Endo Exam 1: Sharm ED + TESTOSTERONE

Normal penile erection is regulated by 3 components:

1. Psychogenic & Neural → _____, _____

2. Vascular → _____

3. Hormonal → _____ (will cover next week)

DA, ACh, NO, Testosterone

Psychogenic & Neural Component

• Visual, Olfactory, Imaginative inputs to preoptic area of _____

  • Visual, Tactile

    • Primary erectogenic NT in hypothalamus is _____ → Erectogenic efferent parasympathetic nerves (S2-2S4) to penile tissue to release _____

  • Olfactory, Imaginative

    • Inhibitory effects are mediated through _____ receptors → Inhibitory efferent sympathetic nerves (T1-L2) to penile tissue to release _____

• Tactile stimuli to penile tissue or some other inputs can also cause erection through spinal pathways

hypothalamus, DA, ACh, alpha-2, NE

Vascular Component

• Penile tissue consists of sinusoid (blood capillaries) rich structures:

  • _____ corpora cavernosa

  • _____ corpora spongiosum

• Neuronal stimulation releases _____ which in turn releases _____ which causes smooth muscle relaxation of walls of sinusoids which fills them with blood to cause erection

• In flaccid penis: Arterial inflow and venous outflow _____ out

• In erect penis: Arterial inflow and rigidity drastically _____ venous outflow

• ACH & NO-mediated vasodilatation: Role in penile erection

  • Under endothelial cells is _____ muscle

  • Activation of muscarinic receptors by ACh on the endothelial cells causes release of NO

  • _____ stimulates GC which converts GTP → _____

  • _____ causes dephosphorylation of myosin filaments thus relaxing the smooth muscles of blood vessels which results in vasodilatation

  • The enzyme phosphodiesterase breaks down cGMP → _____ form GMP

2, 1, ACh, NO, balances, decreases, smooth, NO, cGMP, cGMP, inactive

Hormonal Component

• Normal Levels of Testosterone

  • For normal development + growth of penile tissue

  • Maintenance of _____

libido

Pathophysiology of ED (Causes)

• Psychogenic Causes: No identifiable physical cause

• Organic (80% cases)

• Drug-Induced

  • Drugs that can affect NEURAL & PSYCHOGENIC components

    • _____

    • _____

    • _____ (_____)

    • _____

    • _____

  • Drugs that can affect the VASCULAR component

    • _____

    • _____

  • Drugs that can affect the HORMONAL component

    • _____

    • _____

    • _____

SNRIs, MAOis, Antipsychotics, D2 Blockers, TCAs, Diphenhydramine, Diuretics, BBs, Spironolactone, Ketoconazole, Testosterone Synthesis

PDE5 Inhibitors for ED MOA

• 1. Sildenafil (_____)

• 2. Vardenafil (_____ oral or _____ SL tablet)

• 3. Tadalafil (_____)

• 4. Avanafil (_____)

• _____ of enzyme PDE is expressed in penile tissue

• PDE5 metabolizes cGMP to inactive GMP

• PDE5 inhibitors inhibit _____ to its _____ form → _____ cGMP actions (_____ + penile _____)

Viagra, Levitra, Staxyn, Cialis, Stendra, Isoform 5, cGMP metabolism, inactive, prolonging, vasodilation, erection

Alprostadil MOA: Causes activation of _____ receptors which activates _____ and increases _____ results in penile vasodilatation & penile erection

prostaglandin, AC, cAMP

ED Management

• PDE5 Inhibitors

  • _____ has the longest half life and its effect can last for days (called a weekend pill for that reason) → 17.5 t1/2

Tadalafil

• PDE5 inhibition in peripheral vascular tissue and vasodilation-based SEs:

  • _____, Facial _____, Nasal _____, Hypotension, _____ → vision loss

• PDE_____ in rods + cones: _____ (blue tinge in the vision)

• PDE_____ in striated muscles

• Alprostadil → Increases _____ → _____ smooth muscles

Headache, flushing, congestion, NAION, 6, Cyanopisa, 11, cGMP, relaxes

Regulation of Testosterone Secretion

• _____ releases GnRH in pulses

• GnRH acts on the anterior _____ gonadotrophs to cause _____ & _____ release

• FSH causes _____ in the seminiferous tubules to synthesize & release _____-binding protein (ABP) and help in sperm maturation 

• LH stimulates _____ (interstitial) cells to synthesize and release _____

Hypothalamus, pituitary, LH, FSH, Sertoli cells, Androgen, Leydig, testosterone

Testosterone Negative Feedback

• Binding of testosterone to ABP maintains local high concentration of testosterone for spermatogenesis

• Testis contains _____ concentration of testosterone compared to the circulating concentrations in plasma

• Circulating levels of testosterone exert negative feedback effect on hypothalamus to decrease GnRH and on pituitary gonadotrophs to decrease LH

• When _____ amounts of therapeutic testosterone are administered, it suppresses _____ and _____. Low LH levels in turn impair _____ by decreasing testosterone levels in testis

100x higher, high, GnRH, LH, spermatogenesis

Testosterone Physiological Effects

• At Puberty  

  • Increase Levels of Testosterone → increases testicle SIZE, axillary, facial, and pubic HAIR, 

  • Higher concentration enters circulation →  musculoskeletal GROWTH (increased height + muscle mass and decrease in fat), DEEPENING of voice, stimulates RBC synthesis (hemoglobin and hematocrit)

• During adulthood → Maintenance of spermatogenesis, LIBIDO, RBC synthesis, male pattern BALDNESS, prostate hyperplasia

• During Aging (Senescence) → BIG DECREASE in testosterone, Low testosterone causes decreased energy, muscle mass, libido, and bone density 

KNOW

Testosterone Metabolism (KNOW!!!)

• 1) To a more potent derivative dihydrotestosterone (DHT) by enzyme 5-alpha-reductase in skin, prostate gland, hair follicles, and some other tissues

• 2) To _____ in bone and adipose tissue by enzyme aromatase (CYP19)

• 3) To inactive metabolites androsterone and etiocholanolone in liver

• Active Metabolites → _____ (skin, prostate, other tissues) and _____ (Adipose, Bone)

• Inactive Metabolites → _____ (Liver) and Etiocholanolone

• Testosterone → 5-alpha reductase → _____ → _____ Genitalia, _____ Follicles, and _____

• Testosterone → Androgen Receptor → _____ Genitalia (_____), _____ Muscle, and Marrow Erythropoiesis

• Testosterone → CYP19 (aromatase) → _____ → _____ Receptor → _____ and _____

Estradiol, DHT, Estradiol, Androsterone, DHT, External, Hair, Acne, Internal, testes, Skeletal, Estradiol, Estrogen, Bone, Libido

Androgen Receptors

• Receptors for testosterone → Androgen receptors. They belong to nuclear receptor superfamily of receptors

• The androgen receptors are present in cytosols of testosterone responsive cells and are bound to a repressor _____ (HSP)

• _____ has approximately _____ greater affinity for the androgen receptors than testosterone which makes DHT more potent androgenic steroid at physiologic concentrations

heat shock protein, DHT, 5x

Male Hypogonadism: Etiology

• Primary (Defect in _____)

  • Klinefelter syndrome

  • Injury to the _____

  • _____ or _____ therapy

  • Drugs (_____, _____)

testes, testicles, chemotherapy, radiation, Ketoconazole, Spironolactone

Male Hypogonadism: Etiology

• Secondary hypogonadism

  • Kallmann syndrome (Abnormal development of the hypothalamus)

  • _____ disorders

  • _____ disease (sarcoidosis, histiocytosis and TB)

  • Hemochromatosis (Excessive _____) and pituitary lesions

  • _____

  • _____

  • _____ due to _____ (_____) KNOW!!!

Pituitary, Inflammatory, iron, HIV/AIDS, Obesity, Late-Onset hypogonadism, normal aging, Andropause

Hypogonadism: S/Sxs

• Before Puberty

  • Lack of _____

  • Impaired growth of _____

  • Impaired growth of the penis and _____

  • Eunuchoid

• In Adulthood

  • ED

  • Infertility

  • _____ in muscle mass

  • Gynecomastia

  • Osteoporosis

  • _____ hemoglobin and hematocrit

deep voice, body hair, testicles, decrease, decreased

Testosterone Derivatives

• 1. _____ derivatives: For oral administration

• 2. _____ derivatives: For Parenteral IM administration

17-alpha methyl, Ester

17α-methyl testosterone derivatives are _____

Hepatotoxic

Ester Derivatives

• Testosterone → VERY lipophilic

  • A. _____

  • B. _____

  • C. _____

Undecanoate, Cypionate, Enanthate

The formulations for the following routes contain testosterone (except oral and IM)

• ORAL: Testosterone _____

• Nasal: _____

• Subdermal: _____

• Topical: _____, _____

• Formulations are oily injections containing testosterone ESTERS

  • _____

Undecanoate, Spray pump, Pellets, Gel, Solution, IM

Testosterone Formulations

• _____

  • Formulation: Gel spray pump (Natesto) 

  • Advantages: Quick onset of action and reversal, Noninvasive Lack of transference

  • Limitations: N/A

Nasal

Testosterone Formulations

• Subdermal

  • Formulation: _____

  • Advantages: Good compliance, Lack of transference

  • Limitations: _____, _____ if needed

Pellets, Invasive, No easy w/d

Testosterone Formulations

• _____

  • Formulation: Testosterone undecanoate; Cypionate (cotton seed oil allergy); enanthate injection

  • Advantages: Good compliance, Lack of transference, Less frequent dosing, Less cost

  • Limitations: _____, _____

IM, Invasive, no easy w/d

Testosterone Formulations

• _____

  • Formulation: Testosterone undecanoate

  • Advantages: Noninvasive, Good compliance

  • Limitations: N/A

Oral