. The posterior pituitary is a cerebral diverticulum. The anterior pituitary and the pars intermedia develop from Rathke's pouch in the roof of the primitive buccal cavity. Occasionally, a tumour grows from the remnants of the epithelium of this pouch (craniopharyngioma) These tumours are often cystic and calcified.
What structures run within the cavernous sinus? What is the significance of this?
- intracavernous carotid artery
- 3rd, 4th and upper division of the 5th and 6th cranial nerves
The cranial nerves are located in the lateral and inferior aspects of the sinus, which renders them susceptible to compression by tumours with parasellar extension.
What hormones are produced by the anterior pituitary?
Growth hormone, prolactin, TSH, LH, FSH and ACTH are all produced by cells within the anterior pituitary.
Cells are stimulated to produce these hormones because of "releasing factors" synthesised by hypothalamic nuclei and released into the hypothalamic-hypophyseal portal system.
How are TSH, LH and FSH linked?
These all belong to the same glycoprotein family. Each has an alpha subunit and a beta subunit. The alpha subunits are identical. The beta subunits are different and are responsible for the unique biologic activity of each hormone.
What is POMC?
Proopiomelanocortin (POMC) is a precursor from which ACTH, melanocyte stimulating hormone (MSH), beta lipotropin and beta endorphin are derived from.
What is the function of growth hormone and what hormones is it related to?
Growth hormone is the most important hormone for normal growth to adult size. It is a single chain polypeptide chain that is homologous with prolactin and human placental lactogen.
Describe the regulation of growth hormone
Growth hormone is released in a pulsatile fashion. Secretion is increased by:
- hormones related to puberty, starvation, exercise and hypoglycaemia
Secretion is decreased by:
- somatomedins (e.g. IGF)
How does the hypothalamus control growth hormone?
Growth hormone releasing hormone (GHRH) stimulates the synthesis and secretion of growth hormone. Somatostatin inhibits secretion of growth hormone by blocking the response of the anterior pituitary to GHRH.
What are somatomedins? How do they affect growth hormone secretion?
Somatomedins are produced when growth hormone acts on target tissues. Somatomedins inhibit the secretion of growth hormone by acting directly on the anterior pituitary and by stimulating secretion of somatostatin by the hypothalamus
How does growth hormone and GHRH affect their own secretion?
Both of these cause negative feedback on their release respectively. GHRH inhibits its own secretion from the hypothalamus.
Growth hormone also inhibits its own secretion by stimulating the secretion of somatostatin from the hypothalamus.
What are the actions of growth hormone?
In the liver, growth hormone generates the production of somatomedins (insulin like growth factors [IGF}) which serve as intermediaries of several physiologic actions.
The IGF receptor has tyrosine kinase activity similar to the insulin receptor (but uses the JAK-STAT pathway rather than intrinsic tyrosine kinase activity).
The action of growth hormone can be considered as (i) direct or (ii) indirect via IGF:
(i) Direct: decrease glucose uptake into cells, increase lipolysis, increase protein synthesis in muscle and increase lean body mass, increase production of IGF
(ii) Indirect via IGF: increase protein synthesis in chondrocytes and increase linear growth, increase protein synthesis in muscle, and increase protein synthesis in most organs and increase organ size
How does growth hormone deficiency present?
In children it causes failure to grow, short stature, mild obesity and delayed puberty.
It can be caused by:
- lack of anterior pituitary growth hormone
- hypothalamic dysfunction (decr. GHRH)
- failure to generate IGF in the liver
- growth hormone receptor deficiency
What is the consequence of growth hormone excess?
Hypersecretion of growth hormone causes acromegaly and can be treated with somatostatin analogues (e.g. octreotide).
Before puberty excess growth hormone causes increased linear growth (gigantism). After puberty excess growth hormone causes increased periosteal bone growth, increased organ size, and glucose intolerance.
What is the function of prolactin?
It is the major hormone responsible for lactogenesis and participates, with oestrogen, in breast development. It is structurally homologous to growth hormone.
How is prolactin secretion regulated?
Like all hormones there is a hypothalamic-pituitary-gland axis (mammary glands in this case). Prolactin secretion is tonically inhibited by dopamine (prolactin inhibiting factor) secreted by the hypothalamus. Thus, interruption of the hypothalamic-pituitary tract causes increased secretion of prolactin and sustained lactation. TRH increases prolactin secretion.
Other factors that increase prolactin secretion are:
- breast feeding
- dopamine antagonists
Prolactin inhibits its own secretion by negative feedback and stimulating hypothalamic release of dopamine.
What are the actions of prolactin?
1) Stimulates milk production in the breast
2) Stimulates breast development
3) Inhibits ovulation by decreasing synthesis and release of gonadotropin releasing hormone (GnRH)
4) Inhibits spermatogenesis (by decreasing GnRH)
What causes prolactin deficiency?
This is usually caused by destruction of the anterior pituitary and results in failure to lactate.
What is the pathophysiology of prolactin excess?
This is caused by hypothalamic destruction (due to loss of tonic inhibitory control by dopamine) or from prolactin secreting tumours (prolactinomas).
It causes galactorrhea and decreased libido. It also causes failure to ovulate and amenorrhea because it inhibits GnRH secretion. It can be treated with bromocriptine which reduces prolactin secretion by acting as a dopamine agonist.
What hormones are produced by the posterior pituitary?
The posterior pituitary produces oxytocin and vasopressin (ADH). These are homologous to nonapeptides and are synthesised in hypothalamic nuclei and are packaged into secretory granules with their respective neurophysins. They travel down the nerve axons for secretion by the posterior pituitary.
Where is ADH synthesised? What is its function?
Anti-diuretic hormone (ADH) is synthesised by the supraoptic and paraventricular nuclei of the hypothalamus.
It helps regulate serum osmolarity by increasing the water permeability of the late distal tubules and collecting ducts (it does this by increasing the concentration of luminal aquaporin 2 channels on the principal cells of the late distal tubule and collecting duct).
It also causes constriction of vascular smooth muscle (via a V1 receptor and a IP3/ Ca++ mechanism).
What factors decrease ADH secretion?
Decreased plasma osmolarity
List some factors that increase ADH secretion?
Increased serum osmolarity
Nicotine, opiates antineoplastic drugs
Where is oxytocin synthesised?
Paraventricular nuclei of the hypothalamus.
It causes ejection of milk from the breast when stimulated by suckling.
How is oxytocin secretion regulated?
Is a major stimulus for oxytocin secretion.
Afferent fibres carry impulses from the nipple to the spinal cord. Relays in the hypothalamus trigger the release of oxytocin from the posterior pituitary.
2) Dilation of the cervix and orgasm
Increases the secretion of oxytocin
What are the actions of oxytocin?
1) Contraction of myoepithelial cells in the breast
Milk is forced into the mammary alveoli into the ducts and ejected
2) Contraction of the uterus
During pregnancy, oxytocin receptors in the uterus are upregulated as parturition approaches, although the role of oxytocin in normal labour is uncertain.
Oxytocin can be used to induce labour and reduce post partum bleeding.
How do pituitary disorders present?
They typically present with one or more of the following:
1) Hormone hypersecretion - e.g. excess production of growth hormone in acromegaly and ACTH in Cushing's disease
2) Hormone hyposecretion - e.g. partial or complete hypopituitarism as a consequence of damage to/ suppression of the remaining normal pituitary tissue
3) Local mass effect - due to compression/ infiltration of adjacent structures - e.g. bi-temporal hemianopia (due to optic chiasm compression) third, fourth or sixth cranial nerve palsies (if there is involvement of the cavernous sinus, especially if this occurs acutely, e.g. pituitary apoplexy) or headache (due to invasion of the sphenoid bone)
What are the main causes of hormone hypersecretion of the anterior lobe?
Hyperfunction of the anterior pituitary occurs if functioning adenomas are present. Hypersecretion of the glycoprotein hormones, TSH, LH and FSH is exceedingly uncommon.
Prolactinomas are the most common.
What causes hyperprolactinaemia?
Prolactinomas are the most common cause (and the most common functioning adenoma that causes hormone hypersecretion in general). These can either be:
1) Large pituitary adenoma (macroadenoma), or
2) Small pituitary adenoma (microadenoma)
Some drugs can also cause increase prolactin secretion, including:
- dopamine antagonists
- some antidepressants
Tumours do not need to be functional - i.e. non functioning pituitary adenoma can inhibit dopaminergic tone through pituitary stalk compression.
What are the clinical features of hyperprolactinaemia?
It is associated with reduced libido in both sexes and galactorrhea in females. However, even in the presence of a small prolactinoma, which is insufficient to cause compression of adjacent normal pituitary tissue, hypogonadotrophic hypogonadism is frequently seen as a consequence of the suppressive effect of high prolactin levels on hypothalamic GnRH pulse generator.
This causes oligomenorrhea/ amenorrhea in females and erectile dysfunction in males.
What are the effects of elevated growth hormone?
This depends on whether the GH-secreting tumour occurs:
1) Before epiphyseal growth plate fusion - there is well proportioned growth causing gigantism. Most giants show some features of acromegaly with disproportionate enlargement - e.g. of the hands and jaw
2) After epiphyseal growth plate fusion - excessive GH in an adult results in acromegaly:
- large hands and feet
- overgrowth of jaw and prominance of supraorbital ridges and malar bones/ coarse facial features
- excessive sweating/ oily skin
- carpel tunnel syndrome
- hypertension and cardiomyopathy
- increased risk of colonic neoplasia
What causes raised ACTH?
Raised ACTH can be both physiological and pathological.
Physiological increases in ACTH occur in diseases with reduced plasma cortisol such as Addison's disease or congenital adrenal hyperplasia as a result of reduced negative feedback.
If ACTH is secreted due to a functional pituitary adenoma with intact adrenals then this is Cushing's disease (note that Cushing's syndrome is due to non neoplastic causes of elevated cortisol).
What causes inappropriate ADH secretion?
The syndrome of inappropriate ADH (SIADH) occurs as a complication of other disease. Primary hypersecretion of ADH or oxytocin is not recognised.
It is caused by:
1) Head injury
2) Any intracranial pathology
3) Any thoracic disease, especially carcinoma of the bronchus, pneumonia caused by legionella, and pulmonary embolus
4) Transiently following surgery or major anaesthesia
What are the effects of SIADH?
This is to cause euvolaemic hyponatraemia by water retention and haemodilution. In severe cases cerebral oedema occurs with impaired consciousness.
What is meant by the term hypopituitarism? Which hormones are affected most?
The term hypopituitarism means an insufficiency of one or more of the anterior or posterior pituitary hormones. With pituitary tumours the usual sequence in which pituitary hormone function is lost is GH, followed by LH/FHS, followed by ACTH and finally TSH. Prolactin insufficiency is rare in this setting and the lactotrophs are remarkably resistant to pressure effects, such that prolactin levels often rise as the tonic inhibitory effect of dopamine is lost due to stalk compression.
What causes anterior lobe hypofunction?
1) Hypothalamic tumour - usually cranipharyngioma, more rarely pinealoma, teratoma or secondary from another site
2) Pituitary tumour - expanding to impair production or release from normal pituitary cells
3) Idiopathic deficiency of one or more pituitary hormones or of their releasing factors
4) Spontaneous infarction - occurs either in pre-existing pituitary tumour or else following torrential post partum haemorrhage, Sheehan's syndrome
5) Iatrogenic - previous surgery or radiotherapy to the hypothalamus or pituitary
6) Misc - rare causes include:
- TB, sarcoidosis, syphilis
- Trauma - with or without skull fracture
- Giant cell granuloma of the anterior lobe - a very rare giant cell lesion of unknown aetiology
What are the effects of anterior pituitary hypofunction?
1) Secondary hypoadrenalism - ACTH deficiency
2) Secondary hypothyroidism - TSH deficiency
3) Impotence of amenorrhoea - LH and FSH deficiency
4) Small stature - GH deficiency in childhood
5) Failure of lactation - if post partum haemorrhage complictes the delivery the first indication of pituitary infarction - Sheehan's syndrome - is failure of lactation. Paradoxically, in non pregnant females as well as in males, the first sign of a pituitary tumour may be inappropriate milk production - galactorrhoea due to elevation of serum prolactin
What is Kallman's syndrome?
This is one of a number of congenital syndromes that are associated with various aspects of hypofunction of the anterior pituitary.
Kallman's is isolated LHRH deficiency with defective or absent sense of smell.
What is Laurence - Moon - Biedl syndrome?
This is isolated LHRH deficiency with mental subnormality, retinitis pigmentosa and syndactyly
What is Prader-Willi syndrome?
This is isolated LHRH deficiency with hyperphagic obesity, mental retardation and intraurterine or neonatal hypotonia.
What causes cranial diabetes insipidus?
Diabetes insipidus is very rarely a presenting manifestation of a pituitary tumour. It is more commonly associated with:
1) Surgical trauma
2) Head injury - with or without skull fracture
3) Hypothalamic tumour
4) Infiltrative disease of the hypothalamus - e.g. sarcoidosis, Hand-Schuller-Christian disease
6) DIDMOAD syndrome - hereditary syndrome characterised by: cranial diabetes inspidius, diabetes mellitus, optic atrophy and dementia
NB - when present, cranial DI must be distinguished from nephrogenic DI (in which there is renal resistance to the action of ADH) by desmopressin treatment.
What are the effects of diabetes insipidus?
Lack of ADH action results in passing copious dilute urine (polyuria) with a tendency to dehydration. The night time urine volume nearly always exceeds 1.5L. This in turn stimulates thirst leading to polydypsia.
If there is associated disease of the anterior pituitary, diabetes insipidus may be masked since adequate levels of cortisol are required to excrete a water load. Polyuria may then occur when replacement therapy is commended with corticosteroids.
What are the clinical features of local mass effects of pituitary tumours?
In addition to compression of the normal pituitary gland, sellar/ parasellar lesions may cause compression of the optic chiasm, resulting initially in a superior quadrantic bi-temporal field defect (signifying pressure on the underside of the chiasm), which ultimately gives rise to complete bitemporal hemianopia.
In contrast, lesions originating in the suprasellar region (e.g. craniopharyngioma) may initially give rise to inferior quadrantic field defects, reflecting chiasmal compression from above.
Third, fourth and sixth cranial nerve palsies are relatively rare even with lateral tumour extension, but may be seen with infiltrative lesions of if there is rapid expansion of a tumour for example following haemorrhage as occurs in pituitary apoplexy.
How is hyperprolactinaemia investigated?
Wherever possible the confounding effects of medication and other disorders (e.g. renal failure, macroprolactinaemia (a condition in which prolactin is bound by immunoglobulin thus rendering it biologically inactive)) should be excluded. After this, genuine hyperprolactinaemia can be confirmed on 2 separate samples.
Prolactin is raised when serum concentration >390mU/L
Basal PRL - non stressful venepuncture between 0900 and 1600. It is important to do a pregnancy test, TFT, U&E and an MRI of the pituitary if other causes are ruled out.
How is Cushing's syndrome investigated?
Investigation of pathological hypercortisolaemia is approached in 2 stages:
1) Confirm diagnosis
- 24h urinary free cortisol excretion
- loss of diurnal cortisol variation (measured on serum or salivary samples)
- overnight dexamethasone suppression tests (1mg at 2300h with serum cortisol measured at 0900h the following morning)
- low dose dexamethasone suppression test (0.5mg every 6h for a total of 8 doses with serum cortisol measured at 0900h following the final dose)
2) Define aetiology
Once the diagnosis has been confirmed tests are undertaken to establish the cause. Measurement of plasma ACTH distinguishes between ACTH dependent (pituitary adenoma (i.e. Cushing's disease)) and ectopic ACTH secretion (e.g. due to small cell bronchial carcinoma) and ACTH independent (adrenal adenoma, adrenal nodular disease) causes.
How is acromegaly investigated?
The diagnosis of acromegaly is confirmed by the finding of:
- failure of GH suppression (to <0.4micrograms/L) during an oral glucose tolerance test
- an elevated IGF 1 level
How is hormone hyposecretion investigated?
Screening for hypopituitarism includes measurement of:
- free T4 and TSH (remember TSH alone is unreliable in hypothalamic/ pituitary disease)
- LH, FSH and testosterone or oestrogen
- prolactin (rarely low; typically raised)
- creatinine and electrolytes with paired serum and urine osmolarity if DI suspected
What tests are likely to exclude hypofunction of the anterior pituitary?
1) ACTH reserve. Adequate if:
- random plasma cortisol >550 nmol/L
- stress induced cortisol rise >550 nmol/L (e.g. short synacthin test)
2) GH reserve
- random plasma level >20 mU/l
- stress or otherwise elevated GH peak >20mU/l (e.g. insulin tolerance test or glucagon stimulation test)
3) TSH reserve if thyroxine levels adequate
4) LH reserve adequate if males have normal testosterone
5) FSH reserve adequate if males have normal spermatogeneies, females are ovulating
What tests are likely to exclude posterior pituitary function?
Water deprivation test. The object of the test is to demonstrate progressive haemoconcentration (with unaltered urine concentration) when access to water is restricted. It serves to differentiate diabetes insipidus from psychogenic polydipsia, but is potentially dangerous in patients with diabetes insipidus.
It should not be done unless the urine volume is >3L/d (output of less than this with normal plasma Na+ and osmolality excludes significant disturbances of water balance).
How is hypopituitarism treated?
Treatment involves hormone replacement and treatment of the underlying cause:
- Hydrocortisone for secondary adrenal failure, give BEFORE other hormones (because thyroxine can induce adrenal crisis)
- Thyroxine if hypothyroid and monitor (but TSH is not useful)
- Hypogonadism (for symptoms and to prevent osteoporisis):
F: oestrogen as a transdermal oestradiol patch or contraceptive pill +/- testosterone (may help bone mineral density and lean body mass)
M: testosterone enanthate IM, daily topical gels (i.e. Testogel)
- Gonadotropin therapy is needed to induce fertility in both men and women
- Growth hormone|, refer to endocrinologist for insulin tolerance test
How is hyperprolactinaemia treated?
Hyperprolactinaemia and acromegaly are the key clinical conditions caused by pituitary hormone hypersecretion and are mostly caused by functional adenomas.
1st line Rx for hyperprolactinaemia are dopamine agonists such as bromocriptine or cabergoline. Further treatment depends on the size of the tumour:
1) Microprolactinomas = tumour <10mm on MRI
- bromocriptine first line to reduce tumour size and decrease PRL. SE: nausea, depression postural hypotension. If planning pregnancy use barrier contraception until 2 periods have passed
- cabergoline is an alternative, fewer SE but less data on pregnancy
- transphenoidal surgery is 2nd line if intolerant of dopamine agonists. Risks: prolactinoma recurrence, permanent hormone deficiency
2) Macroprolactinoma = a tumour of >10mm diameter on MRI. They may be near the optic chiasm so cause decreased visual acuity, diplopia, ophthalmoplegia, visual field loss and optic atrophy.
- treat initially with dopamine agonists (bromocriptine if fertility is the goal), surgery is rarely needed but consider if visual symptoms or pressure effects which fail to respond to medical treatment
How should a hyperprolactinaemia be monitored?
PRL should be monitored annually. If there is headache or visual loss following treatment then check the fields and consider MRI.
Medication can be decreased after 2 years but recurrence of hyperporlactinaemia and expansion of the tumour may occur.
How is acromegaly treated? What are safe levels of GH?
The aim is to prevent or correct tumour compression by excising the lesion and to reduce GH and IGF-1 levels to at least a safe level of <2ug/L.
3 part strategy:
1) Transphenoidal surgery is often first line
2) If surgery fails to correct GH/IGF-1 hypersecretion try somatostain analogues (SSA) or radiotherapy. Examples: ostreotide or lanreotide. SE: pain at injection site, loose stools, increased gallstones, impaired glucose tolerance
3) Pegvisomant = GH antagonist is used if resistant or intolerant to SSA. It suppresses IGF-1 to normal in 90% but GH levels may rise
How is cranial diabetes insipidus managed?
Cranial diabetes insipidus is a form of posterior pituitary hypofunction. Remember that a tumour may presents with DI + hypopituitarism.
In cranial DI it is important to find the cause so a head MRI is useful. Test the anterior pituitary function and give desmopressin (a synthetic analogue of ADH). NB - desmopressin will not work on nephrogenic DI.
How should emergency cases of DI be managed?
Start with urgent plasma U&E and serum and urine osmolarities. Monitor urine output carefull and do U&Es twice daily.
- IVI to keep up with urine output. If severe hypernatraemia, do not lower Na+ rapidly as this may cause cerebral oedema and brain injury. If Na+ >170mmol/L use 0.9% saline initially - this contains 150mmol/L of Na. Reduce Na steadily by small amounts each day
- Desmopressin 2 micro gram IM may be used as a therapeutic trial
What is the most common type of pituitary tumour?
There are 3 histological types of pituitary tumour, but chromophobe tumours account for 70%. Many are non secretory and some cause hypopituitarism. Half produce prolactine and a few produce GH or PRL.
What are the clinical features of pituitary tumour?
Symptoms are caused by pressure, hormones (e.g. galactorrhoea) or hypopituitarism.
Features of local pressure include headache, visual field defects, palsy of cranial nerves III, IV, VI (pressure or invasion of the cavernous sinus). Also diabetes insipidus, disturbance of hypothalamic centres of temperature, sleep and appetite and erosion through the floor of the sella leading to CSF rhinorrhoea.