Download Základní vyšetření v endokrinologii

Basic laboratory tests
in endocrinology
Drahomíra Springer
ÚKBLD VFN a 1.LF UK Praha
Hormones



Hormones are chemical messengers secreted
into blood or extracellular fluid by one cell that
affect the functioning of other cells
One hormone type usually affects only target
cells.
A target cell has receptors for the hormone
3

Pineal gland


It produces melatonin, a hormone that affects the
modulation of wake/sleep patterns and photoperiodic
(seasonal) functions
Thymus




located posterior to the sternum
ater puberty begins to decrease in size
the primary function is the processing and maturation of Tlymphocytes
produces a hormone, thymosin, which stimulates the
maturation of lymphocytes in other lymphatic organs
Hormonal pathway
•Endocrine action: the hormone is distributed in blood and
binds to distant target cells.
•Paracrine action: the hormone acts locally by diffusing from
its source to target cells in the neighborhood.
•Autocrine action: the hormone acts on the same cell that
produced it.
Structural groups of hormons

Peptides and proteins




Steroids - derivatives of cholesterol


Glucocorticoids (cortisol), mineralocorticoids (aldosterone),
androgens (testosterone), estrogens, (estradiol), progestogens
(progesterone)
Amino acid derivatives



many protein hormones are synthesized as prohormones
circulate unbound to other proteins, exception – IGF 1
the halflife of circulating peptide hormones is only a few minutes
Thyroid hormones are basically a "double" tyrosine with the critical
incorporation of 3 or 4 iodine atoms
Catecholamines include epinephrine and norepinephrine, which are used as
both hormones and neurotransmitters
Fatty acid derivatives – Eicosanoids

prostaglandins, prostacyclins, leukotrienes and thromboxanes
Concentration of hormons



Rate of production: Synthesis and secretion of hormones
are mediated by positive and negative feedback circuits
Rate of delivery: high blood flow delivers more hormone
than low blood flow to a target organ
Rate of degradation and elimination: Hormones are
metabolized and secreted from the body through several
routes. If a hormone's biological halflife is long, effective
concentrations persist for some time after secretion ceases
Hypothalamus


Secrete hormones that strictly control secretion
of hormones from the anterior pituitary
They are referred to as releasing hormones
and inhibiting hormones, reflecting their
influence on anterior pituitary hormones.
Pituitary gland

anterior and posterior pituitary secrete a battery
of hormones that collectively influence all cells
and affect virtually all physiologic processes
Anterior Pituitary
Hormone
Major target organ(s)
Liver, adipose tissue
Promotes growth
(indirectly), control of
protein, lipid and
carbohydrate metabolism
Thyroid gland
Stimulates secretion of
thyroid hormones
Adrenal gland (cortex)
Stimulates secretion of
glucocorticoids
Mammary gland
Milk production
Ovary and testis
Control of reproductive
function
Ovary and testis
Control of reproductive
function
Growth hormone
Thyroid-stimulating hormone
Adrenocorticotropic hormone
Prolactin
Luteinizing hormone
Follicle-stimulating hormone
Major Physiologic Effects
Posterior Pituitary
Hormone
Major target organ(s)
Antidiuretic hormone
Major Physiologic
Effects
Kidney
Conservation of body
water
Ovary
Stimulates milk ejection
and uterine contractions
Oxytocin
CNS inputs
Hypothalamus
Hypothalamic
hormones
Intrapituitary
cytokines
Pituitary
Pituitary
trophic
hormones
Target Gland
Secretion of pituitary hormones determined by
- hypothalamic hormones
- intrapituitary factors
- peripheral feedback
Peripheral
hormones
Synthesis of Pituitary Hormones
Cell type
% in pituitary
Gonadotrophs
5 - 10
Prolactin
Lactotrophs
10 - 25
TSH
Thyrotrophs
5 - 15
GH
Somatotrophs
35 - 45
ACTH
Corticotrophs
1-2
LH
FSH
Growth hormone

role in stimulating body growth

stimulate the liver and other tissues to secrete
IGF-I, resulting in bone growth
important effect on protein, lipid and
carbohydrate metabolism

Growth hormone

Protein metabolism

stimulates protein anabolism in many tissues
increases amino acid uptake and protein synthesis

decreases oxidation of proteins.


Fat metabolism


enhances the utilization of fat
Carbohydrate metabolism


maintain blood glucose within a normal range
has anti-insulin activity, supresses the abilities of insulin to
stimulate uptake of glucose in peripheral tissues and enhance
glucose synthesis in the liver
Control of GH secretion
 stress, exercise, nutrition, sleep and growth hormone itself

Growth hormone-releasing hormone (GHRH)


Somatostatin (SS)



hypothalamic peptide that stimulates both the synthesis and
secretion of GH
peptide produced by several tissues in the body, including the
hypothalamus
inhibits GH release in response to GHRH and to other stimulatory
factors such as low blood glucose concentration.
Ghrelin


peptide hormone secreted from the stomach
stimulates secretion of growth hormone.
Disease States


Deficiency in growth hormone or defects in its
binding to receptor are seen as growth retardation
or dwarfism. The manifestation of growth hormone
deficiency depends upon the age of onset of the
disorder and can result from either heritable or
acquired disease.
The effect of excessive secretion of growth hormone
is also very dependent on the age of onset and is seen
as two distinctive disorders:
Giantism and Acromegaly
Giantism
 Excessive growth hormone
secretion that begins in young
children or adolescents. It is a very
rare disorder, usually resulting from
a tumor of somatotropes
 220-240 cm
 Lower IQ
 metabolic malfunctions
Acromegaly




excessive secretion of GH in adults
usually benign pituitary tumors
onset of this disorder occurring over several years
overgrowth of extremities, soft-tissue swelling,
abnormalities in jaw structure and cardiac disease
 excessive GH and IGF-I also lead to a number of
metabolic derangements, including hyperglycemia.
IGF-1




insuline like growth factor – I stimulates proliferation
of chondrocytes (cartilage cells), resulting in bone
growth
key player in muscle growth, it stimulates both the
differentiation and proliferation of myoblasts. It also
stimulates amino acid uptake and protein synthesis in
muscle and other tissues.
Transport protein - IGFBP 3
Primary investigation for acromegaly and giantism
diagnosis
ACTH

Adrenocorticotropic hormone



secreted from the anterior pituitary in response to
corticotropin-releasing hormone (CRH) from the
hypothalamus - response to stress
stimulates the adrenal cortex - secretion of
glucocorticoids - cortisol
CRH is inhibited by glucocorticoids – negative
feedback loop
Prolactin






Secreted by the anterior pituitary under the control of
prolactin inhibitory factor secreted by the hypothalamus
levels rise during pregnancy and cause stimulation of milk
production after childbirth
elevated serum prolactin levels are the most common
disorder of the hypothalamic-pituitary axis
inhibits the release of other gonadotropic hormones
Dopamine serves as the major prolactin-inhibiting factor
Estrogens provide a positive control over prolactin synthesis
and secretion
Macroprolactin




Prolactin in human serum exists as multiple forms of
different molecular sizes of which the predominant species
(90%) is the monomeric form (MW - 22.5kD)
In some individuals, however, the predominant circulating
prolactin is the very high molecular weight form
(macroprolactin, MW >100kD)
This phenomenon, termed macroprolactinaemia, is a nonpathological cause of persistent, and often asymptomatic
hyperprolactinaemia
A method for assessing prolactin recovery based on
precipitation of macroprolactin by polyethylene glycol
(PEG) has been proposed as a simple test for detection of
macroprolactinaemia
Hyperprolactinaemia



relatively common disorder in humans
condition - prolactin-secreting tumors and therapy with
certain drugs
Women



amenorrhea -lack of menstrual cycles
galactorrhea - excessive or spontaneous secretion of milk
Men



Hypogonadism
decreased sex drive, impotence, decreased sperm production
breast enlargement (gynecomastia), but very rarely produce
milk.
TSH



Thyroid-stimulating hormone, thyrotropin
stimulates the thyroid gland to synthesize and
release thyroid hormones
glycoprotein hormone composed of two
subunits, non-covalently bound to one. The
alpha subunit is also present FSH, LH and in
the placental hormone chorionic gonadotropin.
Gonadotropins

stimulate the gonads
in men - the testes
 in women - the ovaries
They are not necessary for life, but are essential for
reproduction


TSH, LH and FSH are large glycoproteins
composed of a and b subunits


a subunit is identical in all three hormones
b subunit is unique and endows each hormone
with the ability to bind its own receptor.
FSH
 ovaries contain follicles, (fluid-filled sacs in which eggs grow)
 in the female, FSH stimulates a follicle to mature during each
menstrual cycle
 follicles mature in the ovary and continue to develop in the
fallopian tube, which connects the ovary to the uterus
 FSH is also critical for sperm production. It supports the
function of Sertoli cells, which in turn support many
aspects of sperm cell maturation
LH


Luteinizing hormone
Stimulates secretion of sex steroids from the gonads




In the testes - secretion of testosterone
in the ovary - secretion of estrogen
ovulation of mature follicles on the ovary is induced by a large
burst of LH secretion
LH is required for continued development and function of
corpora lutea
Measurement of anterior
pituitary hormones
1. Baseline measurements
ACTH (Cortisol 9am, 12mn), TSH (FT4), Prolactin, LH/FSH
(Testosterone, Estradiol)
2. Dynamic function tests
Why?
- low pituitary hormone levels not diagnostic
- normal levels do not exclude pituitary disease
- pulsatile excretion + diurnal variation confuse interpretation of
baseline levels
- if baseline levels are high dynamic tests can aid in differential
diagnosis
Hypofunction  stimulation tests
Hyperfunction  suppression tests
Types of pituitary adenomas
Prolactinomas
Somatotroph
Gonadotroph
50-55%
20-23%
< 5%
Non-functional
Corticotroph
Thyrotroph
20-25%
5-8%
< 1%
Thyroid
Thyroid Hormones



Triiodothyronine (T3)
Thyroxine (T4)
Principal actions



Stimulate energy use
Cardiac stimulation
Promote growth &
development
Neurons in the hypothalamus
secrete thyroid releasing hormone
(TRH), which stimulates cells in the
anterior pituitary to secrete thyroidstimulating hormone (TSH).
TSH binds to receptors on epithelial
cells in the thyroid gland, stimulating
synthesis and secretion of thyroid
hormones, which affect probably all
cells in the body.
When blood concentrations of
thyroid hormones increase above a
certain threshold, TRH-secreting
neurons in the hypothalamus are
inhibited and stop secreting TRH.
Calcitonin


The major source of calcitonin is from the
parafollicular or C cells in the thyroid gland
participate in calcium and phosphorus metabolism



Bone: suppresses resorption of bone, releasing Ca and P
into blood
Kidney: Calcitonin inhibits tubular reabsorption Ca and P
Elevated blood ionized calcium levels strongly
stimulate calcitonin secretion
DISORDERS OF THE
THYROID

HYPERFUNCTION: Hyperthyroidism

HYPOFUNCTION: Hypothyroidism


Adult

Child
GOITER:

Simple

Toxic
HYPERTHYROIDISM:
Definition
A state of hypermetabolism and hyperactivity
of cardiovascular and neuromuscular systems
induced by high levels of circulating T3 , T4 ,
or both.
Major cause: Graves Disease
GRAVES DISEASE:
Prevalence
 Young
to middle-aged adults
 Females
more often affected
 Familial
incidence
GRAVES DISEASE

Behavior changes

Goiter

Ocular manifestations

Insomnia, restlessness

Palpitations, hand tremors, nervousness

Increased body temperature
GRAVES DISEASE:
Thyroid Storm

Life threatening form of thyrotoxicosis.

Exagerated clinical features:

Increased temperature

Tachycardia and cardiac arrhythmias

Congestive heart failure

Extreme restlessness, agitation, psychoses

Nausea and vomiting, severe diarrhea
HYPOTHYROIDISM:
Etiology

Congenital: Cretinism

Acquired


Hashimoto thyroiditis

Iodine deficiency or impeded utilization

Iatrogenic events: XRT, thyroidectomy

Goitrogen ingestion
Secondary (pituitary origin)
HYPOTHYROIDISM
 Older
age group (60s)
 Females
more often affected
 Pregnant
women
HYPOTHYROIDISM

Decreased metabolism, reduced appetite
Slow mentation, speech, movement
Goiter (optional)
Skin cool and dry
Weakness, lethargy, fatigability
Intolerance to cold
Deepened voice
Hypercholesterolemia
Menstrual irregularities

In advanced disease: MYXEDEMA








GOITER

Definition:



Thyroid enlargement, with (toxic goiter) or without (simple goiter)
increased hormone production.
Types of goiter:

Diffuse

Nodular
Etiology:

Inflammatory process (thyroiditis)

Functional disorders

Neoplasms
Hashimoto Thyroiditis

Etiology: autoimmune

Prevalence:


Females are more often affected

Disease in males is more severe
Clinical characteristics:

Thyroid enlargement

Symptoms of tracheal/esophageal compression

Malignant transformation risk: 5%

Association with other autoimmune diseases
Neoplasms

Benign tumors:


follicular adenomas
Malignant tumors:

Papillary carcinoma

Follicular carcinoma

Anaplastic carcinoma

Medullary carcinoma
Parathyroid glands



The 4 parathyroid glands (4x2
mm) are located near or attached
to the back side of the thyroid
gland
The glands synthesize and secrete
parathyroid hormone that controls
blood levels of calcium.
The structure of a parathyroid
gland is distinctly different from a
thyroid gland. The cells are arranged in
rather dense cords or nests around abundant
capillaries.
Parathyroid hormone



The most important endocrine regulator of Ca
and P concentration in extracellular fluid
PTH is released in response to low
extracellular concentrations of free calcium
PTH has a circadian rhythm



Max 14. – 16.h
Min 8.h
Sampling in ice, plasma or serum, -20oC
Parathyroid hormone



Mobilization of calcium from bone: stimulates
osteoclasts to reabsorb bone mineral, liberating
calcium into blood.
Enhancing absorption of calcium from the small
intestine: PTH stimulates production of the active
vitamin D. It induces synthesis of a calcium-binding
protein
Suppression of calcium loss in urine
Hyperparathyroidism

Primary hyperparathyroidism



most commonly due to a parathyroid tumor (adenoma)
which secretes the hormone without proper regulation
chronic elevations Ca (hypercalcemia), kidney stones and
decalcification of bone
Secondary hyperparathyroidism



kidney disease - unable to reabsorb Ca
inadequate nutrition – diets deficient in Ca or vitamin D, or
which contain excessive phosphorus
decalcification of bone ("rubber bones„)
Adrenal glands


Cortex
Medulla
Adrenal gland

Cortex (steroid hormon)




glucocorticoids
mineralocorticoids
From cholesterol - steroidogenesis
Medulla ( derivates of aminoacids)

epinephrine and norepinephrine
Adrenal medulla

circulating epinephrine and norepinephrine released from the
adrenal medulla have the same effects on target organs as
direct stimulation by sympathetic nerves

Increased rate and force of contraction of the heart muscle -epinephrine
Constriction of blood vessels - norepinephrine, increase blood pressure
Dilation of bronchioles - assists in pulmonary ventilation
Stimulation of lipolysis in fat cells - energy production
Increased metabolic rate: oxygen consumption and heat production
increase throughout the body in response to epinephrine
Dilation of the pupils
Inhibition of certain "non-essential" processes - gastrointestinal secretion
and motor activity.






Adrenal cortex

Cortisol

circadian rhythm min. 12 mn, max. about 6 am,  by stress

maintain normal concentrations of glucose in blood

Stimulation of gluconeogenesis, particularly in the liver
Mobilization of amino acids from extrahepatic tissues
Inhibition of glucose uptake in muscle and adipose tissue
Stimulation of fat breakdown in adipose tissue



Cortisol

Effects on inflammation and immune function


Glucocorticoids have potent anti-inflammatory and
immunosuppressive properties
glucocorticoids are also among the most frequently used
drugs, and often prescribed for their anti-inflammatory and
immunosuppressive properties
Aldosteron

Mineralocorticoid
critical role in regulating concentrations of minerals particularly Na and K - in extracellular fluids
The major target is the distal tubule of the kidney, where
it stimulates exchange of Na and K




Increased resorption of sodium
Increased resorption of water


an osmotic effect directly related to increased resorption of Na
Increased renal excretion of K
Addison's disease



hypoadrenocorticism
this disease is a result of infectious disease
(e.g. tuberculosis in humans) or autoimmune
destruction of the adrenal cortex
cardiovascular disease, lethargy, diarrhea, and
weakness. Aldosterone deficiency can be
acutely life threatening due to disorders of
electrolyte balance and cardiac function
Cushing’s Syndrome



hyperadrenocorticism
Excessive endogenous production of cortisol,
which can result from a primary adrenal defect
(ACTH-independent) or from excessive
secretion of ACTH (ACTH-dependent)
Administration of glucocorticoids for
theraputic purposes. This is a common sideeffect of these widely-used drugs.
Steroidogenesis in adrenal gland
Cholesterol
Desmoláza
Pregnenolon
17 hydroxy
pregnenolon
Progesteron
17 hydroxy
progesteron
DHEA
Androstendion
11b hydroxyláza
21 hydroxyláza
21 hydroxyláza
11deoxykortiko
Testoste
11
deoxykortizol
Estradiol
steron
ron
11b hydroxyláza
11b hydroxyláza
Kortikosteron
18 hydroxykorti
kosteron
18 hydroxyláza
Aldosteron
Kortizol
Pancreas
The bulk of the pancreas is composed of pancreatic exocrine cells and their
associated ducts. Embedded within this exocrine tissue are roughly one million
small clusters of cells called the Islets of Langerhans, which are the endocrine
cells of the pancreas
Islets of Langerhans

only 1-2% of the mass of the pancreas


Alpha cells (A cells) secrete glucagon.
Beta cells (B cells) produce insulin and are the most
abundant of the islet cells
Delta cells (D cells) secrete somatostatin

F cells secrete pancreatic polypeptid (PP)

Pancreas

Insulin and glucagon are critical participants in
glucose homeostasis and serve as acute regulators
of blood glucose concentration

A deficiency in insulin or deficits in insulin
responsiveness lead to the disease diabetes
mellitus
Glucose from the ingested lactose or
sucrose is absorbed in the intestine and
the level of glucose in blood rises
Elevation of blood glucose concentration
stimulates endocrine cells in the
pancreas to release insulin
Insulin has the major effect of facilitating
entry of glucose into many cells of the
body - as a result, blood glucose levels
fall
When the level of blood glucose falls
sufficiently, the stimulus for insulin
release disappears and insulin is no
longer secreted
Insulin



synthesized in significant quantities only in
beta cells in the pancreas
facilitates entry of glucose into muscle,
adipose and several other tissues
stimulates the liver to store glucose in the form
of glycogen
Insulin and lipid metabolism




Insulin promotes synthesis of fatty
acids in the liver
Insulin inhibits breakdown of fat in
adipose tissue
Insulin facilitates entry of glucose
into adipocytes and glucose can be
used to synthesize glycerol
indirectly stimulates accumulation
of fat in adipose tissue
Types of DM

Type 1 (IDDM) Insulin dependent



Destruction of pancreatic beta cells
No insulin produced
Type 2 (NIDDM) Non-insulin dependent


Cells are less responsive to insulin
Altered insulin secretion
Glukagon

Glucagon has a major role in maintaining normal
concentrations of glucose in blood - increasing blood
glucose levels

Glucagon stimulates breakdown of glycogen stored in the
liver
Glucagon activates hepatic gluconeogenesis - non-hexose
substrates such as amino acids are converted to glucose
Diseases associated with excessively high or low secretion
of glucagon are rare


Somatostatin



secreted by a broad range of tissues, including
pancreas, intestinal tract and regions of the
central nervous system outside the
hypothalamus
Somatostatin was named for its effect of
inhibiting secretion of GH
Somatostatin appears to act primarily in a
paracrine manner to inhibit the secretion of
both insulin and glucagon
Fertility
Ovarian Hormones








Two classes of ovarian sex hormones:
Estrogens and progestins
The most important of the estrogens is estradiol
The most important progestin is progesterone
Estrogens:
Promote proliferation and growth of sex related cells;
cause secondary sexual characteristics
Progestins:
Important for preparation of the uterus for pregnancy and
the breast for lactation
Estradiol
Principal Function: cellular proliferation;
growth of the tissues of sexual organs; growth
of other tissues related to reproduction
Progesterone


Residual cells within ovulated follicles proliferate to
form corpora lutea, which secrete the steroid
hormones progesterone and estradiol
Progesterone is necessary for maintenance of
pregnancy

secreted by the corpus luteum

it prepares the uterus for the development of the fertilised egg

this is called the proliferative phase of the uterus since there is a
proliferation of blood vessels in the uterine lining

these blood vessels serve as a nutrient source for the developing
embryo

Circulating levels (LH,FSH, Prog and Estradiol)
LH and FSH (IU/L)
50
ovulation
Estradiol (pmol/L)
Progesterone
(nmol/L)
1850 25
LH
FSH
40
1500 20
Progesterone
Estradiol
30
1100 15
20
740
10
370
1
7
14
Day of menstrual cycle
21
28
10
5
Investigation of amenorrhoea
Causes of amenorrhoea
 physiological e.g prepuberty, pregnancy, lactation, post
menopause
 anatomical e.g. absence of uterus
 structural endocrine disorders e.g. Kallman’s syndrome
(congenital lack of GnRH), severe head injury, pituitary
adenoma, Sheehan’s syndrome
 functional endocrine disorders e.g. weight loss, anorexia
nervosa, excessive exercise, stress
 all above result in decreased LH and FSH
Causes of amenorrhoea
premature ovarian failure (depletion of primordial
oocytes)
associated with autoimmune disorders (Addison’s
disease)
also caused by radiation/cytotoxic drug therapy for
Ca breast
increased LH and FSH seen
The menopause
time of permanent cessation of menstruation
normally occurs between ages 40-55 yrs, average
age of onset 49 - 51 yrs
decline in follicles leads to lower estradiol
FSH levels rise progressively from 41 yrs to 47 yrs
rise in FSH related to time of menopause
Testosterone






Androgen
testosterone is primarily secreted in the testes
of males and the ovaries of females
Necessary for normal sperm development
Libido
Mental and physical energy
Maintenance of muscle trophism
Infertility



The failure to achieve pregnancy after one year of
unprotected intercourse
the consistent failure to carry a pregnancy to term
treatable condition; > 50% of couples can achieve
pregnancy