BIOCHEMICAL ENDOCRINOLOGY

HORMONES &
CELL COMMUNICATION

LECTURE PRESENTED BY
M. E. SADIQ (Ph. D)

Department of Biochemistry and Molecular Biology, Usmanu

Danfodiyo University, Sokoto
2024
 The Concept of Endocrinology
Definition
Endocrinology is the science of the study of structure
and function of endocrine glands and their secretions
(i.e., hormones)

On a broader perspective, there is an interrelationship with other

systems of the body:
the nervous system (neuroendocrinology)
the immune system
the digestive system etc.

Together the organism is able to respond to internal

and external stimulus and environmental changes.
 Body control system
The two main control system of the body
are the endocrine and nervous system.

Nervous system: Endocrine system:

•mediates its activity through a •operates through chemical
network of nerves messengers collectively known as
hormones.
•Effects of the nervous system are
rapid and short lasting •The effects are slower and longer
lasting
•Basically controls muscles and
glands •Controls activities of cells including
metabolism, reproduction, stress
responses, fluid-electrolyte balance,
acid-base balance and energy balance.
 Understand the differences
Definition of hormones
Hormones can be defined as substances required in small amounts and secreted into the blood
by a variety of ductless glands for transmission to various target tissues where they affect
diverse metabolic processes

Endocrine hormones: secreted into systemic

circulation (blood or lymph) as a means of transport
to sites of action.Hormones also exert local Hormones secreted into ducts
regulatory control at point of secretion. are called exocrine hormones.
Exocrine tissues, such as
Paracrine hormones secretion refers to factors
salivary glands, and sebaceous
released by one cell that act on adjacent cells in the
same tissue e.g. somatostatin secretion by pancreatic
glands, secrete chemical
islet δ-cells which inhibits insulin secretion by substances through ducts into an
nearby β-cells. open space.

Autocrine hormones (regulation) describes action Exocrine tissues are generally

of hormones that are self regulating. not considered a part of the
endocrine system
FUNCTIONS OF HORMONES
The functions of hormones can be
viewed from the broad categories:

•Growth and cell differentiation (morphogenesis)

•Regulation and maintenance of homeostasis

•Reproduction

•Integrative function

•Permissive function
 Growth and Cell Differentiation (morphogenesis)
Multiple hormones and nutritional factors mediate growth requirement.

Examples of growth stimulating hormones:

Growth hormone (GH)

Insulin-like growth factor I (IGF-I)

Thyroid hormone (TH)

Sex steroids such as estrogen promotes epiphyseal closure, thereby

limiting growth stimulating effects.
 Regulation and Maintenance of Homeostasis
Homeostasis generally refers to the normal functioning of all metabolic and
physiologic processes of the body.

Examples of Hormones that regulate homeostasis

Thyroid hormone
responsible for about 25% of basal metabolism in most tissues

Cortisol
exerts a permissive action for many hormones.

Parathyroid hormone (PTH)

regulates calcium and phosphorus levels

Vasopressin
regulates serum osmolality by controlling renal free water clearance
Mineralocorticoids
Aldosterone controls vascular volume and serum electrolytes (Na+, K+) concentration

Insulin
maintains euglycemia in the fed and fasted states
 Reproduction
Hormones are directly responsible for sexual maturation and major
processes leading to reproduction.

The stages of reproduction include

• Sex determination during fetal development

• Sexual maturation during puberty

• Conception, pregnancy, child-bearing, lactation

• Cessation of reproductive capability and menopause

 CONTROL OF THE ENDOCRINE SYSTEM
Chemical signals released for specific target receptors that relay messages for
modulation of biochemical pathways must be controlled since these signals
cannot go on forever.

Control mechanisms regulate the action of either the secreting organ or the
hormones themselves either by humoral, hormonal or neural stimuli which are
achieved by a combination of the mechanisms below:
Simple control
Negative feedback Nervous control
Positive feedback Anatomical architecture and
relationships of glandular systems
Inhibitory control
Metabolic control

Other factors that may regulate hormone secretions include

•External environmental changes e.g. season

•Down (up) regulation of receptors when there is excess (reduced) production of hormone
 Negative feedback
Hormone Regulation

Positive feedback Hormone Regulation

 CHEMICAL NATURE OF HORMONES

Hormones can be divided into five major classes:

Amino acids
Small neuropeptides
Large proteins
Steroid hormones

Vitamin derivatives
 Small neuropeptides
Amino acids TRH
Tyrosine Oxytocin
Catecholamines vasopressin
Thyroid hormone
Histidine
Histamines
Tryptophan
serotonin

Steroid hormones
Large proteins Sex hormones
insulin Corticoids
Prostaglandins
Selected endocrine organs and their anatomical location

Its time for group work

A bit of anatomy
A bit of anatomy
 Hypothalamic hormone Major function
Thyrotropin releasing hormone (TRH) Stimulates release of and as well as
stimulation of release

Gonadotropin releasing hormone Stimulates release of and LH

(GnRH)
Growth hormone releasing hormone Stimulates release of GH
(GHRH)
Growth hormone release inhibiting Inhibits release of GH also gastrin,
hormone (Somatostatin) (SMS) Vasoactive Intestinal Protein, glucagon,
insulin
Corticotropic releasing hormone Stimulates release of ACTH
(CRH)
Dopamine Inhibits release of prolactine

Amino acid derived

neuropeptides and short peptides.

 ANTERIOR PITUITARY HORMONES
Anterior pituitary Chemical Nature Target gland Trophic effect
hormone
Prolactin (PRL) Polypeptide Breast, other tissues Milk production
Growth hormone (GH) Polypeptide Liver other tissues IGF-I production, growth
induction insulin antagonism
Adrenocorticotropin Polypeptide Adrenal Steroid production
hormone (ACTH)
Leutinizine hormone glycoprotein Ovary, testis Sex steroid production, follicle
(LH) growth, germ cell maturation
Follicle stimulating glycoprotein Ovary, testis Sex steroid production, follicle
hormone (FSH) growth, germ cell maturation
Thyroid stimulating glycoprotein Thyroid T4 synthesis and secretion
hormone (TSH)

POSTERIOR PITUITARY HORMONES

Two hormones are produced: Vasopressin (AVP) and Oxytocin

HORMONE SECRETION, TRANSPORT AND DEGRADATION
Hormone secretion
Protein and peptide hormone secreting cells
store newly synthesized hormones in small
vesicles or secretory granules and released by
exocytosis

while steroid secreting cells do not store

hormones in a state ready for secretion but
synthesize hormone for secretion as required.

For example ACTH and LH induce

steroidogenesis by stimulating the activity of
steroidogenic acute regulatory (stAR) protein,
which transports cholesterol into the
mitochondrion.
Most peptide and protein hormones are hydrophilic; they circulate in the blood stream
with little or no association with serum proteins.

Hydrophobic molecules interact more with serum proteins for transport. A high
specificity exist between hormone transport proteins. Minor changes in the structure
of hormones affect their binding to the respective transport protein.

Protein bound hormone is in equilibrium with free unbound hormone. Only unbound
hormones are available to interact with receptors and thereby elicit a biologic
response.
 Examples of hormones and their transporters

Hormone Binding protein

T4 and T3 Thryosine binding globulin (TBG); albumin and
thyroxine-binding prealbumin (TBPA)
Cortisol Cortisol-binding globulin (CBG)
Androgen and estrogen Sex-hormone binding globulin (SHBG)
IGF-I and II IGF binding protein (IGF-BPs)
Growth hormone Growth hormone binding protein (GHBP)
Activin follistatin

Hormone binding to serum proteins

•Serve as a reservoir
•Prevent rapid degradation of unbound hormones
•Restrict hormone access to certain sites
•Modulate the unbound or free hormone concentrations.
 Hormone Degradation
The rapid degradation of hormones allows
target cells to respond transiently;

polypeptide hormones are removed from

circulation by

Steroid hormones are taken up by

the liver and metabolized to
inactive forms which are
excreted into the bile duct or
back into the blood for removal
by the kidneys.
 MECHANISM OF HORMONAL SIGNAL
TRANSDUCTION
Hormone Receptors

Nuclear receptors
estrogens

Cytoplasmic receptors
Most steroid and thyroid hormones

Cell surface membrane receptors

Polypeptide hormones and catecholamines
CLASSIFICATION OF HORMONE RECEPTORS
 General Characteristics of Hormone Receptors

•Hormones react with their receptors in a reversible manner.

•Receptors exhibit a high degree of hormonal specificity

•Location of hormone receptors are tissue specific

•Structure and physicochemical properties of hormones reflects

the subcellular localization of its cognate receptor

•The effects of some hormones are achieved by target tissue

conversion.
 FEATURES OF CELL SURFACE RECEPTORS

The super families of cell surface receptors:

Tyrosine kinase-linked and G-proteins linked receptors.

Features
Both types of receptors have the following common characteristics:
•An extracellular component (the ectodomain)
•A membrane spanning region (which could be linear or
serpentine)
•A cytosolic domain (which initiates intracellular cascade of
reactions)
Structure of Extracellular Receptors
Tyrosine kinase receptor GPCR
 MECHANISM OF HORMONAL SIGNAL TRANSDUCTION
Receptors are either localized on cell surfaces or are localized internally

A majority of the cascades of reactions proceed through

phosphorylation reactions Recruitment of second messengers.

The amino acids serine, threonine and tyrosine each cAMP

can serve as a phosphorylation site by way of DAG
transfer of phosphate group from ATP (or GTP). IP3, etc
This transfer causes conformational changes to the
phosphorylated protein.
 Hormone Membrane
A general model for the Plasma Effects
action of cell surface Membrane
receptors
Receptor
Effector
Cellular
Trafficking

Enzymes Secondary Messenger

or Secondary Signal

Activated Inhibited
Protein
Synthesis
Nucleus DNA Synthesis
RNA Synthesis

A general model for the action of peptide hormones, catecholamines,

catecholamines, and other
membrane--active hormones
membrane hormones.. The hormone in the extra cellular fluid binds to the
receptor and activates associated effector
effector(s)
(s) systems, that may or may not be in the
same molecule
molecule.. This activation results in generation of an intracellular signal or second
messenger that, through a variety of common and branched pathways, produces the
final effects of the hormone on metabolic enzyme activity, protein synthesis, or cellular
growth and differentiation.
differentiation.
 Insulin Receptor
The insulin receptor (IR) is a typical example of receptors with Intrinsic tyrosine
kinase activity.

The receptor consists of two α subunits and two β subunits linked by a disulphide
bridge to form α2β2 heterotetrameric complex.

Insulin binds to the extracellular α subunits (containing the extracellular amino

terminal), which transmits signals across the plasma membrane thereby activating
the intracellular tyrosine kinase domain of the β subunit (which has an intracellular
carboxy terminal).

One β subunit phosphorylates adjacent partner through a trans-phophorylation

process. The receptor also undergoes auto-phosphorylation at other tyrosine residues
in the intracellular tail of the receptor.

The activated IR then phosphorylates tyrosine residues on intracellular substrates

that include the Insulin Receptor Substrate (IRS).
Insulin-mediated
Insulin-mediatedglucose
glucosetransport
transportsignaling
signalingpathway
pathway
Insulin

IR
a a
b b
Cell membrane

P
IRS
PI3K

Glut4 Akt
P

Xiao Chen, 2006

Insulin-mediated glucose transport signaling pathway
Insulin-mediated glucose transport signaling pathway

IR Insulin
glucose a a
b b Cell membrane

P
IRS
PI3K

Akt
P

Xiao Chen, 2006

 Effects of insulin binding to its receptor
Tyrosine phosphorylation of the IRS proteins creates docking sites for additional effector molecules
containing Src homology 2 (SH2) domains.

Examples of small adapter proteins include growth factor receptor bound protein 2 (Grb2) and Nck, the
SHP2 protein tyrosine phosphatase and, type 1A phosphatidylinositol 3–kinase (PI 3-kinase).
•IRS interaction with PI 3-kinase is a necessary step in translocation of glucose transporters from the cytosol
to cell membranes via binding of the p85 subunit of PI 3-kinase leading to translocation of glucose
transporters from intracellular vesicles to the cell membrane.
•The generation of the lipid product phosphatidylinositol 3,4,5-trisphosphate (PIP3) regulates the activities of
numerous proteins including serine/theronine kinases, AKT or protein kinase B (PKB) and protein kinase C.
•The mitogenic effects of insulin signaling via a divergent pathway involving IRS phosphorylation linked to
regulators of small G-protein activity through series of docking and phosphorylation steps leads to activation
of mitogen activated protein kinase (MAPK). MAPK is a multifunctional serine/threonine kinase that induces
both cytoplasmic and nuclear responses. The nuclear response involves gene expression, protein synthesis
and cell growth.
•Glycogen synthase activation through allosteric regulation by elevating the levels of Glucose-6-P via
glucose transport and by promoting the conversion of glycogen synthase from a low activity phosphorylated
form to the high activity dephosphorylated form through the protein kinase B (PKB) also known as Akt-
dependent inactivation of glycogen synthase kinase 3 (GSK3). Dephosphorylation results in significant
changes in the kinetic properties of glycogen synthase.
GLUCOSE TRANSPORTERS

GLUT vs SGLT
 G-PROTEIN COUPLED RECEPTORS (GPCRs)

G- proteins associate intracellular second messengers. Examples of systems that

utilize GCPR signaling are the adrenergic receptors, odorant receptors and the hormone
receptors for glucagon, angiotensin and vasopressin
G-proteins exist as heterotrimeric complexes with α, β and γ subunits.

The functional subunits are Gα and Gβγ. In the absence of hormone, the receptor exists
as complexes of G-protein pool within the membrane. The α-subunit of the trimeric
subunits is responsible for binding of GDP/GTP

Binding of hormone to its G-protein receptor leads to conformational changes that

increases the rate of bound GDP dissociation and replaced by GTP. This exchange
causes the α subunit to dissociate from the heterotrimeric complex.

The released and activated βγ complex serves as a docking site for interaction with
downstream effectors of the signal transduction cascade.
The liberated α subunit
together with its bound GTP
binds to downstream effectors

The Gα subunit has 4 major subfamilies isoforms:

•G
Gsα and Giα:
α activates or inhibits adenylate cyclase cAMP respectively
•Gqα: activates phospholipase C (PLC)
•Goα: activates ion channels

Gα subunits also function as a GTPase which cleaves a Pi from the bound GTP to
give GαGDP. This system endows G-proteins with a mechanism for switching off
their activation of the catalytic subunit and ensures reassociation of GαGDP with
Gβγ. In this way and individual G-protein complex is recycled thereby terminating
its activity.
Key: GEF = guanine nucleotide exchange factors; GAP = GTPase activating proteins
 Intracellular 2nd messengers
The most important second messengers are cAMP, cGMP, Ca2+, inositol triphosphate
(IP3), diacylglycerol (DAG), and nitrogen monoxide (NO)
cAMP: cAMP is synthesized from ATP by membrane-bound adenylate cyclases on the
cytoplasmic side of plasma membrane. Activation of membrane bound adenylate
cyclase catalyzes conversion of ATP to cAMP. cAMP can function as follows:

•interaction with a regulatory subunit on protein kinase A (PKA), unmasking a catalytic

site which phosphorylates threonine and serine residues. Pathways regulated by this
signaling system include lipolysis, glycogenolysis and steroidogenesis.

•PKA is also known to phosphorylate a cAMP response element binding protein (CREB
protein) which then translocate to the nucleus where it binds to a short palindromic
sequence on the promoter region of cAMP regulated genes referred to as cAMP
response enhancer element (CRE-gene) thereby effecting a direct gene transcription.

•cAMP is degraded by conversion of cAMP to the inactive form 5' AMP catalyzed by
phosphodiesterases which are inhibited by methylxanthines such as caffeine.
 Intracellular 2nd messengers
Diacylglycerol: TRH, GnRH, oxytocin are some examples of hormones that stimulate
their target cells by GPCR coupled to membrane bound activation of PLC which
catalyzes the following reaction:
PIP2 →DAG + IP3
Where PIP2 = phosphatidyl inositol 4,5 bisphosphate; DAG = diacylglycerol
DAG and IP3 act as intracellular 2nd messengers. DAG together with the cofactor
phosphatidyl serine activates cell membrane associated protein kinase C (PKC) while
IP3 is released into the cytosol where it binds to calcium mobilizing IP3 receptor
channels in the ER (SER) causing a rapid 10-fold rise in cytosolic Ca2+ from a resting
concentration of about 0.1µM.

Ca2+: Calcium ions activate the protein calmodulin and several Ca2+ sensitive enzymes
including, phospholipase A2 which librates arachidonates from phospholipids
generating local tissue activators including thromboxanes, leucotrienes, lipoxins and
prostaglandins.
Below is a schematic presentation of GPCR signaling:
 INTRACELLULAR HORMONE RECEPTORS

Intracellular receptors generally bind hormones that gain access to the

intracellular environment.

Examples include Steroids and thyroid hormones

The receptors to which these hydrophobic hormones bind are either in

the cytosol or nucleus.

Intracellular receptors function as hormone-regulated transcription

factors controlling the expression of specific target genes by interaction
with regions close to the gene promoters.

The ultimate biological response to steroid and thyroid hormones are

rather slow because response to their signals is via promotion of RNA
and protein synthesis.
 STEROID AND THYROID HORMONE RECEPTORS

There are more than 150 members of super family of steroid-thyroid hormones.

Steroid-thyroid families of receptors generally consist of single poplypeptide chain with

3 distinct domains:
•Hormone specific binding domain containing a region at the C-terminus responsible
for hormone dependent transcriptional activation
•A highly conserved DNA-binding domain (DBD)
•An N-terminal domain which is hyper variable both in length and composition.
All steroids act via cytosolic (class I) receptors whereas calcitriol and T3 utilize nuclear
(class II) receptors.

Class I receptors when in the resting state their DNA binding domain are masked by
heat shock proteins (hsp) e.g. the hsp70 and hsp90. Hsps are specifically distributed in
the cytosol and the nucleus for e.g. glucorticoid hsps are cytosolic while those for
androgens are nuclear.

Class II receptors are associated with DNA and are activated only by binding of
hormone.
 STEROID HORMONES ARE SYNTHESIZED FROM
CHOLESTEROL

The steroidogenic acute regulatory (StAR)

protein transports cholesterol from the outer
mitochondrial membrane to the inner
mitochondrial membrane. The transport process is
a rate limiting step in steroidogenesis.

The four major classes of steroid hormones are:

•Progestins (C-21)

•Androgens (C-19)

•Estrogens (C-18) and Pregnenolone

is the common precursor for
•Corticoids (C-21). steroid hormones
 ENZYMES FOR SYNTHESIS OF STEROID
HORMONES ARE TISSUE SPECIFIC

Steroid synthesis is achieved by the expression of the

appropriate sequence of enzymes by specific cells of the
tissue in question.

The first two enzymes, namely side chain cleavage

enzyme (SCCE) also called cholesterol desmolase and 3-
β-hydroxysteroid dehydrogenase (3β-HSD) are expressed
in steroidogenic cells in both the gonads and adrenal
cortex.
 Steroids and site of synthesis
Enzyme Activity Subcellular location
Desmolase (SCCE) Cholesterol 20, 23 desmolase IMM of steroidogenic tissues

3β-HSD 3β hydroxyl steroid dehydrogenase ER steroidogenic tissues

21-hydroxylase Adds hydroxyl group at the 21- IMM of zona fasciculata and
position of progesterone or 17- reticularis
hydroxy pogesterone
11β-hydroxylase Catalyzes terminal stages of cortisol IMM of zona fasciculata
and aldosterone synthesis
Aldosterone synthase Catalyze conversion of C-18 to IMM of zona glomerulosa
aldehyde
17α-hydroxylase and Catalyzes both 17α-hydroxylation ER steroidogenic tissues
17-lyase and 17, 20 lyase activity at C-17
17β-HSD type 3 17-ketoreductase ER steroidogenic tissues
Estrogen synthetase Aromatase Gonads, brains, adrenals
adipose tissue, bone
Steroidogenic acute Mediates transport of cholesterol All steroidogenic tissues
regulatory protein from outer mitochondrial membrane except placenta and brain
(StAR) to inner mitochondrial membrane
STEROID AND THYROID HORMONES
 Synthesis of Sex Steroids
Sex steroids functions primarily in sexual development and
reproduction.

Sex steroids Regulation: the short and long loop negative

feedback regulation that controls the secretion of FSH and LH
(short loop) and by the gonadotropin releasing hormone
(GnRH) by the hypothalamus (long loop).

There are 3 major classes of sex steroids:

Progestins,
Androgens
and estrogens.
 Progestins
The major progestin in humans is progesterone, a 21-carbon 3-keto
Δ4 steroid, derived from side chain cleavage of cholesterol by P450
scce to give pregnenolone then converted to progesterone by
3β-hydroxysteroid dehydrogenase (3β-HSD).

Deficiencies in either scce or 3β-HSD have profound effects on the

synthesis of all steroids.

Progesterone is a precursor molecule for the synthesis of other

hormonal steroids (androgen and estrogen)

During the peri- and post ovulatory (luteal) phases, Progesterone

however, becomes a primary secretory product

Progesterone synthesis is under the control of FSH during early

stages of folliculogenesis.
 Androgens
The Androgens are synthesized and secreted:

1. Primarily by the leydig cells of the testes

2. Thecal cells of the ovary and
3. The zona reticularis of the adrenal cortex.

Testosterone is the primary androgen in humans

Synthesis is stimulated by circulating LH which up regulates the amount of

17α-hydroxylase C-17, 20 lyase, a rate limiting enzyme for conversion of
C-21 steroids to C-19 steroids.

Once taken up by the target tissue, testosterone is converted to

dihydrotestosterone (DHT) by 5α-reductase.

DHT is the potent form of the hormone with an activity 10 times that of
testosterone.
 Estrogens
Estrogens (and progestins) are synthesized and secreted primarily by
maturing follicles, corpora lutea of the ovaries and placenta during
pregnancy.

Estradiol (E2) is the predominant Estrogen (C-18 steroid)

The aromatase enzyme complex is responsible for the conversion of

testosterone and androstenedione to estradiol and estrone by granulosa
cells.

During pregnancy, the placenta utilizes androgen precursors from the

fetal adrenal gland and secretes large amounts of E2.

In males, many target tissues such as pituitary cells, hypothalamus

neurons convert circulating testosterone to estradiol.
 Synthesis of corticoids
Corticoids hormones are Glucocorticoids and Mineralocorticoids

Cortisol
 Cortisol is the predominant glucocorticoid, synthesized in the zona fasciculata of the
adrenal cortex.
 The synthesis of cortisol involves hydroxylations of progesterone at the 17α, 21 (CYP
21) and 11β (CYP 11B1) positions.

Cortisol synthesis is regulated by ACTH and a negative feedback mechanism in which elevated
levels of cortisol suppresses the release of ACTH. Likewise, release of ACTH is stimulated by
the hypothalamic peptide corticotrophin releasing factor (CRF) produced by the paraventricular
nucleus of the hypothalamus. Thus a short and long loop feedback inhibitory mechanism is
exerted by increased levels of circulating cortisol.
Aldosterone
Aldosterone is the dominant human mineralocorticoid produced in the zona glomerulosa of the
adrenal. Synthesis of aldosterone is from corticosterone and subsequent hydroxylation and
oxidation at C-18 (18α hydroxylase, CYP 11B2) to yield aldosterone.

Aldosterone synthesis is regulated by serum levels of potassium and indirectly by sodium and
blood volume (i.e RAAS)
 Congenital Adrenal Hyperplasia (CAH)
CAH is the consequence of recessive mutations that cause one of
several distinct enzymatic defects in the steroidogenic pathway

Abnormality in cholesterol transport

A baby with this abnormality will not be properly differentiated as a male even if
there are testes present
An impaired CYP21A2 (21 hydroxylase) may lead to cortisol deficiency, decreased
aldosterone secretion thus adrenal virilization
CYP11B1 deficiency causes hypertensive variant of CAH. Hypertension and hypokalamia
occur because of the impaired conversion of 11-deoxycorticosterone to corticosterone
resulting in accumulation of 11-deoxycorticosterone, a potent mineralocorticoid.

Shunting of steroid precursors into androgen pathway results in masculinization of a

female fetus in utero or precocious (accelerated) puberty in a boy exposed to excessive
androgen stimulation

In 3β-HSD2 deficiency, conversion of pregnenolone to progesterone is impaired affecting

synthesis of both cortisol and aldosterone resulting in shunting into adrenal androgen
pathway
 Hormonal Rhythms
The suprachiamastic nucleus in the hypothalamus consisting of over ten
thousand nerves play a significant role in the control of rhythmic secretions of
endogenous chemicals including hormones. Secretions of hormones again can
be influenced or entrained by external cues.

Rhythms based on 24 hours cycle are called ‘circadian’ (circa = about, dies =
day). Circadian hormones include cortisol with maximal secretion between 4
and 8 am, melatonin (regulate sleep-wake cycle), rises in the evening and
decreases in the morning.

Hormones with shorter period of secretion i.e. less than 24 hours are ‘ultradian’
e.g. insulin, GH, LH, FSH, ACTH.

Hormones with longer than 24 hours are termed ‘infradian e.g. 28 day
menstrual cycle in women (progesterone, hCG) or seasonal reproductive
periods in animals (rise in puberty and reproductive hormones).
 Hormonal Rhythms Cont’d

Rhythmicity also changes during life cycle of an individual. In puberty

gonadotropins are secreted in large amounts with maximal concentrations
at night whereas in sexually matured individuals they are secreted in a
pulsatile fashion throughout the 24 hour period.

Knowledge of the rhythmicity of hormone is clearly very important in the

interpretation of hormonal data and this can best done in the context of
other hormonal results relative to when such hormones are maximally
secreted.

For example PTH levels are assessed alongside serum calcium levels. High
serum calcium association with elevated PTH levels is suggestive of hyper
parathyroidism whereas a suppressed PTH level is more likely to be caused
by hyperglycemia or hyperinsulinemia.

Similarly TSH should be elevated when T4 and T3 concentrations are low

etc.
 HORMONAL RHYTHMS AND DIAGNOSTIC SCREENING
Diagnosis of diabetes
Euglycemic blood glucose 4.0 -5.5 mmol/L
The following levels of glucose in venous blood are indicative of
hyperglycemia:
> 7.0 mmol/L in the fasted state (Fasting Blood Glucose)
11.0 mmol/L (Random Blood Glucose)
Glucose tolerance test (oGTT)
A test that involves challenging patient with 75 g of oral glucose
administration then blood samples taken after 2 hours (2HPP). If
glucose levels:
< 7.8 mmol/L – normal glucose tolerance
> 11.0 mmol/L – hyperglycemic state
7.8 – 11.0 mmol/L impaired glucose tolerance;

oGTT is further recommended after some few months. oGTT is used to

rule out or confirm DM after conducting FBG and/or RBG.
 Glycated Haemoglobin in the Diagnosis of Diabetes

The glycated haemoglobin test is used only to evaluate long-term diabetes

compensation. Importantly, clinical assessment of glycated heamoglobin has
proven to be beneficial in recent times due to:

•Better analytical parameters

•Higher stability of the analyte in biological material specimens
•Lower biological variability of HbA1c (under 2 %)
•Higher comfort for the patient (fasting and drinking the glucose solution is not
required);
•Minimal influence of stress on the result
•Use of the same test for the diagnosis and monitoring therapy

The International Diabetes Federation (IDF) recommends 6.5% as a glycated

haemoglobin cut-off for diagnosing diabetes; values from 5.7 to 6.5% are
subsequently indicative of an increased risk of developing diabetes or late
diabetic complications.
 Tests for adrenal hyperfunction
(Cushing’s syndrome/disease)
Cushing disease refers to elevated serum cortisol is secondary to
excessive pituitary ACTH production.

Raised ectopic ACTH, or primary adrenal defect with

overproduction of glucocorticoids and possibly
mineralocorticoids, together with adrenal androgens, such
condition is referred to as Cushing syndrome.

Biochemical investigation requires

(i) The demonstration of elevated baseline serum cortisol and
loss of diurnal variation and

(ii) (ii) identification of the cause.

Tests for adrenal hyperfunction… Cont’d

The first two tests conducted are

1. Measurement of cortisol in a 24-h urinary collection
(Urine free cortisol UFC) and
2. Dexamethasone suppression test.

Dexamethasone is a synthetic glucocorticoid that binds to

cortisol receptors in the pituitary thereby suppressing
ACTH release.

An excretion of excess cortisol (e.g. >300 nmol/L/24 h) is

consistent with elevated serum cortisol.
Tests for adrenal hyperfunction… Cont’d

Dexamethasone (1mg orally at bedtime) is expected to reduce 8 a.m. serum

cortisol the following morning to < 50 nmol/L in a normal subject

In Cushing’s disease, the pituitary is still susceptible to negative feedback by glucocorticoids

but less sensitive than normal. Thus if 1mg dexamethasone-supression test failed to reduce
serum cortisol, an increased dose (e.g. 2 – 5 mg four times daily for 2 days) should be tested.

A large reduction in serum cortisol e.g. 50% will result if the adrenal hypofunction is
secondary to overproduction of ACTH by the pituitary.

In Cushing syndrome caused by adrenal tumors and ectopic ACTH, no response to

dexamethasone would be expected. The ectopic production of ACTH is demonstrated by
immunoassay.

Other factors that could aggravate serum cortisol concentrations include:

•stress
•obesity (diurnal secretion is mostly retained)
•alcoholism
•Depression - a response to insulin-induced hypoglycemia i.e. a rise in plasma cortisol is
retained
Summary of receptor mechanism of signal transduction

Cell surface receptors

Act on nuclear receptors

ENDOCRINE DISEASES

Endocrine diseases can be classified

into 3 major types of conditions:

1. Hormone excess

2. Hormone deficiency

3. Hormone resistance
 Hormone excess
Syndromes of hormone excess can be caused by
Neoplastic growth of endocrine cells
autoimmune disorders
failure to respond to feed-back regulation.
Excess administration.

The inheritance of mutant genes is

also a factor in tumorigenesis which
leads to loss of function of normal
genes.
 HORMONE
DEFICIENCY surgery, Glandular destruction caused by
hemorrhage
tumor infiltration
autoimmunity,
infection,
infarction,

Autoimmune damage to the thyroid gland (Hashimoto’s thyroditis) and

pancreatic islet β-cells (type 1 diabetes mellitus) is a prevalent cause of
endocrine disease.

Mutations in a number of hormones and channels can also lead to

hormone deficiencies.
 HORMONE RESISTANCE
Inherited defects in membrane receptors or nuclear receptors

Defects in the pathways that transduce receptor signals

Could result in hormone resistance syndromes

The pathogenesis of
functional resistance also
involves receptor down-
regulation and post
Examples of hormone resistance effects include: receptor desensitization of
signaling pathway
In complete androgen resistance, mutations in the androgen receptor cause genetic XY males
to have female phenotypic appearance even though LH and testosterone levels are increased.

Insulin resistance in type 2 diabetes mellitus,

Leptin resistance in obesity and GH resistance in catabolic states..

•permissive (T3 + epinephrine)

•Synergisitc (FSH + estrogen)
•Antagonistic (insulin + glucagon)
INAPPROPRIATE PRODUCTION
OF STEROID HORMONES
CHOLESTEROL
Synthesis of steroid hormone
 Overproduction of cortisol
(Cushing’s syndrome)
Excess cortisol could be produced due to:

1. CRH drive of ACTH secretion due to CRH producing tumor

This leads to hyper-stimulation of the pituitary resulting in hyperplasia or
tumor formation.

2. ACTH drive of cortisol production caused by bilateral adrenal hyperplasia resulting

in hyper-secretion of pituitary ACTH or ectopic production of ACTH by non-
pituitary sources (Cushing’s disease)

3. Adrenal tumors with a high propensity to be malignant. Adrenal gland nodular

hyperplasia may result from prolonged ACTH hyper stimulation

4. Iatrogenic causes due to administration of steroids including glucocorticoids

Under-secretion of cortisol (Addison disease)
This disease results from a progressive destruction of adrenals which
involve >90% of the glands before adrenal insufficiency appears.

Majority of cases of Addison disease however are of autoimmune etiology

1. lymphocytic infiltration by cytotoxic T lymphocytes together with disruption of
the cortical histology and cortical atrophy

2. Specific adrenal antigens to which autoantibodies may be directed include 21-

hydroxylase (CYP21A2) and P450scc enzymes

3. Some antibodies cause adrenal insufficiency by blocking the binding of ACTH to

its receptors

In classic Addison disease, high ACTH secretions alongside α-MSH makes patients become
hyperpigmented, especially in skin creases, on scars and inside the mouth (pigmentation of
mucous membrane).

Failure to secrete ACTH results in glucocorticoid and androgen deficiencies which causes
loss of body hair (especially in females),
 Over-secretion of Aldosterone
Primary aldosteronism: excess aldosterone production within the adrenal gland. This is the
result of aldosterone-producing adrenal adenoma (Conn’s syndrome).
Secondary aldosteronism: increased production of aldosterone in response to RAAS
activation. Aldosterone production rate > than in primary aldosteronism.
Secondary aldosteronism occurs in association with an accelerated phase of hypertension or on
the basis of an underlying edema disorder.
Secondary aldosteronism is a normal condition in pregnancy (resposne to high circulating
estrogen levels)
A decrease in renal blood flow and/or perfusion pressure can induce secondary secretion of
rennin causing hypertensive states. Narrowing of one or both of the major renal arteries by
atherosclerosis or by fibromuscular hyperplasia can also cause secondary aldosteronism.

Excess ACTH can probably cause Important to note also that cortisol has
hypersecretion of mineralocorticoids by a weak mineralocorticoid action thus if
enhancing the incorporation of cholesterol into present in large amounts, the action
the adrenal cortex can be significant in causing
aldosterone receptor over-stimulation
 Undersecretion of aldosterone
Isolated aldosterone deficiency accompanied by normal cortisol production
occurs in association with:
Hyporeninism as an inherited biosynthetic defect,

postoperatively following removal of aldosterone secreting adenomas

during heparin administration

severe postural hypotension.

A major feature of this disorder is the inability to increase

aldosterone secretion appropriately in response to salt restriction.
There is hyperkalamia, loss of sodium in the urine, etc, probably a
fall in blood volume (hypovolamia)
 Growth hormone
secretion defects
(b)
(a)

a b

before

after
Copy right Person Education 2013
 DIABETES MELLITUS
Diabetes mellitus (DM) describes a group of interrelated metabolic disorders that share the
phenotype of hyperglycemia. Several distinct types of DM exist and are caused by a complex
interaction of genetics, environmental factors and life style choices.

Common contributing factors to DM onset include reduced insulin secretion, decreased

glucose utilization and increased glucose production.

Dysregulation of glucose metabolism has tremendous effects on associated pathways as well

as organs involved in glucose homeostasis; the combined effect which is referred to as
metabolic syndrome (MS). The central feature of MS is impaired insulin metabolism.
 Insulin action (summary)

Insulin binding to receptor

glycogen synthesis lipogenesis

glycolysis
protein synthesis

down regulation of glucagon

Increased glucose uptake by insulin-dependent
tissue glucose metabolism