Adult Male Hypogonadism
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Transcript of Adult Male Hypogonadism
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Adult Male Hypogonadism
Amy Neumeister, MD FACP
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Objectives:Adult Male Hypogonadism
• Screening
• Diagnosis/Differential
• Treatment
• Adverse events & safety monitoring
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SpermInhibin
Normal Male Reproductive Axis
GnRH
FSH LH
Hypothalamus
Pituitary
Seminiferous Tubule
LeydigCell
Aromatase 5 reductase
EstradiolDHTTestes
TE
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Diagnosis of Hypogonadism
• Failure of testes to produce – Physiologic levels of testosterone – Normal number of spermatozoa
• Primary = testes failure • Secondary = pituitary or hypothalamic
failure• Dual defects are possible (less likely)
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Treatment of HypogonadismDepends on the Cause
• Primary hypogonadism– Generally permanent– Replace testosterone unless contradindicated– Fertility cannot be regained
• Secondary hypogonadism– Distinguish cause– Evaluate for other hormone deficiencies first– Use testosterone + gonadotropins for fertility
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Definition of Androgen Deficiency (AD)
• Consistently low testosterone
• Associated signs/symptoms
• Evidence based review of literature– Data is weak at best
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Don’t Screen Every Man for Low T
• Don’t look for low T in men seeking care for unrelated reasons
• Does not meet any criteria for general screening
• No trials of efficacy or cost-effectiveness
• Mortality impact of untreated low T unknown
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Who to Screen for AD
• Men who ask about it based on symptoms• Case finding in men with high prevalence
clinical disorders– Even in these groups, data on risk/benefits of
T replacement is unavailable-limited
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1. Do you have a decrease in libido (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?"
6. Are you sad and/or grumpy?
7. Are your erections less strong?
8. Have you noticed a recent deterioration in your ability to play sports?
9. Are you falling asleep after dinner?
10. Has there been a recent deterioration in your work performance?
If you answered YES to questions 1 or 7 or any 3 other questions, you may have low testosterone.
**Adapted from Morley JE, et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism. 2000;49(9):1239-1242.
The ADAM Questionnaire
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Symptoms/Signs of AD in Men
• Incomplete sexual development, eunuchoidism Sexual desire & activity Spontaneous erections• Breast discomfort, gynecomastia Body hair (axillary & pubic), shaving• Very small or shrinking testes (esp < 5 ml)• Inability to father children, low/zero sperm counts Height, low-trauma fracture, low BMD Muscle bulk & strength• Hot flushes, sweats
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Less Specific Symptoms/Signs of AD
energy, motivation, initiative, aggressiveness, self-confidence
• Feeling sad or blue, depressed mood, dysthymia• Poor concentration and memory• Sleep disturbance, increased sleepiness• Mild anemia
– Normochromic, normocytic, in the female range
• Increased body fat, BMI• Diminished physical or work performance
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Conditions with a High Prevalence of Low T (Screening Suggested)
• Sellar mass, radiation to sella, other sellar disease• On meds that affect T production or metabolism
– Glucocorticoids, ketoconazole, opioids
• HIV-associated weight loss• ESRD and maintainence hemodialysis• Moderate to severe COPD• Osteoporosis or low trauma fracture (esp if young)• Type 2 diabetes mellitus• Infertility
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Relevant Medical History
• Puberty and sexual development• Past/present major illnesses• Past/present nutritional deficiency• All prescription & nonprescription drugs• Relationship problems• Sexual problems• Major life events• Related family history• Recent changes in body (breasts)• Testicle problems
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Physical Exam
• Amount of body hair• Breast exam for enlargement/tenderness• Size and consistency of testicles• Size of the penis• Signs of severe & prolonged AD
– Loss of body hair– Reduced muscle bulk and strength– Osteoporosis– Smaller testicles
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Guidelines on Screening
• Initial screen = morning total testosterone– Levels are highest in the morning– Normal T is generally 300-1000 ng/dl
• Confirmation = repeat morning total T– Free or bioavailable T in some
• Do not screen during acute or subacute illness– Illness, malnutrition, and certain medications
may temporarily lower testosterone
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History and Physical (Symptoms and Signs)
Exclude reversible illness, drugs, nutritional deficiency
Do you suspect altered SHBG?
Low T
Morning Total T
Normal T, LH+FSH
Not HypogonadismFollow up
Normal T
Repeat TCheck LH+FSH
If altered SHBGUse free or bio T
Semen analysis
if fertility issue
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Testosterone Circulates Mostly Bound to Sex Hormone Binding Globulin
What lowers SHBG– Moderate obesity– Nephrotic syndrome– Hypothyroidism– Use of
• Glucocorticoids• Progestins• Androgenic steroids
What raises SHBG– Aging– Hepatic cirrhosis– Hyperthyroidism– Anticonvulsants– Estrogens– HIV infection
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Confirmed low T (Total < 300 ng/dl)OR
Free or Bio T < normal (Free T <5 ng/dl)
Low TLow or normal LH+FSH
Prolactin, iron satsOther pituitary hormones
Low THigh LH+FSH
KaryotypeKlinefelter SyndromeOther Testicular Insult
Secondary Hypogonadism Primary Hypogonadism
MRI in certain cases
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Case
• 52 y/o male with HTN asks for Viagra after 2 years of low libido
• BP 150/99
• Slight gynecomastia, nl GU exam
• T low, FSH &LH low, Prolactin very high
• What is the best next step?
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Best next step?
A) Prescribe Viagra
B) Testosterone replacement
C) MRI pituitary
D) Neurosurgery consult
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When Should You Get a Pituitary MRI?
• Severe secondary hypogonadism– T <150 ng/dl
• Symptoms/signs of tumor mass– HA, visual impairment, visual field defect
• Persistent hyperprolactinemia• Panhypopituitarism• Cost-effectiveness is unknown
– Don’t bother with a CT
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Should You Get a DXA?
• Recommend DXA in men with– Severe androgen deficiency– Low trauma fracture
• Cost-effectiveness is unknown
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Goals of Testosterone Therapy
• Improve/maintain secondary sexual characteristics
• Improve libido and erections
• Increase energy and well-being
• Improve muscle mass and strength
• Improve bone mineral density
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Who Should be Treated with T?
• Men with low T & signs/symptoms of AD
• Men with low testosterone & low libido
• Men with low testosterone & erectile dysfunction– After evaluation of underlying causes of ED– And consideration of other treatment for ED
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Who Else Should be Treated with T?
• Men with low testosterone, HIV infection & weight loss– Short-term treatment– For weight-maintenance, lean body mass, &
muscle strength
• Men with low testosterone & taking high dose glucocorticoids– Short-term treatment– For lean body mass and bone mineral density
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What About Older Men?
• Recommend against offering T to all older men with low T
• Treat men with consistently low T and clinically significant symptoms– After explicit discussion of pros and cons
• Task force disagreed on T level below which T should be offered to older men with symptoms– Depends on the severity of symptoms– Some T<300– Some T<200
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Case
• 75 y/o male had a lower thoracic vertebral fracture after falling on a wet floor
• Non-smoker, non-drinker, 1 glass milk/day• Poor energy• Libido and erections “not what they used to be”• T low x 2, LH and FSH “normal”• Anemic, normal calcium & phos• DXA T-score at L-spine -2.6, at femur -1.9• What is the best treatment course?
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Best treatment?
A) Nasal calcitonin
B) Bisphosphonate
C) Testosterone replacement
D) Calcium and Vitamin D
E) Testosterone & bisphosphonate
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Who should NOT receive testosterone therapy?
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Contraindications to Testosterone Therapy
• Breast or prostate cancer• Lump/hardness on prostate exam by DRE• PSA >3 ng/ml that has not been evaluated for
prostate cancer• Severe untreated BPH (AUA/IPSS >19)• Erythrocytosis (hematocrit >50%)• Hyperviscosity• Untreated obstructive sleep apnea• Severe heart failure (class III or IV)
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Testosterone for the Following Reasons May be Harmful
• To improve strength/athletic performance
• For physical appearance
• To prevent aging
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How Do You Give Testosterone?
• Start at standard dose• Check levels• Therapeutic target
– Serum testosterone in mid-normal range for healthy, young men
• Target in older men– Considerable disagreement among experts– Total T in the lower part of the normal range for
younger men– 400-500 ng/dl
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Nongenital Transdermal Patch
• Mimics normal diurnal rhythm• Less increase in hemoglobin than
IM shots• Start at 1-2 x 5 mg nightly to the
skin of the back, thigh, or upper arm– Away from pressure areas– Some men need 2 patches
• Skin irritation/redness/rashes
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Testosterone Gel• Starting dose 5-10 grams daily• Skin tolerates it well• Potential transfer to others by skin contact
– Cover the application site– Wash hands with soap and water after application– Wash skin before skin-to-skin contact with others– T levels maintained when skin washed 4-6 hours after
application
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Testosterone Enanthate or Cypionate Injections (IM)
• T levels are supraphysiologic, then gradually drop to hypogonadal range– Peaks and valleys– Fluctuation of mood or libido
• Relatively inexpensive if self-administered• Start at 75-100 mg IM weekly
– Or 150-200 mg IM every other week
• Pain at injection site• Excessive erythrocytosis (esp in older pts)
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Buccal, Bioadhesive T Tablet
• Normalizes T and DHT
• 30 mg to buccal mucosa twice daily q12h
• Gum-related adverse events in 16%– Gum irritation
• Examine gums and oral mucosa for irritation
– Alteration in taste
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Testosterone Pellets
• 4-6 200-mg pellets implanted subQ
• Serum T peaks at 1 month and then is sustained in normal range for 4-6 months
• Requires surgical incision for insertion
• Infection risk
• Pellets may spontaneously extrude
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Monitoring T Levels
• Target the mid-normal range
• Timing– Injections: mid-way between injections
• Target 350-700 ng/dl, adjust dose or frequency
– Patch: 3-12 hours after application– Gel: after 1-2 weeks of treatment– Buccal tab: immediately before next tab
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Safety Monitoring• Baseline
– Testosterone level– DRE– PSA– Hematocrit
• Follow-up ~3 months then annually– Assess improvement/side effects– Testosterone level– DRE– PSA
• age- and race-appropriate interval
– Hematocrit
• If osteoporosis - DXA at 1-2 years
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When to Consult a Urologist• Average PSA increase after starting T
– 0.3 ng/ml in young men, 0.44 ng/ml in older men– Increase >1.4 in any 3-6 month period unusual
• PSA up 1.4 ng/ml in any 1 year• PSA >4.0 ng/ml• PSA velocity >0.4 ng/ml per year
– If sequential PSA’s over 2 years– Using the PSA after 6 months of T therapy as a reference
• Abnormality on DRE• American Urologic Association or IPSS prostate
symptom score of >19
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Hematocrit
– If >54% stop T until safe level– Evaluate for hypoxia and OSA– Then restart at lesser dose
– Smoking cessation– Phlebotomy
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Conclusion
• Screen symptomatic patients & high risk populations
• Evaluate for the underlying cause– Primary vs. Secondary
• Treat symptomatic patients with unequivocally low testosterone levels
• Options: shots, patches, pills, buccal– Pt preference, cost, side effects
• Monitor for adverse events
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Thank You
Questions?
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Case
• 60 y/o male c/o ED, gradual over years• Same sexual partner x 25 years• HTN & CABG• ACE-I and beta blocker• Mildly enlarged prostate on DRE• Testosterone 310 and 350 (ref 280-880)• LH & FSH normal• What should you try first?
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What should you try first?
A) Psychiatry consult
B) IM injections of testosterone
C) Decrease beta blocker
D) Viagra
E) Finasteride
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Case
• 35 y/o male’s wife called worried about her otherwise healthy husband’s sperm count
• Trying to conceive x 2 years• Decreased sex drive x 1 year – pressure?• Exam normal• Afternoon T 240 (ref 280-880)• Sperm count 15 million (ref >20 million)• Best next step?
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Best next step?
A) MRI pituitary
B) Draw AM testosterone, LH, FSH & repeat semen analysis in 3 days
C) Draw LH & FSH
D) Scrotal US
E) Order strict morphology on semen analysis
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Case
• 30 y/o WM with DM-1 x 20y presents for infertility• DM good control (A1c 7.2%), occasional diarrhea• Fair-skinned, completely normal exam• Semen analysis - Normal sperm count, decreased
motility• Testosterone, LH, FSH, prolactin all normal• Anemic, MCV low• ALT 104, AST 83• TSH and Free T4 normal• Best next step?
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Best next step?
A) Pituitary MRI
B) Scrotal skin biopsy with sequencing of androgen receptor
C) Tissue transglutaminase antibodies
D) Iron/TIBC/Ferritin
E) Sperm antibodies
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Case
• 35 y/o man presents with infertility & azoospermia
• Puberty at age 15, normal libido, shaves every other day
• 72” tall, 180#, gynecomastia, small testes
• Normal thyroid & phallus
• T low, LH high, FSH high
• Best test to establish definitive diagnosis?
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Definitive Diagnosis?
A) Scrotal US
B) Karyotype
C) Ferritin
D) LFT’s
E) MRI pituitary
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Eunuchoidal body habitusVariable androgenizationLong extremities (LS>US)Karyotype: XXY
Klinefelter’s SyndromeKlinefelter’s Syndrome
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Klinefelter’s Syndrome
• Most common endocrine cause of primary hypogonadism
• FSH always • T variably affected (T or normal)
• Fertility rare (in mosaics only)
• Treatment: T only if needed– Will not reverse infertility
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Case• 36 y/o man has fatigue, infertility, poor energy x6
months • Few morning erections, cannot sustain intercouse• Decreased shaving frequency• Generalized skin darkening despite no sun exposure• 4 months ago random BG was >200, started on DM
diet and glipizide• Enlarged liver, tan without tan lines• Normal thyroid, breast, GU exam • Testosterone is low, TSH & Free T4 normal