Download S10 Clinicalbiochem2 DrNansy Hypothalamus And Pituitary

Endocrinology
• Introduction
• Dynamic function tests
• Hypothalamus and pituitary function
tests
• Adrenal function
• Thyroid function tests
• Other glands
Hypothalamus and pituitary glands
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Hypothalamus
The pituitary gland
Anterior pituitary hormones
Posterior pituitary hormones
Pituitary tumors
Hypopituitarism
Case 1
Saleem is a 5 year old boy and is much smaller than his
classmates at school. His growth rate has been
monitored and has clearly dropped off markedly in the
past year.
He is a active child, and on examination has normal
body proportions. His mother and father are of average
height. His bone age is that of 3-year-old child.
1. What is likely cause of his condition?
2. Which biochemical tests would be appropriate in the
investigation of this boy?
Hypothalamus
Integrates activities of nervous and endocrine systems
in 3 ways:
1. Secretes regulatory hormones that control
endocrine cells in pituitary gland.
2. Acts as an endocrine organ itself.
3. Contains autonomic centers that exert direct
neural control over endocrine cells of adrenal
medullae (neuroendocrine reflex).
Hypothalamic–Pituitary system
• Hypothalamus secretes regulatory hormones
(releasing hormones).
• Causes anterior pituitary to release
stimulating hormone (tropic hormones).
• Tropic hormones stimulate target cells to
respond, either directly or indirect.
Regulatory
hormone
Negative
feedback
Tropic
hormone
Resulting
hormone
Hypothalamus hormones
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TRH: Thyrotropin-releasing hormone
PRH: Prolactin-releasing hormone
PIH: Prolactin- inhibiting hormone
GH-RH: Growth hormone-releasing hormone
Gn-RH: Gonadotropin-releasing hormone
CRH: Corticotropin-releasing hormone
ADH or AVP: antidiuretic hormone or vasopressin
Oxytosin
Pituitary (Hypophysis) is the
Master Endocrine Gland
• Pea size gland and secretes 9 major
peptide hormones and include two lobes:
– Posterior (neurohypophysis): neural
– Anterior (adenohypophysis):
glandular, synthesis and secretes seven
peptide hormones
The pituitary gland
• Pituitary function is regulated by the hypothalamus, to which it is connected via
pituitary stalk, which comprises portal blood capillaries and nerve fibers.
• The pituitary gland consists of two parts, the anterior pituitary, or
adenohypophysis, which is influenced by a variety of stimulatory and inhibitory
hormones through these capillaries.
• The posterior pituitary, or neurohypophysis, is a collection of specialized nerve
endings that derive from the hypothalamus.
• Though very closely related
anatomically, they are embryologically
and functionally quite distinct. The
anterior pituitary comprises primarily
glandular tissue, while the posterior
pituitary is of neural origin. The
pituitary gland is situated at the base of
the brain, in close relation to the
hypothalamus, which has an essential
role in the regulation of pituitary
function .
Anterior pituitary hormones
TSH (thyroid stimulating hormone)
• Act specifically act on thyroid gland to elicit secretion of thyroid
hormones.
• Secretion of TSH is stimulated by the hypothalamic tripeptide TRH
and this effect, and probably the release of TRH itself, is inhibited by
high circulating concentrations of thyroid hormones.
• Thus thyroid hormone synthesis is regulated by a negative
feedback system: if plasma concentrations of thyroid hormones
decrease, TSH secretion increases, stimulating thyroid hormone
synthesis; if they increase, TSH secretion is suppressed. In primary
hypothyroidism, TSH secretion is increased; in hyperthyroidism it is
decreased. TSH deficiency can cause hypothyroidism.
ACTH (adrenocorticotrophic hormone)
• Its biological function, which is to stimulate adrenal glucocorticoid (but not
mineralocorticoid) secretion. Acts specifically on the adrenal cortex to elicit
secretion of cortisol
• ACTH secretion is pulsatile and also shows diurnal variation, the plasma
concentration being highest at approximately 0800 h and lowest at midnight.
Secretion is greatly increased by stress and is inhibited by cortisol. Thus cortisol
secretion by the adrenal cortex is controlled by negative feedback, but this and the
circadian variation can be overcome by the effects of stress.
• Increased secretion of ACTH by the pituitary is seen with pituitary tumors
(Cushing's disease) and in primary adrenal failure (Addison's disease). The hormone
may also be secreted ectopically by non-pituitary tumors. Excessive ACTH
synthesis is associated with increased pigmentation, owing to the melanocytestimulating action of ACTH.
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Decreased secretion of ACTH may be an isolated phenomenon but is more
commonly associated with generalized pituitary failure.
LH (lutenizing hormone) and FSH (follicle
stimulating hormone)
• Known jointly as the gonadotrophins, act
cooperatively on the ovaries in women and the
tests in men to stimulate sex hormone secretion
and reproductive processes.
• The synthesis and release of both hormones
are stimulated by the hypothalamic
gonadotrophin-releasing hormone (GnRH),
these effects being modulated by circulating
gonadal steroids.
• GnRH is secreted episodically, resulting in
pulsatile secretion of gonadotrophins
• In males, LH stimulates testosterone secretion by Leydig cells in the testes:
both testosterone and oestradiol, derived from the Leydig cells themselves
and from the metabolism of testosterone, feedback to block the action of
GnRH on LH secretion.
• FSH, in concert with high intratesticular testosterone concentrations,
stimulates spermatogenesis; its secretion is inhibited by inhibin, a hormone
produced during spermatogenesis.
• In females, the relationships are more complex.
Oestrogen (mainly oestradiol) secretion by the
ovaries is stimulated primarily by FSH in the
first part of the menstrual cycle; both hormones
are necessary for the development of Graafian
follicles.
• As oestrogen concentrations in the blood rise,
FSH secretion declines until oestrogens trigger
a positive feedback mechanism, causing an
explosive release of LH and, to a lesser extent,
FSH.
• The increase in LH stimulates ovulation and
development of the corpus luteum, but rising
concentrations of oestrogens and progesterone
then inhibit FSH and LH secretion; inhibin
from the ovaries also appears to inhibit FSH
secretion.
• If conception does not occur, declining concentrations of oestrogens and
progesterone from the regressing corpus luteum trigger menstruation, and LH and
FSH release, initiating the maturation of further follicles in a new cycle.
GH (growth hormone)
• Acts directly on many tissues to modulate metabolism. Metabolic
fuels (glucose, free fatty acids) in turn modify GH secretion
• It is essential for normal growth, although in the main it acts
indirectly by stimulating the liver to produce insulin-like growth
factor-1 (IGF-1), also known as somatomedin-C (IGF-1 has
considerable amino acid sequence homology with insulin and shares
some of the actions of this hormone)
• GH also has a number of metabolic effects.
• The release of GH is controlled by two hypothalamic hormones,
growth hormone-releasing hormone (GHRH) and somatostatin. IGF-1
exerts negative feedback at the level of the pituitary, where it
modulates the actions of GHRH, and at the level of the hypothalamus
where, together with GH itself, it stimulates the release of
somatostatin.
• The concentration of GH in the blood varies widely through the day
and may at times be undetectable (<1 mU/L).
GH (growth hormone)
• Physiological secretion occurs in sporadic bursts, lasting for 1-2 h,
mainly during deep sleep.
• The rate of secretion increases from birth to early childhood and then
remains stable until puberty, when a massive increase occurs,
stimulated by testosterone in males and oestrogens in females;
thereafter the rate of secretion declines to a steady level before falling
to low levels in old age.
• Secretion can be stimulated by stress, exercise, a fall in blood
glucose concentration, fasting and ingestion of certain amino acids.
• Excessive secretion (usually due to a pituitary tumor) causes
gigantism in children and acromegaly in adults; deficiency causes
growth retardation in children and can cause fatigue, loss of muscle
strength, impaired psychological wellbeing and an adverse
cardiovascular risk profile (elevated plasma total and LDL-cholesterol
concentrations and hyperfibrinogenaemia) in adults.
Growth disorders and acromegaly
• Physiological secretion occurs in sporadic bursts,
lasting for 1-2 h, mainly during deep sleep.
• The rate of secretion increases from birth to early
childhood and then remains stable until puberty,
when a massive increase occurs, stimulated by
testosterone in males and estrogens in females;
thereafter the rate of secretion declines to a steady
level before falling to low levels in old age.
GH is only one of many hormones involved in
growth. Insulin-like growth factors, thyroxine,
cortisol, the sex steroids and insulin are involved
• Growth hormone insufficiency is a
rare cause of impaired physical growth.
If GH deficiency is diagnosed, and
treatment is required, then the earlier it
is given the better the chance that the
child will eventually reach n normal
size.
• It is important to differentiate between
children whose slow growth or growth
failure is due to illness or disease and
those whose short stature is a normal
variant of the population.
Causes of short stature are:
• having parents who are both short.
• inherited diseases such as achondroplasia, the commonest cause of severe dwarfism.
• poor nutrition.
• systemic chronic illness, such as renal disease, gastrointestinal disorders or
respiratory disease.
• psychological factors such as emotional deprivation.
• hormonal disorders.
Tests of growth hormone insufficiency
• Growth hormone deficiency may be present from birth or due to later pituitary
failure. A variety of stimulation tests have been used to evaluate GH deficiency.
• Serum GH concentrations rise in response to exercise, and this may be used as a
preliminary screening test.
• They also rise during sleep, and high concentrations in a nocturnal sample may
exclude GH deficiency.
• The lack of GH response to clonidine, a potent stimulant of GH secretion, is
diagnostic. Some centers have now abandoned the use of insulin induced
hypoglycaemia as a diagnostic test in children because of its hazards.
• The GH response to stimulation may be blunted before puberty, and priming with
the appropriate sex steroid is necessary before investigating GH reserve.
• Increasingly, urinary growth hormone measurements are being used to assess
possible GH lack in children. Random serum IGF I determinations may be of
value. Levels within reference limits exclude GH deficiency.
Treatment
• Genetically engineered GH is available and is used in the treatment of that small
group of children with proven GH deficiency.
Excessive growth
• GH excess in children is characterized by extremely rapid linear
growth (gigantism). This condition is uncommon and most often due
to a GH secreting pituitary tumor.
• Other causes of tall stature in children are rare and include:
1. Hyperthyroidism: an increased growth rate, with advanced bone age,
is a feature of hyperthyroidism in children, or hypothyroid children
over-replaced with thyroxine.
2. Inherited disorders such as Klinefelter’s syndrome (a 47 XXY
karyotype).
3. Congenital adrenal hyperplasia.
Acromegaly
• Increased GH secretion later
in life, after fusion of bony
epiphyses (is the rounded
end of a long bone). The
most likely cause is pituitary
adenoma. Clinical features
include:
1. Coarse facial features.
2. Soft tissue thickness (e.g. the
lips)
3. Characteristic ‘spade like’
hands
4. Protruding jaw
5. Sweating
6. Impaired glucose tolerance
or diabetes mellitus
Diagnosis
• Formal diagnosis of acromegaly requires an OGTT
with GH measurements.
• Acromegalic patients do not suppress fully in
response to hyperglycemia.
• IGF 1 produced in response to GH and provides
useful additional biochemical information. It is
now routinely measured in the diagnosis and
especially monitoring of treated acromegaly, with
an elevated level suggestive of active disease.
Treatment
1. Surgery. Its success depends on the size of the
tumor.
2. Radiation. This is usually reserved for patients whose disease remains active
despite surgery. It may require years before safe levels of GH are achieved.
Medical treatment is required temporarily.
3.Medical. Dopamine agonists like bromocriptine were widely used in the past, but
response rates were low. Long-acting synthetic somatostatin, such as octreoids
are used today. These are expensive drugs with side effects, and it is sensible
to measure GH after administering the drug (octreotide suppression test).
Prolactin
• Acts directly on the mammary glands to control lactation. Gonadal
function is impaired by elevated circulating prolactin concentrations
• Prolactin is a polypeptide hormone; its principal physiological action
is to initiate and sustain lactation.
• It also has a role in breast development in females; at high
concentrations, it inhibits the synthesis and release of gonadotrophinreleasing hormone (GnRH) from the hypothalamus, and thus
gonadotrophins from the pituitary, inhibiting ovulation in females and
spermatogenesis in males.
• Prolactin secretion is controlled by the hypothalamus through the
release of dopamine, which normally exerts a tonic inhibition.
• The principal physiological stimuli to prolactin secretion are
pregnancy and suckling.
Prolactin
• The secretion of prolactin is pulsatile, increases during sleep, after
meals, exercise and with stress (both physical and psychological), and,
in women, is dependent upon oestrogen status, making it difficult to
define a precise upper limit for plasma prolactin concentration in
normal men and women, although 500 mU/L is often regarded as the
upper reference value in non-pregnant women and 300 mU/L in men.
• There is no useful lower reference value for plasma prolactin
concentration.
• Its secretion increases during pregnancy but concentrations fall to
normal within approximately seven days after birth if a woman does
not breast feed. With breast-feeding, concentrations start to decline
after about three months, even if breast-feeding is continued beyond
this time.
Hyperprolactinemia
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2.
It is common and can cause infertility in both sexes.
Causes of hyperprolactinemia:
Stress.
Drugs (estrogens).
3. Seizures (acutely)
4. Primary hypothyroidism (prolactin is stimulated by the raised TRH).
• If these causes are excluded, the differential diagnosis is between
 A prolactinoma (a prolactin-secreting pituitary tumor).
 Idiopathic hypersecretion, which may be due to impaired secretion
of dopamine.
• Differentiating between these is by detailed pituitary imaging together
with DFTs of prolactin secretion. A rise in serum prolactin following
administration of TRH or metoclopramide is observed in idiopathic
hyperprolactinemia but not in the presence of a pituitary tumor
Posterior pituitary hormones
• Hypothalamic neurons synthesize arginin vasopressin (AVP, ADH,
vasopressin) and oxytocin, which pass along axonal nerve fibers in the
pituitary stalk to the posterior pituitary where they are stored in
granules in the terminal bulbs of nerves in proximity to the systemic
veins.
• Secretion of ADH is stimulated by: increased plasma osmolality,
severe blood volume depletion, stress and nausea.
• Oxytocin is involved in the control of uterine contractility and of milk
release from the lactating breast. Disorders of its secretion are
probably uncommon and are not clinically important.
• A pituitary tumor arising in the anterior gland may cause impaired
secretion of this hormone, with consequent diabetes insipidus.
• In diabetes insipidus, the lack of vasopressin (or resistance to its
actions) results in polyuria (typically >3 L urine/24 h in adults) and
thirst
Pituitary tumors
• Pituitary tumors may be either
functional (they secrete hormones) or
non-functional.
• Local effects include headaches,
papilloedema and visual field
defects.
• There may be specific signs of
hormone excess particularly in
acromegaly, Cushing’s syndrome and
prolactinoma.
• The impact of the tumor on pituitary function requires formal
assessment by DFTs.
• In GH and ACTH secreting cells, an IST may suffice.
• Comprehensive assessment of anterior
pituitary reserve requires a combined
anterior pituitary function test. TRH,
GnRH and insulin are administered. All
hormones are assessed at 0, 30 and 60
minutes, and GH additionally at 90 and
120 minutes.
Treatment
1. Medical.
2. Surgery
3. Radiation: the impact of radiation on
pituitary function is cumulative, and
irradiated patients require annual DFTs
thereafter.
Hypopituitarism
• There are many causes of hypopituitarism, a relatively uncommon
condition in which there is failure of one or more pituitary functions.
• The clinical presentation depends on the age of the patient:
 In infancy, short stature or impaired development may point to
this condition.
 In the reproductive years, women may present with amenorrhea
or infertility. Men may present with decreased libido or a lack of
male secondary sex characteristics.
 Elderly patients may complain of symptoms relating to ACTH
or TSH deficiency such as hypoglycemia or hypothermia.
Hypopituitarism
• If insufficient secretion of one (selective form):
1. Cortisol deficiency: because of lack of ACTH.
2. Thyroid hormones deficiency: because of lack of TSH.
3. ADH defficincy: diabetes insipidus.
4. Defficiency of FSH and LH: gonadal failure and loss of
secondary sex characteristics.
5. Decrease growth hormone: decrease somatomedin (they affect
children growth).
6. Absence of prolactin: postpartum women are unable to lactate.
The End