Session 8

Question 1

What is the hypothalamic pituitary axis?

Answer 1

The hypothalamus and pituitary constitute the major link between the nervous and endocrine systems and act together as one functional unit referred to as the hypothalamic pituitary axis.

Question 2

Where is the hypothalamus ,and briefly, what does it do?

Answer 2

As its name suggests (hypo = below), the hypothalamus is situated beneath the thalamus in the brain and is responsible for monitoring many aspects of the state of the body by integrating input from a wide range of sensory pathways.

Question 3

Describe the structure of the pituitary gland

Answer 3

a wide range of sensory pathways. The pituitary gland is about the size of a pea and is located beneath the hypothalamus in a socket of bone called the sella turcica at the base of the skull. The pituitary consists of two separate parts; the anterior lobe and the posterior lobe which have distinct embryological origins

Question 4

Describe how the pituitary gland forms?

Answer 4

. The anterior lobe (sometimes called the adenohypophysis) arises from a projection of ectoderm (Rathke’s pouch) growing upward from the roof of the mouth whereas the posterior lobe (sometimes called the neurohypohysis) arises from ectodermal tissue growing downwards from the diencephalon of the developing brain. Eventually these two tissues become tightly associated to form the pituitary but their structures remain distinct reflecting their distinct functions.

Question 5

How does the hypothalamus connect to the pituitary?

Answer 5

Axons from the hypothalamus pass down a structure called the infundibulum (pituitary stalk) and terminate in the posterior pituitary.

Question 6

Why is the posterior pituitary gland not actually a gland?

Answer 6

Although it is sometime referred to as the posterior pituitary “gland”, the posterior pituitary is actually not a gland at all since it does not synthesise any hormones and consists of the axons and terminals that originated in the hypothalamus and specialised glial cells called pituicytes.

Question 7

What are the posterior pituitary hormones?

Answer 7

Two hormones, oxytocin (OT) and antidiuretic hormone (ADH), synthesised by neurosecretory cells in the hypothalamus are stored in the posterior pituitary axon terminals for release into the bloodstream (a classic example of neurocrine signalling). An important point to emphasise here is that the posterior pituitary does not actually synthesise the two hormones that it releases. Oxytocin and antidiuretic hormone are synthesized by neurons in the supraoptic and paraventricular nuclei of the hypothalamus and are transported down axons to the posterior pituitary. Release of hormone from the posterior pituitary to the systemic circulation is regulated by neuronal inputs into the hypothalamus.

Question 8

What causes the production and release of oxytocin?

Answer 8

The stimulus of suckling in the milk let-down reflex is transmitted via neurons from the breast to the hypothalamus resulting in release of oxytocin from the posterior pituitary. Once in the bloodstream, oxytocin travels to the mammary glands and causes milk release by activating oxytocin receptors on the myoepithelial cells surrounding the mammary alveoli causing them to contract squeezing milk into the duct system. During childbirth the stimulus of pressure on the cervix and uterine wall is again transmitted to the hypothalamus via neuronal input and the release of oxytocin from the posterior pituitary into the general circulation initiates powerful uterine contractions by activation of oxytocin receptors on uterine smooth muscle cells. Synthetic oxytocin (Pitocin) is often administered to increase uterine tone and control bleeding just after birth.

Question 9

What does ADH do?

Answer 9

Antidiuretic hormone (ADH), as its name suggests, causes a reduction in urine production. Receptors for ADH are present on the distal tubular epithelium of the collecting ducts in the kidneys and when activated by ADH facilitate an increase in permeability by inducing translocation of aquaporin water channels in the plasma membrane of the collecting duct cells allowing more reabsorption of water back into the blood. Drinking alcohol inhibits ADH release from the posterior pituitary explaining the increased urination and ultimately dehydration often experienced with drinking to excess. Osmoreceptors in the hypothalamus detect changes in plasma osmolality and control the amount of ADH released and also the feeling of thirst. An alternative name for ADH is vasopressin and this reflects the ability of ADH to also increase peripheral vascular resistance by activating ADH receptors on the smooth muscle cells of blood vessels causing vasoconstriction and an increase in arterial blood pressure. Vasoconstriction mediated by ADH is particularly important for restoring blood pressure in hypovolemic shock during haemorrhage.

Question 10

How does the hypothalamus control the anterior pituitary?

Answer 10

As well as facilitating the release of oxytocin and ADH from the posterior pituitary, the hypothalamus also controls the hormonal secretions of the anterior pituitary gland. However, unlike the neuronal control present in the posterior pituitary, the control over the anterior pituitary is mediated by tropic hormones released by the hypothalamus into the local blood supply supplying the anterior pituitary.

Question 11

How do tropic hormones travel from the hypothalamus to the anterior pituitary?

Answer 11

The hypothalamus synthesises seven hormones that are transported down axons and stored in a structure called the median eminence situated just above the anterior pituitary. These hormones are termed tropic hormones because they affect the release of other hormones (not to be confused with the term trophic which refers to growth) and are released from the median eminence into a local system of blood vessels called the hypophyseal portal system. Since the blood vessels running away from the median eminence run directly into the anterior pituitary, the anterior pituitary is directly exposed to these hypothalamic tropic hormones which either stimulate or inhibit target endocrine cells within the anterior pituitary gland by binding to hormone specific G-protein coupled receptors on their surface.

Question 12

What are the tropic hormones produced by the hypothalamus?

Answer 12

• TRH Thyrotropin Releasing Hormone • PRH Prolactin Releasing Hormone • PIH Prolactin Release-Inhibiting Hormone (dopamine) • CRH Corticotropin Releasing Hormone • GnRH Gonadotropin Releasing Hormone • GHRH Growth Hormone Releasing Hormone • GHIH Growth hormone inhibitory hormone (also called Somatostatin) (RH= releasing hormone, IH = inhibitory hormone)

Question 13

How is the release of hypothalamic hormones regulated?

Answer 13

The secretion of hypothalamic releasing hormones, anterior pituitary hormones and peripheral effector hormones are regulated by negative feedback loops which act at different levels of the system. In ultrashort loop negative feedback the hypothalamic releasing factor itself (hormone 1) limits its own production in an autocrine/paracrine fashion within the hypothalamus. Further short-loop negative feedback comes either from inhibition of hypothalamic releasing hormone production or stimulation of hypothalamic inhibiting hormone production mediated by the anterior pituitary hormone (hormone 2) released in response to the hypothalamic releasing hormone. The final peripheral effector hormone in the pathway (hormone 3) also acts back on the hypothalamic pituitary axis in negative feedback loops that inhibit production of the respective anterior pituitary hormone via direct long loop negative feedback and the respective hypothalamic releasing factor via indirect long loop negative feedback.

Question 14

What is somatotrophin?

Answer 14

Growth Hormone (somatotrophin)
Growth hormone is a 191 amino-acid single chain polypeptide hormone and is the main stimulator of body growth in human. Growth hormone is produced by somatotrope cells in the anterior pituitary gland under the control of the hypothalamic hormones growth hormone releasing hormone (GHRH), which stimulates production and release and somatostatin which inhibits production and release. Growth hormone secretion occurs in a pulsatile fashion, with circadian rhythm and a maximal release late at night.
In response to GH, cells in the liver and skeletal muscle secrete insulin like growth factors (IGFs) (also called somatomedins) which are hormones that act to stimulate body growth and regulate metabolism.
IGFs are so named because several of their actions are similar to those of insulin. Human GH is essential for the increase in the growth rate of the skeleton and skeletal muscles during childhood and teenage years.
In adults GH and IGFs help maintain muscle and bone mass and promote healing and tissue repair.

Question 15

How is growth hormone secretion controlled?

Answer 15

The secretion of GH is influenced by many factors. The principal point of control is via the hypothalamic production of GHRH (increases GH secretion) and somatostatin (decreases GH secretion). Secretion is regulated metabolically by plasma glucose and free fatty acid concentrations:

• A decrease in glucose or free fatty acid leads to an increase in GH secretion.
• An increase in glucose or free fatty acid leads to a decrease in GH secretion.
• Fasting increases GH secretion whereas obesity leads to a reduction in GH secretion.

The central nervous system also regulates GH secretion via inputs into the hypothalamus effecting GHRH and somatostatin levels:
• There is a surge in GH secretion after onset of deep sleep

• Light sleep (Rapid Eye Movement (REM) sleep) inhibits GH secretion • Stress (e.g. trauma, surgery fever) increases GH secretion
• Exercise increases GH secretion.

The hormone ghrelin has also been shown to increases the production of growth hormone. The regulation of GH secretion occurs via LONG LOOP and SHORT LOOP negative feedback mechanisms.
LONG LOOP negative feedback (both direct and indirect) is mediated by IGFs which:
• Inhibit the release of GHRH from the hypothalamus.

• Stimulate the release of somatostatin from the hypothalamus.
• Inhibit the action of GHRH in the anterior pituitary.

SHORT LOOP negative feedback is mediated by GH itself via the stimulation of somatostatin release from the hypothalamus

Question 16

How does GH exert its effects on cells?

Answer 16

GH acts on cells both directly through its own receptor and indirectly through the induced production of Insulin-like Growth Factor-I (IGF-I). Only those cells expressing GH receptors can respond to GH. The GH receptor is a member of the cytokine receptor superfamily. GH receptors are coupled to an intracellular enzyme called Janus kinase JAK), (kinases are enzymes that phosphorylate target proteins altering their function). In the case of GH activation of JAK, one of the effects is the activation of a transcription factor that turns on production of IGFs. There are 2 forms of IGFs in mammals (IGF-1 and IGF-2) and these are mainly produced in the liver (~75%) and skeletal muscle, although many other tissues such bone, kidney and the central nervous system also respond to GH by producing IGFs. The IGFs circulate in the blood bound to specific binding proteins which modulate their availability to activate IGF receptors on target cells. The IGFs act on target cells through their own specific receptor which shows some similarities to the insulin receptor (a tyrosine kinase). IGF-1 mediates the majority of the effects of GH in adult including:
• Increase in cell size (Hypertrophy)

• Increase in cell number (Hyperplasia)
• Increase in the rate of protein synthesis • Increase in the rate of lipolysis in adipose tissue (fat)
• Decrease in glucose uptake.

IGF-2 appears to be more important during growth and development before birth. The actions of both IGFs can be paracrine and autocrine as well as endocrine. In some tissues IGF-1 inhibits apoptosis and some types of tumour express abundant IGF-I receptors which inhibit apoptosis.

Question 17

What is the most common cause of pituitary malfunction?

Answer 17

The most common cause of pituitary malfunction is a benign tumour (adenoma).

Question 18

How do pituitary tumours cause symptoms?

Answer 18

Most pituitary tumours are “non-functioning” in that the tumour cells themselves do not produce any hormone. Such non-functioning pituitary tumours can result in inadequate production of one or more of the pituitary hormones due to physical pressure from the growing tumour on glandular tissue. Pressure on surrounding structures in the vicinity of the tumour can also result in headaches, visual problems (compression of the optic nerve), vomiting and nausea. Hypersecreting or “functional” pituitary tumours are rarer and cause problems associated with overproduction of one or more of the pituitary hormones. The clinical symptoms of such hypersecreting tumours usually correspond to the systemic effects of the over secreted hormone and may or may not show some degree of hormonal regulation in terms of negative feedback.

Question 19

How do we investigate and diagnose pituitary tumours?

Answer 19

Investigation of a suspected pituitary tumour involves: i) delineation of the anatomy, size and topographical location of the pituitary or parapituitary mass (usually by MRI scan), ii) assessment of visual field defects and ii) assessment of endocrine function to determine whether there is a hormonal excess or deficiency. This is done by measuring hormone levels in blood or by staining sections from a biopsy of the tumour with antibodies for the relevant hormone

Question 20

What is hypopituitarism?

Answer 20

Insufficient pituitary hormone production (hypopituitarism), is most commonly a result of a pituitary adenoma. Rarer causes include radiation therapy, inflammatory disease and head injury. Loss of pituitary hormone secretion is usually secondary to a mass effect from the adenoma. There is typically a progressive loss of anterior pituitary function with GH and LH/FSH usually the first hormones to be affected. Deficiency of all anterior pituitary hormones is referred to as panhypopituitarism. Secretion of antidiuretic hormone and oxytocin from the posterior pituitary is usually only significantly affected if the tumour affects hypothalamic function or, alternatively if an inflammatory process is involved.

Question 21

Give an overview of growth hormone deficiency?

Answer 21

The symptoms of GH deficiency in adults are quite subtle and patients may show a decrease in tolerance to exercise, decreased muscle strength, increased body fat and a reduced sense of “well-being”. Since GH secretion is pulsatile, deficiency is often difficult to diagnose and a combination of direct and indirect measurements are required. GH deficiency in adults is usually due to the mass effects from a pituitary adenoma. Growth hormone deficiency in children is typically idiopathic (of unknown cause) but specific gene mutations (e.g. in the Growthhormone-releasing hormone receptor) and autoimmune inflammation have been identified in some cases. The incidence of growth hormone deficiency in children is ~1 in 3800 live births. GH deficiency has little effect on fetal growth. However, severe prenatal deficiency can result in hypoglycaemia and jaundice. From around 1 year of age until midteens GH deficiency results in poor growth and short stature. Human GH manufactured by recombinant DNA technology can be used as treatment for such cases.

Question 22

What is gonadotropin deficiency?

Answer 22

Gonadotropin deficiency (hypogonadism) due to mass effects from a pituitary adenoma can result in lack of libido, infertility and oligomenorrhea or amenorrhea in women of reproductive age. Hypogonadism in men can also decrease libido and cause impotence

Question 23

How are pituitary tumours linked to TSH & ACTH deficiency?

Answer 23

A pituitary adenoma can sometimes also affect the secretion of TSH and/or ACTH. These consequences of this will be considered in sessions 8 and 9 respectively.

Question 24

Give an overview of ADH deficiency

Answer 24

Antidiuretic hormone is synthesised in the hypothalamus before being transported in neurosecretory granules to the posterior pituitary for release. Deficiency in ADH may result from a hypothalamic tumour or a pituitary tumour that has extended up into the hypothalamus. Other causes of ADH deficiency include cranial radiotherapy, pituitary surgery autoimmune infiltration and infections such as meningitis. Insufficient ADH release from the posterior pituitary leads to an excess excretion of dilute urine resulting in dehydration and an increased sensation of thirst (polydipsia). This condition represents the cranial form of the disease diabetes insipidus (not to be confused with diabetes mellitus which has a completely different aetiology).

Question 25

What is hyperpituitarism?

Answer 25

There are three main conditions caused by excess pituitary hormone production from a hypersecreting pituitary adenoma: prolactin excess, growth hormone access and ACTH excess.

Question 26

What is prolactin excess and what does it do?

Answer 26

The normal physiological function of prolactin is to initiate and maintain lactation and prolactin secretion by lactotropes in the anterior pituitary is regulated by the hypothalamic hormones prolactin releasing hormone (stimulates secretion) and dopamine (inhibits secretion). However, it is the tonic inhibition of prolactin secretion by dopamine which dominates. Hyperprolactinaemia (an abnormally high prolactin level in blood) is the most common form of pituitary disorder and can cause a range of symptoms including:
• galactorrhoea (unexplained milk production (rare in men)) • gynecomastia (hard breast tissue) • hypogonadism (diminished activity of testes or ovaries) • amenorrhea (cessation of menstrual cycle) • erectile dysfunction.
Diminished sex hormone production (hypogonadism) due to hyperprolactinaemia results from a higher level of dopamine in the hypothalamus (resulting from negative feedback of increased plasma prolactin) which inhibits GnRH secretion from the hypothalamus and therefore FSH and LH secretion from the anterior pituitary. The most common cause of hyperprolactinaemia is prolactinoma, a pituitary adenoma that secretes prolactin. However, physiological causes such as pregnancy, suckling, stress and exercise and drugs such as antipsychotics (e.g. haloperidol) and antidepressants (e.g. clomipramine) can also cause hyperprolactinaemia. Prolactin secretion from the anterior pituitary is mainly under the negative influence of dopamine (referred to as prolactin inhibiting hormone in many texts) released from the hypothalamus. Dopamine receptor agonists such as cabergoline are therefore used as the first line of treatment for prolactin excess and this is usually sufficient for most patients. In rare cases however, trans-sphenoidal surgery (a type of surgery used to access the pituitary gland through the nose and sphenoid bone of the skull) or radiotherapy may be required.

Question 27

What is growth hormone excess?

Answer 27

Growth hormone secreting pituitary adenomas are typically large (\>10 mm in diameter) and are therefore also associated with local mass effects such as headache, visual field defects and other cranial nerve palsies. The systemic effects manifested by increased GH secretion are through both the direct actions of GH itself and also through stimulation of local IGF-1 production. The effects of this increased activation of GH and IGF-1 receptors often take several years to manifest as a change in physical appearance meaning that it could be 6 or more years before a diagnosis is made. Changes in physical appearance include a broad nose, coarse facial features, thick lips and a prominent supraorbital ridge (the crest of bone situated on the frontal bone of the skull). Enlargement of the hands and feet also occur and the patient’s skin is often greasy with excessive sweating. Deepening of the voice also occurs due to hypertrophy of the soft tissues of the upper airways. Excessive growth hormone secretion in childhood, before fusion of the epiphyseal plates in the long bones, results in the condition of gigantism. Indeed the world’s tallest man
ever recorded (Robert Wadlow 1918-1940) suffered from a GH secreting pituitary adenoma. In more recent times however gigantism rarely develops due to early diagnosis and treatment. As GH antagonises the actions of insulin, several metabolic complications may also manifest including development of diabetes mellitus and the increased serum IGF-1 levels caused by the disease have recently been associated with some forms of cancer. 
Three types of treatment options are available for patients with acromegaly: surgery to remove the adenoma, radiation therapy and drug therapy. Dopamine receptor agonists have some efficacy in reducing GH levels. However, a much higher dose than that used for prolactin-secreting pituitary adenoma is required. Somatostatin, the hypothalamic hormone which limits GH secretion has limited use due to its very short half-life but the synthetic somatostatin analogs have been developed which produce a prolonged suppression of GH secretion. Antagonists of the GH receptor such as Pegvisomant represent the most recent development in treatment of the disease.

Question 28

What is ACTH excess?

Answer 28

Excess endogenous secretion of ACTH from the anterior pituitary gland is one of the causes of Cushing’s syndrome. This will be covered in more detail in session 9.