Endocrinology: Hormones and Regulation

Endocrinology: Hormones

• Chemical messengers in the body of Greek origin
• Acts at a site distant from its origin
• Feedback mechanism maintains the constancy of chemical composition in both extracellular and intracellular fluid

Regulation of Hormone Production

• Hypothalamic-Pituitary-Target Organ Axis (HPT axis) regulates hormone production
• Positive feedback mechanism increases production
• Negative feedback mechanism decreases production
• In positive feedback, increased product increases system activity and production rate
• In negative feedback, increased product decreases system activity and production rate

H-P-T Axis and Specific Hormones

• CRH from the hypothalamus stimulates ACTH from the pituitary gland. ACTH acts on the adrenal gland resulting in Glucocorticoid, Mineralocorticoid, and Catecholamine
• TRH from the hypothalamus stimulates TSH from the pituitary gland. TSH acts on the thyroid gland resulting in T3 and T4.
• GnRH from the hypothalamus stimulates LH/FSH from the pituitary gland. LH/FSH act on the ovaries/testes resulting in Sex Steroids.
• GHRH from the hypothalamus stimulates GH from the pituitary gland. GH acts on bone resulting in Insulin-like Growth Factor.

Mechanism of Hormone Action

• Hormones bind to a specific receptor molecule on the cell surface or cell interior
• Polypeptide hormones bind to cell surface receptors
• Steroid hormones utilizes diffusion and bind to internal receptors
• Hormone-receptor complex leads to cyclic AMP production
• Cyclic AMP impacts biochemical processes and generates interior enzyme phosphorylation
• Insulin is absorbed by cells without cyclic AMP

Types of Hormone Action

• Autocrine: Acts directly upon itself
• Paracrine: Acts adjacent to cells of origin
• Intracrine: Acts within cells of origin, without exiting
• Endocrine: Secreted and released into blood circulation, binds to receptor
• Juxtacrine: Acts on immediately adjacent cell by direct cell-to-cell contact
• Exocrine: Secreted and interacts with receptors distally via ductal system
• Prohormones are biochemically inactive hormones.
  • Proinsulin is converted to Insulin by removal of C-peptide.
  • Parathormone and vasopressin are also prohormones.

Hormone Classification by Structure

• Proteins and peptides: ~2/3 of hormones
  • Water-soluble
  • Require transport protein to enter cell
• Glycoproteins
  • FSH, HCG, TSH, Erythropoietin
• Polypeptides
  • ACTH, ADH, insulin, glucagon, somatostatin, PTH, calcitonin, Angiotensin, Gastrin
• Steroids: Primarily regulate sexual development/characteristics
  • Cholesterol-based
  • Not water-soluble
  • Do not require transport protein to enter cell
  • Cortisol, Progesterone, estrone, estradiol, testosterone, aldosterone
• Amines: Intermediary between steroids and protein hormones
  • Derived from amino acids
  • Epinephrine, Norepinephrine, Thyroxine & Triiodothyronine
  • TYROSINE: T4 & T3 precursor
• Fatty acids - Prostaglandins

Hormone Transport Proteins

• Steroid and thyroid hormones require transport proteins in blood circulation
• Unbound fraction exhibits hormone activity
• Changes in transport protein affects hormone activity
• Cortisol Binding Protein (CBG) transports Cortisol
• Sex Hormone Binding Protein (SHBG) transports Estradiol and Testosterone
• Thyroid-Binding globulin (TBG) transports T3 and T4
• Thyroxine-Binding Prealbumin transports T4
• Albumin transports all hormones

The Hypothalamus

• Master switchboard
• Located in the walls and floor of the third ventricles
• Hormones produced by magnocellular neurons of the Supraoptic nuclei (ADH) and paraventricular nuclei (OXYTOCIN)
  • Secreted by posterior pituitary gland
• GnRH (Gonadotropin Releasing Hormone) stimulates release of FSH & LH
• TRH (Thyrotropin RH) stimulates release of TSH & Prolactin
• CRH (Corticotropin RH) stimulates release of ACTH
• GH-RH (Growth Hormone RH) stimulates release of GH
• Somatostatin inhibits release of GH

Pituitary Gland

• Known as the hypophysis
• All hormones secreted by it have a circadian rhythm

Anterior Pituitary Gland (Adenohypophysis)

• The true endocrine gland
• Secretes polypeptides & glycoprotein hormones such as prolactin, GH, Gonadotropins (FSH & LH), TSH, & ACTH
  • Somatotrophs secrete growth hormone
  • Lactotrophs or Mammotrophs produce prolactin
  • Thyrotrophs secrete TSH
  • Gonadotrophs secrete LH & FSH
  • Corticotrophs secrete Proopiomelanocortin (POMC)
    • POMC is cleaved to produce ACTH, B-endorphin, & B-lipotropin

Pituitary Hormones and Their Targets

• LH, or Luteinizing Hormone acts on the gonads
• FSH, or Follicle Stimulating Hormone acts on the gonads
• TSH, or Thyroid Stimulating Hormone acts on the thyroid
• ACTH, or Adrenocorticotropic Hormone acts on the adrenal glands
• Growth Hormone acts on multiple areas
• Prolactin acts on the breasts
• Actions are specific for another endocrine gland
• Act directly on peripheral tissue
• TSH, FSH, and LH, share a common alpha chain subunits

Growth Hormone (GH)

• The most abundant of all pituitary hormones
• Structurally it resembles prolactin and human placental lactogen
• It antagonizes insulin action in glucose metabolism
• Stimulates protein synthesis & anabolic metabolism
• Stimulates the liver to produce SOMATOMEDINS
  • A.K.A. Insulin-like Growth Factors (IGFs)
  • Works as a skeletal Growth Amplifier
• Creutzfeldt-Jakob Disease: Untreatable transmissible spongiform encephalopathy transmitted via cadaveric GH

Growth Hormone Deficiency

• GHD causes in adults include:
  • Pituitary adenoma (MC cause)
  • Complete or partial failure of adenohypophysis
  • GH insensitivity -S/S: Social withdrawal, fatigue, loss of motivation, a diminished feeling of well-being, osteoporosis, reduced body mass

Dwarfism

• Pituitary Dwarfism = Decreased GH & IGF
• Laron’s Dwarfism = Decreased IGF & Increased GH

Growth Hormone Excess (Acromegaly)

• Acromegaly results from pathologic or autonomous GH excess, usually from a pituitary tumor
• Diffused skeletal growth occurs if after puberty
• Gigantism is impressive height before epiphyseal closure, from GH excess (longitudinal)
• Signs and symptoms are: Bony soft tissue growth, progressive enlargement of the hands and feet, and growth of facial bones(the mandible and bones of the skull), arthritis, organomegaly, hypermetabolic condition (sweating & heat intolerance), diabetes, hypertension, gaps between teeth

Growth Hormone Deficiency Diagnostic Tests

• For test preparation:
  • Overnight fast
  • Completed rest 30 min prior
• Physical Activity (Exercise test) is used for screening.
• Insulin Tolerance Test/ Insulin-Induced Hypoglycemia Stimulation Test is the gold standard for confirmatory testing.
• The normal result shows 7-10 ug/L; >5 ug/L (adults)
• The Arginine Stimulation Test is the 2nd confirmatory diagnostic test for children.

Prolactin

• Functions in the initiation and maintenance of lactation, and it's a stress hormone.
• Acts with estrogen and progesterone to promote breast tissue development
• Dopamine is the major inhibitor
• There are highest elevations during sleep: 4:00 am, 8:00 am, 8:00 pm, and 10:00 pm
• Stimuli are induced by nursing/nipple stimulation, stress, exercise, and pregnancy

Hyperprolactinemia

• Most common hypothalamic pituitary disorder
• Increase in PCOS, acromegaly, primary & secondary hypothyroidism
• May result to anovulation/ hypogonadism: Amenorrhea and galactorrhea
• Galactorrhea in men is a result of low serum testosterone
• Prolactinoma occurs when the serum is over 150 ng/mL

Oxytocin

• It is a nanopeptide, very similar in composition to ADH
• Stimulates contraction of the gravid uterus & lactation
• Released in response to neural stimulation of receptors in the birth canal & uterus, and touch receptor of the breast
• Burst of oxytocin secretion occurs when anticipating nursing or on hearing a baby cry
• Pitocin is a synthetic to induce labor contraction

Anti-Diuretic Hormone (ADH)/Arginine Vasopressin

• Major Stimulation: -Osmoreceptors in vasculature sense change in serum osmolality -Baroreceptors in vasculature sense change in blood volume
• Inhibitors: Ethanol, cortisol, lithium, and demeclocycline
• Regulates water absorption in the distal convoluted tubule (DCT) and collecting duct (CD)
• ↑Body Hydration = ↓ADH = ↑Urine Volume
• ↓Body Hydration = ↑ADH = ↓ Urine Volume
• Diabetes Insipidus (DI) = ADH DEFICIENCY
• Syndrome of Inappropriate ADH secretion (SIADH) = ADH EXCESS

Types of Diabetes Insipidus

• True/Hypothalamic/Neurogenic/ Cranial/ Central DI

1. Deficiency of ADH with normal ADH receptor
2. Due to the failure of the pituitary gland to secrete ADH
3. 3-20 L of urine excretion

• Nephrogenic DI

1. Characterized by having a normal ADH but abnormal ADH receptor (renal resistance to ADH)
2. Either congenital or acquired

Gonadotropins

• Hormonal Cascade for Reproduction includes:
  • Hypothalamus produces GnRH
  • Anterior pituitary (gonadotroph) produces FSH & LH
  • Testis produces Testosterone
  • Ovary produces Estradiol & Progesterone
  • Placenta produces hCG, Estrogen & Progesterone

Follicle-stimulating hormone

• Aids in spermatogenesis
• Clue in diagnosis of premature menopause
• Increases with the lack of estrogen post menopause

Luteinizing Hormone

• Helps Leydig cells to produce testosterone (male)
• Necessary for ovulation and the final follicular growth; reliable predictor of ovulation
• Acts on theca cells to cause the synthesis of androgens, estrogens, & progesterone Markers for diagnosing fertility and menstrual cycle disorders

Regulation of Male Reproduction

• Testes are made up of the following 2 functions: Exocrine and Endocrine
• • Exocrine: Sperm secretion
• • Endocrine: Testosterone Production Sertoli cells - Aka “nurse cell" Target of FSH Produce testosterone in the seminiferous tubules; supplying nutrients, and other substances required for normal spermatogenesis Produce inhibin, which inhibits (decreases) gonadotrophs such as FSH via negative feedback

Hormones of the Gonads - Progesterone

• A C-21 compound, produced by the corpus luteum
• -Is the predominant hormone responsible for the luteal phase
• Exhibits "Thermogenic effect,” increasing the basal body temperature that occurs after ovulation Functions
• -Prepares the endometrium for embryo implantation
• -Thickens the cervical mucus
• -Reduces uterine contraction

Hormones of the Gonads - Estrogen

• A carbon-18 compound, it's primary source is the ovary
• It is an Estrane, with “phenolic ring A" and methyl group at C-13 Functions:
• -Promotes the development of secondary sexual characteristics in females
• -Development of endometrium in conjunction w/progesterone
• -Responsible for the Proliferative phase of the uterus
• -Drops in level at the end of cycle, triggering the process of menstruation It is important to note the 3 Major Estrogens: Estrone (E1) is the major estrogen in menopause stage 17β-estradiol (E2) is the major estrogen in reproductive years; most potent estrogen Estriol (E3) is the major estrogen in pregnancy

Hormones of the Gonads - Androgens

• They are Carbon-19 compounds Synthesized by Testis, with small amounts in the adrenal cortex Testosterone has a peak at 4:00 am to 8:00 am, with nadir 4:00 pm to 8:00 pm 98% binds to either albumin or SHBG (sex hormone-binding globulin) Functions Facilitate the development of secondary male characteristics Enhance protein synthesis leading to growth in both skeletal muscles and bones Excess production of ovarian androgens in women leads to hair growth (hirsutism), and frank male secondary sex features (virilization) Precursor for dihydrotestosterone (DHT) & Estradiol

Disorders of Sexual Development and Ovarian Hypofunction - Polycystic Ovary Syndrome

• Characterized by the following: Infertility Hirusitism Obesity Various menstrual disturbances Abnormal bleeding patterns from chronic anovulation and lack of progesterone stimulation and with-drawl Ovarian ultrasound- multiple cysts (follicles) in many

Analytical Methods for Reproductive Hormones

Analytical Methods for Reproductive Hormones - Testosterone It is measured by an immunoassay- most common, not precise, and not sensitive To measure the free bound testosterone: salicylates, surfactants, pH alterations, as well as temperature changes must occur You can also run a LC-MS/MS or GC-MS, However The gold standard is -SERUM/HEPARIN: drawn early in the AM; between (4:00-8:00) The Serum can also be ran through Ultrafiltration, precipitation as a radioimmunoassay.

Analytical Methods for Reproductive Hormones Estradiol and Anabolic Steroids

• Estrogen tests include Enzyme Immunoassay's, where a serum marker is detected.
• A urine test for Steroids detects the elevated levels, epitestosterone, or hcG.
• Reference method: Serum tests must use GC-MS.
• A reference tool for these is, Ultrafiltration.
• For testing, patients must visit the lab early between, 4:00-8:00 AM after a prolonged fast.

Human Chorionic Gonadotropin

• Glycoprotein produced by the cytotrophoblast and syncytiotrophoblast cells in the placenta
• Consists of 2 basic subunits, Alpha and Beta
• Chromosome 6-has an identical base pair with FSH, LH, & TSH
• The beta subunit has a direct impact specific to the levels of hcG and can be used in immunoassay tools.
• This serves to Maintain PROGESTERONE production by the corpus luteum during early pregnancy Detected in serum and urine as early as 5 days after conception, peaks 8-10 weeks into gestation, drops during 2nd trimester