Al-Bayan University / College of Pharmacy

Pharmacology & Toxicology Dept. 2019-2020

Fourth stage / Pharmacology III - Lecture 4 / By Dr. Atheer S. Alsabah

Hypothalamic and Pituitary Hormones

• The hormones secreted by hypothalamus & pituitary gland are all peptides or low
molecular weight proteins that act by binding to specific receptors sites on their
target tissues.

• The hormones of anterior pituitary gland "adenohypophysis" are regulated by

neuropeptides called either releasing or inhibiting factors or hormones, which
are produced in cell bodies in the hypothalamus & reach the pituitary cells via
hypophysial portal system (veins).

• Each hypothalamic regulatory hormone (releasing or inhibiting factor) controls

the release of specific hormone from anterior pituitary gland to circulation. And
primarily used for diagnostic purposes for determining pituitary insufficiency &
has no clinical uses.

• The anterior pituitary hormones exert –ve feedback mechanism on both

hypothalamus & anterior pituitary gland. They are act on specific target organ to
exert their biological effects, & they are used for suppression of hormone
overproduction, replacement therapy, & as diagnostic agents.

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• The hormonal dysfunctions " defects" include:
1. Primary dysfunction, when hormone secretion defect occur in the target organ
(target organ secretion defect).
2. Secondary dysfunction, when hormone secretion defect occur in the pituitary
gland (pituitary secretion defect).
3. Tertiary dysfunction, when hormone secretion defect occur in the hypothalamus
(hypothalamus secretion defect).

• The posterior pituitary gland "neurohypophysis" secrete 2 hormones (oxytocin &

vasopressin "ADH"), that have no –ve feedback mechanism because they are
synthesized & released on need.
• Hormones of both anterior & posterior pituitary are administered parenterally
(IM, IV, Sc, or intranasal), but not orally because they are peptides destroyed by
proteolytic enzymes of GIT.

 Hypothalamic Hormones

1. GHRH (Growth Hormone Releasing Hormone) "Sermorelin"

- It is consists of several large peptides (2 shorter synthetic peptides), it is rapidly
increases plasma GH level, & used clinically to determine the causes of GH
deficiency.

2. Somatostatin (Somatotropin Release-Inhibitory Hormone 'SRIH') "GIF"

- It is 14 a.a peptide, found in pancreas, GIT, & CNS. It inhibits release of GH,
thyrotropin, glucagon, insulin, & gastrin. It has no clinical use because of its short
DOA.

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• Octreotide:
- Synthetic somatostatin with longer DOA (45 folds more potent than somatostatin
in inhibiting GH release but only twice potent in inhibiting insulin release). It is
available as regular Octreotide (given Sc 2-4times daily), & long acting Octreotide
(slow release, given IM every 4wks for long term therapy).

- Uses: acromegaly, carcinoid syndrome (serotonin secreting tumor), gastrinoma

(Zollinger-Ellison syndrome), glucagonoma, hypokalemia, diarrhea related to
vagotomy & dumping syndrome, diabetic diarrhea, watery diarrhea, achlorhydria
"WDHA" syndrome, reduces vomiting in palliative care, acute control of bleeding
of esophageal varices, & prevent complications following pancreatic surgery.

- S/E: abdominal cramps, flatulence, steatorrhea with bulky bowel movement,

biliary sludge & gall stones after 6 months use, pancreatitis, sinus bradycardia,
conduction disturbances, pain at injection site, vit. B12 deficiency, & impaired
glucose tolerance.

• Lanreotide: approved for thyroid tumor.

• Pegvisomant: GH-receptor antagonist, used for acromegaly.

3. CRH (Corticotropin-Releasing Hormone)

- It is 41 a.a peptide, stimulates secretion of both ACTH & β-endorphin (closely
related peptide) from pituitary, & used in diagnosis of ACTH secretion
abnormalities by tumor outside pituitary e.g. in lung that rarely increases in
response to stimulation by CRH, whereas secretion by the pituitary in Cushing's
disease consistently increases after CRH stimulation.

4. TRH (Thyrotropin-Releasing Hormone) "Protirelin"

- It is tripeptide, stimulates secretion of thyrotropin from anterior pituitary, &
increases prolactin production but has no effect on the release of GH & ACTH.
And used in diagnosis of thyroid dysfunction.

5. GnRH (Gonadotropin-Releasing Hormone)

- It is decapeptide.
• Leuprolide (also Goserelin, Histrelin, Nafarelin, & Triptorelin):
- Synthetic peptide with GnRH receptor agonistic activity. When given in pulsatile
doses (single doses as physiologic cycling), it stimulates gonadotropin release; in
contrast, steady dosing leads to inhibition of gonadotropin release by causing
down-regulation of GnRH receptors in pituitary cells.

- Clinical uses:
1. Diagnosis & treatment of hypogonadism in males & females (physiologic dosing).
2. Suppresses gonadotropin secretion (steady dosing) in pts with prostatic carcinoma,
endometriosis, & precocious puberty.
3. Suppresses gonadotropin release in women undergoing controlled ovarian hyper-
stimulation, breast & ovarian CA, & in assisted reproduction technology e.g. in
vitro fertilization "IVF" for infertile female with PCOS.

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• Ganirelix (also Cetrorelix, Abarelix, & Degarelix):
- GnRH receptor antagonists. Used instead of GnRH agonist e.g. leuprolide (at
steady dose) to suppresses endogenous gonadotropins production in cases of
advanced prostate CA & for ovulation induction.
- They preferred over GnRH agonist e.g. leuprolide therapy because they not cause
tumor flare up when used for advanced prostate CA, & they are less likely cause
ovarian hyperstimulation syndrome when used for ovulation induction.

6. PIH (Prolactin-Inhibiting Hormone) "Dopamine"

- Dopamine is the physiologic inhibitor of prolactin release, it is not useful
clinically to control hyper-prolactinemia because of its peripheral adverse effects.

• Bromocriptine (also Cabergoline, & Pergolide):

- D2-receptor agonists, they are ergot derivatives effective in reducing prolactin
secretion from normal pituitary gland & in case of prolactinoma. Given orally &
vaginally.
- Dopamine agonists therapy during pregnancy continued in pts with macro-
adenomas because the risk of enlargement is high & discontinued in pts with
micro-adenomas because the risk of enlargement is low.

- Uses of bromocriptine: suppresses lactation, galactorrhea, infertility,

hypogonadism, acromegaly, prolactinoma, cyclical benign breast disease, &
parkinsonism.

- S/E of bromocriptine: N, V, constipation, nasal congestion, headache confusion,

hallucination, postural hypotension, syncope, pleural effusion, retroperitoneal
fibrosis, & vasospasm of fingers & toes.

- D/I of bromocriptine:
1. Octreotide & erythromycin increase its plasma level.
2. Metoclopramide & domperidone antagonize its hypo-prolacinemic effect.
3. Methyl-dopa antagonizes its antiparkinson effect.
4. Antipsychotics antagonize its both hypo-prolacinemic & antiparkinson effects.
5. Memantine enhances its dopaminergic effects.

 Anterior Pituitary Hormones

1. GH (Growth Hormone) "Somatotropin"

- The naturally occurring GH called somatotropin which is large poly peptide
released from anterior pituitary. While synthetic analog called somatropin
"somatrem" which contain an extra terminal methionyl group not found in
natural form & it is synthesized by recombinant DNA technology.
- Excessive secretion of GH before puberty called gigantism, while after puberty it
is called acromegaly. Whereas deficiency of GH called dwarfism.

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- Pharmacological actions:
1. Growth promoting effects mediated by somatomedin C "IGF" (insulin like growth
factor) mainly in the liver.
2. Anabolic effects in muscles & catabolic effects in lipid cells, so increase lean
body mass & weight & reduce central adiposity.
3. Mixed effects of CHO metabolism since GH reduces insulin sensitivity lead to
mild hyper-insulinemia while IGF lowers serum glucose & reduces circulating
insulin.
4. Improve GI function.

- Clinical uses:
1. Growth failure in pediatrics associated with GH deficiency, CRF, & genetic
disorders e.g. Prader-Willi syndrome, Turner syndrome, & Noonan syndrome.
2. Idiopathic short stature in pediatrics.
3. GH deficiency in adults.
4. Wasting in pts with AIDs.
5. Pts with short bowel syndrome who dependent on total parenteral nutrition (TPN).
6. Athletes to increase muscle mass & athletic performance.
7. Antiaging program.
8. Dairy cattle to increase milk production.

- S/E: peripheral edema, arthralgia, myalgia, intracranial hypertension, & carpal

tunnel syndrome.
- C/I: malignancy & critically ill pts (↑mortality).

• Mecasermin: complex of recombinant human IGF-1 & binding protein,

administered parenterally to children with IGF-1 deficiency. It causes
hypoglycemia avoided by snacks or meal shortly before its administration.

2. ACTH (Adrenocorticotropic Hormone)

- It is formed from large peptide precursor called pro-opiomelanocortin, which is
also the precursor for melanocytes stimulating hormone, β-endorphin, & meta-
enkephalin.
- Excessive secretion of ACTH causes cushing syndrome, while deficiency of
ACTH causes addison disease.
- When ACTH binds to its receptors in adrenal cortex, it stimulates cAMP synthesis
lead to conversion of cholesterol to pregnenolone (corticosteroids precursor).
- Chronic use of corticosteroids e.g. dexamethasone, betamethasone, &
hydrocortisone resulting in –ve feedback mechanism (suppression) on both
pituitary & hypothalamus causing adrenal gland atrophy.
- Cosyntropin (cortrosyn) is a synthetic analog of ACTH used to diagnose
abnormality in corticosteroids production (adrenal insufficiency).

3. TSH (Thyroid Stimulating Hormone) "Thyrotropin"

- It increases iodine uptake by thyroid cells to produce thyroid hormones (T3, T4).
- Used as diagnostic tool to distinguish primary from secondary hypothyroidism.

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4. FSH (Follicle Stimulating Hormone)
- It is a glycoprotein stimulates gametogenesis & follicle development in women &
spermatogenesis in men.
- The preparations available for clinical use in combination with other drugs to treat
infertility in both sexes & include:
a. Urofollitropin "uFSH", purified from the urine of postmenopausal women.
b. Recombinant follitropin α & β "rFSHα & rFSHβ", synthesized by recombinant
DNA technology.

5. LH (Luteinizing Hormone)
- In women, it acts with FSH to regulate gonadal steroid production, follicular
development, & ovulation. While in men, it regulates testosterone production.
- There is no pure LH preparation in use, & the available preparations include:
a. Human chorionic gonadotropin "hCG" (Pregnyl®), purified from the urine of
pregnant women & synthesized in placenta. It is used in place of LH for treatment
of hypogonadism in both sexes (hCG has LH like effect).
b. Lutropin, recombinant form of human LH.

• Menotropins (Human menopausal gonadotropins "hMG") (Pergonal®, Gonal-

F®): mixture of FSH & LH purified from the urine of postmenopausal women,
where there is normal secretion of FSH & LH but the ovary not respond at
menopause (after age 45yrs), so excreted in the urine then purified.
- It is used in combination with hCG in treatment of hypogonadism & as a part of
controlled ovarian hyperstimulation & assisted reproductive technology programs.

- Note: Infertile women should receive Menotropins "hMG" (Pergonal®) 75IU at a

period between 5-12 days of the cycle (usually days 5,7,& 9 or days 7,9, & 11) for
growth & maturation of ovarian follicles followed by hCG (Pregnyl®) 5000IU to
stimulate ovulation. In contrast, the infertile men should receive hCG (Pregnyl®)
1500IU for maturation of sexual apparatus followed by Menotropins "hMG"
(Pergonal®) 75IU to induce spermatogenesis.

- S/E of gonadotropins:
1. Ovarian hyperstimulation syndrome which ccc by ovarian enlargement, ascites,
hydrothorax, hypovolemia, hemoperitoneum, & arterial thromboembolism.
2. Multiple pregnancies which increase the risk of GDM, preeclampsia, & preterm
labor.
3. Gynecomastia & ovarian CA.
4. Headache, depression, edema, & precocious puberty.

6. Prolactin
- It is a glycoprotein hormone responsible for lactation & not used clinically.
- It is exert inhibitory effect on FSH & LH also reduces ovary response to FSH &
LH effects. Therefore lactating women has natural contraception & often no need
for contraceptive pills.
- Agents increase prolactin release & causing hyperprolactinemia include
antidopaminergics e.g. antiemetics & neuroleptics, TCAs, MAOIs, & estrogens.

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 Posterior Pituitary Hormones

1. Oxytocin (Syntocinon®, Pitocin®)

- It is a peptide synthesized in the cell bodies of supraventricular nuclei at the
hypothalamus & transported through the axons to the posterior pituitary, where it
released to the circulation.
- Pharmacological actions:
1. Stimulates uterine contraction resulting in propulsive contraction.
2. Stimulates contraction of myoepithelial cells of breast.
3. Weak antidiuretic & pressor activities due to activation of vasopressin receptors.

- Clinical uses:
1. Used IV to induce labor & for uterine inertia.
2. Used IM to control postpartum bleeding & during 2nd trimester abortion.
3. Used nasally to induce milk ejection.
4. For maternal diabetes & diagnostic agent to know placental circulation.

- Over dose of oxytocin cause hypertension crisis, Na-H2O retention, uterine

rapture, & fetal death.

- C/Is: fetal distress, prematurity, abnormal fetal presentation, cephalopelvic

disproportion, & uterine rapture.

• Atosiban: oxytocin receptor antagonist, used as tocolytic for preterm labor.

2. Vasopressin (Anti-Diuretic Hormone "ADH")

- It is synthesized in neuronal cell bodies of hypothalamus & released to posterior
pituitary gland.
- MOA: vasopressin activates 2 G-protein coupled receptors, V1-receptor in
vascular smooth muscles mediating vasoconstriction & V2-receptor in renal
tubules reducing diuresis by ↑H2O permeability & resorption in collecting duct.
Also extra renal V2 -like receptor regulates release of coagulation factor VIII &
Von-Willebrand factor.

- Uses:
1. Delay the action of LA, for esophageal bleeding, & in tooth extraction in
hemophilic pts (V1-vasoconstrictor effect & V2-extra renal effect).
2. Diabetes insipidus " syndrome of polyuria, polydipsia, & hypernatremia caused by
inadequate vasopressin production" (V2-antidiuretic effect).
3. Control ACTH level in pituitary (in CNS, ADH act as NT & neuromodulator).

• Desmopressin: selective V2–receptor agonist, have advantages over vasopressin

include longer DOA, 0.4% less pressor effect, & 12 times more antidiuretic effect.
- It is used as nasal spray in treatment of pituitary diabetes insipidus, nocturnal
enuresis in children, esophageal varices bleeding, & hemophilia.

• Conivaptan & Tolvaptan: vasopressin receptor antagonist, used to offset fluid

retention & associated hyponatremia & acute HF.