Treatment of The Hypogonadal Male William Abeyta MD Associate Professor of Medicine AVAH/UNM SOM

Treatment of The Treatment of The Hypogonadal Male Hypogonadal Male

William Abeyta MDWilliam Abeyta MD

Associate Professor of MedicineAssociate Professor of Medicine

AVAH/UNM SOMAVAH/UNM SOM

OBJECTIVESOBJECTIVES

Understand the clinical features of male Understand the clinical features of male hypogonadism.hypogonadism.

Discuss possible causes.Discuss possible causes. Interpret laboratory tests and how to Interpret laboratory tests and how to

order them in different clinical scenarios.order them in different clinical scenarios. Review and describe the hypothalamic-Review and describe the hypothalamic-

pituitary-testicular axis.pituitary-testicular axis. Understand general principles of Understand general principles of

treatmenttreatment

OBJECTIVES OBJECTIVES

Describe the various testosterone Describe the various testosterone preparations.preparations.

Understand the monitoring required Understand the monitoring required when using testosterone when using testosterone replacement.replacement.

Identify complications of treatment.Identify complications of treatment.

Roles of TestosteroneRoles of Testosterone

In men, testosterone plays a key role in In men, testosterone plays a key role in the development of male reproductive the development of male reproductive tissues such as the testis and prostate tissues such as the testis and prostate as well as promoting secondary sexual as well as promoting secondary sexual characteristics such as increased characteristics such as increased muscle, bone mass, and the growth of muscle, bone mass, and the growth of body hair. In addition, testosterone is body hair. In addition, testosterone is essential for health and well-being as essential for health and well-being as well as the prevention of osteoporosis.well as the prevention of osteoporosis.

HISTORYHISTORY Testosterone first used clinically in Testosterone first used clinically in

1937, only 2 years after it’s Nobel Prize-1937, only 2 years after it’s Nobel Prize-winning discovery.winning discovery.

Annual prescriptions for testosterone Annual prescriptions for testosterone increasd by more than 5-fold from 2000-increasd by more than 5-fold from 2000-2011 reaching 5.3 million prescriptions.2011 reaching 5.3 million prescriptions.

Testosterone prescribing has created a Testosterone prescribing has created a nearly $2 billion annual market.nearly $2 billion annual market.

Surging off-label use (anti-aging, sexual Surging off-label use (anti-aging, sexual tonic, bodybuilding or doping.tonic, bodybuilding or doping.

HYPOGONADISMHYPOGONADISM

Defined as the failure of the testes to Defined as the failure of the testes to produce androgen, sperm, or both.produce androgen, sperm, or both.

Testosterone production decreases Testosterone production decreases with advancing age: 20% of men with advancing age: 20% of men older than 60 and 30-40% of men older than 60 and 30-40% of men older than 80 have serum older than 80 have serum testosterone levels that would be testosterone levels that would be subnormal in their younger male subnormal in their younger male counterparts.counterparts.

HypogonadismHypogonadism

Low levels of testosterone along Low levels of testosterone along with other specific signs and sxs. with other specific signs and sxs. (diminished libido, ED, reduced (diminished libido, ED, reduced muscle mass/bone density, muscle mass/bone density, depression, anemia)depression, anemia)

Affects 2-4 million males in the US.Affects 2-4 million males in the US.


Only 5% of men currently receive rxOnly 5% of men currently receive rx Recent interest in rx d/t media Recent interest in rx d/t media

attention, marketing of new attention, marketing of new preparations, “desire of baby preparations, “desire of baby boomers” to maintain vigor and boomers” to maintain vigor and health into their more mature years.health into their more mature years.

Considerable controversy regarding Considerable controversy regarding indications for testosterone indications for testosterone supplementation in aging males.supplementation in aging males.


No large-scale, long-term studies available No large-scale, long-term studies available to assess risks and benefits of testosterone-to assess risks and benefits of testosterone-replacement rx in part d/t theoretical risk of replacement rx in part d/t theoretical risk of possible stimulation of prostate cancer by possible stimulation of prostate cancer by testosterone.testosterone.

It is estimated that a study would need to It is estimated that a study would need to include 6000 elderly hypogonadal men include 6000 elderly hypogonadal men randomly assigned to receive testosterone randomly assigned to receive testosterone or placebo for 6 years in order to determine or placebo for 6 years in order to determine whether rx increases risk of prostate cancer whether rx increases risk of prostate cancer by 30%.by 30%.

Snyder.Hypogonadism in Elderly Men-What ToUntil the Evidence Comes.N Engl J Med 2004;350:440-442

The TestesThe Testes

60% of testicular volume accounted 60% of testicular volume accounted for by seminiferous tubules.for by seminiferous tubules.

Prepubertal testis 2cm in length and Prepubertal testis 2cm in length and 2ml in volume.2ml in volume.

Testes average 4.6cm in length in Testes average 4.6cm in length in adults but range from 3.5-5.5 cm adults but range from 3.5-5.5 cm according to Harrisons Textbook of according to Harrisons Textbook of Medicine.Medicine.

4-7cm in UpToDate.4-7cm in UpToDate.

TestesTestes

Advanced age does not influence Advanced age does not influence testicular size. (therefore testicular size. (therefore significance of small testes is the significance of small testes is the same at all ages of the adult)same at all ages of the adult)

Testis size varies among ethnic Testis size varies among ethnic groups.groups.

Asian men have smaller testes than Asian men have smaller testes than western Europeans, independent of western Europeans, independent of differences in body size.differences in body size.

Serum Testosterone Serum Testosterone LevelsLevels

Diurnal rhythm.Diurnal rhythm. Values are 30% higher near 8am vs later Values are 30% higher near 8am vs later

in the day.in the day. Normal range varies among laboratories.Normal range varies among laboratories. Usual range for young men is 300-Usual range for young men is 300-

1000ng/d.1000ng/d. In general values < 220-250 are clearly In general values < 220-250 are clearly

low in most laboratories.low in most laboratories. Values 250-350 should be considered Values 250-350 should be considered

borderline low.borderline low.

TABLE 2. Conditions associated with alterations in SHBG concentrations

Conditions associated with decreased SHBG Conditions associated with decreased SHBG concentrationsconcentrations

• • Moderate obesityModerate obesity11

• • Nephrotic syndromeNephrotic syndrome11

• • HypothyroidismHypothyroidism

• • Use of glucocorticoids, progestins, and Use of glucocorticoids, progestins, and androgenic steroidsandrogenic steroids11

Conditions associated with increased SHBG Conditions associated with increased SHBG concentrationsconcentrations

• • AgingAging11

• • Hepatic cirrhosisHepatic cirrhosis11

• • HyperthyroidismHyperthyroidism

• • Use of anticonvulsantsUse of anticonvulsants11

• • Use of estrogensUse of estrogens

• • HIV infectionHIV infection

1Particularly common conditions associated with alterations in SHBG concentrations.

Signs and Symptoms of Signs and Symptoms of HypogonadismHypogonadism

1.1. Diminished libidoDiminished libido

2.2. Erectile dysfunctionErectile dysfunction

3.3. Difficulty achieving orgasmDifficulty achieving orgasm

4.4. Diminished intensity of orgasmic Diminished intensity of orgasmic experienceexperience

5.5. Diminished sexual penile sensationDiminished sexual penile sensation

Signs and Symptoms of Signs and Symptoms of HypogonadismHypogonadism

OtherOther

1.1. Diminished energy/sense of well Diminished energy/sense of well beingbeing

2.2. Increased fatigueIncreased fatigue

3.3. Depressed moodDepressed mood

4.4. AnemiaAnemia

5.5. Diminished bone density/muscle Diminished bone density/muscle massmass

Risks of Testosterone Risks of Testosterone TherapyTherapy

1.1. Coronary Artery DiseaseCoronary Artery Disease::

““Adverse Events Associated with Adverse Events Associated with Testosterone Administration” TOM Testosterone Administration” TOM Trial. NEJM July 8, 2010.Trial. NEJM July 8, 2010.

-209 community-dwelling men 65 years of age -209 community-dwelling men 65 years of age or older, with limitations of mobility.or older, with limitations of mobility.

-total serum testosterone level of 100-350ng/dl -total serum testosterone level of 100-350ng/dl or a free testosterone level of <50pg/mlor a free testosterone level of <50pg/ml

-Randomly assigned to receive placebo gel or -Randomly assigned to receive placebo gel or testosterone gel daily for 6 months.testosterone gel daily for 6 months.

ResultsResults Trial terminated early because of a Trial terminated early because of a

significantly higher rate of adverse CV events significantly higher rate of adverse CV events in the testosterone group than in the placebo in the testosterone group than in the placebo group.group.

Higher rates of cardiac, respiratory, Higher rates of cardiac, respiratory, dermatologic events in the testosterone dermatologic events in the testosterone treated group.treated group.

23 subjects in testosterone group as compared 23 subjects in testosterone group as compared with 5 in the placebo group had with 5 in the placebo group had cardiovascular-related adverse events.cardiovascular-related adverse events.

Testosterone group had significantly greater Testosterone group had significantly greater improvements in leg press and chest press improvements in leg press and chest press strength and in stair-climbing while carrying a strength and in stair-climbing while carrying a load.load.

Risks of Testosterone-Risks of Testosterone-Replacement TherapyReplacement Therapy

““Association of Testosterone Therapy Association of Testosterone Therapy With Mortality, Myocardial With Mortality, Myocardial Infarction, and Stroke in Men With Infarction, and Stroke in Men With Low Testosterone Levels”Low Testosterone Levels”

JAMA 11-6-2013 Volume 310

Retrospective national cohort study Retrospective national cohort study of men with low testosterone levels of men with low testosterone levels (<300ng/dl) who underwent (<300ng/dl) who underwent coronary angiography in the VA coronary angiography in the VA system between 2005-2011.system between 2005-2011.

Primary outcome was a composite of Primary outcome was a composite of all-cause mortality, MI, and ischemic all-cause mortality, MI, and ischemic stroke.stroke.

ResultsResults

At 3 years after coronary At 3 years after coronary angiography cummulative angiography cummulative percentages with events were 19.9% percentages with events were 19.9% in the no-testosterone therapy group in the no-testosterone therapy group vs 25.7% in the testosterone therapy vs 25.7% in the testosterone therapy group…absolute risk difference of group…absolute risk difference of 5.8%.5.8%.

Limitations in the StudyLimitations in the Study

ObservationalObservational Select group of patients in VA Select group of patients in VA

system undergoing angiography.system undergoing angiography. Length of follow-up.Length of follow-up.


2. 2. Lipid ProfilesLipid Profiles: Available data : Available data inconsistent (supraphysiologic doses inconsistent (supraphysiologic doses appear to lower HDL).appear to lower HDL).

Some variability may be explained by Some variability may be explained by dosage. dosage.

Present data taken together suggest that Present data taken together suggest that testosterone replacement therapy within testosterone replacement therapy within the physiologic range is not associated the physiologic range is not associated with worsening of the lipid profile.with worsening of the lipid profile.

Rhoden, et al. Risks of Testosterone-ReplacementTherapy and Recommendations for MonitoringN Engl J Med 2004; 350:482-492


3.3. Polycythemia Polycythemia: Higher testosterone : Higher testosterone levels act as a stimulus for levels act as a stimulus for erythropoiesis. Injections appear to erythropoiesis. Injections appear to be associated with a greater risk be associated with a greater risk than topical preparations.than topical preparations.

No testosterone-associated No testosterone-associated thromboembolic events have been thromboembolic events have been reported to date.reported to date.


4. 4. BPH:BPH: Prostate volume DOES increase Prostate volume DOES increase significantly during testosterone-significantly during testosterone-replacement therapy (determined by replacement therapy (determined by ultrasonography) mainly during the first 6 ultrasonography) mainly during the first 6 months.months.

Poor correlation between prostate volume Poor correlation between prostate volume and urinary sxs.and urinary sxs.

Multiple studies fail to demonstrate Multiple studies fail to demonstrate exacerbation of voiding sxs attributed to exacerbation of voiding sxs attributed to BPH during testosterone supplementation.BPH during testosterone supplementation.


5. 5. Prostate CancerProstate Cancer: Prospective studies have : Prospective studies have demonstrated a low frequency of prostate demonstrated a low frequency of prostate cancer in association with testosterone-cancer in association with testosterone-replacement rx.replacement rx.

Occult prostate cancer in men with low Occult prostate cancer in men with low testosterone levels appears to be substantial testosterone levels appears to be substantial with higher grade prostate cancers.with higher grade prostate cancers.

No compelling evidence to suggest men with No compelling evidence to suggest men with higher testosterone levels are at a greater higher testosterone levels are at a greater risk or that treating men who have risk or that treating men who have hypogonadism with exogenous androgens hypogonadism with exogenous androgens increases this risk.increases this risk.

Rhoden, et al. Risks of Testosterone-ReplacementTherapy and Recommendations for MonitoringN Engl J Med 2004; 350:482-492

*Prostate cancer becomes moreprevalent at the time of a man’slife when testosterone levels decline.


6. 6. PSA:PSA: Studies have inconsistently Studies have inconsistently shown a rise in PSA in testosterone shown a rise in PSA in testosterone treated patients (0.3-0.4ng/ml)treated patients (0.3-0.4ng/ml)

A substantial rise in PSA should A substantial rise in PSA should arouse suspicion that a prostate arouse suspicion that a prostate cancer has developed.cancer has developed.


7. 7. Hepatic EffectsHepatic Effects: Oral preparations of : Oral preparations of testosterone reported to lead to testosterone reported to lead to hepatotoxic effects and neoplasia, hepatotoxic effects and neoplasia, including benign and malignant tumors.including benign and malignant tumors.

IM injections and topical preparations of IM injections and topical preparations of testosterone do not appear to be testosterone do not appear to be associated with hepatic dysfunction and associated with hepatic dysfunction and routine monitoring of LFTs is routine monitoring of LFTs is unnecessary for men on these forms of unnecessary for men on these forms of replacement rx.replacement rx.


8. 8. Sleep ApneaSleep Apnea: Testosterone-: Testosterone-replacement therapy has been replacement therapy has been associated with the exacerbation of associated with the exacerbation of sleep apnea or with the development of sleep apnea or with the development of sleep apnea (Seen in men treated with sleep apnea (Seen in men treated with higher doses of parenteral testosterone higher doses of parenteral testosterone and have other risk factors for sleep and have other risk factors for sleep apnea). Probably by central apnea). Probably by central mechanisms rather than by anatomical mechanisms rather than by anatomical changes in the airway.changes in the airway.

Miscellaneous Effects of Miscellaneous Effects of TestosteroneTestosterone

Breast tenderness and swellingBreast tenderness and swelling Testicular size and consistency diminishTesticular size and consistency diminish Fertility is diminishedFertility is diminished Skin reactions with topicalsSkin reactions with topicals Pain, bruising, soreness, furuncles with Pain, bruising, soreness, furuncles with

testosterone injectionstestosterone injections Fluid retentionFluid retention Acne, oily skinAcne, oily skin No data to suggest acceleration of male-No data to suggest acceleration of male-

pattern baldness.pattern baldness.

Evaluation of the Possible Evaluation of the Possible Hypogonadal MaleHypogonadal Male

Physical examPhysical exam: focus on whether or not : focus on whether or not sexual development is consistent with the sexual development is consistent with the patient’s age.patient’s age.

Testicular size: 4-7cm in length.Testicular size: 4-7cm in length. Normal musculatureNormal musculature Dense pubic hair and in a diamond pattern.Dense pubic hair and in a diamond pattern. Beard should be full and denseBeard should be full and dense Chest and other body hair should be Chest and other body hair should be

present.present.

Endocrine Society GuidelineEndocrine Society Guideline

Who To Treat With Who To Treat With Testosterone-Replacement Testosterone-Replacement

Therapy?Therapy? Testosterone should be given ONLY Testosterone should be given ONLY

to a male who is hypogonadal as to a male who is hypogonadal as evidenced by a low testosterone evidenced by a low testosterone level.level.

There is insufficient evidence that There is insufficient evidence that testosterone benefits elderly males testosterone benefits elderly males without clearly abnormally low without clearly abnormally low testosterone levels.testosterone levels.

Baseline Exam/Tests Before Baseline Exam/Tests Before Beginning Treatment With Beginning Treatment With

TestosteroneTestosterone Voiding historyVoiding history History of sleep apneaHistory of sleep apnea Perform DREPerform DRE Baseline PSA and HCT/hemoglobinBaseline PSA and HCT/hemoglobin GU referral if PSA over 4.0 or GU referral if PSA over 4.0 or

abnormal prostate examabnormal prostate exam

Testosterone Testosterone PreparationsPreparations

1.1. Testosterone Esters: injectable Testosterone Esters: injectable testosteronetestosterone

2.2. Transdermal:Transdermal: Nonscrotal patchNonscrotal patch Testosterone GelTestosterone Gel OintmentOintment SolutionSolution3. Buccal tablet3. Buccal tablet4. Pellet (Testopel Implant)4. Pellet (Testopel Implant)

Testosterone EstersTestosterone Esters

Testosterone Esters: Injectable Testosterone Esters: Injectable testosteronetestosterone

Testosterone enanthate and Testosterone enanthate and cypionate used for years in cypionate used for years in treatment of testosterone deficiency.treatment of testosterone deficiency.

Begin with 200mg IM every 2 weeks.Begin with 200mg IM every 2 weeks. Can change to 100mg every week if Can change to 100mg every week if

fluctuations in libido, mood, energy.fluctuations in libido, mood, energy.

Testosterone Esters: Testosterone Esters: Injectable testosteroneInjectable testosterone

Measure testosterone midway Measure testosterone midway between injections and value should between injections and value should be mid-normal (350-750ng/ml)be mid-normal (350-750ng/ml)

Reduce dose if higher values Reduce dose if higher values obtained.obtained.

Disadvantage is fluctuations in Disadvantage is fluctuations in mood, energy and libido in many mood, energy and libido in many patientspatients

Nonscrotal PatchNonscrotal Patch

One body patch is available One body patch is available (Androderm)(Androderm)

Worn on arm, torso, or thighWorn on arm, torso, or thigh Start with 4mg patchStart with 4mg patch Check level 3-12 hours after Check level 3-12 hours after

application of patch.application of patch.

Testosterone GelTestosterone Gel

Apply once per dayApply once per day Takes a month to reach normal Takes a month to reach normal

levels and remain steady throughout levels and remain steady throughout 24 hours.24 hours.

Can check serum level at any time of Can check serum level at any time of dayday

Buccal TabletBuccal Tablet

Approved by FDA June, 2003 Approved by FDA June, 2003 (Striant)(Striant)

Applied and adheres to a depression Applied and adheres to a depression in the gum above the upper incisors in the gum above the upper incisors and releases testosterone across the and releases testosterone across the buccal mucosabuccal mucosa

Check level immediately before or Check level immediately before or after application of new system.after application of new system.

Follow-up of The Follow-up of The Testosterone-Replaced Testosterone-Replaced

MaleMale Follow-up visit in 3-6 months for efficacy Follow-up visit in 3-6 months for efficacy

evaluation and adverse effects.evaluation and adverse effects. Assess urinary sxs/sleep apneaAssess urinary sxs/sleep apnea Perform DRE at ~3-6 months and see Perform DRE at ~3-6 months and see

below PSA rec.below PSA rec. Testosterone level at 3-6 months.(aim for Testosterone level at 3-6 months.(aim for

mid-normal range 350-750 ng/dl.)mid-normal range 350-750 ng/dl.) PSA at 3-6months and thereafter in PSA at 3-6months and thereafter in

accordance with guidelines for screening accordance with guidelines for screening depending on age and race of patient.depending on age and race of patient.

HCT at 3-6 months and than HCT at 3-6 months and than yearly(discontinue treatment if >54%)yearly(discontinue treatment if >54%)

Obtain Urologic Obtain Urologic Consultation ifConsultation if

Increase in PSA >1.4ng/ml within any Increase in PSA >1.4ng/ml within any 12 month period of testosterone rx.12 month period of testosterone rx.

PSA velocity of >0.4ng/ml using PSA PSA velocity of >0.4ng/ml using PSA level after 6 months of testosterone level after 6 months of testosterone administration as the reference (if PSA administration as the reference (if PSA data are available for a period data are available for a period exceeding 2 years)exceeding 2 years)

Abnl DREAbnl DRE AUA prostate sxs score >19.AUA prostate sxs score >19.

Case I

82 yo male presented to his new PCP with a chief complaint of back pain.The pain began suddenly when he helped move a pool table at the senior center onemonth prior to this visit. Despite worsening pain to the point that he could no longer walk very well, he had refused to come in for evaluation.He had no neurologic/bowel/bladder complaints

Case I

Meds: APAP, viagra.Tobacco: 1PPD x 65 yearsETOH: none x 5 years, formerly heavy usePMH:

1. Right hip fracture with ORIF 2 years ago2. Esophageal stricture with multiple

dilations in the past.FH: neg for osteoporosis that he was aware of.

Case IPE: normal vitalsNeck: no nodes or thyromegalyLungs: decreased BSs throughoutCV: RRR without M/R/GAbd: soft without hepatosplenomegaly or massesBack: Marked thoracic kyphosis with tenderness

at T12 and L1 Testicles: 5cm bilat, normal pubic hair

CXR: HyperinflationThoracic and lumbar spine films: compression

fractures of T12 and L1 appearing acute.

Lab:Hct 38, MCV 95, nl WBC/pltsCalcium 9.2SPEP neg for paraproteinPSA <.03Normal TSH/prolactinFree testosterone 0.3 (11-25)Total testosterone 32 (241-827)

LH 14.1 (1-7)FSH 61.2(1.4-15) DXA: >4SD hip&spinePTH normal

Case II

66 year-old male presented to his resident MDfor general medical f/u. He had been on testosterone injections for 2 years for primaryhypogonadism. His last Hct was one year priorand had been 50. The patient complained of fatigue, headaches, and dizziness.On exam his face appeared very flushed. Labtesting showed a Hct of 62%.

Documents

Treatment of The Hypogonadal Male William Abeyta MD Associate Professor of Medicine AVAH/UNM SOM