Adult Male Hypogonadism

Amy Neumeister, MD FACP

Objectives:Adult Male Hypogonadism

• Screening

• Diagnosis/Differential

• Treatment

• Adverse events & safety monitoring

SpermInhibin

Normal Male Reproductive Axis

GnRH

FSH LH

Hypothalamus

Pituitary

Seminiferous Tubule

LeydigCell

Aromatase 5 reductase

EstradiolDHTTestes

TE

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)

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

Definition of Androgen Deficiency (AD)

• Consistently low testosterone

• Associated signs/symptoms

• Evidence based review of literature– Data is weak at best

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

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

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

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

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

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

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

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

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

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

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

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

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?

Best next step?

A) Prescribe Viagra

B) Testosterone replacement

C) MRI pituitary

D) Neurosurgery consult

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

Should You Get a DXA?

• Recommend DXA in men with– Severe androgen deficiency– Low trauma fracture

• Cost-effectiveness is unknown

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

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

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

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

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?

Best treatment?

A) Nasal calcitonin

B) Bisphosphonate

C) Testosterone replacement

D) Calcium and Vitamin D

E) Testosterone & bisphosphonate

Who should NOT receive testosterone therapy?

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)

Testosterone for the Following Reasons May be Harmful

• To improve strength/athletic performance

• For physical appearance

• To prevent aging

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

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

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

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)

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

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

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

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

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

Hematocrit

– If >54% stop T until safe level– Evaluate for hypoxia and OSA– Then restart at lesser dose

– Smoking cessation– Phlebotomy

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

Thank You

Questions?

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?

What should you try first?

A) Psychiatry consult

B) IM injections of testosterone

C) Decrease beta blocker

D) Viagra

E) Finasteride

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?

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

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?

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

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?

Definitive Diagnosis?

A) Scrotal US

B) Karyotype

C) Ferritin

D) LFT’s

E) MRI pituitary

Eunuchoidal body habitusVariable androgenizationLong extremities (LS>US)Karyotype: XXY

Klinefelter’s SyndromeKlinefelter’s Syndrome

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

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