9WHAT ARE THE SYMPTOMS OF LOW TESTOSTERONE? TAT SyndromeFatigueUSTA SyndromeLoss of muscle massFat gainPoor recoveryPain/InflammationIrritabilityDepressionDecreased memoryLoss of LibidoErectile Dysfunction
10ADAM 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?
11ADAM Questionnaire (con’t) 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?
15MEASURES OF TESTOSTERONE Total Testosterone—all that is produced( ng/dL)Free Testosterone—all that is unbound (2-4%)(80-300pg/dL)--Equilibrium Dialysis, NOT RIA!Bioavailable Testosterone—Gold Standard“Free and Loosely/Weakly Bound”40-60% ( ng/dL)
16“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
17T SAMPLE PREPARATION (SERUM) Refrigerated, no additive serum preferred(Plain, Red Top)Heparanized serum less acceptable(green-top)NO Serum Separator Tubes (SST)
18IMPORTANT ABOUT ESTROGEN TESTING Total 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/ TD’s (TransDermals)Be extra mindful of SHBG level
19Sample Matrixes BLOOD --most common --Total, Free, Bioavailable --”snap shot” only--limited value given TD’s, hormone conversions, etc.URINE--best of all, esp. w/ TD’s--”free” levels provided--limited assays--expanded hormone assay types, incl. metabolites--use only 24 hour collections—no spots--be careful of contamination--better to assess intracellular 5-AR activity
20Many 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.
21COMMON SENSE IN ORDER TO TEST THE LEVEL OF A DRUG, YOU MUST TAKE THE DRUG, ON SCHEDULE!!!
22COMMON SENSE HAVE PATIENT DRAW AT SAME TIME OF DAY EACH TIME, ESPECIALLY WITH TRANSDERMALS (b/c PK’s)
23COMMON SENSE 1. NEVER SMOKE IN BED 2. ALWAYS WEAR PAJAMAS
25DHT Most responsible for All Things Male 5-AR’d from T Unfairly deemed “evil hormone”NOT responsible for prostate morbidity25-75ng/dLSerum assay valid?Metabolite ratios on 24 hour urines bestAvoid finasteride
26Estradiol Major player amongst estrogens Total Estrogens is NOT valid assay for malesMUST be monitored during TRTMasks benefits of TRTAdjunctive cause of serious illnessNumerous benefits for health, so…Must not be driven too low(10-50pg/mL) maintain mid-range ( w/ mid-range SHBG)May rise over timeTD’s elevate E more than IM
27Luteinizing Hormone (LH) Produced by pituitaryStimulates T productionPulsatile productionShort half-lifeAcute phase reactantMust be careful in its interpretationPossible Gn-secreting tumor
28Follicle Stimulating Hormone (FSH) Produced by pituitarySpermatogenesisminute half-lifeInhibited largely by estrogenBetter measure of gonadotrophin output?Possible FSH-secreting tumor
29Prolactin Significant cause of hypogonadism May signal tumor presence Health benefitsMust be maintained within normal rangeRef Range ( ng/mL)>300= tumorElevated by eating, sex (<30)
31Cortisol “Stress hormone” Cause of secondary hypogonadism Healthful benefitsMust be maintained within normal rangeIf elevated: Tx’d with Phosphatidylserine (PS) (300mg po QD)If depressed: Tx’d with Hydrocortisone PO
32“Progesterone puts plaque in the arteries, and wrinkles in the penis” --Dr. John Crisler
35T/E ratio Measure of system performance --ratio does have importance, but…--absolute values of hormones are important--cannot elevate E without consequence as longas T is proportionately highUsed to explain pathophysiology--low T higher proportionate E morbidityNOT to be used as treatment goal
38TESTOSTERONE DELIVERY SYSTEMS Gels and CreamsPatchesImplantable PelletsIMOrals
39Gels and Creams Ease of application May be more convenient—OR NOT Stable across week, not day“Pulsing” [T] may be beneficialQuickly attains stable serum levelsBoosts DHTMay elevate estrogensRisk of accidental transferalBe mindful of application methodAvoid antecubital fossa—looks like AAS useEXTREMELY variable absorption…Especially with hypothyroidism
40Gels and Creams (con’t) “Big House” productsSolvay Pharmaceuticals’ AndrogelAuxilium Pharmaceuticals’ Testim--MUCH more expensive--support physician education (“The Cause”)--covered by insurance--vouchers/sample--1%--be mindful of application technique
41Gels and Creams (con’t) Compounded gels/creams--various bases--1%, 5%, 10, 20%--higher conc. < E, DHT conversion--soy, yam-based T’s--ALL T gels/creams are ”bio-identical”--creams slow absorption--can compound anti-E’s into product--MUCH less expensive--syringe applicators great--pumps coming onto market
42T GEL APPLICATION Jars with measuring spoons Plastic capped syringes Metered Dose Pumps1% apply to outer arms, shoulders, flanks5%, 10% applied to forearmsNO scrotal application!
43Testosterone Patches Convenient—MAYBE! No risk of accidental transfer Stable serum androgen levelsLittle DHT, E boostScrotal patches available (WHEW!)2/3’s--Contact Dermatitis
44Testosterone Injection Convenient—MAYBE!MUST be injected weeklyStable across day, not weekEase of dose titrationInjection risksThe “Gold Standard” NO MORE!
46OTHER 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 deliverySERM’s--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
47SERM’s (con’t) 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)
48CONTRAINDICATIONS TO TRT: Prostate CABreast CAUntreated prolactinoma
50POTENTIAL 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
54INITIAL DOSAGES Transdermal gels/creams 50mgs total QD 5mgs (delivered)Testosterone Cypionate IM:100mg QW--double dose “front load”--split weekly dose for those withanxiety issues (not initially)?
55FOLLOW-UP LABS Total T Bio T LH/FSH (especially with transdermal) FSH—to back up LH interpretation of HPTA statusSHBGEstradiolCBCComp. Metabolic PanelPSA (if over 40)
56FOLLOW UP LABS (con’t) Initial F/U at 2 weeks with TD (transdermal) --stable serum T levels quickly attained--logistical consideration of 30-day doseInitial F/U at 6 weeks with IM--takes that long to equilibrate--interpret by PK’s of T ester (48-72 hour peak)--cypionate/enanthate t1/2 5-8 daysF/U at 4-6 weeks S/P dosage change or estrogen control s/p HPTA-suppression
57FOLLOW-UP LABS (con’t) Once dose is titrated:--q 6 months or yearly--Include PSA--Perform Digital Rectal Exam (DRE)
58TIMING OF LABS FOR IMCypionate, Enanthate esters peak at 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
60TIMING OF LABS FOR TD’s Apply at same time each day Always 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
61ESTROGEN ISSUES Do not Tx until post F/U labs --E2 may actually DROP with TRT--insight into body’s responseMaintain E2 at mid-range--with mid-range SHBG
62Detriments of Elevated Estrogen Suppresses HPTAElevates SHBGImpotenceInfertilityPsychological morbiditiesVasospasmIncreases clotting factorsWater retentionProstate morbidityCancersFemale fat distributionFx on thyroid function↑ “Wimpy Factor”
66ANASTROZOLE Aromatase (“Estrogen synthase”) Inhibitor Competitive Inhibitor#1 use of this med in world: Male TRTother AI’s availableconcerns with Endocrine pathway disruption (as with finasteride)Some c/o H/A’sAI’s as sole TRT is RARE
67ANASTROZOLE DOSING 0.25mg QOD, 0.5mg Q2-3D 2 day t1/2, never >Q3D “Frontload” (double initial dose)Titrate from thereAllow 4-5 weeks prior to f/u labs
68CRISLER HCG PROTOCOL 250IU 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!
69CRISLER HCG PROTOCOL (con’t) Evens out serum androgen levels by t1/2 of cypionate esterPrevents testicular atrophyStimulates all three CHOL pathwaysAbundant boost in libido/sense of well being
70RESTORING PATHWAYS HCG --IM: start at 250IU SC Days5/6 --TD: start at 200IU SC QOD--never more than 500IUDHEA--25mg BID--100mg QD can elevate E1--oral SR>TD>standard oral preparationPregnenolone--50mg TD QD in a cream
72Rescue from “Nipple Issues” Burning, itching, swelling, FREAKINGOccurs with mere changes in hormone levels, even within physiological range, so…DO NOT treat in first month (get F/U labs)40mg QD tamoxifen until gone, then taper--cut dose ½ Q5DPrefer tamoxifen over clomipheneCannot assay estrogens on SERM-class drugs!Hold GhRT (magnifies E fx)Gyno may be caused by progesterones
73NO TRT “CYCLING” Historically “borrowed” from AAS use. No evidence of benefitDoes not do what is claimedLeaves substantial periods of letdownThe body thrives on regularity
74WHAT IS THE FUTURE OF TRT? Elevating T to healthy, happy levelsEstrogen metabolismActions at the androgen, estrogen receptorsRestoring endocrine pathways
75THE 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