Testosterone and Men’s Health...advantages and disadvantages compared to other products. • Compounded gels and liquids can often be the best option for a patient. • Compounded

Testosterone and Men’s Health

Scott D. Isaacs, MD, FACP, FACEHRT SymposiumSavannah GA

July 14‐16, 2016

©2016. All Rights Reserved. 1

Disclosure

Scott D. Isaacs, MD, FACP, FACE, is the Medical Director at Atlanta Center for Endocrinology, Diabetes, Metabolism and Weight Loss. Conflict of interest was resolved through peer review of slide content.

Professional Education Services Group staff have no financial interest or relationships to disclose.


Disclosure

This continuing education activity is managed and accredited by Professional Education Services Group. Neither PESG nor any accrediting organization supports or endorses any product or service mentioned in this activity.


Educational Grant Support

This continuing education activity is supported by an educational grant from PCCA.


Learning Objectives

• At the conclusion of this activity, the participant will be able to:– Discuss the physiology and pathophysiology of testosterone and male hypogonadism.

– Explain pearls and pitfalls in the laboratory evaluation of testosterone in men.

– Review patient cases to highlight the pharmacologic management of male hypogonadism.


Charles Edouard Brown Séquard

• Rejuvenating effects of self‐injecting aqueous extracts (inactive) from dog and guinea pig testes.

• Increased “strength…expulsion of fecal matters…intellectual labour”

Brown‐Séquard CE, Lancet 2: 105‐107, 1889


Physiological Effects of Testosterone


Hypothalamic‐Pituitary‐Gonadal Axis

Median eminence

GnRH

Portal capillary system

Gonadotropes

Hypothalamus

Adipose TissueEstrogen

AromataseFeedback inhibition

LH & FSH

Testes

Sperm

Inhibin B

TestosteroneFeedback inhibition


Symptoms of Hypogonadism• Decreased libido• Erectile dysfunction• Fatigue• Depressed mood• Decreased strength• Decreased muscle mass• Decreased body hair• Osteoporosis, fragility fractures• Hot Flashes• Breast enlargement


Physical Examination

• Body hair distribution• Testicular size and consistency

– 20 to 30 mL– 4.5‐6.5 cm x 2.8‐3.3 cm

• Gynecomastia• Visual fields


Testosterone Binding Proteins

38‐44% Strongly bound to SHBG (not bioavailable)

50‐60% Loosely bound to albumin(partially bioavailable)

Total T= free T + albumin‐bound T + SHBG‐bound TBioavailable T = free T + albumin‐bound T

2‐3% Free Testosterone(bioavailable)


Testosterone Measurements

• Total testosterone (TT): The total amount of circulating testosterone free and protein bound.

• Free testosterone (FT): Unbound, biologically active testosterone.

• Calculated free testosterone (cFT): Free testosterone calculated using a widely established method using total testosterone, SHBG and albumin levels.

• Bioavailable testosterone (BAT): Fraction of circulating testosterone that readily enters cells and is believed to reflect the bioactivity of testosterone.


Causes of Hypogonadism

• Organic‐congenital, destructive, structural– Not reversible– Clinically and biochemically more severe

• Functional‐reversible gonadotropin suppression– Intact reproductive axis– More common than organic causes

Matsumoto, Endocrinol Metab Clin N Amer 42:271‐286, 2013


Primary Hypogonadism(Hypergonadotropic Hypogonadism)

GnRH


Gonadotropes

Hypothalamus

Testes

Testosterone

Feedback inhibition

SpermLH & FSH

Low Testosterone

High LH & FSH Decreased sperm

Median eminence


Causes of Primary Hypogonadism

• Cryptorchidism• Bilateral torsion• Orchitis (Mumps and other viruses)• Autoimmune• Vanishing testis syndrome• Orchiectomy• Klinefelter’s syndrome• Chemotherapy• Toxic damage from alcohol or heavy metals


Secondary Hypogonadism(Hypogonadotropic Hypogonadism)

GnRH


Gonadotropes

Hypothalamus

Testes

Testosterone

Feedback inhibition

SpermLH & FSH

Median eminence

Low LH & FSH

Low Testosterone

Decreased sperm


Secondary Hypogonadism(Hypogonadotropic Hypogonadism)

Don’t miss a pituitary tumor:‐LH‐FSH‐PRL‐MRI‐Visual fields


Tertiary Hypogonadism(Hypogonadotropic Hypogonadism)

GnRH


Gonadotropes

Hypothalamus

Testes

Testosterone

Feedback inhibition

SpermLH & FSH

Median eminence

Low LH & FSH

Low Testosterone

Decreased sperm


Causes of Central Hypogonadism(Primary and Secondary)

• Idiopathic GnRH or LRHR deficiency• Kallman’s syndrome• Pituitary‐hypothalamic injury from:

– Tumors– Trauma– Radiation

• Functional– Endocrine disrupting chemicals– Obesity– Hyperprolactinemia– Medications (opioids, glucocorticoids, GnRH agonist)– Malnutrition– Organ failure– Excess Exercise– Aging?


Mixed Hypogonadism

GnRH


Gonadotropes

Hypothalamus

Testes

Testosterone

Feedback inhibition

SpermLH & FSH

Low Testosterone

Low/Normal LH & FSH Decreased sperm

Median eminence


Causes of Mixed Hypogonadism

• Obesity • Diabetes• Hemochromatosis• HIV• Medications• Endocrine disrupting chemicals


Male HypogonadismDiagnosis

• Clinical manifestations of androgen deficiency AND consistently low T level– Signs and symptoms– T @ least x 2, preferably in the morning, fasting

• Symptoms alone or low T level alone does not diagnosis hypogonadism– Result in over‐diagnosis


Hypogonadism Confirmatory Tests• 2 morning testosterone levels• SHBG• Albumin• Prolactin• LH• FSH• Estradiol• HCT• Ferritin• PSA• Chromosomal analysis


Make a diagnosisPrimary Hypogonadism(Hypergonadotropic Hypogonadism)

• Testicular• Low Testosterone• High LH • High FSH• Impaired sperm production• Testicular atrophy

Central Hypogonadism(Hypogonadotropic Hypogonadism)

• Pituitary (secondary) or Hypothalamus (tertiary)

• Low Testosterone• Low or Low/Normal LH • Low or Low/Normal FSH• Impaired sperm production• Testicular atrophy


Common causes of hypogonadism

PrimaryAlcoholMumps orchitisTraumaAutoimmuneKleinfelter’s

CentralMedications (opioids, corticosteroids) Prior anabolic steroid use/abusePituitary tumors

MixedObesity DiabetesHemochromatosisHIV


Baltimore Longitudinal Study of AgingPercentage of Age Group Testosterone <325 ng/dL

20‐29 30‐39 40‐49 50‐590

20

40

60

80

100

Percen

tage

60‐69 70‐79

Age group (years)

Free T indexTotal testosterone

Harman SM, et al. J Clin Endocrinol Metab. 2001;86:724‐731.


Age‐Related Hypogonadism

• Symptoms non‐specific • Modest decreased T levels may not be hypogonadism

• Combined Primary and Secondary hypogonadism – Primary hypogonadism – organic (age)

• Decreased Leydig cell number and T response to hCG – Secondary hypogonadism – functional (comorbidity)

• Obesity, co‐morbid illness, medications – FSH and LH normal (Secondary – most common) or slightly increased (Primary – advanced old age)

• High prevalence CV and prostate disease


Longitudinal Changes in Serum LH Levels in Older Men

Morley, Metabolism 46: 410‐413, 1997.


Longitudinal Changes in Serum FSH Levels in Older Men

Morley, Metabolism 46: 410‐413, 1997.


Limitations of Previous T Treatment Trials in Older Men

• Heterogeneous • Healthy without symptoms/signs • Men with normal T levels • Short‐term • T Rx: T levels too low or high • Small numbers (under‐powered) • Surrogate, not optimal measures


Causes of Symptoms of Low T Level Other Than Hypogonadism

• Symptoms and signs not caused by Low T– Depression– Medications– Comorbidities

• Low T not caused by hypogonadism– Transient decrease (illness, drugs, malnutrition)– Biological T variability (PM, non‐fasting, 30% day to day variation)

– Low SHBG (obesity‐low TT, normal FT)


Potential Benefits of Testosterone Replacement Therapy

• Improved body composition– decreased fat mass– increased lean body mass– increased muscle strength

• Increased bone density• Improved physical function• Restored libido and erectile function• Increased energy and improved mood


The Testosterone Trials

• Randomized, double‐blind, placebo‐controlled trial of T vs. placebo x 1 yr

• 790 men ≥ 65 yrs, symptoms/signs, T ≤ 275 ng/dL x 2, low risk prostate cancer

• 7 coordinated trials (12 sites): ‐Physical function, sexual function, vitality ‐Cognitive function, anemia, cardiovascular, bone ‐T gel 5 g/d, adjusted to T 500‐800 ng/dL

Cauley JA et al, J Gerontol A Biol Sci Med Sci 70:1105‐1111, 2015


The Testosterone TrialsScreening and Recruitment

• 51,085 screened • 4700/21,940 low T on 1st blood sampling (21%)

• 1490/2163 low T on 2nd blood sampling (69%) • Overall inclusion by T level 14.7%

Cauley JA et al, J Gerontol A Biol Sci Med Sci 70:1105‐1111, 2015


The Testosterone TrialsT vs. Placebo in Sexual Function Trial

• Primary in Sexual Function Trial men –Moderate increased sexual activity by PDQ‐4

• Secondary in Sexual Function Trial men –Moderate increased libido and erectile function

• Secondary in All T Trials men –Moderate increased sexual activity by PDQ‐4

• Global impression of improved libido

Snyder PJ, et al, N Eng J Med 374:611‐624, 2016


The Testosterone TrialsT vs. Placebo in Physical Function Trial

• Primary in Physical Function Trial men –No increase on 6 minute walk

• Secondary in All T Trials men –Small increase on 6 minute walk –Small increase physical function

• Global impression of improved walking ability



The Testosterone TrialsT vs. Placebo in Vitality Trial

• Primary in Vitality Trial men –No improvement in fatigue score

• Secondary in Vitality T Trial men –Small decrease in depression symptoms by PHQ‐9

• Secondary in All T Trials men –Small improvement FACIT‐Fatigue score

• Global impression of improved energy



Potential Risks of Testosterone Replacement Therapy

• Erythrocytosis• Edema• CHF• Precipitation or worsening of sleep apnea• Gynecomastia• Prostate effects• Decreased sperm production• Acne


Contraindications to Testosterone Replacement Therapy

• Known or suspected prostate cancer• Male breast cancer• Known or suspected sensitivity to ingredients used in testosterone therapy systems

• Hematocrit >50%• Use in women• Untreated prolactinoma


Diagnosis of Hypogonadism

• Check: Review the medical history. Only make the diagnosis with consistent signs and symptoms of hypogonadism and documented low serum testosterone levels.

• Test: Perform a morning testosterone level using a reliable assay.

• Exclude: If testosterone levels are low, exclude reversible causes such as obesity, acute or subacute illness, drugs, nutritional deficiency.

• Confirm: Confirm hypogonadism with a second morning testosterone, check LH, FSH and prolactin. Perform additional testing as indicated.

• Diagnose: Primary, secondary or tertiary hypogonadism.


Testosterone Replacement Options

• Buccal tablet• Topical gel (branded vs generic vs compounded)

• Topical solution branded vs compounded)• Nasal gel• Transdermal patch• Intramuscular injection• Subcutaneous pellet


Treating low testosterone

• A low number alone is not enough to establish a diagnosis of hypogonadism.

• Always determine etiology.• Perform secondary testing as indicated based on etiology.

• Start with a low dose and titrate over 6‐12 months.

• Avoid over treating borderline cases.


• There is no perfect testosterone replacement product.

• Match the patient to the treatment.• Caution using gel or solution in homes with small children.

• Use a gel or liquid formulation and concentration that is convenient for the patient.

Treating low testosterone


• Most endocrinologists don’t know that compounded testosterone is an available option.

• Branded testosterone gel products are very expensive.

• Branded testosterone products require time‐consuming prior authorizations.

Compounded Testosterone


• Compounded gels and liquids have advantages and disadvantages compared to other products.

• Compounded gels and liquids can often be the best option for a patient.

• Compounded products must be high quality.• Variability in T level can be due to poor quality compounded products.

• Test samples when possible.

Compounded Testosterone


Choose the best formulation for this patient:

• 14 year old Kallmann’s initiating puberty• 27 year old with high deductible insurance• 39 year old with 2 small children• 49 year old divorced trying to bulk up• 54 year old who forgets to take his meds• 68 year old newly diagnosed• 74 year old with multiple medical problems


Choose the best formulation for this patient:

• Buccal tablet• Topical gel (branded vs generic vs compounded)

• Topical solution (branded vs compounded)• Nasal gel• Transdermal patch• Intramuscular injection• Subcutaneous pellet


Compounding considerations:

• Gel vs Solution• Low vs High Concentration (1‐5+%)• Patient Preference• How does the patient get the Rx? (far drive, signature required for mail, etc.)

• Allergies, skin sensitivity• Compliance• Cost• Child‐proof packaging• Travel packaging


Maintaining Fertility

• Avoid using testosterone• Primary hypogonadism:

– Urology referral – Testicular biopsy

• Central hypogonadism:– hCG– Female fertility medications– Clomiphene– Aromatase inhibitors


Testosterone Enanthate 250 mg Administered IM Every 3 Weeks

Time (weeks)

Seru

m te

stos

tero

neco

ncen

trat

ion

(ng/

dL)

0

400

800

1000

1400

0 3 15

200

600

1200

6 9 12

Lower limit of normal range

Upper limit of normal range

Nieschlag E, Behre HM. Pharmacology and clinical uses of testosterone. In: Testosterone: Action, Deficiency, Substitution. Berlin, Germany: Springer-Verlag; 1998:329-348.


Monitoring

• Check hematocrit at baseline, at 3 months, and then annually. If hematocrit is >52%, stop therapy, reduce dose, and/or evaluate for hypoxia and sleep apnea

• Measure BMD of the lumbar spine and/or the femoral neck as clinically indicated

• Testosterone levels should be measured approximately2‐4 weeks after initial therapy and periodically to ensure proper dosing

Cunningham G, Swerdloff R, et al. Summary from the Second Annual Andropause Consensus Meeting, The Endocrine Society, 2001; Petak SM, et al. AACE Clinical Practice Guidelines. Available at: http://www.aace.com/clin/guidelines/hypogonadism.pdf. Accessed 2/21/05.


Monitoring Prostate during TRT

• Baseline evaluation• Digital rectal examination• Serum PSA • AUA symptom scores or IPSS for benign prostatic hyperplasia

• Follow‐up evaluation at 6 and 12 months, and annually thereafter• Serum PSA• Digital rectal examination• AUA symptom scores or IPSS for benign

prostatic hyperplasia

Bhasin S, et al. J Androl. 2003;24:299‐311.


Summary: Diagnosis and Management of Hypogonadism

• Role of testosterone in male physiology: – Plays a key role in male reproductive tissue, sexual health, sperm production

– Secondary sexual characteristics– Muscle and bone health

• Diagnose the type of hypogonadism and do appropriate follow up testing:– Primary– Secondary– Tertiary



• Use established diagnostic criteria– Signs and symptoms– Organic etiology, exclude reversible causes– 2 morning T levels below normal range– LH,FSH, PRL, E2, Ferritin, CBC, PSA, DEXA

• Identify patients not appropriate for treatment



• Understand TRT options and guidelines for monitoring

• Be aware of conditions associated with hypogonadism

• Schedule appropriate follow up appointments• Monitor patient response to treatment• Consider all therapeutic options


Case 1: History of Present Illness

• 60‐year‐old male• Depressive symptoms x 6 months• Loss of energy, feeling tired• Low libido. Progressive loss of erections


Case 1: Past Medical History• CAD x 8 years• Type 2 DM x 15 years• Hypercholesterolemia x 10 years• Obesity x 20 years• No known drug allergies• Medications

– Aspirin 81 mg once daily– Metformin 1000 mg twice daily– Valsartan 160 mg once daily– Simvastatin 40 mg once daily

• 2 biological children


Case 1: Review of Systems

• General fatigue• No change in weight, muscle mass, or body hair

• Denies chest pain at rest or exertion, no symptoms of CHF

• Remote history of mumps


Case 1: Vital Signs

• HR: 90 beats/minute• BP (sitting): 142/90• RR: 20• Afebrile• Weight: 285 lbs• Height: 6’ 3”• BMI: 35.6 kg/m2


Case 1: Physical Exam

• Normal hair distribution• No gynecomastia• Testes low‐normal (15 cc), moderately decreased consistency

• Normal prostate by rectal exam


Case 1: Tests Serum total testosterone 214 ng/dL, 202 ng/dL FSH and LH FSH: 19 IU/L; LH: 23 IU/L Serum prolactin 12 ng/mL PSA 1.5 ng/mL Chemistry Panel Na, 140mmol/L; K, 4.8mmol/L; Cl,

100mmol/L; bicarb, 27mmo/L; glucose, 210mg/dL; BUN,

18mg/dL; Cr, 1.2mg/dL

Hgb A1c 7.2% Sellar MRI Normal Cardio stress test Normal


What is the diagnosis?• Primary Hypogonadism (mumps orchitis)

What is an appropriate treatment?• Testosterone replacement, if no contraindications exist



• 51‐year‐old male• ED, loss of libido x 2 years• Partial response to sildenafil 50 mg and 100 mg


Case 2: Past Medical History

• No significant PMH• No history of genital trauma• No known drug allergies• Medications

– Sildenafil 100 mg prn

• 2 biological children; does not desire future fertility



• No change in body hair or muscle mass• Increased abdominal girth• No recent nocturnal erection


Case 2: Vital Signs

• BP: 130/80• HR: 80• Afebrile• Height: 6’ 0”• Weight: 182 lbs• BMI: 24.7 kg/m2



• Normal body hair distribution• 2 cm palpable breast tissue bilaterally• Testes 12 cc, normal consistency• Prostate normal by rectal exam• Exam otherwise unremarkable


Case 2: Tests

Hb and Hct Hb, 12.2; Hct, 38% Serum total testosterone 130 ng/dL, 145 ng/dL Free testosterone by equilibrium dialysis 40 pg/mL

FSH and LH FSH: 3.2 IU/L; LH: 1.1 IU/L Serum prolactin 7 ng/mL PSA 1.2 ng/mL Nocturnal penile tumescence study Normal NPT

Sellar MRI Normal Intracorporeal injection with a vasodilator Normal erectile response


What is the diagnosis?• Secondary hypogonadism

What is an appropriate treatment?• Rule out tumor• Testosterone replacement, if no contraindications exist

• Clomiphene, hCG, aromatase inhibitors



• 35‐year‐old male• Increasing fatigue x 3 months• Unintentional 10 lb weight loss (6% of total body weight)

• Increased abdominal fat• Depressed mood


Case 3: Past Medical History

• HIV+, diagnosed 2 years ago– Last CD4+ T lymphocyte count: 340/mm3

– Last viral load: 350 copies/mL

• Medications– Efavirenz 600 mg qd– Tenofovir 300 mg qd– Lopinavir/ritonavir 400/100 mg bid

• 15 pack‐year cigarette smoking history• Moderate ETOH use



• 10‐lb unintentional weight loss over 6 months• Increased abdominal girth• General fatigue• No fever, chills, night sweats, cough, difficulty swallowing, diarrhea

• Mildly depressed mood


Case 3: Vital Signs

• HR: 76 beats/minute• BP (sitting): 134/89• RR: 16• Afebrile• Weight: 150 lbs• Height: 5’ 8”• BMI: 22.8 kg/m2



• Normal body hair distribution• Small posterior cervical adenopathy• No gynecomastia• Testes 15 cc, normal consistency• Prostate normal by rectal exam• Exam otherwise unremarkable


Case 3: Tests

Hb and Hct Hb, 14.8 g/dL; Hct, 42% CD4+ Count 340 cells/mm3

HIV Viral Load 350 copies/mL Chemistry Panel Na, 140mmol/L; K, 4.8mmol/L; Cl,

100mmol/L; bicarb, 27mmo/L; glucose, 110mg/dL; BUN,

18mg/dL; Cr, 1.1mg/dL

Blood, Urine, and Stool Culture No Growth

TB Skin Test <2mm reaction, non-indurated


Case 3: Tests

Chest X-ray Normal Nutritional Assessment Energy intake is 90% of

recommended daily allowance

Serum Total Testosterone 220 ng/dL, 233 ng/dL FSH and LH FSH: 8 IU/L; LH: 4 IU/L Serum prolactin 7 ng/mL TSH 4 microIU/mL Sellar MRI Normal


Case 3: Diagnosis

What is the diagnosis?• HIV‐associated hypogonadism

What is an appropriate treatment?• Testosterone replacement, if no contraindications exist

• Consideration for GH replacement


Chronic Diseases or Conditions Associated with Hypogonadism: HIV/AIDS

• Approximately 30% of HIV+ men and 50% of men with AIDS are hypogonadal– Correlated with lymphocyte depletion and

weight loss– Medications can lower testosterone

concentrations– Age‐related declines


Thank you!

Scott Isaacs, M.D., F.A.C.P., [email protected]


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Documents

Testosterone and Men’s Health...advantages and disadvantages compared to other products. • Compounded gels and liquids can often be the best option for a patient. • Compounded