Transcript Pharmacology of Pituitary and Hypothalamic Hormones

Pituitary and Hypothalamic Hormones
Akrum Hamdy
Introduction
Most pituitary and hypothalamic hormone
are trophic hormones. This and other
factors limit their use as drugs.
Exceptions – growth hormone and
gonadotropins
Growth Hormone
GH or Somatotropin
Chemistry – a single chain polypeptide.
 Significant differences in amino acid
sequence between humans and other
species prevent use of non-human
hormone

Growth Hormone
Physiological Actions
Growth Hormone

Physiological actions
 Mechanism – GH receptor stimulation activates an
intracellular tyrosine kinase, JAK2, resulting in
phosphorylation of proteins and gene regulation.
 Growth – almost all body tissues stimulated to grow
 Nitrogen metabolism – increased nitrogen retention,
amino acid transport into tissues, and incorporation
into protein
 Carbohydrate and lipid metabolism – GH appears to
promote use of lipids as energy source instead of
carbohydrates

GH has a diabetogenic effect in diabetics
Growth Hormone

Physiological actions
 Conserves
muscle at the expense of fat
during stress
 Insulin-like growth factor (IGF, somatomedins)
– peptides produced by liver and other tissues
in response to GH; appear to mediate many
GH effects. rhIGF-1 (mecasermin, Increlix)
now available for treatment of growth failure in
GH-resistant patients
Growth Hormone

Clinical applications – one of the few
pituitary hormones with long-term
therapeutic utility. Recombinant human
growth hormone (rh-GH) is used clinically.
There are two forms, somatotropin and
somatrem.
dwarfism – in children with
insufficient GH secretion, GH will generally
produce an increased growth rate over
several years. Recently, FDA approved use in
children with idiopathic, non-GH-deficient
short stature.
 Hypopituitary
Growth Hormone

Clinical applications
of AIDS – associated wasting
 Treatment of adult onset growth hormone
deficiency
 Turner’s syndrome
 Treatment

Anti-aging supplements – OTC
supplements which suggest they contain
hGH. Contain amino acids that are
supposed to release GH.
Growth Hormone
associated with therapy – possibility
of intracranial hypertension and visual
changes exist, so fundascopic exams needed.
 Also possibility of type 2 diabetes and
respiratory difficulties in patients with obesity
or sleep apnea due to Prader-Willi syndrome.
 Possible contamination of human-derived GH
with Creutzfeldt-Jakob virus.
 Problems
Growth Hormone




Acromegaly – hypersecretion of GH may result
in acromegaly.
Octreotide (Sandostatin) or other somatostatin
analogs are most commonly used to decrease
GH secretion.
Dopamine agonists such as bromocryptine will
inhibit GH secretion from some GH secreting
tumors.
Pegvisomant (Somavert), a GH receptor
antagonist, is now available to treat acromegaly
in patients who have not responded to other
treatment. Pegvisomant prevents GH
stimulation of IGF.
Gonadotropins

Luteinizing hormone (LH, interstitial cell
stimulating hormone)
– glycoprotein hormone with 2
peptide chains.
 Physiological actions
 Chemistry
Mechanism – LH receptor stimulation activates Gs
 Ovary – promotes ovulation and luteinization of
ovarian follicles; stimulates synthesis and secretion
of estrogen and progesterone from corpus luteum.

Gonadotropins

Luteinizing hormone
 Physiological

actions
Testis – stimulate interstitial (leydig) cells to
secrete androgens
Figure 56-4. The hypothalamicpituitary-gonadol axis
A single hypothalamic releasing factor,
gonadotropin-releasing hormone (GnRH),
controls the synthesis and release of both
gonadotropins (LH and FSH) in males and
females. Gonadal steroid hormones
(androgens, estrogens, and progesterone)
cause feedback inhibition at the level of
the pituitary and the hypothalamus. The
pre-ovulatory surge of estrogen also can
exert a stimulatory effect at the level of the
pituitary and the hypothalamus. Inhibin, a
polypeptide hormone produced by the
gonads, specifically inhibits FSH
production by the pituitary.
Gonadotropins

Luteinizing hormone
 Clinical
application
Infertility – menotropins (a mixture of urinary LH
and FSH) and chorionic gonadotropin have been
used to induce ovulation. Recombinant human LH
lutropin alpha (Luveris) is now available.
 Hyperstimulation of ovary may occur
 May also increase fertility in men
 Kits available to predict time of ovulation by
measuring urinary LH

Gonadotropins

Follicle stimulating hormone (FSH)
– glycoprotein with 2 peptide chains.
Agents available are recombinant human FSH,
follitropin (Gonal-F and Follistim), and urinary human
FSH, urofollitropin
 Physiological actions of FSH
 Chemistry



Mechanism – activates Gs
Ovary – promote follicular development
Testis – stimulate testicular growth and maintain seminiferous
tubules
 Clinical
application – promote ovulation
Gonadotropins

Chorionic gonadotropin (HCG) – not a
pituitary hormone but is similar to the
pituitary gonadotropins
– glycoprotein with 2 polypeptide
chains. Synthesized by syncytiotrophoblasts
of placenta. Recombinant human HCG,
choriogonadotropin alfa (Ovidrel) is used
clinically.
 Physiological actions – stimulate and sustain
function of corpus luteum
 Chemistry
Gonadotropins

Chorionic gonadotropin (HCG)
application – induction of ovulation,
promote descent of testes in cryptorchism
 Presence of HCG in urine used to confirm
diagnosis of pregnancy
 Clinical
Prolactin - PRL
Chemistry – single chain polypeptide
hormone
 Physiological actions

– causes growth and development of
breasts, and increased synthesis of milk proteins
 Decreases release or effectiveness of
gonadotropins
 Lactation

Hypersecretion – hyperprolactinemia may
cause galactorrhea, amenorrhea and
infertility. Bromocriptine, pergolide (Permax),
and cabergoline (Dostinex) are useful in
suppressing PRL secreting tumors.
Thyrotropin (TSH)


Chemistry – glycoprotein with 2 polypeptide
chains. Thyrotropin alpha, human recombinant
TSH, is used clinically.
Physiological actions – Receptor stimulation
activates Gs which increases function of thyroid
gland
 Increases
uptake of iodine by thyroid, synthesis and
release of hormone, and growth of gland.
Thyrotropin (TSH)

Clinical application
 Increases
uptake of radioactive iodine. Used
as a diagnostic tool for serum thyroglobulin
testing or whole body scanning in the followup of patients with thyroid cancer.
Corticotropin(Adrenal cortex trophic
hormone, ACTH)
Chemistry – natural hormone is a single chain
polypeptide of 39 amino acids. A synthetic
form containing amino acids 1-24 is available.
 Physiological actions – stimulates adrenal
cortex to synthesize and secrete cortisol,
corticosterone, and aldosterone (slightly).
Prevents atrophy of adrenal cortex.

– receptor interaction results in
activation of adenylate cyclase and synthesis of
cAMP. cAMP activates enzymes involved in
steroid synthesis.
 Mechanism
Corticotropin
Adrenal cortex trophic hormone, ACTH)

Clinical use
 Diagnosis
of adrenal insufficiency
 Treatment of infantile spasms (epilepsy)
Hypothalamic Hormones

Peptides synthesized in hypothalamus and
transported to the anterior pituitary via portal
circulation
releasing hormone and analogs –
drugs available include Gonadorelin (natural
hormone) and
 Long-acting analogs histrelin (Suprelin), leuprolide
(Leupron), gosrelin (Zoladex), triptoreline (Trelstar),
and nafareline (Synarel).
 Gonadorelin is used for induction of ovulation.
 Long acting analogs are used for treatment of PMS,
endometriosis, prostate cancer, and central
precocious puberty. Experimental use as male
contraceptive.
 Gonadotropin
Hypothalamic Hormones

GnRH antagonists – ganirelix (Antagon)
and cetrorelix (Cetrotide)
 Used
to inhibit premature LH surges prior to
harvesting eggs for in vitro fertilization
 Also abarelix (Plenaxis) – a GnRH receptor
antagonist used to treat advanced prostate
cancer. Danger of life-threatening allergic
reactions in 4% of patients.
Hypothalamic Hormones
– an analog, octreotide acetate
(Sandostatin) used to treat acromegaly,
carcinoid, and VIP secreting tumors. Long
acting form now available (once per month).
 Growth hormone releasing hormone –
Semorelin (Geref), a synthetic form of GHRH,
has been approved for treatment of GH
deficiency. Will only work in patients with
functioning pituitary.
 Somatostatin