hormones

Department of Biochemistry, Kathmandu Medical College

2/25/14
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Chemical messengers
Types of chemical messengers: 3 types
1.Nervous system: secretes neurotransmitters
2.Endocrine system: hormones
3.Immune system: cytokines

Hormones
Acts as a means of communication cellular
communication
Biological function achieved by: 1. Nervous system
transmission of electrochemical impulse
2. Endocrine system: wide range of chemical
messengers

Hormones: organic substance, produced in small amount
by specific tissue (endocrine glands)

Regarded as chemical messengers!!
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Classification of hormones
Based on chemical nature
Protein or peptide hormones: insulin, glucagon,
antidiuretic hormones, oxytocin
Steroid hormones: glucocorticoids,
mineralocorticoids, sex hormones
Amino acid derivatives: epinephrine,
norepinephrine, thyroxine (T4), triiodothyronine
(T3)
Based on mechanism of action
Classified into 2 groups (based on location of the
receptor)
Group I & Group 2





Mechanism of action of steroid
hormones
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Mechanism of action of group I
hormones
Lipophilic in nature


Pass across plasma membrane binds to intracellular
receptor (Site: cytosol/nucleus) hormone-receptor
complex binds DNA (HRE) expression of genes
production of protein action of hormone.

Mechanism of action of group II
hormones
Considered as first messenger
Exerts their action through intermediary molecules
Intermediary molecules SECOND MESSENGERS
Second messenger: cAMP
Hormones
Hypothalamic hormones: TRH, CRH, GnRH, GRH, GRIH,
and Prolactin release-inhibiting hormone (PRIH)

Gonadotropin-releasing hormone (GnRH): stimulates
anterior pituitary releases gonadotropins (Luteinizing
hormone (LH), Follicle stimulating hormone (FSH))

Hormones of Gonads
Gonads: testes in male & ovaries in female
Perform closely related dual functions
Synthesize sex hormones
Produce germ cells

Role: Growth, development, maintenance and regulation
of reproductive system.

Primarily for development of germ cells.



Steroid hormones
5 steroid hormones
Precursor: Cholesterol
Glucocorticoids
Mineralocorticoids
Androgens
Estrogen
And Progestin

Synthesized by ADRENAL CORTEX, OVARIES,
TESTES, and OVARIAN CORPUS LUTEUM.





Vitamin D
Steroid hormones
Bile salts
LH and FSH
LH
Group II hormone, binds to cell surface
receptor.
Secreted from anterior pituitary gland.
Stimulates synthesis of estrogen and
progesteron and causes ovulation
Promotes Androgen synthesis by testes.

FSH
Anterior pituitary gland.
Stimulates ovulation and estrogen synthesis.
In male: Promotes spermatogeneis.






Sex Hormones
Categorized into three groups
Androgen: male sex hormones: C-19 steroids

Estrogen: female sex hormone: C-18 steroids.

Progesterone: C-21 steroid, produced during the
luteal phase of menstrual cycle and also during
pregnancy

First two phage of menstrual cycle: follicular phase



Biosynthesis of steroid
hormones
Biosynthesis of steroid
hormones
ANDROGENS
Produced by LEYDIG CELLS of testes, minor amount by
adrenal glands in both sexes
NOTE: Ovaries also produce small amount of
ANDROGENS!!

Biosynthesis of ANDROGENS
Precursor: Cholesterol

Biosynthesis of ANDROGEN
Mostly occurs in
peripheral tissues
Biosynthesis of androgen
Naturally occurring androgens:
Testosterone, Epiandrosteron, Androsterone,
Dehydroepiandrosterone (DHEA)

Common in these androgens: CH3 group at
C10 and C13 and all are C-19.

5 enzymes in 3 proteins:
1.3b-hydroxysteroid dehydrogenase & 5,4-
isomerase
2.17a-hydroxylase & C17,20-lyase
3.17b-hydroxysteroid dehydrogenase
Physiological and biochemical
functions of androgens
Sex related physiological functions:
androgen, primarily DHT and testosterone
influences:
growth, development and maintenance of male
reproductive organs
Sexual differentiation and secondary sexual
characteristics
Spermatogenesis
Male pattern of aggressive behavior
Physiological and biochemical
functions of androgens
Biochemical functions:
ANDROGENS are anabolic in nature.

Effects on protein metabolism: promotes
transcription and translation
Cause positive nitrogen balance and increase
muscle mass

Effect on carbohydrate and fat metabolism:
increase glycolysis, fatty acid synthesis and
citric acid cycle.

Effect on mineral metabolism: promotes
mineral deposition and bone growth
Testosterone metabolites
Metabolic pathways: 2 pathways
1. Oxidation at 17-position: 17-keto steroid,
generally inactive
2. Reduction of A ring double bond and 3-
ketone: DHT
Metabolites of testosterone
Most potent: DHT
Sites: prostrate, external genital, and some areas
of skin

Plasma content: 1/10th. Of testosterone (400
mg/dl).

Reaction catalyzed: NADPH-dependent 5a-
reductase

5a-reductase: type 1 and type 2

Pseudohermaphroditism: mutation in type 2





Regulation of testicular
hormone
Testicular steroidogeneis: stimulated by LH

Binds to receptor on plasma membrane of Leydig
cells activates adenylase cyclase increase
intracellular cAMP enhance rate of cholesterol
transport by STAR and side chain cleavage by
P450scc.

Spermatogeneis: regulated by FSH and
Testosterone
FSH binds to sertoli cells ABP synthesized
ABP secreted in lumen of seminiferous tubules
testosterone produced by Leydigs cells is
transported to site of spermatogenesis
ESTROGENS
Predominantly ovarian hormones
Synthesized by follicles and corpus luteum of ovary.
ESTROGENS (contd.)
Responsible for maintenance of menstrual cycle and
reproductive process in women.

Synthesis of ESTROGENS
Precursor: Cholesterol
Produced by aromatization of androgens
Ovary: Produce Estrone (E1) and Estradiol (E2)
Placenta: E1,E2 and E3

Synthesis is under control of LH and FSH.
ESTROGEN
Physiological and Biochemical functions of
ESTROGENS

1. Sex-related physiological functions: growth,
development and maintenance of female reproductive
organs.

2. Maintenance of menstrual cycles

3. Development of female sexual characteristics

ESTROGEN (contd.)
Biochemical functions
Involved in many metabolic functions

Lipogenic effect: increases lipogenesis in adipose
tissues

Hypocholesterolemic effect: lower plasma total
cholesterol
LDL fraction of lipoprotein is decreased, while HDL fraction is
increased

Anabolic effect: promotes transcription and translation, synthesis of
protein in liver is elevated (E.g transferrin, ceruloplasmin)
ESTROGEN (contd.)
Effect on bone growth: promotes calcification and bone
growth

Effect on transhydrogenase: estrogen activates
transhydorgenase.

Reducing equivalents of NADPH + H+ are transferred to NAD+
(catalyzed by transhydrogenase)

After menopause deficiency of estrogen
transhydrogenase activity low diversion of NADPH
towards lipogeneis Obesity
Synthesis of estrogen and
progesterone
Ovarian production of estrogen, progesterone and
androgen requires cytochrome p450 family of oxidative
enzymes.

Ovarian estrogen: C18 steroid with phenolic hydroxyl
group on C3 and either hydroxyl group/ketone group on
C17.

Major steroid producing compartments of ovary:
granulosa cells, theca cells, stromal cells, cells of
corpus luteum.
Synthesis of estradiol in granulosa cells:
Mechanism
Anterior pituitary gland follicle stimulating
hormone (FSH) stimulates granulosa cells
along with catalytic activity of p450 aromatose
testosterone to estradiol
Progesterone
Synthesized and secreted by CORPUS
LUTEUM and PLACENTA.

Intermediate product during formation of
steroid hormone from cholesterol.

Production of progesterone is controlled by
LH.
Biochemical functions of
progesterone
Required for the implantation of fertilized ovum and
maintenance of pregnancy.

Promotes glandular tissue in uterus and mammary gland.

Increases body temperature by 0.5-1.5 0F.

Exact mechanism is not known.

Rise in temperature is indication for ovulation.
Metabolism
Site: Liver
Estradiol, estrone to estriol substrates for hepatic
enzymes
Conjugated form vs Unconjugated form.

Conjugated form: water soluble comes out of feces,
bile and urine.

Progestins: liver, ineffective when administered orally.
Major: sodium pregnanediol-20-glucuronide
3 phase of menstrual cycle
1.Menstrual period: thickening of endometrium lining
begin to shed off, continues from 4 to 6 days

1.Follicular phase: an egg follicle on an ovary gets ready
to release an egg, can be longer or shorter (determines the
length of cycle),

1.Luteal phase (premenstrual phase): phase starts
on ovulation day, the day the egg is released from the egg
follicle on the ovary.
1.It can happen any time from Day 7 to Day 22 of a normal
menstrual cycle.
Luteal phase during
menstrual cycle
Begins on Day 14, after ovulation occurs and continues
until Day 1 of your next period.

Estrogen and progesterone increase work together to
create changes in the lining of the uterus prepare it to
accept an embryo should conception occur.

When pregnancy does not occur
Estrogen & Progesterone level declines endometrial lining
sheds off leads to menstrual cycle

Hormonal and physiological changes
during menstrual cycle
Gonadal function
Testes cells testosterone
Regulated by: Pituitary LH.
Responsible for secondary sexual characteristics.

Estradiol main product of ovary
Responsible for secondary sexual characteristics.
Development of ovarian follicle & proliferation of uterine
endothelium.

Hypogonadism in male: Primary & Secondary
Primary: failure of testosterone or spermatogenesis.
Secondary: problem in hypothalamus/ pituitary
Gonad dysfunction in women
Primary amenorrhoea
Secondary amenorrhoea
Difference between Oligomenorrhoea
and Amenorrhoea
Amenorrhoea Oligomenorrhoea
Complete absence of menstruation Intermittent
(4 to 9 times/year)
Congenital (absence of uterus),
developmental problem
Result of prolactinomas (adenomas
of anterior pituitary gland)
Biochemical test for infertility
Failure to conceive even after a year of unprotected
intercourse.

Data to be taken for examination:
Birth control pills taken, congenital disease,
chemotherapy/radiotherapy, STD, smoking habit, drug habit,
contraceptive practice.
Physical examination in female: Cushing syndrome,
Galactorrhoea, and Hirsutism






Cushing syndrome
Biochemical test for infertility
In male:
Sperm analysis details: sperm count, sperm volume, sperm
density, motility, and abnormal spermatozoa.

In female:
Endocrine abnormality: in 1/3rd. Of patients

In male:
Endocrine abnormality: Rare
NOTE: In some couple abnormalities might not be
observed.





Endocrine investigations in sub-
fertile women
Investigation depends on phase of menstrual
cycle.
If irregularities are observed,
Check for serum progesterone (In middle of
luteal phase (Day 21))
If level of progesterone >30 nmol/L patient has
ovulated.
If level of progesterone <10 nmol/L ovulation
has not occurred.
In women: condition of no menstruation
(oligomenorrhoea/ amenohhhoea) not ovulating
hormone measurement may be diagnostic.






Subfertility in women because of
endocrine function
1.Insulin resistance: excess androgen synthesis.

1.Primary ovarian failure: because of elevation in
gonadotropins and low estradiol concentration (Post-
menopausal pattern)
1.Hormone replacement therapy assist libido, prevents
osteoporesis, but does not restore fertility.

1.Hyperprolactinemia: condition of amenorrhoea and
galactorrhoea in women.
1.In male: No early sign of symptoms shows.

Investigation of male
infertility
Investigation of female infertility in
patients with normal menstrual
cycle
Investigation of oligomenorrhoea and
amenorrhea
Investigation of oligomenorrhoea and
amenorrhea
Biochemical, metabolic and
endocrine changes in PCOS
Contraceptives
Synthetic agonist and antagonist
Prevent conception and tumor growth
ESTROGENS
Have estrogenic activity & pharmacological
features
Modifications done to decrease hepatic
metabolism so that can be given orally
First development: diethylstilbestrol
Others: 17a-ethinyl estradiol, mestranol: oral
contraceptives
Antagonist
Competes with estradiol for intracellular
receptor





Clomiphene competes with estradiol GnRH
release not retrained increase amount of LH
and FSH multiple follicle mature
simultaneously multiple pregnancies can
ensue.

Antagonist
Nafoxidine and tamoxifen combine with
estrogen receptor forms stable complex with
chromatin receptor cant recycle inhibit
action of estradiol for prolonged period.

Progestins
Difficult to synthesize compound with progestin
activity with no androgenic activity
Example: norethindrone,
medroxyprogesterone (Provera)
Inhibit ovulation for several months
Inhibit cell growth against endometrial
carcinoma.
Pathophysiology of male
reproductive system
Hypogonadism: lack of testosterone synthesis

Primary hypogonadism: affect testes, causes
testicular failure.

Secondary hypogonadims: defect in
secretion of gonadotropin.

5 different genetic defect in testosterone
synthesis
Example: 5a-reductase deficiency
Pathophysiology of female
reproductive system
Primary hypergonadism: directly involve
ovaries cause ovarian deficiencies
(decreased ovulation, decreased hormonal
production)

Secondary hypergonadism: loss of pituitary
gonadotropin function

Gonadal dysgenesis (Turners syndrome)

Polycystic Ovarian Syndrome (PCOS):
hirsutism, obesity, irregular menses, imparied
infertility
Normal hormonal values for men
Testosterone 300 - 1100 ng/dl

Prolactin 7 - 18 ng/ml

Luteinising Hormone ( LH) 2 - 18 mIU/ml

Follicle Stimulating Hormone ( FSH): 2 - 18
mIU/ml

Estradiol ( Day 3): < 50 pg/ml
Normal values for women
Follicle Stimulating Hormone (FSH) < 10 mIU/ml >
15 mIU/ml

Luteinising Hormone (LH) < 7 mIU/ml > 15 mIU/ml
-

Prolactin < 25 ng/ml

Thyroid Stimulating Hormone 0.4 - 3.8 uIU/ml
(TSH)
Phase of Cycle
Hormone Follicular Day of LH Surge Mid-luteal
Estradiol ( E2) < 50 pg/ml ( Day 3) > 100 pg/ml
Progesterone < 1.5 ng/ml > 15 ng/ml

The Day 3 estradiol level should be less than 50 pg/ml. A high Day 3
estradiol level suggests poor ovarian reserve.

A mature follicles produces more than 200-300 pg/ml of estradiol

The progesterone level should be more than 15 ng/ml about 7 days after
ovulation. This suggests that the corpus luteum is functioning normally.