Endocrine System: Hypothalamus and Pituitary Hormones

• The endocrine system releases hormones into the bloodstream, acting as chemical messengers to target cells
• Hormones have a broader response time than nerve impulses, ranging from seconds to months
• The hypothalamus connects the nervous system with the endocrine system via the pituitary gland

Hypothalamic and Anterior Pituitary Hormones

• Hypothalamus and pituitary hormones are peptides or glycoproteins that bind to specific receptor sites on target tissues
• Anterior pituitary hormones are regulated by neuropeptides ("releasing" or "inhibiting" factors/hormones)
• These neuropeptides are produced in the hypothalamus and reach the pituitary via the hypophyseal portal system

Adrenocorticotropic Hormone (Corticotropin)

• Corticotropin-releasing hormone (CRH) synthesizes and releases proopiomelanocortin in the pituitary
• ACTH or corticotropin results from the posttranslational processing of proopiomelanocortin
• CRH differentiates Cushing syndrome and ectopic ACTH-producing cells
• ACTH is released in pulses, with the highest concentration in the early morning and the lowest in the late evening
• Stress stimulates ACTH secretion, while cortisol suppresses it via negative feedback
• ACTH binds to receptors on the adrenal cortex surface which activates G protein-coupled processes
• This stimulates the rate-limiting step in adrenocorticosteroid synthesis (cholesterol to pregnenolone)

Therapeutic Uses of ACTH

• Synthetic adrenocorticosteroids limit corticotropin use, mainly as a diagnostic tool
• Differentiates between primary adrenal insufficiency (Addison disease) and secondary adrenal insufficiency (inadequate ACTH secretion)
• Therapeutic corticotropin preparations are extracts from animal pituitary glands or synthetic human ACTH (cosyntropin), is preferred for diagnosis of adrenal insufficiency
• ACTH treats infantile spasms and multiple sclerosis

Adverse Effects of ACTH

• Short-term ACTH use for diagnostic purposes is well-tolerated
• Long-term ACTH use carries toxicities similar to glucocorticoids, including hypertension, peripheral edema, hypokalemia, emotional disturbances, and increased infection risk

Growth Hormone (Somatotropin)

• Somatotropin is released by the anterior pituitary in response to growth hormone (GH)-releasing hormone.
• Somatostatin inhibits GH secretion with the highest levels occurring during sleep
• GH secretion decreases with age, with a decrease in lean muscle mass
• Somatotropin influences cell proliferation and bone growth
• Synthetic human GH (somatropin) is produced using recombinant DNA technology
• The physiological effects of GH are exerted directly at targets or mediated through somatomedins/insulin-like growth factors 1 and 2 (IGF-1 and IGF-2)

GH details

• GH is a large peptide with the exogenous version from gene technology used as injection, the animal one ineffective for humans
• Oversecretion of GH before puberty leads to Gigantism
• Oversecretion of GH after puberty leads to Acromegaly
• Reduced secretion of GH leads to Dwarfism
• GH functions include Glycogenolysis, Lipolysis, Protein Synthesis, and increases cell number/density

Therapeutic Uses for Somatropin

• GH deficiency
• Growth failure in children
• treatment of HIV patients with cachexia
• GH replacement in adults with confirmed deficiency

Synthetic GH

• Synthetic GH (somatrem) has a longer half-life (t1/2 = 25 min)
• Given to dwarf patients before puberty because of long bones epiphysis closure
• GH administration after puberty causes acromegaly

Adverse Effects of Somatropin

• Pain at the injection site, edema, arthralgias, myalgias, nausea, and increased diabetes risk
• Should not be used in pediatric patients with closed epiphyses, patients with diabetic retinopathy, or obese patients with Prader-Willi syndrome

Somatostatin (Growth Hormone-Inhibiting Hormone)

• Somatostatin binds to pituitary receptors that suppress GH and thyroid-stimulating hormone (TSH) release
• It is a small polypeptide found in neurons throughout the body, including the intestine, stomach, and pancreas
• It inhibits release of GH, insulin, glucagon, and gastrin
• Octreotide and lanreotide are synthetic somatostatin analogs with longer half-lives
• Depot formulations allow administration every 4 weeks
• Used to treat acromegaly, severe diarrhea/flushing episodes associated with carcinoid tumors, and bleeding esophageal varices when given through intravenous infusion

Adverse Effects of Octreotide

• bradycardia, diarrhea, abdominal pain, flatulence, nausea, and steatorrhea
• Gallbladder emptying is delayed, and asymptomatic cholesterol gallstones can occur with long-term treatment

Gonadotropins: FSH and LH

• Produced in the anterior pituitary
• Regulation of gonadal steroid hormones depends on these agents
• Menotropins treats infertility, are obtained from urine of postmenopausal women, and contain both FSH and LH
• Urofollitropin is FSH obtained from postmenopausal women and is devoid of LH
• Follitropin alfa and follitropin beta are human FSH products manufactured using recombinant DNA technology

Gonadotropins

• Human chorionic gonadotropin (hCG) is a placental hormone excreted via urine of pregnant women.
• HCG and choriogonadotropin alfa have effects identical to LH
• Both preparations are administered via intramuscular injection

Administration of Gonadotropins

• For infertile women, menotropin is given at 5-12 days of the menstrual cycle, followed by HCG at day 13-15 for ovulation
• For infertile men, HCG is given for maturation of external sexual organs, followed by menotropin for spermatogenesis induction

Adverse effects of Gonadotropins

• Ovarian enlargement
• Possible ovarian hyperstimulation syndrome
• Multiple births

Prolactin

• Prolactin, a peptide hormone secreted by the anterior pituitary, stimulates and maintains lactation, decreases sexual drive/reproductive function
• Thyrotropin-releasing hormone stimulates prolactin release, and dopamine inhibits secretion at D2 receptors
• Dopamine antagonists (metoclopramide, antipsychotics) can increase prolactin secretion

Hyperprolactinemia

• Associated with galactorrhea and hypogonadism
• It is treated with D2 receptor agonists like bromocriptine and cabergoline
• Both agents treat pituitary microadenomas
• Bromocriptine also treats type 2 diabetes

Adverse effects

• Nausea
• Headache
• Psychosis

Hormones of the Posterior Pituitary

• In contrast to the hormones of the anterior lobe of the pituitary, vasopressin and oxytocin, are not regulated by releasing hormones
• Instead, they are synthesized in the hypothalamus, transported to the posterior pituitary, and released in response to specific physiologic signals, such as high plasma osmolarity or parturition
• Both hormones are administered intravenously and have very short half-lives

Oxytocin

• Oxytocin stimulates uterine contraction and induces labor
• It causes milk ejection by contracting myoepithelial cells around mammary alveoli
• Uncommon toxicities include hypertension, uterine rupture, water retention, and fetal death
• Antidiuretic and pressor activities are less than those of vasopressin

Vasopressin

• Vasopressin (antidiuretic hormone) is structurally related to oxytocin
• It Increases water permeability and reabsorption in the collecting tubules via V2 receptors
• Used to treat diabetes insipidus, septic shock, and bleeding due to esophageal varices
• V1 receptors are found in the liver and vascular smooth muscle (causing constriction)
• Major toxicities include water intoxication and hyponatremia
• Abdominal pain, tremor, and vertigo can occur

Desmopressin Details

• Desmopressin has minimal activity at the V1 receptor, making it largely free of pressor effects
• It is longer acting than vasopressin and preferred for diabetes insipidus and nocturnal enuresis
• Desmopressin is administered intranasally or orally
• Nasal spray should not be used for enuresis due to reports of seizures in children
• Local irritation may occur with the nasal spray

Thyroid Hormones

• The thyroid gland facilitates normal growth and maturation

• Maintains a level of metabolism in the tissues

• Two major thyroid hormones are triiodothyronine (T3; the most active form) and thyroxine (T4)

• Normal TH concentration: Euthyroid

• High TH concentration: Hyperthyroidism or Graves' disease or thyrotoxicosis

• Low TH concentration in children: Cretinism

• Low TH concentration in adults: Myxoedema

• Hyper or hypothyroidism may or not be associated with goiter formation

• The half-life of T3 is 2 days, while the half-life of T4 in euthroid is 7 days, in hyperthyroidism is 3 days, and in hypothyroidism is 14 days.

Thyroid Hormone Synthesis and Secretion

• The thyroid gland comprises multiple follicles with a layer of epithelial cells surrounding a lumen filled with thyroglobulin (thyroid hormone storage form)
• Thyroid function is controlled by TSH (thyrotropin), synthesized by the anterior pituitary
• The hypothalamic thyrotropin-releasing hormone (TRH) governs TSH generation
• TSH action is mediated by cAMP and leads to iodide stimulation

Steps of TH Synthesis

• Iodide trapping: active uptake of iodide from circulation into thyroid cells leading to the thyroid glands concentration of iodide becoming 25x more than in the blood
• Oxidation of iodide to iodine....... 2 I = I²
• Coupling of iodide with tyrosine (a.a) forming mono iodic tyrosine in the presence of peroxidase enzyme
• Condensation of 2 molecules of mono iodic tyrosine forming di-iodic tyrosine and then tri iodic tyrosine and tetra-iodic tyrosine in the presence of peroxidase enzyme
• About 80% Of T4 converted to T3 which is biologically 5 times more active than T4
• Both T3 and T4 are highly protein binding forming thyroglobulin (TG), especially T4
• Both are metabolized by cytochrome p-450 in the liver, so they may get affected by enzyme inducers and inhibitors

Mechanism of Action

• Circulating T3 and T4 is bound to thyroxine-binding globulin in the plasma
• The hormones must dissociate before entering cells
• Inside the cell, T4 is enzymatically deiodinated to T3, which enters the nucleus and attaches to receptors, promoting RNA formation and protein synthesis
• Both T4 and T3 are absorbed after oral administration
• Food, calcium preparations, iron salts, and aluminum-containing antacids can decrease T4 absorption. The Metabolism major route is deiodination
• T3 also undergoes sequential deiodination
• Hormones are also metabolized via conjugation with glucuronides/sulfates, excreted into bile

Treatment of Hypothyroidism

• Hypothyroidism usually results autoimmune distruction
• Diagnosed by elevated TSH
• Levothyroxine (T4) is preferred over T3 (liothyronine) or T3/T4 for treatment of hypothyroidism

Levothyroxine

• better tolerated than T3 preparations and has a longer half-life
• Dosed once daily, with steady state achieved in 6-8 weeks
• Toxicity is directly related to T4 levels and manifests as nervousness, palpitations, tachycardia, heat intolerance, and unexplained weight loss
• Drugs that induce cytochrome P-450 enzymes (phenytoin, rifampin, phenobarbital) accelerate thyroid hormone metabolism and decrease effectiveness

Treatment of Hyperthyroidism (Thyrotoxicosis)

• Graves' disease, an autoimmune disease, is the most common cause
• TSH levels are low due to negative feedback
• Therapy decreases synthesis and/or release of additional hormone, accomplished by the following:
• Removing part/all of the thyroid gland
• Inhibiting synthesis of the hormones
• Blocking release of hormones from the follicle

Removal of the thyroid

• Surgically
• Destruction of the gland with radioactive iodine (131I), which thyroid follicular cells selectively take up
• Hypothyroidism occurs after radioactive iodine

Inhibition of thyroid hormone synthesis

• Thioamides, propylthiouracil (PTU) and methimazole, are concentrated in the thyroid
• They inhibit iodination of tyrosyl groups and condensation (coupling) of iodotyrosines to form T3 and T4
• PTU also blocks the peripheral conversion of T4 to T3
• These drugs have no effect on thyroglobulin already stored in the gland, which is why delayed clinical effects until thyroglobulin stores are depleted

Comparison of Methimazole vs PTU

• Methimazole is typically preferred over PTU because it has a longer half-life, allowing for once-daily dosing, and a lower incidence of adverse effects
• PTU is recommended during the first trimester of pregnancy due to a greater risk of teratogenic effects with methimazole
• PTU has been associated with hepatotoxicity and agranulocytosis

Blockade of Hormone Release

• A pharmacologic dose of iodide inhibits the iodination of tyrosine ("Wolff-Chaikoff effect"), but this effect lasts for only a few days
• Iodide inhibits the release of thyroid hormones from thyroglobulin, which is why iodide is employed for thyroid storm or prior to surgery, because it decreases the thyroid gland's vascularity
• Iodide, administered orally, is not useful for long-term therapy

Adverse Effects of Iodide

• Sore mouth and throat
• Swelling of the tongue or larynx
• Rashes
• Ulcerations of mucous membranes
• Metallic taste

Thyroid storm

• Presents with extreme symptoms of hyperthyroidism
• Treatment is the same as for hyperthyroidism

Β-blockers

• Metoprolol or propranolol
• effective in blunting the widespread sympathetic stimulation that occurs in hyperthyroidism
• but cannot be considered as anti- hyperthyroid drugs

Lec 7: Adrenal Hormones

• The adrenal cortex secretes two types of corticosteroids: glucocorticoids and mineralocorticoids and adrenal androgens.
• The adrenal cortex has three zones, synthesizing different steroid hormones
• The outer zona glomerulosa produces mineralocorticoids (aldosterone) responsible for regulating salt and water metabolism
• The middle zona fasciculata synthesizes glucocorticoids (cortisol) involved with metabolism and response to stress
• The inner zona reticularis secretes adrenal androgens
• Secretion by the two inner zones and, to a lesser extent, the outer zone is controlled by pituitary adrenocorticotropic hormone (ACTH; also called corticotropin)
• ACTH is released in response to hypothalamic corticotropin-