Adult Male Hypogonadism

Amy Neumeister, MD FACP

Objectives: Adult Male Hypogonadism

• Screening • Diagnosis/Differential • Treatment • Adverse events & safety monitoring

Normal Male Reproductive Axis

Hypothalamus

GnRH

Pituitary

FSH LH

Testes

Sperm Inhibin T E

Seminiferous Tubule Leydig Cell Aromatase 5  reductase Estradiol DHT

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 Hypogonadism Depends 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

The ADAM Questionnaire

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.

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) Morning Total T Normal T Low T Exclude reversible illness, drugs, nutritional deficiency Do you suspect altered SHBG?

Not Hypogonadism Follow up Semen analysis if fertility issue Repeat T Check LH+FSH If altered SHBG Use free or bio T Normal T, LH+FSH

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 T Low or normal LH+FSH Low T High LH+FSH Secondary Hypogonadism Primary Hypogonadism Prolactin, iron sats Other pituitary hormones Karyotype Klinefelter Syndrome Other Testicular Insult 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) B) Prescribe Viagra 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) B) C) D) E) Nasal calcitonin Bisphosphonate Testosterone replacement Calcium and Vitamin D 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) B) C) D) E) Psychiatry consult IM injections of testosterone Decrease beta blocker Viagra 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) B) C) D) E) MRI pituitary Draw AM testosterone, LH, FSH & repeat semen analysis in 3 days Draw LH & FSH Scrotal US 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) B) Pituitary MRI 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

Syndrome

Eunuchoidal body habitus Variable androgenization Long extremities (LS>US) Karyotype: XXY

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