Pituitary And Thyroid

Pharmacology Team
Naim Kittana, Suhaib Hattab, Ansam Sawalha, Adham Abu Taha, Waleed Sweileh,
Ramzi Shawahneh

Faculty of Medicine & Health Sciences

An-Najah National University 1
 Hormones of the Hypothalamus & Pituitary gland

Hypothalamus (GHRH,
GnRH,CRH, TRH)
Direct action

PIH, GHIH Pituitary

gland

Anterior Posterior

Growth
FSH & LH TSH ACTH Prolactin ADH Oxytocin
Hormone

Ovary & Adrenal Renal Uterus &

Liver Thyroid Breast
testis cortex tubules breast
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Anterior Pituitary Hormones

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Hormones of the hypothalamus

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1. Agents Affecting Growth Hormone (Somatotropin)

– Growth hormone-releasing hormone (GHRH)

• Released from the hypothalamus
• Binds to specific membrane GHRH receptors on pituitary.
• GHRH rapidly elevates serum growth hormone (somatotropin)
levels with high specificity.
 

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Growth-promoting and metabolic actions of GH

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 Growth hormone (GH)

• Hypersecretion causes
gigantism in children and
acromegaly in adults

• Hyposecretion in children
causes pituitary dwarfism.

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1. Agents Affecting Growth Hormone (Somatotropin)

– Somatotropin release-inhibiting hormone (SST, somatostatin)

• Inhibits the release of Somatotropin (GH) & TSH from the pituitary

• Inhibits the release of glucagon and insulin from the pancreas.

• Inhibits the secretion of gut peptides such as vasoactive intestinal

polypeptide (VIP) and gastrin

• It inhibits the growth and proliferation of many cell types.

 Example of SST analogue: Octreotide

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1. Agents Affecting Growth Hormone (Somatotropin)

• Octreotide is an SST analog administered by SC, IM, or IV injection.

• Octreotide is used to treat:

– Acromegaly
– Severe diarrhea associated with hypersecretory states such as VIP-
secreting tumors (VIPomas)
– Gastrinoma
– Glucagonoma
– TSH-secreting adenomas
– Variceal and upper GI bleeding (mediated by a splanchnic vasoconstrictive effect)

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2. Gonadotropin-releasing Hormone (GnRH) and Analogs

• GnRH Analogs
– GnRH Receptor Agonists
• Leuprolide
• Gonadorelin
• Triptorelin
• Nafarelin
• Goserelin
• Histrelin
 

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2. Gonadotropin-releasing Hormone (GnRH) and Analogs

Pulsatile administration
– Short-term or pulsatile administration of GnRH agonists (every 1–4 h)
increases the synthesis and release of both LH & FSH

– Treatment of certain types of infertility

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2. Gonadotropin-releasing Hormone (GnRH) and Analogs

Chronic administration
– 2–4 weeks of daily administration of GnRH inhibits the release of both
LH & FSH by causing a reduction in the number of GnRH receptors on
the anterior pituitary.

– Leads to reduced production of gonadal steroids; Androgens &

Estrogens (chemical castration).

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2. Gonadotropin-releasing Hormone (GnRH) and Analogs

Chronic administration

• Useful in the treatment of

– Precocciuos puberty
– Hormone-dependent cancers and hyperplasias such as prostate
cancer, breast cancer, endometriosis, and fibroids.

• Available as implantable formulation

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2. Gonadotropin-releasing Hormone (GnRH) and Analogs

Adverse effects in Women:

– Hot flushes and sweating
– Diminished libido and depression
– Ovarian cysts
– Contraindicated in pregnancy and breast-feeding

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2. Gonadotropin-releasing Hormone (GnRH) and Analogs

Adverse effects in Men:

– Hot flushes and edema
– Bone pain due to initial rise in testosterone levels
– Diminished libido
– Gynecomastia

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GnRH Receptor Antagonists

– Common example:
• Ganirelix
• Abarelix
• Cetrorelix

• GnRH antagonists competitively and reversibly bind to GnRH receptors in

the pituitary gland, blocking the release of LH and FSH from the pituitary.

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GnRH Receptor Antagonists

• In men, the reduction in LH subsequently leads to rapid suppression

of testosterone release from the testes

• In women it leads to suppression of estrogen release from the ovaries.

• Unlike the GnRH agonists, which cause an initial surge in testosterone or

estrogen levels, GnRH antagonists have an immediate onset of action,
rapidly reducing sex hormone levels without an initial surge

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Clinical Uses of GnRH Receptor Antagonists

• Prostate cancer
• Hormone-sensitive breast cancer and some benign disorders such
as endometriosis and uterine fibroids
• Some cases of infertility: Prevents premature LH surge

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3. Prolactin-releasing factor (PRF) and prolactin-inhibiting
factor (PIF)

– Secretion of prolactin from the pituitary is controlled by both:

• Stimulation (mediated by PRF)
• Inhibition (mediated by PIF = dopamine)

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 Prolactin-releasing factor (PRF)

• Drugs that reduce CNS dopaminergic activity (antidopaminergics) cause an

increase in prolactin secretion:
₋ Antipsychotics
₋ Antidepressants
₋ Anti-anxiety

• Drugs that promote prolactin secretion can be used to treat lactation

failure.

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 Prolactin-inhibiting factor (PIF) (dopamine agonists)

• Inhibition of prolactin secretion can be produced by a number of dopamine

agonists:
– Bromocriptine acts as an agonist of dopamine D2-receptors and an
antagonist of D1-receptors.

– Cabergoline
 A potent D2 agonist with greater D2 selectivity.
 It is more effective in reducing hyperprolactinemia than bromocriptine
 Has a long half-life that permits twice-weekly dosing.

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 Prolactin-inhibiting factor (PIF) (dopamine agonists)

–   Therapeutic uses of PIF:

• Inhibition of prolactin secretion in amenorrhea, galactorrhea, and
prolactin-secreting tumors

• The correction of female infertility secondary to hyperprolactinemia

• Treatment of Parkinson disease.

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Hormones of the anterior pituitary

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 Growth hormone

– Growth hormone agonists: (GH, somatotropin), methionyl-growth

hormone (somatrem)
– GH is released in a pulsatile manner, with the highest levels during
sleep
– GH secretion decreases with increasing age
– Administered SC or IM
– Half-life: 25 min, but sufficient to induce IGF-1 release by the liver,
which is responsible for the GH-like actions

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 Growth hormone

– Therapeutic uses of GH:

• Replacement therapy in children with GH deficiency before
epiphyseal closure
• Growth failure due to Prader-Willi syndrome
• To stimulate growth in patients with Turner syndrome
• Other approved uses include long-term replacement of GH
deficiency in adults, treatment of cachexia and AIDS wasting

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 Growth hormone

– Side effects of GH:

• Edema
• Arthralgias and myalgias
• Flue-like symptoms
• Increase the risk of Diabetes
• Should not be given to children with closed epiphysis

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 Growth hormone antagonists

–  Pegvisomant

• Pegvisomant is a GH receptor antagonist

• Blocks the action of endogenous GH
• Used specifically for the treatment of acromegaly
• Pegvisomant is administered SC

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 Gonadotropins (LH & FSH)

• Gonadotropins (Luteinizing hormone and follicle-stimulating hormone)

– Actions and pharmacologic properties:

• In women,
– LH increases estrogen production in the ovary and is required for
progesterone production by the corpus luteum after ovulation
– FSH is required for normal development and maturation of the
ovarian follicles

• In men,
– LH induces testosterone production by the interstitial (Leydig) cells
of the testis
– FSH acts on the testis to stimulate spermatogenesis and the
synthesis of androgen-binding protein
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Regulation of the Ovarian Cycle

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 Gonadotropins (LH & FSH)

– FSH and LH of pituitary origin are not used pharmacologically.

– Menotropins (human menopausal gonadotropins, hMG) :

• Isolated from the urine of postmenopausal women
• Contain a mixture of LH and FSH
• Urofollitropin (Bravelle) is immunologically purified FSH from the
urine of pregnant women.

– Follitropin α/β are recombinant FSH products

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 Gonadotropins (LH & FSH)

– hCG:
• hCG is nearly identical in activity to LH

• Produced by the placenta and can be isolated and purified from the
urine of pregnant women

• The alpha subunit is made by recombinant DNA technology

(choriogonadotropin α)

– All of these hormones must be administered parenterally (SC or IM)

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 Gonadotropins (LH & FSH)
• Therapeutic uses:

– hCG can be used in both M &F to stimulate gonadal steroidogenesis in

cases of LH insufficiency

– hCG can be used to induce external sexual maturation and

spermatogenesis in men with secondary hypogonadism, but this may
require months of treatment
– In the absence of an anatomic block,
hCG can also promote the descent of
the testes in cryptorchidism

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 Gonadotropins (LH & FSH)

• Therapeutic uses:

– Menotropins (hMG) are used in concert with hCG to stimulate

ovulation in women with functioning ovaries:

Injection of hMG or FSH products over a period of 5-12 days causes

ovarian follicular growth and maturation, then hCG is injected one day
after the last dose of FSH to induce ovulation.

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 Gonadotropins (LH & FSH)

• Adverse effects

– Menotropins and hCG cause ovarian enlargement in about 20% of treated

women

– Menotropins and hCG may cause ovarian life-threatening

hyperstimulation syndrome in up to 1% of patients:
– Ascites
– Hypovolemia and shock
– Acute respiratory distress

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Hormones of the posterior pituitary

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 Anti-diuretic Hormone (ADH, Vasopressin)

– ADH is synthesized in the hypothalamus and stored in the posterior pituitary

– ADH is released in response to increasing plasma osmolarity or a fall in blood
pressure

– The actions of ADH are mediated by three types of specific receptors:

• V1a: located in vascular smooth muscle, myometrium, and kidney
• V1b: located in the CNS and adrenal medulla
• V2: located in renal tubules

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 Anti-diuretic Hormone (ADH, Vasopressin)

• In renal tubules, ADH causes the permeability of water to increase and also
increases the transport of urea in the inner medullary collecting duct, which
increases the urine-concentrating ability of the kidney

• ADH causes vasoconstriction at higher doses

• ADH stimulates the hepatic synthesis of coagulation factor VIII and

von Willebrand factor.

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 Anti-diuretic Hormone (ADH, Vasopressin)

– ADH preparations
• Aqueous vasopressin (Pitressin), a short-acting preparation that acts on
both V1 and V2 receptors, is administered parenterally and lasts 2–6 hours

• Desmopressin acetate (DDAVP, Stimate) is a longer lasting (10–20 h)

preparation administered intranasally, parenterally, or orally

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 Anti-diuretic Hormone (ADH, Vasopressin)

– Therapeutic uses
• Desmopressin is the most effective treatment for severe central diabetes
insipidus because its V2 activity is 3,000 times greater than its V1 activity;
but it is not effective in the nephrogenic form of the disease

• Desmopressin is useful in nocturnal enuresis by reducing nighttime urine

production

• Vasopressin is included in the advanced cardiac life support protocol as a

substitute for epinephrine in cardiac arrest with asystole

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 Oxytocin

– Oxytocin is synthesized in the hypothalamus and secreted by the

posterior pituitary.

– Actions and pharmacologic properties

• Elicits milk ejection from the breast.
• Stimulates contraction of uterine smooth muscle.
• The plasma t1/2 of oxytocin is 5–10 minutes.

– Therapeutic uses
• Is used for induction and maintenance of labor.
• Stimulates milk ejection from the breast.
• Postpartum uterine bleeding.

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The Thyroid Gland

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 Synthesis of thyroid hormones

• Thyroid hormones:
 Triiodothyronine (T3)
 Tetraiodothyronine (T4, thyroxine)

• Synthesis materials: iodine & tyrosine

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Synthesis of thyroid hormones

• Steps:
1. Iodide (I-) is trapped by sodium-iodide
2. Iodide is oxidized by thyroidal peroxidase to iodine (I.)
3. Tyrosine in thyroglobulin is iodinated and forms MIT & DIT
4. Iodotyrosines condensation
MIT+DIT→T3; DIT+DIT→T4 44
Regulation of Thyroid Hormone

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 Physiological actions of thyroid hormones

• To normalize growth and development, body temperature, and energy

levels

• Eitiology of hypothyroidism:
 Hashimoto disease
 Simple goiter
 After surgery and ablation of thyroid after surgery
 Congenital

• Insufficiency (Hypothyroidism) causes:

 Cretinism (infant & child)
 Myxedema (adult)

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 Myxedema

• Full-blown hypothyroid syndrome In adults.

• Symptoms include:
 Low metabolic rate
 Feeling chilled
 Constipation
 Thick dry skin
 Puffy eyes
 Edema
 Lethargy
 Mental sluggishness (but not mental retardation)

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 Goiter

• An enlarged protruding thyroid gland

• Occurs if myxedema results from lack of Iodine

• The follicular cells produce colloid but cannot

iodinate it and make functional hormones.

• The pituitary gland secretes increasing amounts

of TSH in an attempt to stimulate the thyroid to
produce TH, but the only result is that the
follicles accumulate more and more unusable
colloid.

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 Cretinism
• Severe hypothyroidism in infants

• The child is mentally retarded and has a short, disproportionately sized

body and a thick tongue and neck

• Thyroid hormone replacement therapy can prevent cretinism if

diagnosed early enough

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 Physiological actions of thyroid hormones

• Excess secretion of thyroid hormone (Hyperthyroidism) most commonly

results from: Graves disease and toxic goiter

• Severe Hyperthyroidism: results in thyrotoxicosis (thyroid storm)

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 Graves’ disease
• The most common hyperthyroid disease

• It is an autoimmune condition, where abnormal antibodies are directed

against thyroid follicular cells.

• Rather than marking these cells for destruction as antibodies normally

do, these antibodies mimic TSH and continuously stimulate TH release.

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 Typical symptoms of Graves’ disease

• Elevated metabolic rate

• Sweating
• Rapid and irregular heartbeat

• Nervousness
• Weight loss despite adequate food

• Eyeballs may protrude (exophthalmos) if the

tissue behind the eyes becomes edematous
and fibrous

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• Mechanism of actions of thyroid
hormones

• Some of T4 are converted to T3

in kidney and liver T3, via its nuclear
• The actions of T3 on several receptor, induces new
organ systems are shown proteins generation
which produce effects

BMR: basal metabolic rate 53

 Thyroid drugs

•Representative drugs: levothyroxine (L-T4), liothyronine (T3)

Clinical use:
1. Hypothyroidism: cretinism & myxedema;
2. simple goiter
3. Others

Adverse reactions:
Overdose leads to thyrotoxicosis and angina or MI (usually in ageds)

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 Anti-thyroid drugs

Class Representative

Thioamides Propylthiouracil (PTU)

Methimazole

Iodides KI, NaI

Radioactive iodine I
131

β-adrenoceptor blockers Propranolol

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 Thioamides

Pharmacological action: They inhibit thyroid hormone synthesis

Mechanism of action: All thioamides inhibit

Peroxidase-catalyzing reactions
Iodine organification
Iodotyrosines condensation
Propylthiouracil also inhibit T4 conversion into T3

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 Thioamides

• Thioamaides have no effects on thyroglobulin already stored in the gland, as

a result the clinical effects appears slowly until thyroglobulin stores are
depleted.

• Methemazole is preferred over PTU because it has a longer t1/2 (given once
daily)

• PTU is recommended during the first trimester of pregnancy, due to a

greater risk of teratogenecity associated with methimazole.

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 Clinical use of Thioamides

• Mild hyperthyroidism and for those surgery & 131I are not permitted;

• Operation preparation
• Thyroid crisis (comprehensive therapy).

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 Adverse effects of Thioamides

• Long-term use leads to thyroid hyperplasia

• Pruritic maculopapular rash is the most common adverse reaction
• Agranulocytosis

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 Iodides (NaI, KI)

• Pharmacological action (Wolff-Chaikoff effect): Inhibition of T3 & T4

release and synthesis.

• This effect lasts only for few weeks

• Decrease of size & vascularity of the hyperplastic gland

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 Iodides (NaI, KI)

Clinical use
• Treatment of Thyroid Storm

• Prior to surgery (Decrease of size & vascularity of the gland)

Adverse reactions
• Acneiform rash
• Swollen salivary glands and mucous membrane ulcerations

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 Radioactive iodine (131I)

• I is the only isotope for treatment of thyrotoxicosis.

131

• Its therapeutic effect depends on emission of β rays with an effective

half-life of 5 days & a penetration range of 0.4-2 mm.

• Woman in pregnancy or lactation is forbidden!

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 β-adrenoceptor blockers

• βblockers are effective in treatment of thyrotoxicosis.

• Propranolol is the most widely studied and used.

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 Anti-thyroid drugs

peroxidase

Perchlorates
Thiocynates.

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