Endocrine lecture HYPOTHALAMUS

1. Drugs affecting endocrine
system. Hypothalamus &
Pituitary Hormones.
SULAYMAN ADEMOLA
Department of Pharmacology
MEDICAL SCHOOL,IUIU
IUIU

2. BIBLIOGRAPHY
• Goodman and Gilman’s. The pharmacological basis of
therapeutics.
• Basic and Clinical Pharmacology. Bertram G. Katzung.
• Pharmacology. Rang and Dale’s. 6th edition.
• Pharmacology. 3rd edition. Lippincott´s.

3. SUMMARY
1. Introduction to endocrine system.
2. Introduction to Hypothalamus Hormones
3. Anterior pituitary hormones.

4. MAJOR ENDOCRINE GLANDS

5. • Are recognized six main groups of drugs acting on
endocrine system. Some of them are employed in
clinical practice like replacement therapy because
these types of drugs can act as natural hormone
secretion.
• Others may act stimulating the natural hormonal
production, secretion or potentiating their
physiological action.
• But, also are employed in clinical practice a lot of
drugs which can act on contrary, by inhibition of
natural hormone action in biochemical or
physiological level.
Introduction

6. The Hypothalamus
Small structure at the base of
the brain.
Regulates many body
functions, including appetite
and body temperature.
Regulates the pituitary gland.

7. What is the endocrine system?
The primary
endocrine glands are
Hypothalamus (the
master gland), the
pituitary, pineal,
thyroid, parathyroid,
islets of Langerhans,
adrenals, ovaries in
the female and testes
in the male.
The function of the endocrine system is the
production and regulation of chemical
substances called hormones.

8. Hormones…
A hormone is a chemical transmitter. It is released
in small amounts from glands, and is transported
in the bloodstream to target organs or other cells.
Hormones are chemical messengers, transferring
information and instructions from one set of cells
to another.

9. The Pituitary Gland
• A sort of master gland.
• It is a cherry-sized
endocrine gland.
• The hormones it
secretes affect the
growth and secretion of
other endocrine glands.
• The real boss is the
hypothalamus.

10. Interaction between hypothalamus and
pituitary (hypothalamic-pituitary axis)
HIPÓFISIS
A
NTE
RI
O
R
Hipotálamo
Hipotálamo
Ó
RGA
NO
S EFECT
O
RE
S
HO
RM
O
NA
S
INHI
BI
DO
RA
S
HO
RM
O
NA
S
LIBERA
DORA
S
GL
ÁNDULA
S
Hypothalamus
Anterior
pituitary
Endocrine Glands
ORGANS
Releasing Factors Inhibitory Factors
This interaction
is a feedback
control system.

11. Pituitary Hormones
Neurohypophysis
Adenohypophysis
Hypothalamic
neuron cells
Bone
Growth Hormone
(GH)
Adrenocorticotropi
c Hormone (ACTH)
Adrenal
cortex
Ovary
Thyroid gland
Mammary
glands
Testicle
Thyroid
stimulating
hormone (TSH)
Gonadotropic
Hormones
(LH & FSH)
Prolactin Uterine
muscle
Antidiuretic
Hormone
(ADH)
Mammary
glands
Renal tubules
Oxytocin
Skin
Melanocyte
stimulating
hormone

12. ANTERIOR PITUITARY
HORMONES

13. Anterior Pituitary
• Derived during embryological development from
the roof of the mouth.
• Most of the hormones are released from the
anterior pituitary.
• Hormones released from the anterior pituitary
are dormant unless directed to be released by
the hypothalamus via Releasing Factors.
• They are:
Growth hormone (GH), Luteinizing hormone
(LH), Follicle stimulating hormone (FSH),
Prolactin (PRL), Adrenocorticotropic hormone
(ACTH), Thyroid stimulating hormone (TSH).

14. Hypothalamic Hormones:
Gondotropin RF Corticotropin RF
(CRF)
Thyrotropin RF Growth Hor RF
Pituitary Hormones:
Follicle SH &
Lutenizing Hor.
Thyrotropin SH
Adrenocorticoptropic
Hormone (ACTH)
Prolactin
Growth
Hormone
Target Gland or Structure:
Ovaries & Testes
(androgens, estrogen)
Adrenal Gland
(cortisol)
Cells of body
Thyroid Gland
(thyroxine)
Bones, breasts
& cells of body

15. Anterior Pituitary hormones & their
Receptors
They are classified according to their structure and the types of
receptors that they activate:
• GH & prolactin are single-chain protein hormones with
significant homology. Both hormones activate receptors of the
JAK/STAT superfamily (Janus kinase family of intracellular
tyrosine kinases and the Signal Transducer and Activator of
Transcription family of nuclear transcription factors).
• TSH, FSH & LH are dimeric proteins that activate G protein-
coupled receptors. They share a common chain. Their chains,
though somewhat similar to each other, differ enough to confer
receptor specificity.
• ACTH is a single peptide that is cleaved from a larger precursor
that also contains the peptide endorphin. It acts through a G
protein-coupled receptor.

16. GROWTH HORMONE (GH)
• It is a peptide hormone with 191-amino acids.
• Structurally similar to prolactin and chorionic
somatomammotropin.
• GH stimulates somatic growth and regulates metabolism.
• Growth hormone–releasing hormone (GHRH) is its major
stimulator.
• Somatostatin is the major inhibitor of its synthesis and release.

17. GROWTH HORMONE (GH)
• GH controls synthesis of insulin-like growth factor 1 (IGF-1,
also called somatomedin-C), which largely controls growth.
• Although IGF-1 is produced by many tissues, the liver is the
major source.
• A variant of IGF-1 occurs in muscle, where it plays a role in
enhancing muscle strength. It is less under control of GH than
is the liver variant.

18. GH- Pharmacological effects
• The metabolic effects of GH are biphasic.
• Initially exerts insulin-like effects, increasing
glucose uptake in muscle and fat, stimulating
amino acid uptake and protein synthesis in liver
and muscle, and inhibiting lipolysis in adipose
tissue.
• Several hours later, more profound anti–insulin-like
metabolic effects occur:
Inhibition of glucose uptake and use, causing
blood glucose and lipolysis to increase, which
increases plasma free fatty acids.

19. GH- Pharmacological effects cont.
• Promotes longitudinal growth indirectly through:
Somatomedins (IGFs).
GH stimulates growth plate cartilage & liver
synthesis of: IGF-I & IGF-II
Somatomedins are mediators of processes
promoting bone growth:
–cellular proliferation,
–increased proline to hydroxyproline conversion
(cartilage synthesis).
GH deficiency Reduced somatomedin Short
stature

20. Indirect effects
• skeletal growth
• cell proliferation
• protein anabolism
Direct effects
•  lipolysis   fat utilization
•  blood sugar (anti-insulin
effect)
GH- Summary of Pharmacological effects

21. GH as Juvenile
Gigantism

22. GH as an Adult
Acromegaly

23. Acromegaly

24. GH = Pituitary dwarfism

25. GH- Pharmacokinetics
• Endogenous GH has a half-life of 20-25 min and is
predominantly cleared by the liver.
• Recombinant human GH (rhGH) is administered
SC 3-6 times per week.
• Peak levels occur in 2-4 hrs and active blood
levels persist for approximately 36 hrs.
• Somatropin injectable suspension is a long-acting
preparation of rhGH enclosed within
microspheres. These microspheres degrade
slowly after SC injection such that the rhGH is
released over about 1 month.

26. GH- Uses
 Growth failure in pediatric patients associated with:
• GH deficiency.
• Turner’s syndrome (chromosomal anomaly in girls).
• Chronic renal failure.
• Small for gestational age babies unable to catch up by 2.
• Prader-Willi syndrome(genetic disease associated with growth f
ailure, obesity & carbohydrate intolerance).
 Growth hormone deficiency in adults.
 Wasting in patients with HIV infection (Increased lean body mass,
weight, and physical endurance).
 (?) adult athletes – to increase muscle mass.
 (?) anti-aging.
 (?) Idiopathic short stature (Non-GH deficient short stature
(NGHDSS) children).

27. GH- Adverse effects
• Creutzfeldt-Jakob disease (is a brain damage).
• Children generally tolerate the treatment well: rarely-
hypothyroidism, scoliosis, intracranial hypertension.
Following rapid growth:
- Slipped capital femoral epiphyses: limp;
lower extremity pain (rare).
• In adults: peripheral edema, myalgia, arthralgia, pancreatitis,
gynecomastia. Leukemia incidence (slight increase may not
be causal). Screening suggested for hypothyroidism &
diabetes during GH treatment.

28. GH- Preparations
Recombinant forms are used.
• somatropin (191-amino acid form).
• somatrem (192 amino acid form (additional methionine).

29. GH- Antagonists
• Needed from the tendency of GH-producing cells to
form secreting tumors.
• Pituitary adenomas occur most commonly in adults.
• Acromegaly adversely affects the skeletal, muscular,
CVS, respiratory and metabolic systems.
• Small GH-secreting adenomas can be treated with GH
antagonists.
• Larger pituitary adenomas are treated with
transsphenoidal surgery or radiation.
- Somatostatin & somatostatin analogs.
- Bromocriptine- a dopamine receptor agonist reduce
the production of GH.
- Pegvisomant- prevents GH from activating its receptor.

30. SOMATOSTATIN
• Major inhibitor of GH synthesis and release.
• Also inhibits the release of TSH, insulin and
glucagon; it decreases the release of most GI
hormones and reduces gastric acid and
pancreatic secretion.
• Octreotide and Lanreotide are long-acting
analogues of somatostatin, used for the
treatment of tumours secreting vasoactive
intestinal peptide, carcinoid tumours,
glucagonomas and various pituitary adenomas.
They has a place in the therapy of acromegaly
and of bleeding oesophageal varices.

31. SOMATOSTATIN
• Generally given SC.
• Peak action is at 2 hours,
• Suppressant effect lasts for up to 8 hours.
ADR: Pain at the injection site and GI disturbances. Gallstones,
postprandial hyperglycaemia and acute hepatitis has occurred
in a few cases.

32. GONADOTROPIC HORMONES and Analogues
• FSH– stimulates gametogenesis.
• LH– regulates gonadal steroid hormone production.
• Human chorionic gonadotrophin (hCG): extracted
from urine of pregnant women. Contains the biologic
activity of LH. It is secreted by the chorion and
placenta. Stimulates ovarian corpus luteum to
produce progesterone and to maintain placenta.
• Human menopausal gonadotrophin (hMG):
extracted from urine of postmenopausal women.
Contains a mixture of LH and FSH.

33. GONADOTROPIC HORMONES
• Both control the production of the sex
hormones.
• Their synthesis and release are stimulated by
GnRH and suppressed by estrogen and
testosterone by negative feedback mechanism.
• Pulsatile GnRH is required to stimulate the
gonadotroph cells to produce and release LH &
FSH.
• Sustained, nonpulsatile administration of GnRH
or GnRH analogs inhibit the release of FSH &
LH by the pituitary in both women and men,
resulting in hypogonadism.

34. GONADOTROPIC HORMONES
• In women, they stimulate ovarian follicular
development and ovulation.
• In men, FSH acts in Sertoli cells and is
essential for spermatogenesis; LH acts on
Leydig cells of the testes to stimulate
testosterone biosynthesis.

35. GONADOTROPIC HORMONES
• Therapeutic Uses:
• Female infertility
• controlled ovarian hyperstimulation in assisted
reproductive technology (ART) such as in vitro
fertilization.
• anovulation
• Male infertility: oligospermia – hCG + hMG
• Adverse Effects:
• Multiple pregnancies (15-20%)
• Ovarian hyperstimulation (OHSS) (0.5-4%)
• Headache, Depression, Precocious puberty
• Edema, Gynecomastia in men

36. GONADOTROPIC HORMONES
• Preparations
• hCG (Pregnyl, Profasi, APL®)
• Menotropin (hMG)
• Urofollitropin (uFSH)
• rFSH – shorter t1/2 , more expensive
• Follitropin  (Gonal-f®)
• Follitropin  ( Puregon®)
• rLH (Lutropin, Luveris®)
r- recombinant
u- urinary

37. Prolactin (PRL)
• Produced in lactotrophs (constitute about 30% of the
cells of the anterior pituitary).
• The pituitary doubles in size during pregnancy, largely
because of hyperplasia and hypertrophy of lactotrophs.
• In humans, its major function is stimulating milk
production when appropriate circulating levels of
estrogens, progestins, corticosteroids, and insulin are
present. Its release also occurs during sexual activity
and stress.
• It may be a sensitive indicator of pituitary dysfunction; it
is the hormone most frequently produced in excess by
pituitary tumors and it may be one of the hormones to
become deficient from infiltrative disease or tumor
compression of the pituitary.

38. Prolactin (PRL)
• Estrogens increase both prolactin secretion and
proliferation of lactotrophs through release, from a
subset of lactotrophs, of the neuropeptide galanin.
• Prolactin production is inhibited by the catecholamine
dopamine acting through the D2 subtype of dopamine
receptors.
• Agonists of Dopamine (bromocriptine, pergolide,
cabergoline, quinagolide) suppress prolactin
release. Bromocriptine and pergolide are
antiparkinson drugs.
• Dopamine antagonists (used mainly as antipsychotic
drugs) are potent stimulants of prolactin release
(chlorpromazine, thioridazine, fluphenazine,
haloperidol, etc.).

39. Adrenocorticotropic hormone (ACTH)
• Also known as corticotropin.
• Corticotropin-releasing hormone (CRH) is the
primary stimulator of its release.
• ACTH induces the adrenal cortex to release cortisol
and several weak androgens, such as
dehydroepiandrosterone (DHEA).
• Circulating cortisol and other corticosteroids
(including exogenous corticosteroids) inhibit the
release of CRH and ACTH.
• The CRH-ACTH-cortisol axis is a central component
of the response to stress. Without ACTH, the
adrenal cortex atrophies and cortisol release virtually
ceases.

40. ACTH- Preparations
• ACTH is available as a synthetic derivative in the forms of
cosyntropin (trade name cortrosyn), and synacthen.
• Both are very rarely used in place of glucocorticoids to treat
secondary adrenal insufficiency, but are used primarily to
conduct the ACTH stimulation test.

41. Moon face in a patient suffering
Cushing’s syndrome
Signs & symptoms associated with prolonged exposure
to inappropriately high levels of hormone cortisol. Can
be caused by taking glucocorticoid drugs, or diseases that
result in excess cortisol, ACTH or CRH levels.

42. Thyroid hormones
• Thyrotrophin-releasing hormone (TRH), released
from the hypothalamus in response to various
stimuli, is the major stimulus for the release of TSH
(thyrotrophin) from the anterior pituitary.
• Thyroid gland releases two different types of
hormones:
1. Tetraiodothyronine or Thyroxine (T4) and
Triiodothyronine (T3). They have functions in
growth, metabolism and the regulation of thyroid
function.
2. Calcitonin (involved in the control of plasma
Ca2+).

43. • THE WORLD MAKES ROOM FOR PEOPLE
• WHO KNOW WHERE THEY ARE GOING

44. End and
44
THANK YOU FOR YOUR ATTENTION