Testosterone

• What secretes testosterone?

• average level of testosterone in mens

• do women need testosterone

• Leydig cells (testes)

• o.6 mcg/dL

• women need testosterone for normal libido

sertoli cells

synthesize androgen-binding protein

process of testosterone production

• hypothalamus → (GnRH) → anterior pituitary → (FSH, LH) → sertoli cells (ABP) and Leydig cells (testosterone)

testosterone negative feedback loop

feedback to

• hypothalamus to decrease GnRH

• pituitary to decrease LH

• testosterone — with age (40+)

• peaks in —

• decrease

• AM

• testosterone is —bound

• binds to — receptors

• plasma bound

• androgen receptors (nuclear)

what is testosterone metabolized to?

DHT → 5x more affinity for androgen receptor → more potent

primary hypogonadism

• low testosterone w/ elevated gonadotropin (FSH, LH)

• testicular defects

  • Klinefelter syndrome (XXY)

  • Undescended testicles

  • Mumps orchitis

  • Injury

  • Chemotherapy

  • Drugs (ketoconazole, spironolactone, marijuana)

secondary hypogonadism

• low testosterone w/ low-normal gonadotropin

  • Kallman syndrome (abnormal hypothalamus development)

  • Pituitary disorders

  • Inflammatory diseases

  • Hemochromatosis (excessive iron)

  • HIV/AIDS

  • Obesity

  • Late onset hypogonadism due to normal aging (andropause)

    • Can have mixed gonadotropin levels

hypogonadism symptoms

• Pre-puberty

  • Low muscle mass

  • Lack of voice deepening

  • Impaired growth of body hair, penis, and testicle size

  • Gynecomastia

  • Eunuchoid

• Adulthood

  • Erectile dysfunction

  • Infertility

  • Low muscle mass

  • Gynecomastia

  • Osteoporosis

  • Decreased hemoglobin and hematocrit ← monitor CBC

dihydrotestosterone (DHT)

• produced from skin and prostate

• metabolized by 5a reductase

• masculination of external genitalia + growth of hair follicles

estradiol

• produced by adipose and bone

• metabolized by aromatase (CYP19)

• bone growth, libido

inactive metabolites of testosterone

• etiocholanlone

• androsterone

• produced in liver

medchem of testosterone

• ketone at carbon 3

• hydroxyl at carbon 17

testosterone limitations

rapid oral absorption but extensive 1st pass → low systemic concentrations

17a methyl derivatives

• alpha methyl group at carbon 17 position

• PO due to less susceptible to hepatic metabolism

• less 1st pass metabolism → hepatoxic

ester derivatives

• parenteral/IM admin

• high lipophilicity and long DOA

• esterification of hydroxyl group at carbon 17

  • Testosterone undecanoate (Jatenzo, TLando) — PO bypass FPM

  • Testosterone cypionate

  • Testosterone enathate

formulations

• nasal

  • quick onset and reversal, noninvasive

• topical

  • quick onset and reversal, noninvasive

  • risk of transference

• subdermal

  • good compliance

  • invasive

• IM

  • good compliance, less frequent dosing, less cost

  • invasive

• oral

  • noninvasive, good compliance

Contraindications of testosterone replacement therapy

• prostate/breast cancer

• PSA > 4 (definite) OR PSA > 3 with risk of prostate cancer

• severe LUTS (score > 19)

• erythrocytosis (HCT > 48%)

• untreated severe obstructive sleep apnea

• uncontrolled HF

• hypercoagulable state

• recent MI/stroke (past 6 months)

begin replacement therapy and monitor within — for treatment modification

1 - 3 months

diagnosis of hypogonadism

• sx + low testosterone

  • 2 total levels on different days

  • drawn AM

  • < 300 ng/dL (normal = 250 - 800)

  • fasting not needed

monitoring for replacement therapy: baseline

• Testosterone

• PSA

• CBC

• Liver, lipids, BP

monitoring for replacement therapy: 3 months

• T*

• PSA

• CBC (hematocrit)

• BP

• Symptoms of low-T

• ADEs

• Liver, lipids

monitoring for replacement therapy: 6 - 12 months once stable

• T*

• CBC (hematocrit)

• PSA*

• BP

• Symptoms of low-T

• ADEs

• Liver, lipids

discontinue replacement therapy if

• PSA

  • increase > 1.4

  • > 4 total count

  • worsening of LUTS

• hematocrit

  • Hematocrit

    • > 54%

      • Can reinitiate if it lowers back to normal levels

  • Natesto, Tlando

    • d/c if total serum testosterone consistently outside normal range

oral testosterone therapy

• testosterone undecanoate capsule

  • Kyzatrex

  • Jatenzo

  • Tlando

  • Undecatrex

Kyzatrex, Jatenzo, Undecatrex monitoring

monitor after 1 week, dose adjust

Tlando

• cannot be adjusted

• fixed dosing only

• monitor after 3 - 4 weeks

how is testosterone undecanoate capsule aborbed by?

lypmphatic system = no FPE

testosterone undecanoate capsule dosing

BID dosing

IM testosterone therapy

• 75-100 mg Qweek

• 150-200 mg Q2weeks

• 50-400 mg Q2-4 weeks

• Cypionate

  • Azmiro

    • Monitor T at the midpoint

• Enanthate

  • Monitor T at the midpoint

• Undecanoate

  • Aveed

    • Monitor T just prior to the next dose

• Generics available

IM ADEs

• Mood swings ← think puberty, teen hormones give you mood swings

• BBW for pulmonary oil microembolism (POME) ← oil from formulation could get into lungs

  • Requires monitoring for ≥ 30 minutes after injection

SQ formulation

• Enanthate

  • Xyosted → Qweek injection

    • Monitor T at trough, after 6 weeks, and 7 days after the most recent dose

  • Testopel → implant every 3-6 months (not recommended)

    • Monitor T at the end of the dosing interval

intranasal formulation

• Natesto

  • TID

• Monitor T periodically every month after starting

• ADEs

  • Nasal irritation

topical formulation

• Gel

  • AndroGel

  • Testim

  • Vogelxo

  • Generics

• Pumps or tubes

• 1-2%

• Solution

  • Applied to the armpit (axillae) ← better absorption + reduced transference 

• Recheck testosterone 2-8 hours after application in the AM after 2 

• Recheck after 4 weeks of starting therapy/changing dose

topical formulation: counseling

• Applied in the AM

• Cover the site of application

• BBW to secondary exposure (virilization)

• Avoid swimming, showering, or washing the site for 2-5 hours after application

• Prime pump before using

T or F: testosterone is CII

false → CIII

testosterone CI

• Men with breast or prostate cancer

• Pregnancy ← women use testosterone 

• For oral medication

  • Asymptomatic low testosterone

• For IM

  • Serious cardiac, hepatic, or renal disease (oils not good for that)

• For intranasal or transdermal solution

  • Avoid in breastfeeding 

testosterone BBW

• Topical

  • Secondary exposure

• Injection

  • POME

• Oral

  • Increased BP

general warnings/precautions

• Hypercalcemia, especially in cancer patients

• Depression ← mood swings

• Hepatic/renal impairment

• Sleep apnea

• Patients > 65

general ADEs

• Low sperm count ← low gonadotropins from feedback

• Increase prostate-specific antigen (PSA)

• Increase BPH and worsen LUTS

• Increased BP and worsened HF due to fluid retention

• Hyperlipidemia

• Increased LFTs

• Polycythemia (increased hematocrit) → thicker blood

• Gynecomastia

metabolic effects of testosterone

feminizing hormone therapy (for transgender women)

estrogen + androgen blocker

masculizing hormone therapy (for transgender men)

• Testosterone

  • Any testosterone product may be used

  • All are used off-label for masculinizing therapy in transgender men

  • Dosing: use initial dosing for hypogonadism, but may increase dose to further suppress female traits

monitoring for masculinizing hormone therapy

• CBC: hemoglobin and hematocrit based on the MALE reference range

• Normal physiologic testosterone range (males): 300-1100 ng/dL