Hypothalamic Hormones

HYPOTHALAMIC & PITUITARY HORMONES
Prof. Francis R. Capule
Department of Pharmacy U.P. College of Pharmacy

Hypothalamic-Pituitary Endocrine System

ANTERIOR PITUITARY HORMONE

Pharmacological Applications
• replacement therapy for deficiency states • antagonists for diseases that result from excess production of pituitary hormones • diagnostic tools for identifying several endocrine abnormalities

HORMONE Thyrotropin-releasing hormone (TRH) Corticotropin-releasing hormone (CRH) Growth hormone-releasing hormone (GHRH) HORMONE Thyroid-stimulating hormone (TSH) Adrenocorticotropin (ACTH)

CLINICAL USE Used rarely to diagnose hyperor hypothyroidism Used rarely to distinguish Cushing's disease from ectopic ACTH secretion Used rarely as a diagnostic test for GH responsiveness DIAGNOSTIC USE In patients who have been treated surgically for thyroid carcinoma In patients suspected of adrenal insufficiency & congenital adrenal hyperplasia

Anterior Pituitary & Hypothalamic Hormone Receptors
All of these hormones act through G protein-coupled receptors except GH & prolactin, which act through JAK/STAT receptors.

Growth Hormone

Human Growth Hormone (hGH)
• somatotropin • most plentiful anterior pituitary hormone • stimulates liver, muscle, cartilage, bone & other tissues to synthesize & secrete insulin-like growth factors (IGFs)
IGF-1 or somatomedin C IGF-2

IGFs
• promote:
growth of body cells protein synthesis tissue repair lipolysis elevation of blood glucose concentration

Recombinant Human Growth Hormone (rhGH)
Somatropin • identical with the predominant native form of hGH Somatrem

rhGH
Somatropin injectable suspension • long-acting preparation of rhGH enclosed within microspheres • rhGH is released over about 1 month

MOA
• GH mediates its effects via cell surface receptors of the JAK/STAT cytokine receptor superfamily.

*JAK: Janus-kinase *STAT: signal transducers & activators of transcription

Indications
• GH deficiency
children adults

Indications
• Prader-Willi syndrome
autosomal dominant genetic disease associated with:
growth failure obesity carbohydrate intolerance

Indications
• Turner Syndrome
associated with a 45,XO karyotype absent or rudimentary ovaries - combined with gonadal steroids

• Idiopathic Short Stature
non-GH-deficient short stature

Mecasermin
• complex of recombinant human IGF-1 (rhIGF-1) & human insulin-like growth factor-binding protein-3 (rhIGFBP-3) • severe IGF-1 deficiency that is not responsive to exogenous GH
causes: - mutations in the GH receptor - devt. of neutralizing antibodies to GH

Mecasermin
• most important adverse effect: hypoglycemia

GH Antagonists
• Octreotide • Bromocriptine • Pegvisomant

Somatostatin
• found in the hypothalamus, other parts of the CNS, the pancreas, and other sites in the GIT • inhibits the release of:
GH glucagon insulin gastrin

• has limited therapeutic usefulness

Octreotide
• somatostatin analog • 45x more potent than somatostatin in inhibiting GH release • 2x as potent in reducing insulin secretion

Octreotide
• reduces symptoms caused by a variety of hormone-secreting tumors:
 acromegaly  carcinoid syndrome  gastrinoma  glucagonoma  nesidioblastosis  watery diarrhea, hypokalemia, & achlorhydria (WDHA) syndrome  diabetic diarrhea

Bromocriptine
• dopamine receptor agonist • reduces the production of GH • alone or in combination with octreotide: acromegaly

Pegvisomant
• polyethylene glycol (PEG) derivative of a mutant GH, B2036
B2036 has increased affinity for one site of the GH receptor but a reduced affinity at its second binding site

• useful for the treatment of acromegaly

Gonadotropins

Follicle-Stimulating Hormone (FSH)
Females: • directs ovarian follicle development • stimulates the conversion by granulosa cells of androgens to estrogens Males: • regulates spermatogenesis • stimulates the conversion by Sertoli cells of testosterone to estrogen

Luteinizing Hormone (LH)
Females: • stimulates androgen production by theca cells in the follicular stage of the menstrual cycle • controls estrogen & progesterone production in the luteal phase of the menstrual cycle Males: • main stimulus for the production of testosterone by Leydig cells

Human Chorionic Gonadotropin (hCG)
• placental protein nearly identical to LH • excreted into the urine • stimulates the corpus luteum in the ovary to continue the production of estrogens & progesterone to maintain pregnancy

Gonadotropins
• infertility
to stimulate spermatogenesis in men to induce ovulation in women

• controlled ovulation hyperstimulation
most common clinical use

Gonadotropins
Women: • ovarian hyperstimulation syndrome
ovarian enlargement ascites hydrothorax hypovolemia

• multiple pregnancies Men: • gynecomastia

Commercial Gonadotropins

Menotropins
• human menopausal gonadotropins (hMG) • purified extract from the urine of postmenopausal women
contains FSH- & LH-like substances

Purified FSH
Forms: • Urofollitropin • Follitropin alfa • Follitropin beta

Urofollitropin
• uFSH • purified extract from the urine of postmenopausal women

Follitropin Alfa & Follitropin Beta
• rFSH • have a shorter half-life than preparations derived from human urine

Lutropin
• rLH • in combination with follitropin alfa:
stimulation of follicular development in infertile women with profound LH deficiency

Choriogonadotropin Alfa
• rhCG • packaged & dosed on the basis of weight rather than units of activity

Gonadotropin-Releasing Hormone & Its Analogs

Gonadotropin-Releasing Hormone
• GnRH • stimulates the gonadotroph cell to produce & release LH & FSH

Gonadorelin
• acetate salt of synthetic human GnRH

GnRH Analogs
• • • • • Goserelin Histrelin Leuprolide Nafarelin Triptorelin

GnRH Agonists
• occasionally used for stimulation of gonadotropin production
female infertility male infertility diagnosis of LH responsiveness

GnRH Agonists
• more commonly used for suppression of gonadotropin release
Controlled ovarian hyperstimulation Endometriosis
syndrome of cyclical abdominal pain in premenopausal women presence of estrogen-sensitive endometrium-like tissue located outside the uterus

GnRH Agonists
• continuation
 Uterine leiomyomata (uterine fibroids)
 benign, estrogen-sensitive, fibrous growths in the uterus  can cause menorrhagia, with associated anemia & pelvic pain

 Prostate cancer  Central precocious puberty
 onset of secondary sex characteristics before: - 8 years in girls - 9 years in boys

Controlled Ovarian Hyperstimulation Central Precocious Puberty Endometriosis Uterine Leiomyomata Prostate cancer

Leuprolide Nafarelin Leuprolide Nafarelin Goserelin Leuprolide Goserelin Histrelin Triptorelin

GnRH Antagonists
• Ganirelix • Cetrorelix • prevent the LH surge during controlled ovarian hyperstimulation

GnRH Antagonists
• advantages over continuous treatment with a GnRH agonist:
shorter duration of administration less negative impact on the ovarian response to gonadotropin stimulation lower risk of ovarian hyperstimulation syndrome

Prolactin

Prolactin
• resembles GH in terms of structure • principal hormone responsible for lactation

Dopamine
• prolactin-inhibiting hormone • agonists:
Bromocriptine Cabergoline Pergolide Quinagolide

Dopamine Agonists
• standard treatment for hyperprolactinemia • Parkinson’s disease

POSTERIOR PITUITARY HORMONES

Oxytocin
• acts through G protein-coupled receptors & the phosphoinositide-calcium secondmessenger system • stimulates the release of prostaglandins & leukotrienes • causes contraction of myoepithelial cells surrounding mammary alveoli

Oxytocin
• initiation & augmentation of labor • control of postpartum bleeding

Oxytocin
• C/I:
fetal distress prematurity abnormal fetal presentation cephalopelvic disproportion other predispositions for uterine rupture

Oxytocin Antagonist
Atosiban • modified form of oxytocin • preterm labor (tocolysis)

Vasopressin
• antidiuretic hormone (ADH) • released in response to rising plasma tonicity or falling BP • possesses antidiuretic & vasopressor properties

Vasopressin
• activates 2 subtypes of G protein-coupled receptors
V1 receptors
 found on vascular smooth muscle cells  mediate vasoconstriction

V2 receptors
 found on renal tubule cells  reduce diuresis through ↑ water permeability & resorption in the collecting tubules

Vasopressin
I: • treatment of choice for pituitary DI • esophageal variceal bleeding & colonic diverticular bleeding C/I: • patients with CAD

Desmopressin Acetate
• 1-desamino-8-D-arginine vasopressin (DDAVP) • long-acting synthetic analog with:
minimal V1 activity antidiuretic-to-pressor ratio 4000x that of vasopressin

Indications
• treatment of choice for pituitary DI • coagulopathy in:
hemophilia A von Willebrand's disease

Vasopressin Antagonists
• Conivaptan
high affinity for both V1a & V2 receptors

• Tolvaptan
30-fold higher affinity for V2 than for V1 receptors

• hyponatremia or acute heart failure

THANK YOU.