PHAR 555 Exam #1 (Review)

From least to most stable level of chemical communication in the endocrine system (with examples)…

• Ion channels (fastest, taking milliseconds)

  • Example: Fast-twitch muscles

• Modulators (GPCRs) (tweaks things slightly in the positive or negative direction—nothing long-term—at a moderate speed, taking minutes to hours)

  • Example: Most drugs

• Transcription (nuclear) of new proteins and enzymes, altering things like metabolism and the long-term function of a cell

• Metabolism (receptor kinases), altering fundamentals of cells

  • Example: Insulin

glands

secretory organs/tissues that produce and release substances for use in other tissues

exocrine gland

releases substances via ducts (usually epithelial) to specific tissues

endocrine gland

releases substances into the bloodstream, often to distal sites

hormones

longer-acting chemicals that act on distal tissues by transport in the bloodstream

• Usually to maintain prolonged homeostasis, aid in bone formation, etc.  

• Can be either small water-soluble molecules, peptides/proteins, or lipid-soluble steroids

• Most then act on specific target tissues (save growth hormone) using receptors, which can elicit further hormone release from those peripheral tissues

How can the hypothalamus send hormones to the pituitary gland?

The hypothalamus…

• Sends hormones down axons that lead to the posterior pituitary at which they are released

  • Receives mostly neural positive feedback

• Sends “releasing hormones” through the blood portal system to the anterior pituitary, a hub of different specialized cells that receive the signal and produces/releases “stimulating hormones” to peripheral tissues

  • Peripheral tissues themselves oftentimes produce their own hormones

  • Regulated by negative feedback from too high of peripheral hormone levels, as do hypothalamic-releasing hormones

types of anterior pituitary cells and hormones

• Gonadotroph

  • Product: LH, FSH

  • Target: Gonads

• Somatotroph (makes up about half of the cells within the anterior pituitary area)

  • Product: Growth hormone (GH)

  • Target: All tissues, liver

• Lactotroph

  • Product: PRL

  • Target: Breasts, gonads

• Thryotroph

  • Product: TSH

  • Target: Thyroid gland

• Corticotroph

  • Product: ACTH, β-lipotropin

  • Target: Adrenal gland, adipocytes, melanocytes

general idea of the HP_ system

The hypothalamus sends out “releasing hormones” as positive stimulation to the cells of the anterior pituitary gland, prompting them to release their own specific “stimulating hormones” into the target peripheral tissues—and then the peripheral tissues themselves can release their own hormones to exert physiological actions

• Most releasing hormones are excitatory

supraoptic nucleus

sits directly adjacent to the ventricle receiving blood from external circulation (sensing function) for the pituitary

• The pituitary has both arterial and venule circulation to obtain chemical input from the periphery, as well as exit routes to external tissues

hypopituitarism

pituitary gland fails to produce one or more essential hormones

• Can be developmental, but is often associated with head trauma or damage to the area

hyperpituitarism

pituitary gland makes too many hormones

• Often associated with tumors that lead to excessive production of stimulating hormones

• Can cause:

  • Gigantism, acromegaly → Excess GH (growth hormone)

  • Goiter and enlarged adrenal cortex → Excess TSH and ACTH, respectively

  • Precocious sexual development → Excess GnRH 

  • Cushing's syndrome → Excess ACTH and cortisol

  • Occasionally lactation → Excess prolactin

general treatment approach for “hypo” conditions

Replace and maintain normal peripheral hormone levels

general treatment approach for “hyper-” conditions

Slow or diminish signals—which is often done with either dopamine D₂ agonists or somatostatin agonists that broadly inhibit hypothalamic and pituitary activity

How does the posterior pituitary receive signals? What does it then produce?

The posterior pituitary receives direct innervation from the hypothalamus and releases vasopressin (also known as antidiuretic hormone = ADH or arginine vasopressin = AVP) and oxytocin

• Vasopressin and oxytocin are relatively stable (lasting minutes to hours) and quite structurally interchangeable

feedback system for posterior pituitary

Feedback is primarily positive neuronal signals for further production and release

What is the trigger(s) for vasopressin release from the posterior pituitary?

Dehydration causes high particle concentration in the blood, sending signals to the hypothalamus to trigger the release of ADH from the posterior pituitary gland until balance is restored

What is the trigger(s) for oxytocin release from the posterior pituitary?

Physical stimulation in the periphery (e.g., contractions in labor, breastfeeding, sexual intercourse) sends positive neuronal signals to the hypothalamus, triggering the posterior pituitary gland to release oxytocin, which amplifies the physical response in a continuous loop until the stimulation ends

physiological actions of oxytocin

• Dilation of the birth canal causes a reflex stimulus for the release of oxytocin, leading to rhythmic contractions of the uterus → expulsion of the fetus and placenta

  • The uterus is 10x more sensitive to oxytocin at term compared to the first trimester. This change in sensitivity dictates that oxytocin is most and only therapeutically useful at term, making it a DOC for inducing labor

• Promotes release of milk from mammary glands

What sex hormone antagonizes oxytocin’s actions on the uterus?

High levels of progesterone have wide effects on the body and can help prevent premature labor by antagonizing oxytocin’s actions on the uterus. Progesterone levels then plummet just prior to full term

• Note: Effects of oxytocin are reduced when estrogen levels are low, which may suggest a role in co-regulation of libido

drugs for labor and contractions

• Oxytocin (Pitocin): primary drug for labor induction

  • Increases contraction rate and intensity without altering resting tension (i.e., you get full relaxation, unlike ergots)

• Ergometrine (ergonovine): ergot derivative with contractile activity, often used to prevent uterine postpartum bleeding

• Oxytocin/ergometrine (Syntometrine): given postpartum to reduce bleeding and delivery of placenta

How is the release of vasopressin regulated naturally?

Primary control is volume and osmolarity

• Having either a low blood volume or hyperosmolarity (e.g., severe dehydration, infusion with hypertonic solution) causes ADH release to dilute your blood with water content and vasoconstrict your blood vessels

Which drugs affect the release of vasopressin?

• Nicotine (and ACh) increases the release of ADH (→ kidneys reabsorb water from the urine and vasoconstrict your blood vessels)

• Alcohol decreases the release of ADH (→ kidneys send extra water to the bladder → frequent urination and dehydration)

types of vasopressin receptors

• V_1A: Located in numerous tissues, particularly smooth muscle of vasculature. Causes IP₃-Ca²⁺ stimulation of blood vessels to promote contraction if your blood volume gets too low

• V_1B: Cross-regulates anterior pituitary release (mostly ACTH) via similar IP₃ intracellular mechanism

• V₂: primarily acts in the kidney through Gs signaling to promote insertion of aquaporin channels → reabsorption of very clean water from urine if your blood volume gets too low

physiological functions of vasopressin

• Renal V₂ receptor action: Increases renal tubular reabsorption of water → decreases the volume of urine output (concentrating urine)

• Vascular smooth muscle V_1A receptor action: Contracts all smooth muscle of the vasculature → causes ↑ in BP and reflexively a ↓ in HR

Dysfunction of vasopressin leads to…

• Types

diabetes insipidus (→ excessive urine excretion and constant thirst), which can either be:

• Nephrogenic: Failure of the kidney tubules to reabsorb water due to ADH insensitivity

  • Some drugs (lithium/antivirals) can cause it temporarily  

  • Treatment: Water replacement to prevent dehydration

• Neurogenic: ADH deficiency caused by head injury, tumor, cerebral aneurysms, CNS ischemia, etc.

  • Treatment: Typically desmopressin

vasopressin therapeutics (replacements)

• ADH replacement (vasostrict or pitressin)

  • Disadvantages: Short duration of action; must be injected; both antidiuretic and vasopressor activity are roughly equal (nonselective)

• Desmopressin (DDAVP or Nocdurna): Analog of ADH with longer duration of action

  • In pill/nasal forms

  • More V₂ selectivity to favor antidiuretic activity (hold onto water)

  • Can be used for nighttime bedwetting

• Tolvaptan (Jynarque): V₂ selective antagonist (blocker) to excrete water

  • Can remove water without proportionally getting rid of sodium, which aids in either congestive heart failure or ADH overactivity, conditions that result in hyponatremia

growth hormone-releasing hormone (GHRH)

• A 44-amino acid peptide synthesized in the arcuate nucleus

• Binds to GHRH receptors on the anterior pituitary → G_s signaling → growth hormone (GH) is released

• Can also promote prolactin release

• Drug forms of GHRH (1-44; somatorelin) or its truncated analog (1-29; sermorelin) can be used to diagnose pituitary deficiencies, rather than for treatment

growth hormone (GH)

• Large peptide of two splice lengths (22kDa = ~90%, 20kDa = ~10%), both of which are equally active

  • Exogenous is all in the 22kDa form (key for detecting blood doping)

• Released in pulsatile fashion from the pituitary gland

  • While release through the day is irregular, it is generally highest during the initial stage of sleep

• Levels generally:

  • Rise and fall alongside insulin (energy abundance for growing!)

  • Can be stimulated by both stress and exercise

  • Increase approaching puberty across the lifespan, then progressively decrease with age

functions of growth hormone (GH)

Directly promotes metabolic switch of…

• ↓ glucose uptake/use → glucose is spared and fat is burned for energy instead

• ↑ lipolysis → ↑ fatty acids used for energy

• ↑ protein synthesis → ↑ tissue/muscle growth

Rather than GH, what hormone is responsible for actual growth and proliferation?

Actual growth and proliferation occurs via the insulin-like growth factor 1 (IGF-1)

• IGF-1 promotes growth of bone length, muscle and tissue growth, and burning of fat

• High levels of IGF-1 appear to inhibit GHRH and increase somatostatin release, both of which provide negative feedback on GH release

GH receptor

sends signals through the tyrosine kinase JAK/STAT cascade to promote gene expression of IGF-1

• Most IGF-1 is produced in the liver

IGF-1 receptor

has extensive overlap in function (and even low-affinity cross-binding) with the insulin receptor

• Primarily acts via strong Akt activity to promote cell survival (stop apoptosis)

• Secondarily ERK activity to promote cell proliferation (division)

Overproduction of GH is often the result of…

Underproduction of GH is a consequence of…

• Overproduction is often the result of a pituitary tumor

• Underproduction is often the result of pituitary damage (and, in rare cases, a receptor mutation)

GH disorders

• Gigantism: Excess GH signaling during development → Overactivity of IGF-1 → Excessive growth in all directions

• Proportional dwarfism: Underproduction of GH → Lack of IGF-1 → Delayed growth, short stature, possible poor muscle development and exercise tolerance

• Acromegaly: Post-pubertal GH excess (after epiphyses of bones fuse) →  Not all tissues respond equally to growth signals → Abnormal growth of hands/feet, protruding brow and chin, barrel chest, excessive pubertal effects (hair, sweat, voice changes), general swelling of soft tissues

  • Other common symptoms: Headaches, joint pain, glucose intolerance, and hypertension

treatment for excess GH

• Somatostatin analogs (octreotide and lanreotide): formulated in month-long injectable forms to slow GH release and even slow tumor growth in acromegaly

  • Downsides:

    • Nasty GI effects and long-term hyperglycemia

    • Slows or inhibits actions of most anterior pituitary hormones, having widespread potential impacts of energy metabolism, sex hormones, immune function, etc.

• Dopamine (D₂) agonists (bromocriptine): can lower GH, IGF-1, and prolactin levels in roughly half of acromegaly patients

  • Neither a first-line option nor as effective as somatostatin (can be combined with somatostatin treatment)

• HGH analog antagonist (Pegvisomant (Somavert)): a modified and stable antagonist at the GH receptor that can more selectively slow acromegaly without altering the entire endocrine system

treatment for deficient GH (growth receptor drugs)

• HGH (Somatropin): synthetic GH given to deficient children to promote growth through puberty

  • Can be used for off-label growing and also used controversially in athletic and for anti-aging properties

  • Due to proliferative effects and the added risk of tumorigenesis, exercise extreme caution

• Somatrogon (Ngenla): modified stable hGH analog that can be taken weekly in an autoinjector pen

• Mecasermin (Increlex): synthetic IGF-1 given only to children who don’t respond to GH and have extremely low IGF-1 levels

HPG axis

• The gonadotropin-releasing hormone (GnRH) couples with G_q/11 proteins to stimulate the release of two stimulatory hormones from the pituitary gland: luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to cell development and sex hormone production

• FSH and LH receptors (both Gs) are in distinct populations of gonadal cells

• Typical levels of sex hormones suppress further GnRH or LH/FSH production and release

  • Exception: Ovulation and pregnancy violate this notion, as excess during these times leads to more excess

temporal patterns of GnRH in…

• Females

• Males

• Females:

  • Relatively low and inhibited by estradiol until just prior to puberty, and then exponential increase

  • Once cycling, pulses become increasingly frequent leading up to just a few days after ovulation, drop dramatically, and then slowly speed up again

• Males:

  • Slow build from youth to puberty (less estradiol suppression), then rapid but shallow pulsatile control

• Pulses occur every 2-5 hours

• Both sexes show increases of GnRH throughout the lifespan. However, too frequent pulsing or constant stimulation results in the loss of FSH/LH release

Puberty is a result of…

the hypothalamus releasing an increasing number (in both amplitude and frequency) of gonadotropin-releasing hormone (GnRH) → gonadotropic hormones, such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH), are released from the pituitary gland → sexual maturity (sex hormones)

• These are found in both males and females but lead to different results depending on sex

• LH leads to the release of estrogen from the ovaries and androgen release from the testes

• FSH allows for maturation of sperm and eggs

Note: Both males and females produce small amounts of the other gender’s sex hormones (estrogen or androgens). This is largely controlled by aromatase levels

hypogonadotropic hypogonadism

a condition where the brain's hypothalamus or pituitary gland fails to make enough hormones to stimulate the gonads, leading to low sex hormone levels

• May be either hormone or receptor functional disruption

• Result: Sexual infantilism/delayed puberty, which can be dysfunction at almost all levels of HPG axis

• Treatment: Hormone replacement regardless of cause

hypergonadotropic hypogonadism

results from loss of central GnRH inhibition, leading to increased pulsing

• Result: Premature/precocious puberty

• Diagnosis and treatment: GnRH agonists (e.g. leuprolide depot) to prevent pulsating activity and shut down sex hormone production

prolactin (PRL)

a large peptide structurally related to GH and released by similar stimuli

prolactin (PRL) levels

• Levels are primarily controlled by inhibitory signaling through dopamine D₂ (Gi) receptor activation on lactotrophs

  • Thyrotropin-releasing hormone (TRH) plays a minor role in PRL release (only observed in thyroid disorders)

• Levels…

  • Increase dramatically as pregnancy comes to full term and remains with suckling stimulation

  • Gradually desensitize with time and eventually decline over months

PRL receptor activity

member of the cytokine family, just like GH, binding to a homodimer that activates the JAK/STAT signaling pathway

• Primarily initiates and maintains lactation (gene transcription of milk proteins among them)

  • Estrogen and progesterone block these prolactin actions during pregnancy

• Prepares the mammary glands for breastfeeding by promoting the growth of breast tissues (both proliferation and differentiation of mammary ductal and alveolar epithelium)

  • (GH can also weakly bind to a PRL receptor, so lactation is a possible side effect of acromegaly)

• Inhibits LH and FSH release and their effects on ovaries and gonads (If a drug has sexual dysfunction as a side effect… prolactin could be the culprit)

hyperprolactinemia

excessive PRL release due to a number of potential factors:

• Dopamine antagonists (reserpine, haloperidol)

• Hypothalamic or pituitary disorder

• Excess TRH release (simple goiter)

• Oral contraceptives

• Prolactin-secreting tumors, which come in two clusters

  • Galactorrhea: excessive or spontaneous lactation

  • Amenorrhea in women, or even loss of libido/fertility in both sexes

treatment for hyperprolactinemia

any dopamine agonist, with bromocriptine as the DOC

• Side effects: N/V, headaches, postural hypotension, CNS activity (in rarer cases and at high doses)

thyroid

crucial for energy balance, temperature regulation, increasing carbohydrate burning and protein synthesis, and fetal limb development

thyrotropin-releasing hormone (TRH)

a small tripeptide (half-life: ~6 minutes) produced in the paraventricular nucleus (PVN) of the hypothalamus and transported to the anterior pituitary

• Binds to TRHR (G_q) in thyrotroph cells to stimulate secretion and further synthesis of thyroid-stimulating hormone (TSH) (sometimes referred to as thyrotropin) from the anterior pituitary, which signals the thyroid gland to release thyroid hormones

• Besides thyroid hormones, the thyroid also produces calcitonin

How can we inhibit TRH activity?

can be inhibited by dopamine (D₂), somatostatin, glucocorticoids, and negative feedback of T3/T4

What synthetic TRH is given IV for differential diagnosis of hypothyroidism?

protirelin (Thyrel TRH)

• Measure TSH levels at baseline and 30 minutes post-infusion

• Quite outdated now

thyroid-stimulating hormone (TSH)

large glycoprotein structurally related to FSH/LH (same α subunit but different β)

• Promotes thyroid hormone production, and binds to TSH receptors in the thyroid to stimulate (G_s) the release of thyroid hormones from stores

• Maintains overall health of thyroid

  • TSH deficiency leads to atrophy

  • TSH excess leads to goiters

• Blood tests for TSH levels is the primary method of determining hypothyroidism, even in asymptomatic cases

What human TSH is given to promote uptake of radioactive iodine (¹³¹I) into thyroid tumors?

thyrotropin α (Thyrogen)

• Formerly used for diagnostic purposes to examine responsiveness of thyroid to TSH by examining uptake of contrast iodine (¹²³I)

thyroid hormone synthesis

• What element on the periodic table do thyroid hormones contain?

• What is the major building block?

• Heavily involves dietary iodine (i.e., iodized salt) uptake

  • At any given time, the thyroid has 20-50x the iodine concentration (like a storage house) as plasma

  • A lot of energy is needed to take up iodine, so the process recycles and scavenges anything in the thyroid that isn’t released as thyroid hormones

• Tyrosine is a major building block that gets iodinated in the process into T₄ (thyroxine, 80%) as the primary product, followed by T₃ (20%)

thyroid receptors

nuclear receptors that promote gene expression (thyroid hormone response elements)

• Includes TRα1, TRβ1, TRβ2

  • α isoform is primarily expressed in muscle and skeletal tissues

  • β isoforms primarily expressed in liver, kidney, and brain

  • TRβ2 can also have a repressive role in gene expression

    • T₃ binding suppresses the transcription of TRH and TSH in the hypothalamus and pituitary, respectively

When unbound, TR acts as…

When bound by T₃/T₄, TR acts as…

When unbound, TR acts as a gene repressor; when bound by T₃/T₄, TR recruits co-activator proteins to turn on gene expression

• Activation often occurs in heterodimers with other nuclear promoter complexes, most notably the retinoic acid receptors (RXRs)

How is T₄ transported into cells?

Soluble hormones like T₄ are heavily protein-bound and transported into cells primarily via monocarboxylate transporters (MCT8/10) before getting converted into T₃

How would you compare the circulating levels of T4 versus T3?

• Basal circulating levels of T₄ are roughly 30-50x that of T₃

  • Estrogen and analogs can increase protein binding in plasma, while corticosterone and testosterone can lower

  • Many prescription drugs can alter protein binding and circulating plasma hormone levels

How would you compare the activity of T4 versus T3?

T₄ lasts long in the blood and is protein-bound, but has about 10x less affinity for receptors. Thus, most activity is due to T₃ conversion in peripheral tissues and binding

How would you compare the stability of T4 versus T3?

Peripheral T₄ is more metabolically stable (T_1/2 of T₄ = 7 days, T_1/2 of T₃ = 1.5 days), and is converted to either T₃ or inactive rT₃ based on tissue-specific enzymes

functions of thyroid hormones

• Developmental

  • Cell survival and proliferation, growth of most organs, neurogenesis

  • T₃ mediates metamorphosis of tadpoles into frogs (limb growth and tail resorption)

• Thermogenic

  • T₃ can control the efficiency of mitochondrial energy production processes → Burns extra calories to produce heat (it’s how the thyroid determines your thermal setpoint and regulates your body temperature!)

  • Can increase utilization of carbohydrates and glycogen (although insulin/glucagon usually compensates for actions on glucose levels)

• Cardiovascular

  • Excess thyroid function → Tachycardia and increased stroke volume and tension

  • Hypofunction → Bradycardia and lowered pulse pressure

baby hypothyroidism disorder

• Congenital hypothyroidism (cretinism): deficient thyroid function from birth

  • The thyroid is critical to brain development, limb differentiation, fertility, and thermal regulation

  • Treatment: Early detection and supplementing T₄

• Two ways to have a hypothyroid from birth:

  • Endemic form: iodine deficiency in pregnancy (mother) and infancy (baby)

  • Sporadic form: congenital defect of an enzyme or receptor in the process of thyroid synthesis

adult hypothyroidism disorder

• Adult hypothyroidism results in edema, thick and rough skin, loss of hair, cold intolerance, lethargy, cognitive impairment, anemia, and infertility (likely mediated by TRH-stimulated prolactin)

  • Primary: Iodine deficiency → Goiter (still have lots of TSH)

  • Secondary: TSH deficiency, atrophied thyroid

  • Tertiary: TRH deficiency, atrophied thyroid

• Hashimoto's thyroiditis: autoimmune antibody production against thyroglobulin or other synthetic proteins

  • Most common cause in the developed world

  • Falls under primary hypothyroidism

hyperthyroid disorders

• Thyrotoxicosis

• Graves’ disease

• Plummer’s disease (toxic multinodular goiter)

thyrotoxicosis

syndromes from excess T₃/T₄ hormone release

• Symptoms may include:

  • Goiter with excess hormone release

  • Increased energy use and alertness/anxiety

  • Hyperthermia

  • Symptoms characteristic of SNS overactivity

Graves’ disease

autoimmune production of antibodies that activate TSH receptors directly, bypassing any negative feedback

• Recurring, remitting disorder

• ~5-7x more common in women

• Usually manifests in young adults

• Characteristic inflammation around eyes (bulging look)

• Falls under secondary hyperthyroidism

Plummer’s disease (toxic multinodular goiter)

typical hyperthyroidism in older patients of unknown origin

• However, evidence points to mutated TSH receptors that can turn on spontaneously (so secondary hyperthyroidism)

• About 20% of cases

• Rare ophthalmopathy

“thyroid eye disease (TED)”

a term mostly invented by pharmaceutical companies that refers to a symptom/disorder of Graves’ disease: ophthalmopathy (bulging of eyes and redness/irritation of fatty tissues and tear ducts)

treatment options for thyroid eye disease (TED)

• Teprotumumab (Tepezza), veligrotug (Lumvoa)

  • Monoclonal antibodies that target IGF-1 receptors, the key mediator of causing inflammation in the area of your eyes

  • Prevents abnormal growth in tissues behind the eye and reduces bulging

• Milder cases can be treated with steroids for inflammation and treating the underlying thyroid condition

treatment options for hypothyroidism

• Commonly treated via T₄ (levothyroxine, Synthroid) for long-acting (lifelong) replacement

  • Mostly taken orally as tablets

  • Best absorbed on an empty stomach

  • Food, drugs that slow acid secretions, and chelating/resorption-blocking drugs can impair uptake

  • T₄ levels will peak within a couple hours, but remain mostly stable for days (half-life: ~7 days)

• T₃ (liothyronine, Cytomel) is often only given in emergency situations (i.e., coma) (since T₃ is the “active form”) for immediate action due to short half-life of few hours

  • Relatively impractical as replacement therapy

• 4:1 preparations of T₄:T₃ (Thyrolar) are available, but the benefits are unclear. Armour Thyroid is ground up pig thyroid gland that provides T₄:T₃  in similar ratios, but giving synthetic instead of natural has a much lower risk of reactions

main treatment options for hyperthyroidism

• Thionamides (MMI and PTU) are antithyroid drugs that interfere with the iodine peroxidase and synthesis of hormones

  • Does not alter iodide uptake or hormone release

  • Methimazole is more common for Graves’ and Plummer’s, as it is long-acting enough for QD pills (1-hr versus 6-hr half-life)

  • Propylthiouracil can also inhibit the conversion of T₄ → T₃ in the periphery, so it is more commonly given during “thyroid storms”

• Lugol’s solution (5% I and 10% KI) or saturated solution potassium iodide (SSKI; 50% KI) consist of excess iodine that increases plasma iodine concentration and slows both uptake and hormone release

  • Used temporarily to stabilize thyroid activity in a crisis or preoperative (before surgery) to shrink the thyroid

adjuvant treatment options for hyperthyroidism

β-adrenergic antagonists and Ca²⁺ channel blockers are often used in thyrotoxicosis to counteract sympathetic and cardiac symptoms

How are thyroid tumors treated?

can often be TSH-driven, so high T₄ can be given to aid in shrinking the tumor

• Typically treated with either surgery or ¹³¹I radioactive iodine which concentrates in the overactive thyroid and produces destructive localized radiation (has a low risk of secondary cancers)

  • PTU can be used with ¹³¹I to prevent any integration into circulating hormones in the bloodstream

parathyroid gland

• What serum levels does it control?

four small nodular glands located within the thyroid gland

• Calcium and phosphate, both of which are typically abundant in diet, central to bone mineralization, and critical to all intracellular function

What four substances specifically regulate levels of circulating calcium and phosphate?

• Calcitonin from thyroid

• Parathyroid hormone (PTH) from parathyroid

• 1,25-dihydroxyvitamin D (calcitriol) from kidney

• FGF23 from bone cells

parathyroid hormone (PTH)

short-lived peptide (84 AA) with a half-life of minutes once cleaved

• Its job is to maintain normal levels of calcium in your blood

  • Primarily targets 1) kidney to increase calcium reabsorption + phosphate excretion and 2) bone to promote resorption

  • Activates a kidney enzyme to convert vitamin D into calcitriol, which targets 1) intestines to increase calcium reabsorption + phosphate reabsorption and 2) bone to promote resorption

Describe the feedback loop on the parathyroid hormone (PTH)

The parathyroid glands have a negative feedback loop controlled by parathyroid-secreting cells, which have calcium-sensing receptors (CaSR) that, when occupied by Ca²⁺, activate:

• G_q-mediated suppression of PTH synthesis, AND

• G_i-mediated suppression of PTH release

parathyroid hormone 1 receptor (PTH1R)

present in bone and kidney and mediates resorption of calcium-phosphate complexes

• Can also be activated by parathyroid hormone-related protein (PTHrP), which is produced in stem cells of bone/cartilage, including excess by tumors

osteoblasts

cells that collect calcium for new mineralization and promote extracellular release

• Acted upon by PTH and calcitriol

• Note: Although PTH and calcitriol’s effects on phosphate oppose each other, both ultimately increase free Ca²⁺

vitamin D

family of fat-soluble hormones that bind to nuclear vitamin D receptors (VDR)

• Binding to VDRs has rapid, non-genomic actions

• Dietary sources provide vitamin D₂ (somewhat less stable and potent but a commonly prescribed supplement)

• UV interacting with skin produces D₃ (cholecalciferol)

What is vitamin D converted into?

Vitamin D is eventually converted into calcitriol, which increases the absorption of Ca²⁺/phosphate from the intestine (↓ fecal loss), as well as bone resorption

• Conversion is activated by PTH, and high levels of calcitriol causes negative feedback onto PTH production itself

• PTH also promotes the production of fibroblast growth factor 23 (FGF23) from bone, which increases the metabolism of calcitriol (a miniature negative feedback system to prevent excess resorption and making your bones brittle)

calcitonin

short, 32-AA peptide with really low circulating basal levels and a short half-life (~10 minutes)

• Secreted from C cells in the thyroid and has bidirectional (and opposite) control of serum Ca²⁺ levels as that of PTH

  • Binds to calcitonin receptors via G_s and G_q to produce opposing actions to PTH that ultimately lower free Ca²⁺

• Aids in maintenance of bone integrity and sustains minimal structure of bone during “calcium stress” events

• Inhibits osteoclast activity and differentiation—the cells primarily responsible for bone breakdown

hypoparathyroidism

results from tissue or autoimmune damage, with symptoms commonly related to low blood calcium:

• Muscle spasm and tetany, hair/nail/dental demineralization and brittleness

• Rare cases of depression and anxiety

hyperparathyroidism

leads to…

• Hypercalcemia → Muscle weakness, constipation, flatulence, N/V

• Hypercalciuria and hyperphosphaturia → Formation of kidney stones and calcification in kidneys

Hyperparathyroidism can be broken down into…

• Primary: tissue damage or lesion (Treatment: Surgical removal)

• Secondary: low calcium due to other disorders, such as kidney disease (Treatment: Besides correcting the underlying cause, you may use cinacalcet (sensipar), an allosteric agonist of Ca²⁺-sensing receptor that lowers PTH)

calcium regulation disorders

• Rickets

• Osteoporosis

• Paget’s disease

rickets

developmental deficiency of vitamin D, resulting in porous and under-mineralized bones and joints

• To compensate → Leg curvatures and wide joints, enlarged abdomen, smaller ribs

osteoporosis

• Types

lowering of bone mass and risk of fractures, increasing with age

• Type I is associated with estrogen loss in women and is responsive to hormone replacement

• Type II is natural loss of bone modeling efficiency and PTH activity with age

Paget’s disease

malformations of bone due to bone resorption, followed by disorganized and excessive reformation (i.e., because of excessive osteoclast activity, some parts of bone can end up highly mineralized and parts right next to it can be under-mineralized, which increases the risk of fractures)

• Likely a strong genetic component is involved

hormone treatments for parathyroid and calcium regulation disorders

• Vitamin D and calcium: treatment for rickets and osteoporosis

• Calcitriol: treatment for hypoparathyroidism

  • Comes in injectable/pill forms

• Calcitriol analogs (paricalcitol/Zemplar): treatment for hyperparathyroidism

  • Designed to reduce PTH activity via a negative feedback loop without affecting bone or calcium

• Calcitonin (miacalcin): short-term treatment for Paget’s to reduce remodeling, as well as some forms of osteoporosis to help stave off demineralization

  • Causes short-term hypercalcemia

  • Contains synthetic salmon calcitonin, as it’s more active than human form

• PEGylated teriparatide (Yorvipath): long-term treatment for hypoparathyroidism

  • Daily injectable PTH analog, with less need for Vitamin D and calcium supplements

bone formation treatments for calcium regulation disorders

• Bisphosphonates

• PTH analogs: Teriparatide (Forteo) and abaloparatide (Tymlos)

bisphosphonates

drug class that chelates and binds calcium in bone, and accumulates at active bone remodeling sites → gets taken up by osteoclasts during bone resorption → inhibits osteoclast function and causes apoptosis → can treat Paget’s and osteoporosis (especially postmenopausal)

• Integrates into the bone structure, so it can last for a long time

• Includes:

  • Etidronate (Didronel) = daily pill

  • Risedronate (Actonel), alendronate (Fosamax) = weekly pills

  • Ibandronate (Boniva) = monthly pill or quarterly injection

  • Zoledronic Acid (Reclast) = yearly injection

PTH analogs

can treat osteoporosis and reduced fracture in high-risk patients  

• Uses periodic-burst activation that promotes more osteoblast activity than osteoclasts (Despite it causing a short period of bone demineralization, it is followed by a period of active, aggressive remineralization)

• Typically limited to 2-year treatment before it loses its effectiveness

targeted monoclonals for bone formation

• Burosumab (Crysvita): targets and inhibits FGF23 = increased phosphate to prevent softening of bones in rare inherited hypophosphatemia and tumor-induced wasting

• Denosumab (Prolia): targets receptor activator of the NF-kB ligand RANK-L, a mediator known to cause differentiation and activation of osteoclasts in bone

  • Blocking can reduce bone loss, though only indicated if bisphosphonates fail or in bone cancers

• Romosozumab (Evenity): inhibits sclerostin (known to inhibit bone formation by reducing osteoblast activity) and regulated by PTH/calcitonin

  • Shown to reduce spinal fracture risk alone or in combination with bisphosphonates

adrenal glands

• Receive central blood flow inputs from the aorta and then outputs through the vena cava and renal vein

• Produce steroid hormones that regulate carbohydrate metabolism (glucocorticoids) and fluid/electrolyte retention (mineralocorticoids)

• Also produce precursor steroids that are building blocks for sex hormones

central regulation of the HPA axis

• What provides positive feedback on the axis? What provides negative feedback?

1. Corticotropin-releasing hormone (CRH/CRF): released from hypothalamus in diurnal fashion (peaks in early morning) to bind to CRH1 receptors in the pituitary gland

2. In the pituitary gland, CRH1 receptors (G_s) regulate the translation of proopiomelanocortin (POMC), a long peptide that is cut up to create corticotropin (adrenocorticotropic hormone; ACTH) to then be released

Note: Inflammation stimulates the production of CRH and ACTH. Cortisol provides negative feedback to the production of CRH and ACTH (via membrane and nuclear glucocorticoid receptors)

the products of POMC

• ACTH and melanocyte-stimulating hormone (MSHs) are released from the pituitary and bind to melanocortin receptors (MC1R and MC2R)

  • ACTH activates MC2R (G_s) → Synthesis and activation of steroid side-chain cleaving enzyme (CYP11A1) and cholesterol recruitment

  • ACTH is also key to maintenance and structure of adrenal glands

  • MSH and lipotropin activate MC1R → Pigmentation

What is the starting material for all steroid hormones (steroids)?

free cholesterol

• Note: Cholesterol can either come from LDL/HDL in the blood, or made by the adrenal cell itself

• A transport protein shuttles cholesterol into adrenal cells

• Once cholesterol is inside an adrenal cell, the steroidogenic acute regulatory protein (StAR) transports it from the outer mitochondrial membrane toward the inner inner mitochondrial membrane, where steroid hormone synthesis begins

types of steroid hormones

• Glucocorticoids

  • Cortisol is the main glucocorticoid in humans; corticosterone is the main glucocorticoid in rodents

• Mineralocorticoids

Because they are lipid-soluble, many steroids have to travel through the blood by attaching to binding proteins.

• What carries cortisol?

• What carries testosterone and estradiol?

• What is another protein that some steroid hormones can loosely bind to and travel with?

• Corticosteroid-binding globulin (CBG) → carries cortisol

• Sex hormone-binding globulin (SHBG) → carries testosterone and estradiol

• Some steroid hormones also travel loosely bound to albumin

glucocorticoid receptor (GR) activity

1. Cortisol is lipid-soluble, so it can cross cell membranes to bind to the nuclear receptor GRα in the cytoplasm

2. Binding causes dissociation from stabilization proteins

3. GR is activated and can either:

• Increase expression via binding glucocorticoid response elements (GREs), or 

• Suppress expression of other transcription factors (e.g., POMC promoter, NF-kB production of cytokines)

Note: Cortisol is 3x more potent at the GR than corticosterone. Progesterone is a moderate GR and MR antagonist