TESTOSTERONE REPLACEMENT THERAPY-A RECIPE FOR SUCCESS-

--John Crisler, DO Lansing, MI USA MSU-COM www.AllThingsMale.com

Everything You Always Wanted to Know About TRT But Didnt Have Time to Ask

WHAT IS TESTOSTERONE REPLACEMENT THERAPY?

TRT: Restoration of Testosterone to HEALTHY physiological levels.

TRT is NOT:Total T>normal rangeSteroidsViagra

SCREENING FOR HYPOGONADISM

WHAT ARE THE SYMPTOMS OF LOW TESTOSTERONE?TAT SyndromeFatigueUSTA SyndromeLoss of muscle massFat gainPoor recoveryPain/InflammationIrritabilityDepressionDecreased memoryLoss of LibidoErectile Dysfunction

ADAM Questionnaire 1. Do you have a decrease in sex drive? 2. Do you have a lack of energy? 3. Do you have a decrease in strength and/or endurance? 4. Have you lost height? 5. Have you noticed a decreased enjoyment of life?

ADAM Questionnaire (cont)6.Are you sad and/or grumpy? 7.Are your erections less strong? 8.Has it been more difficult to maintain your erection throughout sexual intercourse? 9.Are you falling asleep after dinner? 10. Has your work performance deteriorated recently?

INITIAL LAB WORK

INITIAL HYPOGONADISM PANELTotal TestosteroneBioavailable/Free TSHBGDHT (?)LH/FSHDHEA-SEstradiolTotal Estrogens (urine)Prolactin

CortisolThyroid Panel (TSH, FT4, FT3)Comp Metabolic PanelCBCLipid PanelPSA (if over 40)Progesterone

MEASURES OF TESTOSTERONETotal Testosteroneall that is produced (300-1000ng/dL)

Free Testosteroneall that is unbound (2-4%) (80-300pg/dL) --Equilibrium Dialysis, NOT RIA!

Bioavailable TestosteroneGold Standard Free and Loosely/Weakly Bound 40-60% (120-600ng/dL)

Laboratory reference values for testosterone vary widely, and are established without clinical considerations. Lazarou S, et al. Harvard Medical School, Division of Urology, Beth Israel Deaconess Medical Center

T SAMPLE PREPARATION(SERUM)Refrigerated, no additive serum preferred (Plain, Red Top)

Heparanized serum less acceptable (green-top)

NO Serum Separator Tubes (SST)

IMPORTANT ABOUT ESTROGEN TESTINGTotal Estrogens is NOT a valid assay for adult males --cross reactivity w/ progesteroneEstradiol MUST be by ultrasensitive method, LC/MS assay--ALL OTHERS NOT VALIDGold standard is 24 hour urine, esp w/ TDs (TransDermals)Be extra mindful of SHBG level

Sample MatrixesBLOOD --most common --Total, Free, Bioavailable --snap shot only --limited value given TDs, hormone conversions, etc. URINE --best of all, esp. w/ TDs --free levels provided --limited assays --expanded hormone assay types, incl. metabolites --use only 24 hour collectionsno spots --be careful of contamination --better to assess intracellular 5-AR activity

Many times T on bloods (especially for morning draw) will be well within normal range. But when you collect a 24 hour urine, T will be deficient. Thus a spurt of T in the morning, then very little the rest of the day.

COMMON SENSE

IN ORDER TO TEST THE LEVEL OF A DRUG, YOU MUST TAKE THE DRUG, ON SCHEDULE!!!

COMMON SENSE

HAVE PATIENT DRAW AT SAME TIME OF DAY EACH TIME, ESPECIALLY WITH TRANSDERMALS (b/c PKs)

COMMON SENSE

1. NEVER SMOKE IN BED 2. ALWAYS WEAR PAJAMAS

DHTMost responsible for All Things Male5-ARd from TUnfairly deemed evil hormoneNOT responsible for prostate morbidity25-75ng/dLSerum assay valid?Metabolite ratios on 24 hour urines bestAvoid finasteride

EstradiolMajor player amongst estrogensTotal Estrogens is NOT valid assay for malesMUST be monitored during TRTMasks benefits of TRTAdjunctive cause of serious illnessNumerous benefits for health, soMust not be driven too low(10-50pg/mL) maintain mid-range ( w/ mid-range SHBG)May rise over timeTDs elevate E more than IM

Luteinizing Hormone (LH)

Produced by pituitaryStimulates T productionPulsatile productionShort half-lifeAcute phase reactantMust be careful in its interpretationPossible Gn-secreting tumor

Follicle Stimulating Hormone (FSH)

Produced by pituitarySpermatogenesis180-240 minute half-lifeInhibited largely by estrogenBetter measure of gonadotrophin output?Possible FSH-secreting tumor

ProlactinSignificant cause of hypogonadismMay signal tumor presenceHealth benefitsMust be maintained within normal rangeRef Range (3.0-18.0 ng/mL)>300= tumorElevated by eating, sex (

HYPERPROLACTINEMIACAUSESPituitary tumorStalk compressionPrimary hypothyroidismChronic renal failureCirrhosisOpiatesTri-cyclicsD2 antagonistsMetoclopramideVerapamilChest wall trauma

CortisolStress hormoneCause of secondary hypogonadismHealthful benefitsMust be maintained within normal rangeIf elevated: Txd with Phosphatidylserine (PS) (300mg po QD)If depressed: Txd with Hydrocortisone PO

Progesterone puts plaque in the arteries, and wrinkles in the penis --Dr. John Crisler

T/E ratioMeasure of system performance --ratio does have importance, but --absolute values of hormones are important --cannot elevate E without consequence as long as T is proportionately high

Used to explain pathophysiology --low T higher proportionate E morbidity NOT to be used as treatment goal

LABS (cont)Thyroid Panel (TSH, FT4, FT3)

CBC ( anemia mimics T )

Comprehensive Metabolic Panel

Lipid Profile

PSA (if over 40)

TESTOSTERONE DELIVERY SYSTEMSGels and Creams

Patches

Implantable Pellets

IM

Orals

Gels and CreamsEase of applicationMay be more convenientOR NOTStable across week, not dayPulsing [T] may be beneficialQuickly attains stable serum levelsBoosts DHTMay elevate estrogensRisk of accidental transferalBe mindful of application methodAvoid antecubital fossalooks like AAS useEXTREMELY variable absorptionEspecially with hypothyroidism

Gels and Creams (cont)Big House products Solvay Pharmaceuticals Androgel Auxilium Pharmaceuticals Testim --MUCH more expensive --support physician education (The Cause) --covered by insurance --vouchers/sample --1% --be mindful of application technique

Gels and Creams (cont)Compounded gels/creams --various bases --1%, 5%, 10, 20% --higher conc. < E, DHT conversion --soy, yam-based Ts --ALL T gels/creams are bio-identical --creams slow absorption --can compound anti-Es into product --MUCH less expensive --syringe applicators great --pumps coming onto market

T GEL APPLICATIONJars with measuring spoonsPlastic capped syringes Metered Dose Pumps1% apply to outer arms, shoulders, flanks5%, 10% applied to forearmsNO scrotal application!

Testosterone PatchesConvenientMAYBE!No risk of accidental transferStable serum androgen levelsLittle DHT, E boostScrotal patches available (WHEW!)2/3s--Contact Dermatitis

Testosterone InjectionConvenientMAYBE!MUST be injected weeklyStable across day, not weekEase of dose titrationInjection risksThe Gold Standard NO MORE!

NEEDLE SIZESGlutes: 22ga 1 Thighs: 25ga 1

OTHER MEDICATIONS:HCG --LH analog --traditional treatment-of-choice for 2nd low T --not just fertility drug --best use is adjunctive to TRT --does not produce subjective benefits of T deliverySERMs --elevates T, but --does not bring subjective benefits of TRT --for testing, purposes of HPTA intactness --HPTA recovery PCT (AAS Post Cycle Therapy) --rescue Tx for gynocomastia (Tamoxifen) --possible issues with respect to brain function

SERMs (cont)Clomiphene --racemic mixture (antagonist AND agonist) --enclomiphene+zuclomiphene --may bring untoward visual effects --may bring untoward emotional effectsTamoxifen --pure estrogen antagonism --great for nipple issues -- progesterone receptor [conc]Raloxifen --great estrogen antagonism --MUCH more expensiveOthers (more to come)

CONTRAINDICATIONS TO TRT:Prostate CABreast CAUntreated prolactinoma

RELATIVE CONTRAINDICATIONS:PSA >4.0 or accel>0.75H/H> 18/55Sleep ApneaCardiac, Hepatic, Renal Dz

POTENTIAL RISKS (listed)Increased risk of bladder outlet symptoms due to increase in prostate volumeEdema in patients with preexisting cardiac, renal, or hepatic diseaseGynecomastiaErythrocytosis (monitor H/H)Precipitation or worsening of sleep apneaAcneDecreased sperm productionStimulation of growth in previously undiagnosed prostate cancer

DRUG INTERACTIONS:Diabetic MedicationsPropranololOxyphenbutazone

The Meat and Potatoes of TRT

INITIAL DOSAGESTransdermal gels/creams 50mgs total QD 5mgs (delivered)

Testosterone Cypionate IM: 100mg QW --double dose front load --split weekly dose for those with anxiety issues (not initially)?

FOLLOW-UP LABSTotal TBio TLH/FSH (especially with transdermal)FSHto back up LH interpretation of HPTA statusSHBGEstradiol CBCComp. Metabolic PanelPSA (if over 40)

FOLLOW UP LABS (cont)Initial F/U at 2 weeks with TD (transdermal) --stable serum T levels quickly attained --logistical consideration of 30-day dose

Initial F/U at 6 weeks with IM --takes that long to equilibrate --interpret by PKs of T ester (48-72 hour peak) --cypionate/enanthate t1/2 5-8 days

F/U at 4-6 weeks S/P dosage change or estrogen control s/p HPTA-suppression

FOLLOW-UP LABS (cont)Once dose is titrated: --q 6 months or yearly --Include PSA --Perform Digital Rectal Exam (DRE)

TIMING OF LABS FOR IMCypionate, Enanthate esters peak at 48-72 hours s/p IM injectionDecline thereafterT1/2=5-8 daysNo lab draw on injection day --no urines first three daysUse these facts to interpret labs

TIMING OF LABS FOR TDsApply at same time each dayAlways ask pt. when they apply (lifestyle)Split dose?Consider TD carrier!Allow at least 2 hours prior to draw2-4 hours is best with T gelsAbove no consequence with 24 hour urinesAbsorption is slowed, lost with T creams

ESTROGEN ISSUESDo not Tx until post F/U labs --E2 may actually DROP with TRT --insight into bodys response

Maintain E2 at mid-range --with mid-range SHBG

Detriments of Elevated EstrogenSuppresses HPTAElevates SHBGImpotenceInfertilityPsychological morbiditiesVasospasmIncreases clotting factorsWater retentionProstate morbidityCancersFemale fat distributionFx on thyroid function Wimpy Factor

ESTROGEN ELEVATORSAgeObesityETOH over-consumption (incl HOPS in beer!)Liver DzZinc deficiency (50mg Zn/2mg Cu QD)Vitamin C deficiencyExcessive DHEA supplementation (100mg QD)Androstenedione supplementationXenoestrogens (incl Vinyl IV bags!) --Lavender, Tea Tree OilLiver Detoxification issuesSoyFlax seedFoods

ANASTROZOLEAromatase (Estrogen synthase) InhibitorCompetitive Inhibitor#1 use of this med in world: Male TRTother AIs availableconcerns with Endocrine pathway disruption (as with finasteride)Some c/o H/AsAIs as sole TRT is RARE

ANASTROZOLE DOSING0.25mg QOD, 0.5mg Q2-3D2 day t1/2, never >Q3DFrontload (double initial dose)Titrate from thereAllow 4-5 weeks prior to f/u labs

CRISLER HCG PROTOCOL250IU twice per week SC (starting dose)NEVER more than 500IU QD (or elevates estrogens, progesterone)Transdermal T patients: --every third dayTest cyp IM patients: --T-2/T-1 prior to IM injection --Fri/Sat c/ Sun IM is nice!

CRISLER HCG PROTOCOL (cont)Evens out serum androgen levels by t1/2 of cypionate esterPrevents testicular atrophyStimulates all three CHOL pathwaysAbundant boost in libido/sense of well being

RESTORING PATHWAYSHCG --IM: start at 250IU SC Days5/6 --TD: start at 200IU SC QOD --never more than 500IU DHEA --25mg BID --100mg QD can elevate E1 --oral SR>TD>standard oral preparationPregnenolone --50mg TD QD in a cream

Rescue from Nipple Issues

Burning, itching, swelling, FREAKINGOccurs with mere changes in hormone levels, even within physiological range, soDO NOT treat in first month (get F/U labs)40mg QD tamoxifen until gone, then taper --cut dose Q5DPrefer tamoxifen over clomipheneCannot assay estrogens on SERM-class drugs!Hold GhRT (magnifies E fx)Gyno may be caused by progesterones

NO TRT CYCLINGHistorically borrowed from AAS use.No evidence of benefitDoes not do what is claimedLeaves substantial periods of letdownThe body thrives on regularity

WHAT IS THE FUTURE OF TRT?Elevating T to healthy, happy levelsEstrogen metabolismActions at the androgen, estrogen receptorsRestoring endocrine pathways

THE GOAL? The ultimate goal of TRT medicine is to optimize health and happiness in our patients, which means producing an environment where we have elevated testosterone to sufficient levels, with the body responding as if it is unaware of the exogenous manipulations.

--John Crisler, DO