Managing the Young Hypogonadal Male

Paul J. Turek MD, FACS, FRSMPaul J. Turek MD, FACS, FRSMDirector, The Turek ClinicDirector, The Turek Clinic

San Francisco, CASan Francisco, CA

Managing Managing thethe Young Young Hypogonadal Male Hypogonadal Male

At the conclusion of this presentation, participants At the conclusion of this presentation, participants should be able to:should be able to:

Learning ObjectivesLearning Objectives

•Describe the “saturation point” concept of T effects Describe the “saturation point” concept of T effects on the body.on the body.•Delineate two ways of providing T replacement that Delineate two ways of providing T replacement that also maintain fertility.also maintain fertility.•Provide a differential diagnosis of at least 5 Provide a differential diagnosis of at least 5

conditions besides hypogonadism that conditions besides hypogonadism that result in low libdio or erectile dysfunction.result in low libdio or erectile dysfunction.

DisclosuresDisclosures

•NIHNIH•Doximity.comDoximity.com•Fertility Planit.comFertility Planit.com•Healthloop.comHealthloop.com•BioQuiddity, IncBioQuiddity, Inc•MandalMed, IncMandalMed, Inc

Case #1Case #1

30 yo engaged man with azoospermia. Arrives in office 30 yo engaged man with azoospermia. Arrives in office alone. Admits to recent history of anabolic steroids (4 alone. Admits to recent history of anabolic steroids (4 cycles/year for past 3 years) but stopped 6 mos ago.cycles/year for past 3 years) but stopped 6 mos ago.

Labs: Labs: Testosterone 1050 ng/mLTestosterone 1050 ng/mLLH LH 0.7 IU/mL0.7 IU/mLFSH FSH 0.9 mIU/mL0.9 mIU/mLProlactin 9 ng/mLProlactin 9 ng/mL

Case #1 contCase #1 cont

Asked what he is taking now. Asked what he is taking now. Admits to taking 6 pumps of testosterone gel daily. Admits to taking 6 pumps of testosterone gel daily.

““I’m scared to stop the juice….really need your help.”I’m scared to stop the juice….really need your help.”

Anabolic Steroids: AbuseAnabolic Steroids: Abuse

College SportsCollege Sports

NCAA drugs tests, NCAA drugs tests, 2002-4: 2002-4: 182/283 182/283 (64%(64%) were positive ) were positive for steroids.for steroids.

Pro Sports “rampantPro Sports “rampant””

Testing in baseball began in 2003 Testing in baseball began in 2003 with with >5%>5% of athletes testing positive. of athletes testing positive.This year: 5 in majors and 50 in minors This year: 5 in majors and 50 in minors suspendedsuspended

#756#756

Anabolic Steroids: HypogonadismAnabolic Steroids: HypogonadismHypogonadotrophic hypogonadismHypogonadotrophic hypogonadism

++

++++

--

--AnteriorAnterior PituitaryPituitary

Sertoli CellsSertoli Cells

Leydig CellsLeydig Cells

FSHFSHFSHFSH

LHLH

TTTT

TT

TT

GGRRHH

TT

Anabolic Steroids: Reversibility in TestisAnabolic Steroids: Reversibility in Testis

Turek et al. J. Urol. 1995, 153, 1628 Turek et al. J. Urol. 1995, 153, 1628

•Effects on native testosterone and sperm production Effects on native testosterone and sperm production thought to be reversible.thought to be reversible.

•But may not be…But may not be…

Anabolics: Testis Recovery and Restoration Anabolics: Testis Recovery and Restoration

1.1. Spontaneous recoverySpontaneous recovery2.2. SERM treatmentSERM treatment3.3. Gonadotropin treatment (hCG, FSH)Gonadotropin treatment (hCG, FSH)4.4. Aromatase inhibitorsAromatase inhibitors

Anabolics: Spontaneous Recovery Anabolics: Spontaneous Recovery

StopStopHormonal Hormonal

ContraceptiveContraceptive

3 mill/mL3 mill/mL@ 2.5 mos@ 2.5 mos

10 mill/mL10 mill/mL@ 3 mos @ 3 mos

20 mill/mL20 mill/mL@ 3.4 mos@ 3.4 mos00

11

44

•Analysis of Analysis of 15491549 eugonadal eugonadal men men age age 18-5118-51 years years (90% of (90% of published data)published data)

•Followed after discontinuation of androgen or androgen-Followed after discontinuation of androgen or androgen-progestagen contraceptivesprogestagen contraceptives

•Variables: older age, Asian, shorter treatment duration, Variables: older age, Asian, shorter treatment duration, higher baseline counts, less time to suppression, higher baseline counts, less time to suppression, lower lower baseline LHbaseline LH

67% @ 6 mos67% @ 6 mos90% @ 12 mos90% @ 12 mos100%@ 24 mos100%@ 24 mos

Liu et al. Lancet. 2006, 367: 1412Liu et al. Lancet. 2006, 367: 1412

Anabolics: Recovery Anabolics: Recovery of of Spermatogenesis Spermatogenesis withwith SERMS SERMS

StopStophormoneshormones

00

11 4 mos4 mos

•Initial hypogonadotrophic hypogonadism may be Initial hypogonadotrophic hypogonadism may be intolerableintolerable•Consider adding Consider adding clomiphene citrate clomiphene citrate or or tamoxifentamoxifen to to stimulate earlier return of anterior pituitary functionstimulate earlier return of anterior pituitary function•May bring sperm production back faster than May bring sperm production back faster than spontaneous recoveryspontaneous recovery

3322Doldrums!!Doldrums!!

Moskovic et al. BJU Int. 2012. Epub March 28Moskovic et al. BJU Int. 2012. Epub March 28

Clomiphene CitrateClomiphene Citrate ClomipheneClomiphene Citrate Citrate

Leydig CellsLeydig Cells

GnRHGnRHGnRHGnRH

LHLHLHLH

TTTTTTTT

FSHFSHFSHFSH

EE22EE22Nonsteroidal hormoneNonsteroidal hormoneAn anti-estrogen (SERM)An anti-estrogen (SERM)Increases GnRH outputIncreases GnRH output

RRxx12.5-25 mg/day12.5-25 mg/dayCheck FSH, T in 4 weeksCheck FSH, T in 4 weeksMonitor semen q 3 mosMonitor semen q 3 mos

Side Effects: gynecomastia,Side Effects: gynecomastia, weight gain, visuals, acneweight gain, visuals, acne

Anabolics: Recovery Anabolics: Recovery ofof Spermatogenesis Spermatogenesis withwith SERMS SERMS

Taper off Taper off anabolicsanabolics

00 11 4 mos4 mos

•Goal: drive native testosterone production while tapering Goal: drive native testosterone production while tapering off anabolicsoff anabolics

•Goal: earlier return of endogenous T levels and sperm Goal: earlier return of endogenous T levels and sperm production (unproven)production (unproven)


3322

Clomipene citrate 50mg qdClomipene citrate 50mg qdTamoxifen 10-20mg qdTamoxifen 10-20mg qd

Reduce SERM Reduce SERM by 50%by 50%

Stop SERM Stop SERM

GonadotropinsGonadotropinsGonadotropinsGonadotropins(hCG, hMG, Recombinant FSH)(hCG, hMG, Recombinant FSH)

RRxx

hCG, 1,500-3,000 IU S.Q. 3x weeklyhCG, 1,500-3,000 IU S.Q. 3x weekly hMG 75-150 IU S.Q 2x weeklyhMG 75-150 IU S.Q 2x weeklyrFSH 150 IU SQ 3x weeklyrFSH 150 IU SQ 3x weekly

Check serum testosterone levels after 4 weeksCheck serum testosterone levels after 4 weeksFollow semen analyses q 3 months.Follow semen analyses q 3 months.

Efficacy: Efficacy: No controlled trials.No controlled trials.

Side Effects: expensive, compliance, cellulitis.Side Effects: expensive, compliance, cellulitis.

Give LH and FSH formulations to drive testicle. Give LH and FSH formulations to drive testicle.

Anabolics: Recovery Anabolics: Recovery of of Spermatogenesis Spermatogenesis withwith GonadotrophinsGonadotrophins

Taper off Taper off anabolicsanabolics

00 11 4 mos4 mos

•Goal: drive native testosterone production while tapering Goal: drive native testosterone production while tapering off anabolicsoff anabolics

•Goal: earlier return of endogenous T levels and sperm Goal: earlier return of endogenous T levels and sperm production (unproven)production (unproven)

3322

hCG 2500 IU 3x weeklyhCG 2500 IU 3x weekly+/- rFSH 150 IU 3x weekly +/- rFSH 150 IU 3x weekly

Reduce GtropesReduce Gtropesby 50%by 50%

Stop GtropesStop Gtropes

Menon DK. Fertil Steril. 2003, 79: suppl 3, 1659 Menon DK. Fertil Steril. 2003, 79: suppl 3, 1659

Karila et al. Int J Sports Med. 2004, 25: 257 Karila et al. Int J Sports Med. 2004, 25: 257

Anabolics Anabolics andand hCG Preserve Sperm Counts hCG Preserve Sperm Counts

AnabolicsAnabolics

00 11 22hCG 500IU 2x weeklyhCG 500IU 2x weekly

•N=18 Finnish power athletes on “massive anabolic doses”N=18 Finnish power athletes on “massive anabolic doses”•Instructed to also take hCG 500 IU 2x weekly with anabolicsInstructed to also take hCG 500 IU 2x weekly with anabolics•Followed semen quality over time on combination therapyFollowed semen quality over time on combination therapy•Spermatogenesis maintained despite prolonged, massive

doses of anabolics

Cycle endsCycle ends

33 mill/mL33 mill/mL1/18 azoospermic1/18 azoospermic

30 mill/[email protected] mos30 mill/[email protected] mos70 mill/mL@ 6 mos70 mill/mL@ 6 mos

Case #2Case #230 yo single man with recent low libido and erectile 30 yo single man with recent low libido and erectile dysfunction. “I never see morning wood anymore.”dysfunction. “I never see morning wood anymore.”

•Recently broke up with girlfriend after 6 years.Recently broke up with girlfriend after 6 years.•Lost half of his personal wealth in Facebook IPO. Lost half of his personal wealth in Facebook IPO.

Labs: Labs: Testosterone 175 ng/mLTestosterone 175 ng/mLLH LH 1.7 IU/mL1.7 IU/mLFSH FSH 1.9 mIU/mL1.9 mIU/mLProlactin 10 ng/mLProlactin 10 ng/mLIron studies, HgbA1c normal Iron studies, HgbA1c normal

Evaluating LibidoEvaluating Libido

Turek, GoogleHealth LectureTurek, GoogleHealth Lecture

ObesityObesity

StressStressMedicationsMedications

AlcoholAlcohol&&

DrugsDrugs

DiabetesDiabetes

CholesterolCholesterol

ProlactinProlactin

SurgerySurgery

InjuryInjury

Organ Organ FailureFailure

Low Low TestosteroneTestosterone

High BloodHigh BloodPressurePressure

SleepSleep

Turek, GoogleHealth LectureTurek, GoogleHealth Lecture

Copyright ©2006 American Physiological SocietyCopyright ©2006 American Physiological Society

Mean LH level over 12 hrsMean LH level over 12 hrs

•N=10 male soldiersN=10 male soldiers [mean 22 yr] [mean 22 yr] •Blood drawn every 20 min overnight: Blood drawn every 20 min overnight:

After a “control” week After a “control” week After 84 hrs of military “operational”After 84 hrs of military “operational” stressstress

Effect of Extreme Physical Stress on LH and TEffect of Extreme Physical Stress on LH and T

Results: Results: 46%46% increase in LH levels with stress (but with increased burst interval) increase in LH levels with stress (but with increased burst interval)24%24% lower T and lower T and 30%30% lower free T levels with stress lower free T levels with stressSuggests decreased testis sensitivity to LH with stressSuggests decreased testis sensitivity to LH with stress

PhysicalPhysical: Continuous combat : Continuous combat drills, marchesdrills, marchesSleep:Sleep: 2 x 1 hrs/day 2 x 1 hrs/dayCaloric:Caloric: 1 meal, 1 snack/day 1 meal, 1 snack/day

Libido and StressLibido and Stress

• What’s a man to do?What’s a man to do?• Encourage Encourage “rest and restore” “rest and restore”

nervous system with: nervous system with: - Regular exerciseRegular exercise- MassageMassage- AcupunctureAcupuncture- YogaYoga

Simple RxSimple Rxforfor Stress Stress

Recovery Recovery ofof Testosterone Testosterone withwith SERMS SERMS

00 11 4 mos4 mos

•Goal: support testosterone production during stressGoal: support testosterone production during stress•Goal: taper off SERM as stress fallsGoal: taper off SERM as stress falls•Reasonable to consider for mild hypogonadotrophic Reasonable to consider for mild hypogonadotrophic hypogonadism and sexual symptomshypogonadism and sexual symptoms


3322

Clomipene citrate 25mg qdClomipene citrate 25mg qdTamoxifen 10mg qdTamoxifen 10mg qd

Reduce SERM Reduce SERM by 50%by 50%

Stop SERM Stop SERM


•N=86 men with T < 300 ng/mL from 2002-2006 N=86 men with T < 300 ng/mL from 2002-2006 •Given CC 25mg qod. Titrated dose to T 500-600Given CC 25mg qod. Titrated dose to T 500-600•Followed labs q 6 mos (T/gonadotropins); ADAM toolFollowed labs q 6 mos (T/gonadotropins); ADAM tool•Indications: Infertility (64%) with other symptomsIndications: Infertility (64%) with other symptoms

•Mean follow-up 19 mos; age 29 yrsMean follow-up 19 mos; age 29 yrs•All men responded hormonallyAll men responded hormonally•No tolerance to CC developedNo tolerance to CC developed•No major side effectsNo major side effects

Katz DJ et al. BJU Int. 110: 573, 2012Katz DJ et al. BJU Int. 110: 573, 2012

Response to clomiphene citrateResponse to clomiphene citrate


•N=46 men with T < 300 ng/mL from 2002-2006 N=46 men with T < 300 ng/mL from 2002-2006 •Given CC 25mg qod. Titrated dose to T 500-600Given CC 25mg qod. Titrated dose to T 500-600•Followed labs q 6 mos (T/gonadotropins)Followed labs q 6 mos (T/gonadotropins)

•Mean age 44 yrs. Mean baseline T=228 ng/mLMean age 44 yrs. Mean baseline T=228 ng/mL•Mean T @ 1 yrMean T @ 1 yr = 612 ng/dL= 612 ng/dL•Mean T @ 2 yrsMean T @ 2 yrs = 562 ng/dL= 562 ng/dL•Mean T @ 3 yrsMean T @ 3 yrs = 582 ng/dL= 582 ng/dL•Mean FN and LS BD higherMean FN and LS BD higher•ADAM scores 7 to 3 at 3 yrsADAM scores 7 to 3 at 3 yrs


3 Yr response to clomiphene citrate3 Yr response to clomiphene citrate

The Morgentaler Theory The Morgentaler Theory

Case #3Case #3

30 yo married man with low libido and infertility. 30 yo married man with low libido and infertility. PMhx: significant for_____________ (PMhx: significant for_____________ (Choose one:Choose one:) )

•DiabetesDiabetes•Chronic opiate useChronic opiate use•ObesityObesity•ProlactinomaProlactinoma•Homozygous thalessemia majorHomozygous thalessemia major•Sickle cell diseaseSickle cell disease•HemochromatosisHemochromatosis•Other cause of secondary hypogonadismOther cause of secondary hypogonadism

Case #3 contCase #3 cont

Labs:Labs: Testosterone 180 ng/mLTestosterone 180 ng/mLLH LH 0.9 IU/mL0.9 IU/mLFSH FSH 0.7 mIU/mL0.7 mIU/mL

Exam: Exam: Left grade III varicoceleLeft grade III varicocele

Semen analysis:Semen analysis:Volume Volume 1.5 mL1.5 mLConcentrConcentr 5 mill/mL5 mill/mLMotilityMotility 22%22%ProgressionProgression 2 (average)2 (average)

How Semen Quality Changes How Semen Quality Changes inin Hypogonadal Men Hypogonadal Men onon Clomiphene Citrate Clomiphene Citrate

Carson Lawall MDCarson Lawall MDUche Ezeh MD Uche Ezeh MD Blake Tyrell MDBlake Tyrell MDPaul Turek MDPaul Turek MD

ASRM 2004ASRM 2004

Study ObjectiveStudy Objective

Assess changes in hormones, symptoms and Assess changes in hormones, symptoms and semen quality in men taking clomiphene citrate semen quality in men taking clomiphene citrate for secondary hypogonadotrophic for secondary hypogonadotrophic hypogonadism.hypogonadism.

MethodsMethods

•Prospective analysis of men treated with CC.Prospective analysis of men treated with CC.

•Inclusion criteria: Inclusion criteria:

Total testosterone <250ng/mL. Total testosterone <250ng/mL. Normal or Low LH level. Normal or Low LH level. Clinical symptoms (ED, infertility, libido)Clinical symptoms (ED, infertility, libido)

•Given CC at 12.5-25mg daily. Hormone response Given CC at 12.5-25mg daily. Hormone response assessed 3 weeks later. Titrated treatment to assessed 3 weeks later. Titrated treatment to achieve testosterone levels in the 400-700ng/mL achieve testosterone levels in the 400-700ng/mL rangerange

ResultsResults

•22 men enrolled. Mean age 40 y.o. (range 21-56)22 men enrolled. Mean age 40 y.o. (range 21-56)

•Indications and pathology: Indications and pathology: InfertilityInfertility 14 patients 14 patients Infertility/libidoInfertility/libido 2 patients 2 patients ED and libido ED and libido 2 patients2 patientsEDED 1 patient 1 patient Infertility and ED Infertility and ED 1 patient 1 patient Decreased libido Decreased libido 1 patient 1 patient ED and gynecomastia ED and gynecomastia 1 patient1 patient

Prolactinoma Rxn 4 patients Acromegaly 2 patients Intracranial germinoma 1 patient Idiopathic 15 patients

ResultsResults

•Chemical response to clomiphene citrate:Chemical response to clomiphene citrate:

Laboratory Laboratory Pre-clomiphene Pre-clomiphene Post-clomiphenePost-clomiphene

Total TestosteroneTotal Testosterone 143 ng/mL143 ng/mL 479 ng/mL FSH 479 ng/mL FSH 3.4 mIU/mL 3.4 mIU/mL 6.9 mIU/mL LH 6.9 mIU/mL LH 2.0 mIU/mL 5.7 mIU/mL 2.0 mIU/mL 5.7 mIU/mL

•A subset of 11 men with infertility had pre- A subset of 11 men with infertility had pre- and post-treatment semen analysis available for and post-treatment semen analysis available for comparisoncomparison

86% of patients had >50% increase in testosterone.86% of patients had >50% increase in testosterone.

ResultsResults

•Semen quality response (mean values) to clomiphene Semen quality response (mean values) to clomiphene citrate treatment (n=11 men):citrate treatment (n=11 men):

•Responders:Responders: 7/11 men (64%) had a >50% increase in 7/11 men (64%) had a >50% increase in total motile sperm count. Gains mainly in counts total motile sperm count. Gains mainly in counts (5.8x). 2/7 men conceived naturally.(5.8x). 2/7 men conceived naturally.

•Non-respondersNon-responders: 2/4 had bilateral varicoceles and 2/4 : 2/4 had bilateral varicoceles and 2/4 had extensive pituitary resection.had extensive pituitary resection.

Parameter Parameter Pre-clomiphene Pre-clomiphene Post-clomiphenePost-clomipheneVolume Volume 2.5 mL 2.5 mL 2.6 mL 2.6 mL Sperm concentrationSperm concentration 15.7 mill/mL 30.8 mill/mL 15.7 mill/mL 30.8 mill/mL MotilityMotility 15% 15% 24% 24% Total Motile Sperm Total Motile Sperm 11 million 11 million 33 million 33 million

Whitten et al. Fertil Steril. 2006, 86: 1664Whitten et al. Fertil Steril. 2006, 86: 1664

Response to Clomiphene Citrate in HH men with Response to Clomiphene Citrate in HH men with Male InfertilityMale Infertility

• n=10 men; 2 centers; 5 years. Testosterone <164 ng/dLn=10 men; 2 centers; 5 years. Testosterone <164 ng/dL• Treated 3 classes of HH with CC 50mg 3x weeklyTreated 3 classes of HH with CC 50mg 3x weekly

With anosmia (Kallmann)With anosmia (Kallmann) 44 0/40/4No anosmia (idiopathic, acquired)No anosmia (idiopathic, acquired) 44 3/43/4Panhypopituitary patientsPanhypopituitary patients 22 1/21/2

CategoryCategory # Pts # Pts Semen Semen ResponseResponse

• Stated that CC may work for idiopathic, adult onset, HHStated that CC may work for idiopathic, adult onset, HH

Hypogonadism: What About the Varicocele?Hypogonadism: What About the Varicocele?

• Compared baseline T levels in 2 cohorts before Rx:Compared baseline T levels in 2 cohorts before Rx:N=200 infertile men clinical varicoceleN=200 infertile men clinical varicoceleN=510 men undergoing vasectomy reversalN=510 men undergoing vasectomy reversal

• Mean T in Varicocele cohort= Mean T in Varicocele cohort= 416 ng/mL416 ng/mL• Mean T in Reversal cohort= Mean T in Reversal cohort= 469 ng/mL469 ng/mL (p<0.001) (p<0.001)• 70%70% of men had “improvement” in T after repair of men had “improvement” in T after repair• Change in T level with varicocele repairChange in T level with varicocele repair

Pre-repair: Pre-repair: 358 ng/mL358 ng/mLPost-repair: Post-repair: 454 ng/mL 454 ng/mL (p<0.001)(p<0.001)

Tanrikut C et al. BJU Int. 2011, 108: 1480Tanrikut C et al. BJU Int. 2011, 108: 1480

Managing Managing thethe Young Young Hypogonadal Male Hypogonadal Male

•Must consider fertility issues in managing hypogonadism Must consider fertility issues in managing hypogonadism in young men. in young men.

•Most cases of secondary hypogonadism respond to SERM Most cases of secondary hypogonadism respond to SERM therapytherapy

•Tolerance to SERMs relatively uncommonTolerance to SERMs relatively uncommon•hCG therapy is an excellent alternativehCG therapy is an excellent alternative•hCG with testosterone replacement may also work.hCG with testosterone replacement may also work.•Take the opportunity to treat the whole manTake the opportunity to treat the whole man

Health & Medicine

Managing the Young Hypogonadal Male