Structure
1. Also
known as hypophysis and called the “master gland.”
2. Size:
1.2 – 1.5 cm across; weight: 0.5 grams
3. Located
on the ventral surface of the brain within the skull
4. Infundibulum
– stemlike stalk that connects pituitary to the hypothalamus
5. Made
up of two separated glands, the adenohypophysis (anterior pituitary gland) and
the neurohypophysis (posterior pituitary gland).
THE
ADENOHYPOPHYSIS
Divided into two parts
1. Pars
anterior – forms the major portion of the adenohypophysis
2. Pars
intermedia
The tissue is
composed of irregular clumps of secretory cells supported by fine connective
tissue fibers and surrounded by a rich vascular network. Three types of cell
can be identified base on staining reaction:
a. Chromophobes
– make up approximately one half of all cells in adenohypophysis.
b. Acidophils
– make up approximately 40% of all cells in adenohypophysis; secretes GH and
PRL
c. Basophils
– form about 10% of adenohypophysis; secretes TSH, ACTH, FSH, LH and MSH.
Control of secretion in the
adenohypophysis
1. Hypothalamus
secretes releasing hormones into the blood, which are then carried to the
hypophyseal portal system.
2. Hypophyseal
portal system carried blood from the hypothalamus directly to the
adenohypophysis where the target cells of the releasing hormone are located.
3. Releasing
hormones influence the secretion of hormones by acidophils and basophils.
4. Through
negative feedback, the hypothalamus adjusts the secretions of the
adenohypophysis, which then adjusts the secretions of the target glands that in
turn adjust the activity of their target tissues.
5. In
severe pain or intense emotion, the hypothalamus translates nerve impulses into
hormone secretions by endocrine glands, basically creating a mind–body link.
A.
The Growth
Hormone: Somatotropin
Functions of
GH
1. Promotes
growth of bone, muscle and other tissues by accelerating amino acid transport
into the cell.
2. Stimulates
fat metabolism by mobilizing lipids from storage in adipose cells and speeding
up catabolism of the lipid after they have entered another cell.
3. GH
tends to shift cell chemistry away from glucose catabolism and toward lipid
catabolism as an energy source; this leads to increase blood glucose level.
4. GH
and insulin function as antagonist and are vital to maintaining homeostasis of
blood glucose levels.
5. Found
in highest concentration in all cells on adenohypophysis
Regulation of
secretion of GH
1. First,
the liver is stimulated by GH to produce proteins called somatomedins
(growth factors). Two somatomedins are found in human plasma: insulinlike
growth factor II or IGF–II (somatomedin A) and insulinlike growth
factor I or IGF–I (somatomedin C). The compound that was known as somatomedin
B is actually acidic glial cell growth factor and not one
of the somatomedins.
2. Second,
IGF–I binds to receptors on the cartilage and bone cells to stimulate DNA
synthesis and cell growth. The regulation of GH secretion appears to be
multifaceted. The hypothalamus contains growth hormone–releasing hormone
(somatocrinin), a small peptide that induces the secretion of GH. Also present
in the hypothalamus is growth hormone–inhibiting hormone (GHIH) or
somatostatin. These two hormones act together to cause increases and decreases
in the concentration of circulating GH. In addition, hypoglycemia induces the
secretion of GH as well as some amino acids.
3. Peak
levels occur 1–4 hours after the onset of sleep. These nocturnal sleep bursts,
which account for nearly 70% of daily GH secretion, are greater in children and
tend to decrease with age. Glucose infusion will not suppress this episodic
release. Emotional, physical and chemical stress, including surgery, trauma,
exercise, electroshock therapy and pyrogen administration, provoke GH release
and impairment of secretion leading to growth failure.
4. Glucose
administration, orally or intravenously, lowers GH in healthy subjects and
provides a single physiologic maneuver useful in diagnosis of acromegaly. In
contrast, hypoglycemia stimulates GH release. This effect depends on
intracellular glycopenia, since the administration of 2– deoxyglucose also
increases GH.
5. A
protein meal or intravenous administration of amino acids causes GH release.
Paradoxically, states of protein–calorie malnutrition also increase GH,
possible as a result of decreased IGF–I production and lack of inhibitory
feedback.
6. Fatty
acids suppress GH responses to certain stimuli, including arginine and
hypoglycemia. Fasting stimulates GH secretion, possible as a means of
mobilizing fat as an energy source and presents protein loss.
7. Neurotransmitters:
Increased Decreased
α–adrenergic
agonist clonidine phentolamine
β–adrenergic
agonist propranolol isoproterenol
Serotonin precursors
antagonist
Dopamine agonist antagonist
levodopa
phenothiazines
apomorphine
bromocriptine
Clinical significance of GH
1.
Hypersecretion
a.
Acromegaly and
Gigantism: Signs and symptoms
(1) Soft
tissue proliferation with enlargement of the hands and feet accompanied by
increased sweating, heat intolerance, oiliness of the skin, fatigue and weight
loss.
(2) Increased
in ring, gloves and shoe size
(3) Acne,
sebaceous cysts and fibromata mollusca, skin tags and papillomas are common, as
in acanthosis nigricans of the axillae and neck and hypertrichosis in women
(4) Photophobia,
paresthesias, degenerative arthritis, cardiomegaly, and renal calculi also
occur.
(5) Hyperinsulinemia,
glucose intolerance, irregular or absent menses, decreased libido,
hypothyroidism, galactorrhea, gynecomastia, hypoadrenalism
Laboratory
findings
(1) Postprandial
plasma glucose may be elevated
(2) Serum
insulin is increased
(3) Elevated
serum phosphorous due to increased renal
tubular resorption of phosphate
(4) Hypercalciuria
2.
Hyposecretion
a.
Laron’s
dwarfism: Signs and symptoms
(1) Very
short, poorly growing children with delayed skeletal maturation, normal GH and
IGF–I values, and no signs of organic disease.
Laboratory
findings:
(1) Characterized
by high plasma GH and low plasma IGF–I concentrations. Growth rate does not
increase and IGF–I values do not rise when exogenous hGH is administered.
However, IGF–I administration raises growth rate and suppresses GH
concentrations. The basic defect is an inability to produce IGF–I in response
to growth hormone because of impaired or absent GH receptors. GHBP is absent in
the serum. It is inherited as an autosomal recessive disorder.
b.
Pygmies
(1) They
have a normal plasma GH, low IGF–I and normal IGF–II concentrations. They would
not respond to exogenous GH with improved growth rate or a rise in IGF–I, which
is of greater importance in stimulating growth than IGF–II.
Laboratory diagnosis
1.
Levodopa Test
a.
Method
The patient
should be fasting and at bed rest after midnight. Levodopa (500 mg) is given by
mouth.
b.
Sample
collection
Blood samples
for plasma GH determinations are obtained at 0, 30 and 60 minutes.
c.
Contraindication
Nausea and
vomiting may occur 45–60 minutes after levodopa is given. This test is safer
than the insulin hypoglycemia test in older patients.
d.
Interpretation
A normal
response is maximal level of GH greater than 6 ng/ml (279 pmol/L); however the
peak response is usually more than 20 ng/ml (930 pmol/L)
2.
Arginine
infusion Test
a.
Method
The patient
should be fasting after midnight. Give arginine hydrocholoride, 0.5 g/kg
intravenously, up to a maximum of 30 grams over 30 minutes. Pre–treatment with
estrogen in post–menopausal women and in men can also be done.
b.
Sample
collection
Blood for
plasma GH determination is collected at 0, 30, 60, 90 and 120 minutes. Arginine
infusion also stimulates insulin and glucagon.
c.
Contraindication
Nausea and
vomiting may occur. This test is contraindicated in patients with severe liver
disease, renal disease or acidosis.
d.
Interpretation
The response
is greater in women than in men. The lower limit of normal for the peak GH
response is 6 ng/ml (279 pmol/L) in non–estrogen treated patients and 10 ng/ml
(465 pmol/L) in estrogen – treated patients and pre –menopausal women.
3.
Glucose–Growth
Hormone Suppression Test
a.
Method
The patient
should be fasting after midnight. Give glucose, 75–100 grams orally.
b.
Sample
collection
GH and glucose
should be determined at 0, 20 and 60 minutes after glucose administration
c.
Contraindication
Patients may
complain of nausea after the large glucose load
d.
Interpretation
GH levels are
supposed to be less than 2 ng/ml (93 pmol/L) in healthy subjects. Failure of
adequate suppression or a paradoxical rise may be seen in acromegaly,
starvation, protein–calorie malnutrition and anorexia nervosa
4.
GRH Test
a.
Method
GRH (1ug/kg)
is given intravenously as bolus injection.
b.
Sample
collection
Blood samples
for GH are drawn at 0, 30 and 60 minutes.
c.
Contraindication
Mild flushing
and a metallic taste or smell occurs in a few patients.
d.
Interpretation
The range of
normal responses is wide. Most patients have a peak GH response of greater than
10 ng/ml (465 pmol/L) at 30–60 minutes.
B.
The Prolactin
(PRL): Lactogenic Hormone
Functions of
PRL
1. During
pregnancy, PRL promotes development of the breasts, anticipating milk
secretion; after the baby is born, PRL stimulates the mother’s mammary glands
to produce milk.
2. PRL
plays a supportive role (with luteinizing hormone) in maintaining the corpus luteum
of the ovary during the final phase of the menstrual cycle; sometimes called luteotropic
hormone.
Regulation of
secretion of PRL
Secretion of
PRL appears to be under the control of prolactin–inhibiting factor (PIF),
known as dopamine and comes from the hypothalamus. If dopamine
levels decline, PRL is secreted. If dopamine levels increases, PRL secretion is
inhibited. No prolactin–releasing factor has ever been identified, but
thyrotropin–releasing hormone (TRH) has been shown to induce increases in PRL
levels. The actual role of TRH in regulating PRL secretion has not been
established.
PRL secretion
is episodic. An increase is observed 60–90 minutes after sleep but in contrast
to GH, is not associated with a specific sleep phase. Peak levels are usually
attained between 4 and 7 AM. This sleep–associated augmentation of PRL release
is not part of a circadian rhythm like that of ACTH; it is related strictly to
the sleeping period regardless of when it occurs during the day.
Other stimuli
like stresses, including surgery, exercise, hypoglycemia and acute myocardial
infarction, cause significant elevation of PRL levels. Nipple stimulation in
non–pregnant women also increases PRL. This neurogenic reflex may also occur
from chest wall injury such as mechanical trauma, burns, surgery and herpes
zoster of thoracic dermatomes. This reflex discharge of PRL is abolished by
denaturation of the nipple or by spinal cord or brain stem lesions.
Pharmacologic
agents affecting PRL secretion
Increase Decrease
Dopamine
antagonist: phenothiazines, Dopamine
agonist: levodopa,
Haloperidol,
metaclopramite, reserpine, apomorphine,
bromocriptine,
methyl–dopa,
amoxipine, opiates pergolide
Opiods GABA
Neuramine
oxidase inhibitors
Cimetidine,
verapramil, licorice
Clinical
significance of PRL
1.
Hypersecretion
a.
Prolactinomas:
Clinical Features
(1) Galactorrhea
– maybe induced by a wide variety of stimuli ranging from local irritation or
stimulation of the chest wall to
ingestion of drugs that interfere with hypothalamic release of dopamine or its
binding to the pituitary lactotrophs. Careful breast examination is required in
most patients to demonstrate it.
(2) In
women – amenorrhea, oligomenorrhea with anovulation, decreased vaginal
lubrication, osteopenia, weight gain, fluid retention and irritability,
elevated levels of dehydroepiandrosterone (DHEA) sulfate, anxiety and
depression
(3) In
men – hypogonadism, decreased libido, headache, visual impairment or
hypopituitarism, decreased testosterone levels.
(4) Tumor
progression
b.
Microadenomas – intrasellar
adenomas less than 1 cm in diameter that present with manifestations of
hormonal excess without sellar enlargement or extrasellar extension.
Panhypopituitarism does not occur and such tumors are very successfully treated.
c.
Macroadenomas – those larger
than 1 cm in diameter and cause generalized sellar enlargement. Tumors 1–2 cm
in diameter confined to sella turcica can usually be successfully treated;
however, larger tumors and especially those with suprasellar, sphenoid sinus or
later extensions – are much more difficult to manage. Panhypopituitarism and visual
loss, increase in frequency with tumor size and suprasellar size are also
evident.
C.
The
Adrenocorticotropic Hormone (ACTH)
Functions of
ACTH
1. Stimulates
the secretion of glucocorticoids, minerolocorticoids and androgenic steroids
from the adrenal cortex.
2. Increase
RNA, DNA and protein synthesis.
3. Its
biologically active fragment beta–lipotropin (B–LPH) and beta–endorphin acts as
endogenous opiates suggesting a roloe in pain appreciation.
4. Stimulates
cyclic AMP production and subsequent lipolysis from adipose tissue.
5. It
is associated with Melanocyte Stimulating Hormone (MSH), thereby has a role on
hyperpigmentation.
Regulation of
synthesis
ACTH is
synthesized from a large precursor molecule called proopiomelanocortin.
The physiologic secretion of ACTH is mediated through neural influences by
means of a complex of hormones, the most important of which is
corticotropin–releasing hormone (CRH).
1. The
circadian rhythm is superimposed on episodic secretion; it is the
result of central nervous system events that regulate both the number and
magnitude of CRH and ACTH secretory episodes. Control secretion is low in the
late evening and continues to decline in the first several hours of sleep, at
which time plasma cortisol levels may be undetectable. During the third and
fifth hours of sleep, there is an increase in secretion; but the major
secretory episodes begin in the sixth to eight hours of sleep and then begin to
decline as wakefulness occurs. About half of the total daily cortisol output is
secreted during this period. Cortisol secretion then gradually declines during
the day with fewer secretory episodes of decreased magnitude; however, there is
increased cortisol secretion in response to eating and exercise.
Although this
general pattern is consistent, there is considerable intra and interindividual
variability, and the circulation rhythm maybe altered by changes in sleep
pattern, light dark exposure and feeding times. Cyproheptadine
inhibits the circadian rhythm, possible by its antiserotonergic effects,
whereas other drugs usually have no effects. The rhythm is also changed by:
a. Physical
stress such as major illnesses, surgery, trauma or starvation.
b. Psychologic
stress, including severe anxiety, endogenous depression and manic phase of
manic depressive psychosis.
c. Central
nervous system and pituitary disorders
d. Cushing’s
syndrome
e. Liver
disease and other conditions that affect cortisol metabolism
f.
Chronic renal failure
g. Alcoholism
h. Pyrogen
and vasopressin administration
2. Fast
feedback inhibition of ACTH secretion is rate–dependent – i.e., it
depends on the rate of increase of the glucocorticoid but not the dose
administered. This phase is rapid and basal and stimulated ACTH secretion both
diminish within minutes after the plasma glucocorticoid level increases. This
fast feedback phase is transient and last less than 10 minutes, suggesting that
this effect is not mediated via cystolic glucocorticoid receptors but rather
via actions on the cell membrane.
3. Delayed
feedback inhibition after the initial rate–dependent effects on
glucocorticoid further suppress CRH and ACTH secretion by mechanisms that are
both time and dose–dependent. Thus with continued glucocorticoid, ACTH level
continue to decrease and become unresponsive to stimulation. The ultimate
effect of prolonged glucocorticoid administration is suppression of CRH and
ACTH release and atrophy of the zona fasciculate and reticularis as a
consequence of ACTH deficiency. The suppressed hypothalamic– pituitary–adrenal
axis fails to respond to stress and stimulation. Delayed feedback appears to
act via the classic glucocorticoid receptor, thus reducing synthesis of the
messenger RNA for pro–opiomelanocortin, the precursor of ACTH.
Clinical
significance of ACTH
1.
Hypersecretion
a.
Cushing’s
syndrome
(1) ACTH–dependent
(a) Cushing’s
disease 68%
(b) Ectopic
ACTH syndrome 15%
(2) ACTH–independent
(a) Adrenal
adenoma 9%
(b) Adrenal
carcinoma 8%
Signs and
symptoms:
(a)
Obesity
Weight gain is
the first symptom usually affecting mainly the face, neck, trunk, abdomen with
relative sparing of the extremities. Accumulation of fat in the face leads to
typical “moon faces” which is present in 75% of cases and is accompanied by
facial plethora in most patients. Fat accumulation around the neck is prominent
in the supraclavicular and dorsocervical fat pads; the latter is responsible
for the “buffalo hamp.”
(b) Skin
changes
Atrophy of the
epidermidis and its underlying connective tissue leads to thinning (a
transparent appearance of the skin) and facial plethora. Easy bruisability
following minimal trauma is present in about 40%. Striae occur in 50–70% which
is typically red to purple, depressed below the skin surface secondary to loss
of underlying connective tissue, and wider than the pinkish white striae that
may occur with pregnancy or rapid weight gain. These striae are most commonly
abdominal but may also occur over the breast, hips, buttocks thighs and
axillae.
Mucocutaneous
fungal infections are frequent including tinea versicolor,
involvement of the nails (onchomycosis) and oral candidiasis. Minor wounds and
abrasions may heal slowly and surgical incisions sometimes undergo dehiscence.
(c)
Hirsutism
Present in 80%
of female patients owing to hypersecretion of adrenal androgens. Facial
hirsutism is most common but increased hair growth may also occur over the
abdomen, breasts, chest and upper thighs. Acne and seborrhea usually accompany
hirsutism. Virilism is unusual except in cases of adrenal carcinoma, in which
it occurs in about 20%.
(d) Hypertension
The diastolic
blood pressure is greater than 100 mmHg and is responsible for mortality and morbidity
of the syndrome.
(e)
Gonadal
dysfunction
This is very
common as a result of elevated androgens (in females) and cortisol (in males
and to a lesser extent in females). Amenorrhea occurs in 75% of premenopausal
women and is usually accompanied by infertility. Decreased libido is frequent
in males and some have decreased body hair and soft testes.
(f)
Psychologic
disturbances
Mild symptoms
consist of emotional lability and increased irritability. Anxiety, depression,
poor concentration and poor memory may also be present. Euphoria is frequent
and occasional patients manifest overtly manic behavior. Sleep disorders are
present in most patients, with either insomnia or early morning awakening.
Severe
psychologic disorders occur in a few patients and include severe depression,
psychosis with delusions or hallucinations and paranoia. Some patients have
committed suicide.
(g)
Muscle
weakness
This occurs in
about 60% of cases; it is more often proximal and is usually most prominent in
the lower extremities.
(h) Osteoporosis
Osteoporosis
is present in most patients; back pain is an initial complaint in 58% of cases.
Pathologic fractures in severe cases involving the ribs and vertebral bodies.
Compression fractures of the spine are demonstrable radiographically in 16 –
22%.
(i)
Renal calculi,
thirst and polyuria
Laboratory
findings in Cushing’s syndrome
(a) High
normal hemoglobin, hematocrit and red cell count are usual; polycythemia is
rare.
(b) Total
white blood cell counts are usual normal, however, both the percentage of
lymphocytes and total lymphocytes count may be subnormal. Eosinophils are also
depressed, a total eosinophil count less than 100/ul is present in most
patients.
(c) Normal
serum electrolytes, however, hypokalemic alkalosis occurs when there is marked
steroid hypersecretion with ectopic ACTH syndrome or adrenocortical carcinoma.
(d) Serum
calcium is normal; serum phosphorous is low normal or slightly depressed.
Hypercalciuria is present in 40% cases.
(e) Glycosuria
is present in patients with fasting or post prandial hyperglycemia. Most
patients have secondary hyperinsulinemia and abnormal glucose tolerance.
2.
Hyposecretion
a.
Addison’s
disease: Primary Adrenocortical Deficiency
Signs and
symptoms:
(1) Hyperpigmentation
of the skin and mucous membrane and is increased in sun–exposed areas and
accentuated over pressure areas such as the knuckles, toes, elbows and knees.
It is accompanied by increased numbers of black or dark brown freckles.
(2) General
weakness, fatigue and malaise, anorexia and weight loss are invariable features
of the disorder.
(3) Increase
in gastrointestinal symptom maybe misdiagnosed with primary intraabdominal
process.
(4) Hypotension
is present in about 90% of patients and is accompanied by orthostatic symptoms
and occasionally syncope. Salt cravings occur in about 20% of patients.
(5) Severe
hypoglycemia may occur in children. This finding is unusual in adults but may
be provoked by fasting, fever, infection or nausea and vomiting especially in
acute adrenal crisis.
(6) Amenorrhea,
loss of axillary and pubic hair as a result of decreased secretion of adrenal
androgens.
Types of
Primary Adrenocortical Deficiency
(1)
Autoimmune
Adrenocortical Insufficiency
Characterized
by lymphocytic infiltration of the adrenal cortex histologically. The adrenals
are small and atrophic and the capsule is thickened. The adrenal medulla is
preserved, though cortical cells are largely absent, show degenerative changes
and are surrounded by a fibrous stroma and lymphocytic infiltrates.
Alopexia,
malabsorption syndrome, chronic hepatitis, vitiligo and pernicious anemia are
also common.
Two
polyglandular syndromes accompanying Autoimmune Adrenocortical Insufficiency
(a) Adrenal
insufficiency, hyperparathyroidism and chronic mucocutaneous candidiasis
(b) Adrenal
insufficiency, Hashimoto’s thyroiditis and insulin – dependent diabetes
mellitus
(c) Ovarium
failure is common in both syndrome
(2)
Adrenocortical
insufficiency due to invasive and hemorrhagic disorders
(a) Adrenal
tuberculosis and other destructive cause – due to hematogenous infection of the
cortex and usually occurs as a complication of systemic tuberculous infection
(lung, gastrointestinal tract or kidney). The adrenal glands are replaced by
caseous necrosis; both cortical and medullary tissue is destroyed.
Calcification of the adrenals is frequent and is radiologically demonstrable.
(b) Bilateral
adrenal hemorrhage – in children, cause by fulminant meningococcemia and Pseudomonas
septicemia.
– in adults,
cause by anticoagulant therapy given for other major illnesses, septicemia,
coagulation disorder, adrenal vein thrombosis, adrenal metastases, trauma,
abdominal surgery and obstetric gestational and postpartum complication.
b.
Secondary
Adrenocortical Deficiency
Manifested by weakness, lethargy, easy
fatigability, anorexia, nausea and occasionally vomiting. Myalgia and
arthralgia also occur. Hypoglycemia is occasionally the presenting features.
Acute decompensation with severe hypotension or shock unresponsive to
vasopressors may occur.
Laboratory
diagnosis of ACTH
1.
ACTH
stimulation test
a. Procedure
Two 24 hour urine collections are
obtained, prior to and the day after. The rest for baseline 17–KS and 17–OHCS
or ketogenic steroid is determined.
25 I.U. of ACTH is added to 500 ml of
normal saline and is administered to a patient continuously for exactly 8
hours. The timing of the infusion is critical.
Urine is collected during the
administration and is continued for a total of 24 hours. It is assayed for 17–OHCS
and 17–KS.
b. Result
Normal person – urinary steroid level
is raised three to five times above the baseline
No increase is observed in
(1) Addison’s
disease
(2) Primary
adrenocortical failure
Very little increase above the already
high value in:
(1) Cushing’s syndrome
(2) Adrenocortical
tumors
Little if any response in
(1) Congenital
adrenal hyperplasia
2.
Metopirone
test (metyrapone)
a. Method
Overnight test: Metyrapone is given
orally between 11 and 12 PM with a snack to minimize gastrointestinal
discomfort. The dose is 2 grams for patients weighing less than 70 kg; 2.5
grams for patients weighing 79 – 90 kg and 3 grams for patients weighing over
90 kg.
Three day test: Twenty four hour urine
collections are made for 3 consecutive days and metyrapone, 750 mg is given
every 4 hours for six doses on the second day.
b. Sample
collection
Overnight test: Blood for plasma 11–deoxycortisol
and cortisol determination is obtained at 8 AM in the morning after the
metyrapone is given.
Three day test: The three consecutive 24–hour
urine samples are analyzed for 17–hydroxycorticosteroids and creatinine
determinations.
c. Possible
side effects, contraindication:
Gastrointestinal upset may occur.
Adrenal insufficiency may occur. Metyrapone should not be used in sick patients
or those in whom primary adrenal insufficiency is suspected.
d. Interpretation
Overnight test: Serum 11–deoxycortisol
should increase to >7 ug/dL (0.19 umol/L). Cortisol should be <10 ug/dl
(0.28 umol/L) in order to ensure adequate inhibition of 11β–hydroxylation.
Three day test: Urine 17–hydroxycorticosteroid
should be double on day 2 or 3.
3.
Dexamethasone
suppression test
This is used
to differentiate Cushing’s syndrome caused by adrenal tumor from adrenal
hyperplasia. ACTH is suppressed with a synthetic glucocorticoid, dexamethasone.
A drug is
administered in doses of 0.5 mg at 6 hours intervals on two successive days and
2 mg at 6 hours intervals in the following days. Prior to the test, two 24 hour
baseline control urine specimen are collected and a specimen on each second day
of suppression therapy (0.5 mg and 2 mg, respectively) for measurement of
17–OHCS or 17–ketogenic steroids levels.
Normal
subjects show a decrease of about one–half in urinary corticosteroid levels
after administration of 0.5 mg dexamethasone.
In bilateral
adrenal hyperplasia, suppression will be observed only after repetition of the
procedure with the larger dose. Normal subjects show suppression to less than 3
mg/day or 2 mg dose but patients with Cushing’s syndrome do not suppress.
4.
CRH Test
a.
Method
CRH (1 ug/kg)
is given intramuscularly as a bolus injection.
b.
Sample
collection
Blood samples
for ACTH and cortisol are taken at 0,15, 30 and 60 minutes.
c.
Contraindication
Flushing often
occurs. Transient tachycardia and hypotension have also been reported.
d.
Interpretation
The ACTH
response is dependent on the assay utilized and occurs 15 minutes after CRH is
administered. The peak cortisol response occurs at 30 – 60 minutes and is
usually greater than 10 ug/dl (276 nmol/L)
D.
The
Gonadotropins
1.
Follicle
Stimulating Hormone (FSH): Functions:
a. In
females, stimulates primary graafian follicles to grow toward maturity and
stimulates follicle cells to secrete estrogen
b. In
males, stimulates development of the seminiferous tubules of the testes and
maintains spermatogenesis.
2.
Luteinizing
Hormone (LH): Functions:
a. In
females, stimulates the formation and activity of the corpus luteum of the
ovary. It also stimulates corpus luteum to secrete estrogen and progesterone.
b. In
males, stimulates interstitial cells in the testes to develop and secrete
testosterone.
Regulation of
secretion of LH and FSH
1.
Episodic
secretion
2.
Positive
feedback
During the
menstrual cycle, estrogens provide a positive influence on GnRH effects on LH
and FSH secretion, and the rise in estrogen during the follicular phase is the
stimulus for the LH and FSH ovulatory surge. This phenomenon suggests that the
secretion of estrogen is to some extent influenced by an intrinsic ovarian
cycle. Progesterone amplifies the duration of the LH and FSH surge and augments
the effect of estrogen. After this midcycle surge, the developed egg leaves the
ovary. Ovulation occurs approximately 10–12 hours after the LH peak and 24–36
hours after the estradiol peak. The remaining follicular cells in the ovary are
converted, under the influence of LH, to a progesterone–secreting structure,
the corpus luteum. After about 12 days, the corpus luteum involutes, resulting
in decreased estrogen and progesterone levels and then uterine bleeding.
3.
Negative
feedback
In women,
primary gonadal failure or menopause results in elevations of LH and FSH, which
can be suppressed with long term, high dose estrogen therapy. However, a
shorter duration of low dose estrogen may enhance the LH response to GnRH.
In men,
primary gonadal failure with low circulating testosterone levels is also
associated with elevated gonadotropins. However, testosterone is not the sole
inhibitor of gonadotropins in men, since selective destruction of the tubules
(e.g., by cyclophosphamide therapy) results in azoospermia and elevation of
only FSH.
Inhibin, a
polypeptide secreted by the Sertoli cells of the seminiferous tubules, is the
major factor that inhibits FSH secretion by negative feedback. Androgens
stimulate inhibin production, thus peptide may help to locally regulate
spermatogenesis.
Laboratory
evaluation of LH and FSH
1.
GnRH Test
Method
The patient
should be at rest but need not be fasting. Give GnRH (gonadorelin), 100 ug
intravenously, over 15 seconds.
Sample
collection
Blood samples
for LH and FSH determinations are taken at 0, 30 and 60 minutes. Since the FSH
response is somewhat delayed, a 90 minutes specimen may be necessary.
Possible side
effects / Contraindication
Side effects
are rare and no contraindication have been found
Interpretation
This response
is dependent on sex and time of the menstrual cycle. An increase of LH of 1.3 –
2.6 ug/L (11.7 – 23.4 IU/L) is considered to be normal; FSH usually responds
more slowly and less markedly and may not increase in healthy subjects.
2.
Clomiphene
Test
Method
Clomiphene is
administered orally. For women, give 100 mg daily for 5 days (being on day 5 of
the cycle if the patient is menstruating); for men, give 100 mg daily for 7–10
days.
Sample
collection
Blood for LH
and FSH determinations is drawn before and after clomiphene is given.
Possible side
effects / Contraindications
This drug may,
of course, stimulate ovulation, and women should be advised accordingly.
Interpretation
In women, LH
and FSH levels peak on the fifth day to a level above the normal range. After
the fifth day, LH and FSH levels decline.
In men, LH
should double after 1 week; FSH will also increase, but to a lesser extent.
E.
The Thyroid
Stimulating Hormone (FSH)
Functions of
TSH or thyrotropin
1. Increases
the size of the thyroid follicular cells.
2. Increases
he uptake of iodides by the thyroid cells for the ECF.
3. Increases
the release of the thyroxine from the thyroid colloid follicles. TSH stimulates
growth of the thyroid and biosynthesis of thyroxine.
Regulation of
secretion of TSH
1. Regulation
of TSH is also under control of thyrotropin–releasing hormone (TRH) released by
hypothalamus
2. TSH
secreted by the pituitary binds to receptors on the basal side of the
follicular cell resulting in rapid stimulation of both endocytosis
(transport of thyroglobulin from the lumen into circulation on the basal
membrane side) and exocytosis (transport of thyroglobulin into
the follicular lumen), making extensive movement of the apical membrane
necessary.
3. The
membrane formation and redistribution are activated by adenylate cyclase and
consequential increase of cAMP is evident.
4. Initial
stimulation of TSH (0–5 minutes) results in a decrease in exocytic vesicles and
a corresponding increase in the apical membrane surface area returns to
prestimulation levels, and there is a marked increase in the surface area of
the endocytic structures.
5. Within
20–30 minutes, the endocytic structures separate into pseudopods and colloid
droplets.
6. The
colloid droplets fuse with lysosomes, digesting thyroglobulin and present
thyroid hormone to the basal membrane surface.
7. This
cascade of events accounts for the rapid increase of thyroid hormone observed
in response to TSH stimulation. Slightly longer TSH stimulation enhances
exocytic processes, resulting in formation of prothyroid hormone storage
(thyroglobulin) in the follicular lesions.
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