Hypothalamic & Pituitary

Hormones
Marwa Qadri, Pharm.D, Ph.D.
Assistant Professor of Pharmacology
433 PHL-2 Pharmacology-IV
Spring 2023 (2)
 Learning Objectives
• To describe the role of the Hypothalamic-Pituitary axis in regulating the production of the major anterior and
posterior pituitary hormones.
• To list the drugs used in the treatment of growth hormone deficiency and describe their specific indications,
contraindications, mechanism(s) of action and major adverse effects.
• To list the drugs used in the treatment of growth hormone excess and describe their specific indications,
contraindications, mechanism(s) of action and major adverse effects.
• To list members of the GnRH agonist and antagonist class of drugs and describe their indications,
contraindications, mechanism of action and major adverse effects.
• To list the drugs used to treat disorders of the Hypothalamic-Pituitary-Prolactin axis and describe their
indications, contraindications, mechanism(s) of action and major adverse effects.
• To list the drugs used to treat disorders of the Hypothalamic-Pituitary-ACTH axis and describe their indications,
contraindications, mechanism(s) of action and major adverse effects.
• To describe the indications, mechanism of action, and major adverse effects of oxytocin.
• To describe the indications, mechanism of action and major adverse effects of desmopressin and the
vasopressin receptor antagonists.
 Pituitary Gland Hormones

Ø The posterior lobe hormones Ø The anterior lobe does synthesize

are synthesized in the hormones.
hypothalamus and transported Ø The hormones of the anterior
to the posterior pituitary, and pituitary are regulated by
released in response to specific neuropeptides (produced by
physiologic signals, such as high hypothalamus) that are called either
plasma osmolarity or “releasing” or “inhibiting” factors or
parturition. hormones.

Ø These hormones are not Ø Examples: Growth hormone (GH),

regulated by releasing Prolactin (PRL),
hormones. Adrenocorticotropic hormone
(ACTH), Thyroid stimulating hormone
Ø Examples: Oxytocin and (TSH), Gonadotropins: (i) Follicle
Antidiuretic hormone (ADH) or stimulating hormone (FSH), and (ii)
vasopressin. Luteinizing hormone (LH).
 Pituitary Gland Hormones
Drugs that mimic or block the effects
of hypothalamic and pituitary
hormones have pharmacologic
applications in three primary
areas:

(1) as replacement therapy for

hormone deficiency states.

(2) as antagonists for diseases

caused by excess production of
pituitary hormones.

(3) as diagnostic tools for identifying

several endocrine abnormalities.
 Hormones that Integrate the Hypothalamic-Anterior Pituitary-
Endocrine Axis

GHRIH (growth hormone release inhibitory hormone)

 (I) Anterior Pituitary Hormones: A). GH (Somatotropin)
HYPOTHALAMUS

GHRH GHRIH (Somatostatin)

Long e
tiv
nega ack
b
feed
Anterior Pituitary

GH

Direct actions (metabolic, Indirect actions (growth promoting)

anti-insulin)
Liver and other tissues
Liver
Carbohydrate metabolism Insulin-like growth factor (IGF-1)
Fat metabolism
Break down
Increases blood glucose and glycogen to
other anti-insulin effects glucose Skeletal Extra-skeletal
Increases fat breakdown

Increases cartilage formation Increases protein synthesis and

and skeletal growth cell growth and proliferation
 (I) Anterior Pituitary Hormones: A). GH (Somatotropin)

Dysfunction of GH:

Before Puberty After Puberty

Hypofunction (lack of GH Dwarfism Generalized obesity,
releasing factor or IGF) reduced muscle mass
Hyperfunction Gigantism Acromegaly
Preparations:
Somatropin Ø It is recombinant human growth hormone (rhGH) and contains 191 amino acids. MOA: direct
(Norditropin®) agonist to GH receptor and stimulates gene expression e.g. IGF-1.
Ø Somatropin is used as replacement therapy in various conditions of growth failure, growth
hormone deficiency, and weakness in children and adults.
Ø It is administered by S.C. or IM injection. Although the half-life of GH is short (approximately 25
minutes), it induces the release of IGF-1 from the liver, which is responsible for subsequent GH-like
actions.

Somatrem A hGH analog and contains an extra terminal methionyl amino-acid residue. Both somatropin and
somatrem have similar biological actions and potencies as the endogenous hGH polypeptide.
 (I) Anterior Pituitary Hormones: A). GH (Somatotropin)

Mecasermin -
It is a recombinant human insulin-like growth factor-1 (IGF-1) used for the long-term treatment of
growth failure in pediatric patients with primary IGF-1 deficiency or with growth hormone gene
-
-

deletion due to the development of neutralizing antibodies to GH.

-

·
:

Pegvisomant Direct GH receptor antagonist, and it is indicated in acromegaly due to small pituitary adenomas.
-

Adverse effects of hGH analogs:

Adverse effects of somatropin include pain at the injection site, edema, arthralgias, myalgias, flu-like symptoms,
and an increases risk of diabetes.
-
 (I) Anterior Pituitary Hormones: A). GH (Somatotropin)
HYPOTHALAMUS
Other preparations:
Ø Infusion of rhGHRH (recombinant human growth hormone releasing hormone) is
-
known as sermorelin. GHRIH (Somatostatin)
-

GHRF
-
Sermorelin (discontinues in some countries) (I.V,
Coc S.C, NAS) stimulates the pituitary
gland by binding to specific receptors to increase production and secretion of Anterior Pituitary
endogenous OhGH within 1 hr.
-

Ø GHRIH (growth hormone release inhibitory hormone) or somatostatin is used in the

GH
treatment of acromegaly (short t1/2).

Somatostatin binds to somatostatin receptors (SST) subtypes and mediates:

1- An antisecretory effect on growth hormone (acromegaly)
- Liver
-
2- It attenuates the release of most gastrointestinal hormones such as gastrin and
-

causes splanchnic vasoconstriction (used in peptic ulcer and to control bleeding

-
-

from esophageal varices). IGF-1

3- Reduces cells proliferation (anti-neoplastic action).
-
-

Ø Octreotide is a synthetic analog of somatostatin and it has long

O t1/2. (depot
formulation). Growth of peripheral
tissues
Ø Both GHRH and GHRIH are also used in diagnostic evaluation of pituitary function.
 (I) Anterior Pituitary Hormones: B). Gonadotropin-
Releasing Hormone (GnRH)
GRI -
Hypothalm = LH , FSH = Gondd Haman
Ø Anterior pituitary secretes 2- gondotrpoin hormones FSH and LH to
-

regulate hormonal activity of gonads (ovaries & testes).

&D
Ø Gonadal steroid hormones (androgens, estrogens, and -
-
progesterone)
exert feedback inhibition at the level of the pituitary and the
hypothalamus.

Ø If the gonads fail to create enough estrogen, testosterone and/or inhibin

- -
-
-

→↑FSH and LH production from the pituitary gland

=
- -

(hypergonadotrophic-hypogonadism)→ >primary ovarian failure or

-
-

5 · E
- -

testicular failure.
-

&
-

- -
-
-
-

Ø (Hypogonadotrophic-hypogonadism)→↓
-
> -
FSH and LH→&
infertility.
-

&
is
-
-
 (I) Anterior Pituitary Hormones: B). Gonadotropin-Releasing Hormone (GnRH)
Preparations
1- Follicle stimulating hormone (FSH) Ø Menotropins (Humegon) (FSH+LH): is a preparation obtained from urine of menopausal
women.
MOA: q Used to treat -male and female infertility
Stimulate follicular development. q Males: hypogonadism -infertility
Jibl
q Females: amenorrhea and - IVF programs.·
-
-

Adverse effects : -
&

Y - -
-

v Ovarian enlargement and possible Ø Urofollitropin~(Pure FSH), obtained from the urine of menopausal women and preferred
-

over combined FSH + LH preparation for induction of ovulation in women with polycystic
=

ovarian hyperstimulation syndrome, S

which may be life threatening. ↑ ovarian disease.

Ø Follitropin alfa and beta are human FSH products manufactured using recombinant DNA
v Multiple births are not uncommon. technology.
q Injected via the IM or subcutaneous route.
- -

q Injection of FSH products over a period of 5 to 12 days causes ovarian follicular growth and
- -

maturation.- 2 =59/
2-Luteinizing hormone (LH) Lutropin (rhLH) approved in 2004 for use in combination with Follitropin alfa for stimulation of
=

follicular development in infertile women with profound LH deficiency.

-

-
&

Lutropin + Follitropin = infertile women

3- Human chorionic gonadotropin (hCG) It is a placental hormone that is excreted in the urine of pregnant women.
-

MOA: -used to trigger ovulation via LH-E-

Ø Choriogonadotropin alfa (rhhCG ) (Pregnyl, Profasi) : used for the treatment of=>
infertility and
-
is E & J·
-
receptor in females. ·
g
undescended testicles.
-
-

-Used to trigger endogenous testosterone

-
- Cheriogouture
synthesis via LH receptor in males.
-
-
 (I) Anterior Pituitary Hormones: B). Gonadotropin-
Releasing Hormone (GnRH)
C as)
&

10 ; 196
-
-

Preparations:

-
&
GnRH and GnRH analogs (Leuprolide): it can be administered IM, SC, and as nasal spray.
-

The method of injection of GnRH determine its mechanism of action: -

Ø If injected in a pulsatile manner à gonadotropins (trophic effect)

-
&

Ø If injected in a= continuous manner à FSH and LH release by pituitary gland, so it used in prostatic
=

- -
carcinoma or hypertrophy together with anti—androgens, and to suppress endogenous gonadotropin
-

-
&

- x

release in women who are undergoing controlled ovarian hyperstimulation and in IVF programs.
-

Adverse effects :
Hot flashes, decreased bone
-
density, vaginal
- dryness, and erectile dysfunction.
 (I) Anterior Pituitary Hormones: B). Gonadotropin-
Releasing Hormone (GnRH)
Therapeutic indications:

i. Ovulation Induction: The gonadotropins are used to induce follicle development and ovulation in women with
anovulation that is secondary to hypogonadotropic hypogonadism, polycystic ovary syndrome, obesity, and other
causes.

ii. Male Infertility

iii. Cryptorchism (crypt=hidden, orch=testes) hCG can be tried between the age 1-7 years if there is no
anatomical obstruction.

iv. To aid in vitro fertilization: Menotropins (FSH+LH or pure FSH) for simultaneous maturation of several ova
and timely ovulation, to facilitate in vitro fertilization.
 (I) Anterior Pituitary Hormones: C). Prolactin (PRL)

Prolactin is a peptide hormone that is also secreted by the

anterior pituitary. Its primary function is to stimulate and
maintain lactation.

Ø In females:
a) It stimulates lactogenesis (milk production from the
mammary gland at the end of pregnancy) (N.B. milk
ejection is stimulated by oxytocin by a reflex
mechanism).

a) It inhibits gonadotropins release à leads to infertility.

Ø In males:

It has a role in testosterone synthesis, but excessive prolactin

(hyperprolactinemia) leads to infertility.
 (I) Anterior Pituitary Hormones: C). Prolactin (PRL)
Regulation of PRL secretion:

Ø Prolactin releasing hormone (PRH) and thyrotropin releasing

hormone (TRH) àstimulate PRL releases.

Ø Prolactin inhibiting hormone (PIH) ”dopamine” inhibits PRL

release.

Ø Suckling reflex: suckling induces PRL secretion.

Ø Stress, exertion & hypoglycaemia stimulate prolactin release.

Ø Prolactin levels are low in childhood, increased in girls at

puberty and are higher in adult females than in males.

Hyperprolactinemia:
In females: amenorrhea and menstrual disturbance. Treated by the dopaminergic agonists: bromocriptine
In males: gynecomastia and impotence. (Parlodel), cabergoline (Dostinex)
 (I) Anterior Pituitary Hormones: C). Prolactin (PRL)
Bromocriptine It is a potent dopamine agonist and has greater action on D2 receptors.
ü D2 agonistic effect on the D2 receptors of anterior pituitary lactotrophic cells →blocks prolactin
Parlodel® exocytosis and gene expression, reducing the harmful effects of hyperprolactinemia in galactorrhea and
- -

other prolactin-related conditions.

ü Bromocriptine’s dopaminergic effect can cause paradoxical blocking of GH release, decreasing circulating
blood concentrations of GH, so it can be used in patients with acromegaly.
-

ü In Parkinson disease, bromocriptine binds directly to striatal dopamine D2 receptors, stimulating

locomotion and attenuating the bradykinetic symptoms.
ü In Type II DM, bromocriptine alters monoamine neurotransmitter concentrations in the the
hypothalamus
~
→decreases
e-
hepatic glucose production and insulin resistances. (novel MOA).

Pharmacokinetics:
ü Only 1/3 of an oral dose is absorbed; bioavailability is further lowered by high first pass metabolism in
liver. Metabolites are excreted mainly in bile. Its plasma t1/2 is 3-6 hours.
-

ü Bromocriptine metabolized primarily in the liver via the cytochrome P450 3A4 enzymes and should be
avoided in anyone with hepatic impairment.
Adverse effects:
Stimulating dopaminergic receptors in the CNS leads to nausea, headache, vertigo, constipation, light-
headedness, abdominal cramps, nasal congestion, diarrhea, and hypotension.
 (I) Anterior Pituitary Hormones: C). Prolactin (PRL)

Cabergoline ü A new D2 agonist; more D2 selective and longer acting (t1/2 > 60 hrs) than bromocriptine.
Dostinex® ü Given only twice weekly.
ü Indicated for the treatment of hyperprolactinemic disorders, either idiopathic or due to pituitary
adenomas (preferred in hyperprolactinemia).
ü Cabergoline is extensively metabolized by liver, it should be avoided in anyone with hepatic
impairment.
ü Pulmonary fibrosis and cardiac valvulopathy are associated with long-term treatment.
 (I) Anterior Pituitary Hormones: D). Adrenocorticotropic Hormone
(ACTH)
v Corticotropin-releasing hormone (CRH) àsynthesis and release of ACTH àbinds to
receptors on the surface of the adrenal cortex à stimulate the adrenocorticosteroid
synthetic pathway (cholesterol to pregnenolone).

q Functions:
ü It is trophic to the adrenal cortex, so it increases its growth, blood flow, and the release
of cortisol, as well as decreases cholesterol level by cholesterol esterase activation.

ü ACTH is similar to MSH (melanocyte stimulating hormone) and it binds to the MSH-
receptors expressed by the melanocyteà increases in skin pigmentation.

ü Adrenal cortex (AC) hyperfunction à ↑ cortisol (Cushing’s syndrome), ↑ aldosterone

(Conn’s syndrome).

ü Adrenal cortex hypofunction à primary AC hypofunction (low cortisol and high ACTH;
Addison’s disease), or secondary AC hypofunction (low ACTH).
 (I) Anterior Pituitary Hormones: D). Adrenocorticotropic Hormone
(ACTH)
Preparations:
1- Soluble ACTH injection (Acthar®, Cortrophin Gel®).
2-Tetracosactrin (Synacthen Depot®) IM injection.
3- Cosyntropin (Cortrosyn®). (IV injection).
q Therapeutic uses:
ü Replacement therapy in case of ACTH deficiency.
ü Used as a diagnostic tool for differentiating between primary adrenal insufficiency
(Addison disease, associated with adrenal atrophy).

ü Other conditions: variety of allergic, autoimmune conditions, and (infantile spasm;

unknow mechanism).

q Adverse effects:
With longer use, toxicities are similar to those of glucocorticoids and include hypertension,
peripheral edema, hypokalemia, emotional disturbances, and increased risk of infection.
 (II) Posterior Pituitary Hormones: A). Oxytocin
q Oxytocin binds to specific G protein-coupled receptors(OXTR)àactivates PLCβ-IP3-Ca2+ pathway à
activates voltage Ca2+ channels à stimulates smooth muscle contraction in the uterus and
myoepithelial contractions in the breast à involved in parturition (delivery) and the letdown of milk.

q Oxytocin also stimulates the release of prostaglandins and leukotrienes that augment uterine
contraction.

q Therapeutic uses:
Ø Oxytocin (Syntocinon®) is usually administered I.V. via infusion pump to induce labor or nasal spray.
Ø Oxytocin can also be used in the immediate postpartum period to stop vaginal bleeding.
 (II) Posterior Pituitary Hormones: A). Oxytocin
q Adverse effects: Serious toxicity is rare.
Ø Excessive stimulation of uterine contractions before delivery can cause fetal distress,
placental abruption, or uterine rupture.

Ø High concentrations of oxytocin with activation of vasopressin receptors can cause

excessive fluid retention, or water intoxication, leading to hyponatremia, heart failure,
seizures, and death.

Ø Atosiban (oxytocin antagonist): is a modified form of oxytocin that is administered by I.V

infusion for 2–48 hours and is currently registered for clinical use in women suffering from
preterm labour.
 (II) Posterior Pituitary Hormones: B). Antidiuretic hormone (ADH) or Vasopressin

Action of ADH:
ü ADH binds and activates V2 receptors in the kidneys and promotes water reabsorption
from the distal and collecting tubules.
ü At higher ADH concentration, ADH binds to V1 receptors in liver and vascular smooth
muscle causing vasoconstriction.
ü ADH increases ACTH and the coagulation factors.
ü ADH stimulates glycogenolysis.

Regulation of vasopressin secretion:

a) Through osmoreceptors in the hypothalamus: these receptors are sensitive to osmotic

pressure change, so when the osmolarity rises, the ADH released and causes water
retention.
b) Blood volume depletion.
c) Drugs such as alcohol which inhibits ADH.
 (II) Posterior Pituitary Hormones: B). Antidiuretic hormone (ADH) or Vasopressin

ADH disorder:
ü Deficiency of ADH is known as diabetes insipidus. Diabetes insipidus is caused by lack of ADH and failure of
the kidney to respond to ADH à polyuria and polydipsia.
ü Nephrogenic diabetes insipidus: characterized by normal level of ADH but the V2 receptor in the renal
tubules are insensitive to ADH.

Preparations:

(1) Vasopressin tannate injection (Pitressin®) MOA: Full agonist of both V1 and V2 receptors.
(2) Vasopressin aqueous solution.
(3) Desmopressin acetate (vasopressin analog):
Ø MOA: selectively activates V2 vasopressin receptor in the kidney and endothelial cell.
Ø It is given as nasal spray or as tablet for the treatment of diabetes insipidus and in children with
uncontrolled urination (it has longer duration of action than vasopressin).
 (II) Posterior Pituitary Hormones: B). Antidiuretic hormone (ADH) or Vasopressin

Indications of ADH preparations:

Ø Vasopressin and desmopressin are treatments of choice for pituitary diabetes insipidus.
Ø Bedtime desmopressin therapy, ameliorates nocturnal enuresis by decreasing nocturnal
urine production
Ø Vasopressin infusion is effective in some cases of esophageal variceal bleeding and colonic
diverticular bleeding.
Ø Desmopressin is also used for the treatment of coagulopathy in hemophilia A by increasing
factor VIII.

Toxicity:
Water intoxication, hyponatremia, headache, bronchoconstriction, and allergic reaction.

Vasopressin antagonists: Conivaptan (selectively blocks both V1 and V2 receptors) and

Tolvaptan (selectively blocks V2 receptor) àpromote water excretion and increase serum
Na+.
These drugs are used in patients with hyponatremia or acute heart failure which is associated
with elevated concentration of vasopressin.