Pharmacology of Hypothalamic-Pituitary Axis
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Questions and Answers

What hormone's analogs and antagonists are included in the pharmacological agents covered?

  • Adrenocorticotropic hormone
  • Insulin
  • Thyroid hormone
  • Growth hormone (correct)

    • Which of the following is not a GnRH analog or agonist?

  • Goserelin
  • Lutropin alfa (correct)
  • Gonadorelin
  • Leuprolide

    • Which of the following is an example of a prolactin regulator?

  • Cabergoline (correct)
  • Conivaptan
  • Octreotide
  • Somatropin

    • In the context of adrenal insufficiency, which hormone deficiency might ACTH promote investigation for?

    <p>Cortisol deficiency</p> Signup and view all the answers

    Which of the following represents an ADH analog?

    <p>Desmopressin</p> Signup and view all the answers

    What is the primary role of hypothalamic hormones in relation to the pituitary gland?

    <p>They stimulate or inhibit the release of pituitary hormones.</p> Signup and view all the answers

    Which class of drugs is used to stimulate growth hormone (GH) signaling?

    <p>rhGH and rhIGF-1</p> Signup and view all the answers

    What is a common condition associated with altered signaling of growth hormone?

    <p>Acromegaly</p> Signup and view all the answers

    What is the primary purpose of pharmacologic treatments related to the hypothalamic-pituitary axis?

    <p>To mimic or block hormones affecting the endocrine system.</p> Signup and view all the answers

    What defines a super-agonist in the context of gonadotropin-regulating drugs?

    <p>A drug that mimics the natural hormone with higher efficacy.</p> Signup and view all the answers

    Which of the following hormone treatments is used as a replacement therapy for hormone deficiency?

    <p>Estrogen/progesterone</p> Signup and view all the answers

    What is one of the mechanisms of action for drugs that inhibit growth hormone signaling?

    <p>Competition with endogenous GH at receptor sites.</p> Signup and view all the answers

    Which of the following is true about water homeostasis-regulating drugs?

    <p>They can include both agonists and antagonists.</p> Signup and view all the answers

    What role do agonists at endogenous receptors play in medical treatments?

    <p>Mimic natural hormone effects.</p> Signup and view all the answers

    What is a key pharmacokinetic consideration for gonadotropin-releasing hormones?

    <p>They have a rapid clearance from the bloodstream.</p> Signup and view all the answers

    Which hormone acts primarily via nuclear receptors to influence transcription in target cells?

    <p>Testosterone</p> Signup and view all the answers

    What is the main purpose of antagonists used in endocrine treatments?

    <p>Block the effects of excess pituitary hormones.</p> Signup and view all the answers

    What adverse effect might be associated with the use of stimulants for GH signaling?

    <p>Joint and muscle pain</p> Signup and view all the answers

    Which class of hormones typically act via membrane receptors for rapid effects?

    <p>Peptide hormones</p> Signup and view all the answers

    What kind of abnormalities can be diagnosed using the ACTH stimulation test?

    <p>Central or peripheral adrenal insufficiency</p> Signup and view all the answers

    Which hormone is primarily associated with the JAK/STAT signaling pathway?

    <p>Growth hormone (GH)</p> Signup and view all the answers

    What is the primary mechanism of action (MOA) of Leuprolide?

    <p>Agonist at GnRH receptors</p> Signup and view all the answers

    Which of the following statements is true regarding Ganirelix?

    <p>It acts as a competitive antagonist at GnRH receptors.</p> Signup and view all the answers

    What is the physiological effect of prolonged continuous administration of Leuprolide?

    <p>Decreased LH and FSH secretion</p> Signup and view all the answers

    In which clinical scenario is Oxytocin NOT typically indicated?

    <p>Treatment of premature ovarian failure</p> Signup and view all the answers

    What side effects are commonly associated with Leuprolide use?

    <p>Headache, nausea, and lightheadedness</p> Signup and view all the answers

    Which GnRH analog may take up to four weeks to exert its clinical effects?

    <p>Leuprolide</p> Signup and view all the answers

    What is the main therapeutic use of Vasopressin?

    <p>Reducing water excretion in the kidneys</p> Signup and view all the answers

    Which factor primarily differentiates Relugolix from traditional GnRH super antagonists?

    <p>Peptide vs. non-peptide structure</p> Signup and view all the answers

    What is a consequence of using growth hormone therapy in patients with acute critical illness?

    <p>Increased mortality.</p> Signup and view all the answers

    Which condition is NOT a contraindication for growth hormone therapy?

    <p>Chronic kidney disease.</p> Signup and view all the answers

    In patients with growth hormone receptor mutations, what is the appropriate clinical use of Mecasermin?

    <p>In cases of non-responsiveness to exogenous GH therapy.</p> Signup and view all the answers

    What is the mechanism of action of Mecasermin?

    <p>Agonist at IGF-1 receptors.</p> Signup and view all the answers

    Which of the following side effects is associated with Mecasermin?

    <p>Hypoglycemia.</p> Signup and view all the answers

    Which neurotransmitter inhibits growth hormone signaling?

    <p>Somatostatin.</p> Signup and view all the answers

    What class of drugs would typically be used to inhibit GH signaling in cases of acromegaly?

    <p>Somatostatin analogs.</p> Signup and view all the answers

    What is the recommended route of administration for Mecasermin?

    <p>Subcutaneous.</p> Signup and view all the answers

    Which hormone is used rarely as a diagnostic test for GH and GHRH sufficiency?

    <p>Growth hormone-releasing hormone</p> Signup and view all the answers

    What is the clinical use of Dopamine agonists such as bromocriptine?

    <p>Treatment of hyperprolactinemia</p> Signup and view all the answers

    Which hormone is currently not available for clinical use in the United States?

    <p>Thyrotropin-releasing hormone</p> Signup and view all the answers

    What condition may be assessed using Gonadotropin-releasing hormone in a single dose?

    <p>Assessment of puberty initiation</p> Signup and view all the answers

    For what purpose is Thyroid-stimulating hormone (TSH) primarily utilized?

    <p>To test for cancer recurrence in thyroid carcinoma patients</p> Signup and view all the answers

    Which hypothalamic hormone is specifically mentioned for use in pulses to treat GnRH deficiency-related infertility?

    <p>Gonadotropin-releasing hormone</p> Signup and view all the answers

    Which hormone is rarely used to distinguish Cushing disease from ectopic ACTH secretion?

    <p>Corticotropin-releasing hormone</p> Signup and view all the answers

    What is a significant clinical use of long-acting analogs of Gonadotropin-releasing hormone?

    <p>To block endogenous puberty in transgender adolescents</p> Signup and view all the answers

    Study Notes

    Endocrine Pharmacology: Hypothalamic & Pituitary

    • This area focuses on hypothalamic and pituitary hormones.
    • Control of metabolism, growth, and reproduction is done by the hypothalamus/pituitary system.
    • Hypothalamus produces releasing hormones to stimulate or inhibit the pituitary.
    • Pituitary responds by producing/releasing hormones which then influence specific endocrine tissues/glands.
    • This influence produces a biological effect.
    • Hypothalamus-Pituitary-Adrenal (HPA) axis, and Hypothalamus-Pituitary-Thyroid (HPT) axis are key examples.

    Lecture Objectives - 1

    • Explain hypothalamic & pituitary hormones with respect to:
      • Stimulation & inhibition of anterior pituitary hormones.
      • Secretion of posterior pituitary hormones.
      • Tissue effects and subsequent hormone secretion.
      • Conditions that arise from altered growth hormone signaling.
    • Explain significant aspects of drugs in GH signaling:
      • Drugs that stimulate GH signaling (rhGH and rhIGF-1).
      • Drugs that inhibit GH signaling (SST analogs, pegvisomant).
      • Mechanism of action and pharmacokinetics.
      • Indications, contraindications, and adverse effects.

    Lecture Objectives - 2

    • Explain specifics of drugs regulating water homeostasis:
      • Listing and differentiating agonists and antagonists.
      • Mechanisms of action, pharmacokinetics, and structure-activity relationships (SAR).
      • Indications, contraindications, and adverse effects.
    • Explain specifics of gonadotropin regulating drugs:
      • Listing/differentiating analogs, super-agonists, and antagonists.
      • Mechanisms of action, pharmacokinetics, and SAR.
      • Indications, contraindications, and adverse effects.

    Hormone Receptors

    • Hormones that act primarily through nuclear receptors modulate gene transcription in target cells (e.g., steroid hormones, thyroid hormone, vitamin D).
    • Hormones acting through membrane receptors rapidly influence signal transduction pathways (e.g., peptide and amino acid hormones).

    Classification of Hormones

    • Based on structure and/or receptor type.
      • Growth hormone (GH) and prolactin (PRL) are single-chain proteins with homology (JAK/STAT).
      • TSH (thyrotropin), (FSH),(LH) (GPCR), (ACTH), a peptide precursor (GPCR).

    Hypothalamus-Pituitary-Endocrine Axes

    • Hypothalamus produces releasing factors, stimulating or inhibiting anterior pituitary hormone release.
    • Pituitary releases trophic hormones, influencing various endocrine glands.
    • Endocrine glands respond producing specific hormones that cause the biological effect.

    Pharmacological Treatments

    • Drugs treat endocrine disorders by regulating the hypothalamic-pituitary axis (HPA).
    • Mimic or block endogenous hormones' actions.
    • Uses include agonists at endogenous receptors (e.g., hormone replacement therapy), and antagonists to block excess hormones.
    • Diagnostic tools for identifying endocrine abnormalities are included.

    Drugs That Mimic or Block hypothalamic/pituitary Hormones

    • Replacement therapy for hormone deficiencies.
    • Antagonists for diseases caused by pituitary hormone excess.

    Hormone Classifications

    • Hormones are classified based on their structure and activated receptor type.
    • Chain proteins are grouped together; single chain, proteins with homology, and others with similar receptors.

    Regulation of Growth Hormone

    • Growth hormone-releasing hormone (GHRH) acts on GPCRs (somatotropes), stimulating cAMP, which results in the production of growth hormone (GH)
    • Somatostatin, acts on G protein-coupled receptors (GPCRs), and inhibits adenylate cyclase, K+ channels, and protein phosphatases.
    • Dopamine, 5-HT, and α2-adrenergic agonists; ghrelin can also stimulate growth hormone secretion.

    Growth Hormone

    • Splice variants of endogenous GH differ from rhGH.
    • About 50% of growth hormone circulates as a complex with a binding protein.
    • GH can act as a reservoir and is cleared slowly.
    • GH-induced secretion is pulsatile and high in children.
    • GH-receptors are cytokine-type 3 receptors.
    • Receptors dimerize after binding.
    • Stimulates IGF-1 synthesis via JAK/STAT pathway. 

    Natural GH / IGF-1 Signaling Agonists

    • 191 amino acids; 22.1 kDa.
    • Binds to cell surface cytokine receptors (JAK/STAT).
    • Anabolic effects on muscles, bones, and various organs.
    • Reduces insulin sensitivity (t1/2 ~ 20–25 minutes).
    • Insulin-like growth factor 1 (IGF-1) inhibits insulin secretion, promotes glucose production, and affects protein, cellular, and organ related growth.
    • IGF-1 receptor tyrosine kinase is homologous to insulin receptors.

    Increased GH Signaling Benefits

    • Used to treat growth hormone deficiency in pediatric patients.
    • Includes Prader-Willi syndrome, Turner syndrome, and idiopathic short stature (ISS).
    • Also used in adults with growth hormone deficiency due to chronic wasting diseases (AIDS, HIV).
    • Useful for conditions like short bowel syndrome, dependent on TPN, and severe burns.

    Somatropin

    • Recombinant human growth hormone 191 a.a.
    • Agonist at GH receptors, promotes IGF-1 production.
    • Absorbed slowly via SubQ or IM, with a duration of action of 18–20 hours.
    • Possible side effects include abdominal pain, headache, peripheral edema, and nausea.
    • Interactions can diminish hypoglycemic effects from anti-diabetic agents and inhibit the effect of 11-β HSD type 1.

    Contraindications for Using Growth Hormone Therapy

    • Patients with acute critical illnesses and postoperative complications.
    • Multiple accidental traumas and acute respiratory failures.
    • The use of growth hormone in patients with preexisting neoplasms or malignancies, proliferative retinopathy has been associated with increased mortality..

    Mecasermin

    • Non-responsive to exogenous GH therapy; GH receptor mutations or neutralizing GH antibodies are present.
    • Doses of 0.4-0.8 mg/kg subcutaneously twice a day, with intake around 20 minutes prior to mealtime.
    • The drug's MOA is to act as an agonist at IGF-1 receptors in the liver, bone, etc.
    • The half-life is 6 hours.
    • Side effects include hypoglycemia and lipohypertrophy.

    Inhibition of Growth Hormone Release

    • Surgery is often the initial treatment for excess GH secretion.
    • Medical intervention is necessary with large adenomas or persistent GH secretion.
    • Neurotransmitters, including somatostatin, regulate GH signaling.

    Somatostatin (SST) and Synthetic Analogs

    • Cyclic peptide (14 amino acids).
    • Four residues (#7–10) critical for activity.
    • Binds to SST receptors preventing GH release (SSTR1, 2, 3, 4, 5.).
    • Analogs are designed for increased half-life and specificity.
    • Includes octreotide and lanreotide.

    Octreotide

    • Modified octapeptide SST analog.
    • Doses of 100 mcg SubQ or IM three times per day or 20 mg IM depot every four weeks.
    • MOA: an agonist at somatostatin receptors, inhibiting GH release through actions on cAMP, K+ channels and pTYR.
    • 25 times more potent than somatostatin.
    • Possible side effects are diarrhea, nausea, abdominal pain, biliary sludge, cholelithiasis, sinus bradycardia, and hypothyroidism.

    Lanreotide

    • Modified octapeptide SST analog.
    • Dose of 90 mg SubQ depot once per month.
    • MOA: an agonist at SSTR-2 and -5 receptors, inhibiting GH release.
    • Half-life of 23–36 days.
    • Side effects similar to octreotide, including bradycardia, hypertension and hypo- or hyperglycemia.

    Pegvisomant

    • Pegylated peptide; competitive antagonist at GH receptors.
    • Binds one receptor site; higher affinity, but not the second dimerization site.
    • Dose of 10 mg subcutaneously once daily.
    • Half-life of 3–6 days.
    • Side effects may include elevated liver function tests (LFTs), neutralizing antibodies, diarrhea, nausea and altered glucose metabolism .

    Regulation of Prolactin (i.e., Lactation)

    • Prolactin is the only anterior pituitary hormone not directly regulated via stimulatory control. Essentially constitutively active.
    • Dopamine inhibits prolactin release via D₂ receptors.
    • TRH can stimulate prolactin release.
    • Prolactin levels remain low in males and increase during the menstrual cycle in females.

    Reducing Prolactin Signaling

    • Prolactin is produced by the anterior pituitary and induces lactation.
    • High prolactin levels inhibit ovulation.
    • Prolactinomas are associated with hyperprolactinemia and may result in hypogonadism and infertility.
    • Visual disturbances, associated with the tumor mass, and acromegaly may occur in high dose conditions.
    • Dopamine receptor agonist like bromocriptine may be used to reduce prolactin secretion.

    Bromocriptine

    • Used for hyperprolactinemia, hypogonadism, and acromegaly.
    • Slightly selective D₂ receptor agonist.
    • Extensive first-pass metabolism via CYP3A4.
    • Half-life of 5–6 hours.
    • Common side effects include orthostatic/postural hypotension, nausea, and vomiting.

    Cabergoline

    • Used for hyperprolactinemia, arising from pituitary adenomas.
    • Highly selective D₂ receptor agonist, metabolized via hepatic hydrolysis.
    • Half-life is 65 hours.
    • Side effects include headache, dizziness, nausea, and orthostatic hypotension, and less severe nausea/vomiting.
    • Interactions with β-adrenergic agonists and anti-psychotics should be considered. 

    Regulation of Gonadotropin Hormones

    • Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and human chorionic gonadotropin (hCG) regulate various reproductive processes.

    GnRH Signal Gonadotropin Hormone Analogs

    • Used for follicle development, ovulation, male infertility, and prepubertal cryptorchidism.
    • Includes follitropin alpha, follitropin beta, urofollitropin, lutropin alpha, menotropins, choriogonadotropin alpha, and choriogonadotropin. 

    Urofollitropin (Bravelle)

    • Purified FSH from menopausal women's urine.
    • Administered Subcutaneously or Intramuscularly. 
    • Used for follicle development.
    • Requires hCG for ovulation.
    • Contraindicated in pregnancy.

    Follicle Stimulating Hormone (FSH), Follistin

    • Recombinant FSH from CHO cells.
    • Purified by immunochromatography using FSH antibodies.
    • Agonist at FSH receptors.
    • Used for controlled ovulation and ovarian hyperstimulation.
    • Associated side effects include headache, depression, edema, ovarian hyperstimulation syndrome (OHSS), and multiple pregnancies.

    Luteinizing Hormone Analogs

    • Lutropin alpha; a recombinant LH used for follicular development in conjunction with follitropin.
    • Can induce androgen secretion.
    • Essentially equivalent cautions to FSH analog cautions during pregnancy.

    Human Chorionic Gonadotropin (hCG)

    • Endogenous LH analog.
    • Used to initiate ovulation, manage ovarian follicle development in women with hypogonadism, or stimulate gonadal steroid production in men. 
    • Administered via injection.
    • Side effects include headache, depression, edema, ovarian hyperstimulation syndrome (OHSS), and possible multiple pregnancies in women and gynecomastia in men.

    Inhibting GnRH Signaling

    • GnRH receptor super agonists (gonadorelin, goserelin, histrelin, leuprolide, nafarelin, and triptorelin) and GnRH receptor antagonists (ganirelix, cetrorelix, and degarelix) are used to inhibit GnRH signaling, causing gynecomastia in males; depression and reduced libido; and contraindications during pregnancy and breast-feeding.

    GnRH Analogs

    • Synthetic human GnRH (gonadorelin) and its analogs (goserelin, histrelin, nafarelin, and triptorelin) are used clinically to treat conditions. Includes similar mechanisms, physiological effects, clinical indications, and side effects to endogenous GnRH. 

    GnRH Superagonists

    • Gonadorelin, goserelin, histrelin, leuprolide, nafarelin, and triptorelin are synthetic/modified.
    • GnRH analogs and super agonists have increased half-lives and are potent.
    • Constant administration results in downregulation of GnRH receptors.
    • Reductions in LH/FSH and gonadal steroids occur.

    Leuporlide

    • MOA: agonist at GnRH receptors
    • Physiological effects: increased LH and FSH secretion initially, but then decrease when continuously administered.
    • Administration routes: intravenous (IV), subcutaneous (SubQ), intramuscular (IM), and intranasal.
    • Side effects associated with this administration can include headache, nausea, lightheadedness, and injection site reactions, as well as hypogonadism with continuous use.

    Ganirelix

    • GnRH antagonist that blocks GnRH receptor binding., resulting in lost activity, decreased endogenous LH and FSH production and decreased downstream gonadal steroids. 
    • Used for controlled ovarian hyperstimulation during controlled stimulation.
    • Ganirelix acts in 5 days, whereas other similar agents require additional time.

    Posterior Pituitary Hormones

    • Vasopressin analogs and antagonists, and oxytocin are produced by the hypothalamic neuronal cell bodies and transported to the posterior pituitary via neuronal axons. 
    • Posterior Hormones regulate fluid balance through V₁ and V₂ receptors, influencing vasoconstriction and water reabsorption via the aquaporin channels. 

    Oxytocin

    • A nine-amino acid peptide.
    • Works by acting as an agonist at oxytocin receptors to cause contractions of the uterus and stimulation of lactation.
    • Clinically used for labor induction/augmentation, and to control uterine hemorrhage and other conditions.
    • Side effects include fluid retention and hypotension.

    Arginine Vasopressin

    • A nonapeptide responsible for water balance in the body.
    • Administered either intravenously (IV) or intramuscularly (IM).
    • Affects the vasculature by causing vasoconstriction and increasing arterial pressure.
    • Increases water reabsorption via upregulation of aquaporin channels. 
    • Deficiency in this peptide can cause diabetes insipidus.

    Desmopressin

    • Synthetic peptide analog.
    • Relates to vasopressin.
    • Relatively selective V₂ receptor agonist; causes a decreased excretion of water in the kidneys.
    • Also increases factor VIII and von Willebrand factor (VWF).
    • Administered orally, intravenously (IV), subcutaneously (SubQ), or intranasally.

    Conivaptan

    • V₁a/V₂ receptor antagonist.
    • Oral use is not recommended, because of lower bioavailability.
    • The main use is intravenous infusion.
    • Side effects can include infusion site reactions.
    • Also blocks the effects of excess vasopressin.

    Hypothalamus and Pituitary Endocrine Pearls

    • Peptide hormones affect growth, development, reproduction, response to stress, and metabolic processes.
    • Hypothalamic hormones influence synthesis and secretion of pituitary hormones.
    • Growth hormone's primary effect is bone development.
    • Excess GH is treated with somatostatin analogs (e.g., octreotide).
    • Deficiency in GH is treated with recombinant human growth hormone (e.g., somatropin).
    • GnRH analogs are used to treat advanced prostate cancer.
    • Diuresis is regulated by vasopressin analogs/antagonists.

    Hypothalamic-Pituitary Organ Pathways

    • The hypothalamic-pituitary system controls various bodily functions through specific hormones influencing particular organs.
    • These hormones regulate growth, thyroid function, adrenal cortex function, and gonads, and milk production.

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    Introduction to Endocrine System PDF

    Description

    Test your knowledge on pharmacological agents related to the hypothalamic-pituitary axis. This quiz covers various hormones, their analogs, and antagonists, alongside conditions associated with hormone signaling. It also highlights the primary roles and mechanisms of these hormones in the endocrine system.

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