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Principles of endocrinology

Semmelweis University
First Department of Medicine
Dr. Szathmári Miklós
01. February 2010.
Scope of endocrinology 1.

• The term endocrinology contrast the actions of


hormones secreted internally (endocrine) with
those secreted externally (exocrine) or into a
lumen, such as the gastrointestinal tract
• The hormone, derived from a Greek phrase
meaning „to set in motion” aptly describes the
dynamic actions of hormones as they elicit
cellular responses and regulate physiologic
processes through feedback mechanisms.
Scope of endocrinology 2.
Unlike many other specialties in medicine, it is not
possible to define endocrinology strictly along
anatomic lines
• The classic endocrine glands – pituitary, thyroid,
parathyroid, pancreatic islets, adrenal, and gonads-
communicate with other organs through the nervous
system, hormones, cytokins, and growth factors.
• The brain – in addition to its traditional synaptic function
– produces peptide hormones,such as hypothalamic
releasing factors, which exert regulatory influence over
pituitary hormonal secretion.
• The peripheral nervous system stimulates adrenal
medulla
• The immune and endocrine systems are also intimately
intertwined. Autoimmune thyroiditis and type 1 diabetes
mellitus are caused by dysregulation of immune
tolerance
Scope of endocrinology 3.
• The cytokins and interleukins have profound effects on
the functions of the pituitary,adrenal, thyroid, and gonads
• The kidney produces erythropoietin that stimulates
erythropoiesis in the bone marrow. Moreover the kidney
is also integrally involved in the renin-angiotensin axis,
and is a target of several hormones.
• The gastrointestinal tract produces a large number of
peptid hormones (cholecystokinin, ghrelin, gastrin,
secretin, VIP, etc.)
• The heart is the source of atrial natriuretic peptide,
which acts in classic endocrine fashion to induce
natriuresis at a distant target organ in the kidney).
Nature of hormones
• Amino acid derivates: dopamine, catecholamine and
thyroid homones
• Small neuropeptides: GnRH, TRH, somatostatin, and
vasopressin
• Large proteins: insulin, LH, and PTH produced by
claasic endocrine glands
• Steroid hormones: cortisol, estrogen that are
synthesized from cholesterol-based precursors
• Vitamin derivates: retinoid (vitamin A) and vitamin D

– Amino acid derivates and peptide hormones interact with cell


surface membrane receptors
– Steroids, thyroid hormones, vitamin D and retinoids are lipid
soluble and interact with intracellular nuclear receptors
Hormone and receptor families
• The hormones can be grouped into families,
reflecting their structural similarities.
– Glycoprotein hormones (TSH, FSH, LH, hCG) have
the α-subunit in common, the β subunits are distinct
and confer specific biologic action. The related
GPCRs have evolved for each of the glycoprotein
hormones. These receptors are structurally similar,
and each coupled to the Gsα signaling pathway
• Minimal overlap of hormone binding wit with subtle
physiological consequences (hCG stimulates TSH
receptor, and increase thyroid hormone levels.
– Insulin, IGF-I and IGF II
• Structural similarities with moderate cross-talk among the
members of the insulin/IGF family
– PTH and PTHrp
• These hormones share amino acid sequence similarity. Both
hormones bind to a single PTH receptor that is expressed in
bones and kidney
Membrane receptor families and signaling pathways

Receptors Effectors Signaling pathway


G protein coupled seven transmembrane
Β-adrenergic, LH, Gsα, adenylate Stimulation of cAMP, proteine
FSH, TSH, hCG cyclase kinase A
PTH, PTHrp, ACTH, Ca-channels Calmodulin, Ca-dependent kinase
MSH, CRH
α-adrenergic, Giα Inhibition of cAMP production
somatostatin
TRh, GnRH Phospholipase C, protein kinase C
Receptor tyrosine kinase
Insulin, IGF-I, IGF-II Tyrosine kinase MAP kinase, posphtaylinositol-3
kinase, etc.
Cytokine receptor-linked kinase
GH, prolactin JAK tyrosine MAP kinase, posphtaylinositol-e
kinase
Nuclear receptor families

• Type 1 receptors bind streoids (adrenal and


gonadal hormones)
• Type 2 receptors bind thyroid hormones,
vitamin-D, retinoid acid, or lipid derivates
The hormone-binding domains are variable,
providing diversity in the array of small
molecules that bind to different nuclear receptors
(the hormone binding is highly specific for a
single type of nuclear receptor, exception GR,
MR)
Hormone secretion, degradation

• The circulating level of a hormone is determined


by its rate of secretion and its circulating half-life
– Peptid hormones (GnRH, insulin, GH) are stored
in secretory granules. The stimulus for hormone
secretion is a releasing factor or neural signal that
induces rapid changes in intracellular calcium
concentrations., leading to a secretory granule fusion
with the plasma membrane and release of its
contents into the circulation
– Steroid hormones, in contrast, diffuse into the
circulation as they are synthesized. Thus, their
secretory rates are closely aligned with rates of
synthesis.
Hormone secretion, degradation
• Hormone transport and degradation dictate the rapidity
with which a hormonal signal decays.
– Because somatostatin exert effects in virtually every tissue, a
short half-life allows its concentration and action to be
controlled locally
– TSH action is highly specific for the thyroid gland. Its long half-
life accounts for relatively constant serum levels, even though
TSH is secreted in discrete pulses.
• Hormone half-life is important for achieving physiologic
hormone replacement, as the frquency of dosing and the
time required to reach steady state are intimately linked
to rates of hormone decay.
– T4 has a long (7 days) circulating half-life, consequently more
than 1 months is required to reach a new steady state, but single
daily doses are sufficient to achieve constant hormpne levels.
– T3 has a short hal life (1 day), it must be administered two or
three times per day.
Hormone synthesis, secretion,
degradation
• Rapid hormone decay is useful in certain clinical
settings.
– The short half-life of PTH allows the use of intraoperative PTH
determination to confirm succesful removal of an adenoma.
• Many hormones circulate in association with serum-
binding globulin (T4 and T3 – TBG, cortisol – CBG,
androgen – SHBG, IGFs – IGFBG, etc.)
– These interactions provide a hormonal reservoire, prevent
otherwise rapid degradation of unbound hormones,and restrict
hormone acces to certain sites
– The binding proteins abnormalities (liver disease, certain
medications) can cause short-term change in circulating free
hormone levels, which in turn induce compensatory adaptation
through feedback loops. Exception: SHBG decrases because of
insulin resistance or andrrogen excess, the unbound
testosterone levels is increased, potentially leading to hirsutism
(because estrogen, and not testosterone, is the primary regulator
of the reproductive axis)
Functions of hormones 1.

• Growth
– Multiple hormones and nutritional factors
mediate the complex phenomenon of growth
• Short stature may be caused by GH deficinecy,
hypothyroidism, Cushing’s syndrome, precocious
puberty, malnutriton, and genetic abnormalities
• GH, IGF-1, thyroid hormones stimulate growth
• Sex steroids lead to epiphyseal closure
Functions of hormones 2.
• Maintenance of homeostasis
– Thyroid hormones control about 25% of basal
metabolism in different tissues
– Cortisol exerts a permissive action for many
hormones in addition to its own direct effects
– Parathormone regulates calcium and phosphorus
levels
– Vasopressin regulates serum osmolality by controlling
renal free water clearance
– Mineralocorticoids control vascular volume and serum
electrolyte concentrations
– Insulin maintains euglycemia in the fed and fasted
states
Integrated hormone action against
hypoglycemia

Fasted state and falling blood glucose

Decreased glucose uptake


and enhanced glycogenolysis,
rotelolysis, and gluconeogenesis
Hypoglykaemia develops
To mobilize fuel sources

Glukoagon and epinephrine


GH and cortisol act
stimulate glycogenolysis
over several hours
and gluconeogeneis

Rapid stimulation of
To antagonize insulin action
gluconeogenesis and glycogenolysis
Functions of hormones 3.

• Reproduction
– Sex determination during fetal development
– Sexual maturation during puberty
– Conception, pregnancy, lactation
– Cessation of reproductive capability at
menopause
Each of these stages involves an orchestrated
interplay of multiple hormones
Regulatory systems of hormone
production 1.
• Feedback control: both negative and positive, is
fundamental feature of endocrine system.
– Each of the major hypothalamic-pitutary-hormone axes is
governed by negative feedback:
• Thyroid hormones on the TRH-TSH axis
• Cortisol on the CRH-ACTH axis
• Gonadal steroids on the GnRH-LH/FSH axis
• IGF-1 on the GHRH-GH axis
– Feedback regulation also occurs for endocrine systems that do
not involve the pituitary gland:
• Calcium inhibits PTH secretion
• Glucose inhibition of insulin secretion
– Positive feedback control:
• Estrogen mediated stimulation of mid-cycle LH-surge
Regulatory systems of hormone
production 2.
• Local regulatory systems, often involving
growth factors:
– Paracrine regulation (factors released by one cell
that act on an adjacent cell in the same tissue:
somatostatin secretion of pancreatic δ-cells inhibits
insulin secretion from nearby β-cells
– Autocrine regulation (the action of a factor on the
same cell from which it is produced): IGF-1 acts on
many cells that produce it (gonadal cells etc.)
Regulatory systems of hormone
production 3.
• Hormonal rhythms. The feedback regulatory
systems are superimposed on hormonal
rhythms that are used for adaptation to the
environment (seasonal changes, the daily
occurence of light-dark cycle, sleep, meals, and
stress)
– Menstrual cycle is repeated on every 28 days
– All pituitary hormone rhythms are entrained to sleep
and to the circadian cycle, generating reproducible
patterns that are repeated appr. every 24 h.
– Other endocrine rhythms occur on a more rapid time
scale. LH and FSH secretion are exquisitely sensitive
to GnRH pulse frequency. Intermittant pulses of
GnRH are required to maintain pituitary sensitivity,
whereas continuous exposure to GnRH causes
pituitary gonadotrop desensitization
Pathologic mechanisms of
endocrine disease 1.
• Hormone excess
– Benign endocrine tumors, including parathyroid, pituitary, and adrenal
adenomas, often retain the capacity to produce hormones, indicating
the fact that they are relatively well differentiated.
• Many tumors exhibit subtle defects in their set points for feedback
regulation (Cushing’s disease, parathyroid adenomas, and autonomously
functioning thyroid nodules)
• Loss of function of a tumor-suppressor gene (menin). MEN1 syndrome
(parathyroid, pancreas islet, and pituitary tumor)
• Activating mutations of RET protooncogene, which encodes a receptor
tyrosine kinase, leads to medullary thyorid carcinoma, pheochromocytoma
and hyperparathyroidism (MEN2)
– Mutations that activate hormone receptors signaling (in several
GPCRs). These mutations induce receptor copuling to Gsα, even in the
absence of hormone Consequently, the adenylate cyclase is activated,
and cyclic AMP levels increase in a manner that mimics hormone action
(LH receptor mutation causes a dominantly transmitted form of male-
limited precocious puberty)
– Autoimmune disorders (Graves’ disease: antibody interactions with the
TSH receptor mimic TSH action, leading to hormone overproduction
Pathologic mechanisms of
endocrine disease 2.
• Hormone deficiency
– Glandular destruction caused by
autoimmunity, surgery, infection, inflammation,
infarction, hemorrhage, or tumor infiltration
– Autoimmun damage : thyroid gland
(Hashimoto’s thyroiditis, type 1 diabetes
mellitus)
– Mutation of hormones, hormone receptors,
transcription factors, enzymes, and channels
Pathologic mechanisms of
endocrine disease 3.
• Hormone resistance
– Inherited defects in membrane receptors, or
the pathway that transduce receptor signals
– Defective hormone action, despite the
presence of increased hormone levels
• Relatively rare genetic forms, such as androgen
receptor mutation in complete androgen
resistance: female phenotypic appearance in
genetic (XY) males
• More common aquired forms: insulin resistance in
type 2 diabetes, leptin resistance in obesity
Hormone measurements and
endocrine testing 1.
• Radioimmunoassay are the most important diagnostic
tool in endocrinology. The use of two different antibodies
to increase binding affintiy and specificity.
• The assays are sensitive enough to detect plasma
hormone concentration in the picomolar to nanomolar
range
• A variety of other techniques are used to measure
specific hormones, including mass spectroscopy, various
forms of chromatography, and enzymatic methods
• The urinary hormone determinations remain useful for
evaluation of some conditions. Collection of the sample
over 24 h provide an integrated assesment of the
hormone production, many of which vary during the day.
Hormone measurements and
endocrine testing 2.
• The normal range for most hormone is relatively
broad, varying by a factor of two to tenfold. The
correct normative database is essential part of
interpreting hormone tests.
• For many endocrine systems, much information
can be gained from basal hormone testing,
when different components of the endocrine
axis are assessed simultaneously.
– Testosterone and LH
– TSH and free thyroxine
– Parathormone and serum calcium
– ACTH and cortisol
Hormone measurements and
endocrine testing 3.
• It is not uncommon, however, for baseline
hormone levels associated with pathologic
endocrine conditions to overlap with the
normal hormone range. In this
circumstance, dynamic testing is useful
for further separate the two gropus:
– Suppression in case of suspected
hyperfunction
– Stimulation in the setting of suspected
hypofunction
Prevalence of endocrine and
metabolic disorders
Disorder Prevalence in adults Testing
Obesity 31% BMI>30 BMI calculation

Type 2 diabetes Appr. 8% Fasting plasma glucose,


OGTT
Hyperlipidemia 20-25% Cholesterol screening

Hypothyroidism 5-10% in women, 0,5-2% in men TSH

Graves’ disease 1-3% in women, 0,1% in men TSH, free thyroxin

Osteoporosis 10% in women, 2-4% in men BMD measurement

Hyperparathyroidism 0,1-0,5% (women>men) Serum calcium, PTH

Polycystic ovary 5-10% of women Testosterone, DHEAS,


syndrome abdominal ultrasound
Hyperprolactinemia 15% in women with amenorhea or Prolactin level, sella MRI
galactorrhea
Klinefelter syndrome 0,2% of men Karyotype, testosterone