What is [Low-T]? Definition of Male Hypogonadism Hypogonadism in men is a clinical syndrome that...

http://www.isitlowt.com

What is [Low-T]?

Definition of Male Hypogonadism• Hypogonadism in men is a clinical syndrome that

results from failure of the testis to produce physiological levels of testosterone (androgen deficiency) and a normal number of spermatozoa due to disruption of one or more levels of the hypothalamic-pituitary testicular axis

Endocrine Society clinical practice guideline

Wang C et al. Aging Male 2009;12(1):5– 12

Clinical Diagnosis – H&P

• Symptoms (non-specific)– Fatigue, decreased libido, erectile dysfunction– Androgen Deficiency in Aging Males (ADAM) test

http://www.isitlowt.com

Screening test for depression?

Clinical Diagnosis – H&P• Symptoms (non-specific)– Fatigue, decreased libido, erectile dysfunction– Androgen Deficiency in Aging Males (ADAM) test

• Associated disease statese.g. obesity, COPD, metabolic syndrome, diabetes, etc.– Is low-T the cause of these diseases?– Is it a complication of these diseases?– Is it a co-morbidity?

Clinical Diagnosis – H&P• Symptoms (non-specific)

– Fatigue, decreased libido, erectile dysfunction– Androgen Deficiency in Aging Males (ADAM) test

• Associated disease statese.g. obesity, COPD, metabolic syndrome, diabetes, etc.– Is low-T the cause of these diseases?– Is it a complication of these diseases?– Is it a co-morbidity?

• Signs– Mostly associated with congenital or developmental

hypogonadism (e.g. Klinefelter’s, undescended testes)

Definition of Male Hypogonadism

Hypogonadism in men is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone (androgen deficiency) and a normal number of spermatozoa due to disruption of one or more levels of the hypothalamic-pituitary testicular axis

Endocrine Society clinical practice guideline

Wang C et al. Aging Male 2009;12(1):5– 12

Lab Diagnosis of HypogonadismTotal testosterone <300 ng/dl• Based upon lower limit of total testosterone in young

men (usually quoted normal range of 300-1000 ng/dl)• No generally accepted lower limit of normal (lower limit

is 220 ng/dl at the Cleveland Clinic)• Does not necessarily reflect free testosterone levels• Should 70-yr old men be judged by norms for 30-yr olds?• 15% of healthy young men will have a testosterone level

below the normal range in any 24 hour period• Not necessarily indicative of “physiological levels of

testosterone”

Hypogonadism defined as Total Testosterone <300ng/dl

Definition of Male Hypogonadism

Hypogonadism in men is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone (androgen deficiency) and a normal number of spermatozoa due to disruption of one or more levels of the hypothalamic-pituitary testicular axis

Endocrine Society clinical practice guideline

Wang C et al. Aging Male 2009;12(1):5– 12

Low-T ≠ T-Deficiency• Low Testosterone levels do NOT necessarily

indicate hypogonadism or testosterone deficiency – testosterone levels can be low in normal, healthy young

men with normal sperm counts– lots of false positives with low serum testosterone

levels alone• Low sperm counts are necessary for the diagnosis

of hypogonadism, but seldom done

Low-T + Oligospermia = Hypogonadism

Work-up of Hypogonadism• LH/FSH primary vs. secondary• If LH/FSH are inappropriately low, need to get – TSH – am cortisol level – prolactin level to rule out S.O.L.– Consider MRI

Diagnosis of Low-T is made without ANY blood work in 20% of cases

Diagnosis of Low-T generally made without sperm counts or LH/FSH levels

Primary Hypogonadism• Testicular etiology• Causes:

Undescended testesKlinefleter’s syndromeHemochromatosis Mumps orchitisInjury to testes (e.g. cancer therapy)

Classification of Hypogonadism

Classification of Hypogonadism

Secondary Hypogonadism• Extra-testicular etiology• Causes:

Hypothalamic disorders (e.g. Kallmann syndrome)Pituitary disorders (e.g. tumor, surgery, radiation)Inflammatory disorders (e.g. TB, sarcoidosis)Medications (especially opioids)ObesityHIV

http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/endocrinology/male-hypogonadism/

Testosterone Declines Age

Late-Onset Male Hypogonadism

“Late onset hypogonadism (LOH, also referred to as age-associated testosterone deficiency, TDS) is a clinical and biochemical syndrome associated with advancing age and characterized by symptoms and a deficiency in serum testosterone levels (below the young healthy male reference range)”

ISA, ISSAM, EAU, EAA and ASA recommendations (2009)

Bhasin S et al. J Clin Endocrinol Metab 2010;95(6):2536–2559

Late-Onset Hypogonadism (LOH)Alternate Terminology

• Testosterone-Deficiency Syndrome (TDS)• Age-Related Testosterone Deficiency• Andropause• Androgen Deficiency of the Aging Male (ADAM)• Partial Androgen Deficiency of the Aging Male

(PADAM)

LOH = Low-T(+ oligospermia)

OK, Testosterone declines with age …

But is LOH a deficiency syndrome?or a degenerative syndrome?

DEFICIENCY DEGENERATIVE

Pathological Normal in the context of Aging?

Completely Reversible Not Readily Reversed

No Side Effects if in Physiological Range

Side Effects Possible (No Therapeutic Target Range)

If Low-T were a deficiency …

Artwork from: http://www.sci-news.com/medicine/science-low-testosterone-heart-problems-01418.html

then the syndrome should be completely reversible

Artwork from: http://www.sci-news.com/medicine/science-low-testosterone-heart-problems-01418.html

If Low-T were degenerative …

Artwork from: http://www.sci-news.com/medicine/science-low-testosterone-heart-problems-01418.html

then the syndrome is not so reversible

Artwork from: http://www.sci-news.com/medicine/science-low-testosterone-heart-problems-01418.html

Reversing Effects of Low-T ?

• Maintains bone density• Supports collagen• Face/body hair• Male-pattern baldness• Aggressiveness• Promotes prostate growth• Red blood cell production

• Sex drive• Erectile function• Well-being & energy• Builds muscle mass• Sperm production• Promotes heart health• Anti-obesity/diabetes• Prevents Alzheimer’s

Effects Attributed to Testosterone

Reversing Effects of Low-T ?

• Maintains bone density• Supports collagen• Face/body hair• Male-pattern baldness• Aggressiveness• Promotes prostate growth• Red blood cell production

• Sex drive• Erectile function• Well-being & energy• Builds muscle mass• Sperm production• Promotes heart health• Anti-obesity/diabetes• Prevents Alzheimer’s

Effects Attributed to Testosterone

Risks of Treating Low TPossible adverse effects of treatment• BPH / elevation of PSA• Acceleration of prostate CA / breast CA• Mortality, MI and stroke*• DVT• Worsening of OSA• Polycythemia

No physiological target range

*Vigen et al. JAMA 2013 Nov 6;310(17):1829-36; Basaria et al. NEJM 2010 Jul 8;363(2):109-22

Originator of “Low-T”• Dr. Abraham Morgentaler claims to have coined the term

“years ago”– Founder of Men’s Health Boston– Author of “Testosterone for Life”– associate clinical professor of urology at Harvard Medical

School– On Speaker Bureaus for Watson, Abbott (Abbvie),

Auxillium, Endo (not up to date)– Industry funded research/investigator for GSK (not up to

date)Claims testosterone does NOT cause prostate cancer

Is it a deficiency syndrome or a triumph of marketing?

Excerpt from Abstract:

In the absence of any new indications, off-label testosterone prescribing has increased in most countries in 2000–2011, especially over the last half of the period …

… By eliminating the fundamental distinction between pathological and functional androgen deficiency, these guidelines tacitly promote increased testosterone prescribing, bypassing the requirement for high-quality clinical evidence of safety and efficacy and creating dramatic increases in prescription of testosterone products.

Handelsman DJ. Med J Aust. 2013 Oct 21;199(8):548-51

Low “T” as in “Template” How to Sell Disease

Schwartz and Woloshin, JAMA Intern Med. 2013;173(15):1460-1462

Three strategies:1. Lower the bar – broaden the criteria for definition

to include more people2. Raise the stakes – “It is one thing to tell men that

Low T can make them grumpy; it is another to say that it can kill them.”

3. Spin the evidence – list symptoms/conditions associated with low endogenous testosterone; implication problems reversed with restoration exogenous testosterone

For baby-boomers, it’s all about SEX!

You know it’s really working when …

A man on TV is selling me a miracle cure that will keep me young forever. It’s called Androgel…for treating something called Low T, a pharmaceutical company–recognized condition affecting millions of men with low testosterone, previously known as getting older.

The Colbert Report, December 2012

Direct to Consumer Advertising fromAbbvie (formally Abbott) (makers of Androgel)

Are our memories really that short?

Remember What?

Women are Clearly Smarter than Men

Hello …?

RememberPremarin?

Women are Clearly Smarter than Men

Published in 1964Dr. Robert Wilson

“… menopause is a Hormone deficiencyand totally preventable”

Today, it wouldbe called: [Low-E]

Purported Benefits of Premarin• Prevents hot flushes• Prevents osteoporosis• Prevents vaginal atrophy• Keeps skin young by maintaining collagen• Reduce risks of heart attacks & strokes• Prevents Alzheimer’s• Prevents age-related macular degeneration• Reduce colon cancer risk• Help prevent diabetes, Parkinson’s, tooth loss, etc.

http://www.hotzehwc.com/en-US/Resource-Center/Articles/Broken-Promises--The-History-of-HRT.aspx

Data Actually Showed …• 1997: meta-analysis of 51 epidemiological studies increased risk of breast cancer

• 1998: Heart Estrogen/Progestin Replacement Study (HERS) no heart benefit, higher rates of cardiovascular disease

• 2002: Women’s Health Initiative (WHI) halted 3 years early due to risks of breast cancer and DVT/PE

• 2003: further analysis of WHI showed increased risks of breast CA and cardiovascular events

• 2013: estrogen might not increase cardiovascular toxicity in early menopause

Estrogen safe in early menopause?- Comparing Menopause & Andropause

Diagnosis of menopause is very specific, but diagnosis of LOH is plagued by false positives

Menopause = Low-ELow-T ≠ Andropause

Menopause is abrupt; andropause is gradualwhat is early andropause?Ok to treat flushing, osteoporosis, not as a hormone to restore youth

SAFETY OF TESTOSTERONE THERAPY CANNOT BE INFERED FROM WHI

Bottom Line:Testosterone replacement therapy is

probably not warranted at this time and should not be recommended until and unless long-term studies demonstrate

benefits outweigh risks of therapy

MEDICALIZATION

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MEDICALIZATION

Medicalization is a social process through which a previously normal human condition (behavioral, physiological or emotional) becomes a medical problem in need of treatment under the jurisdiction of medical professionals.

Examples of Medicalization

Less Controversial• Low-T• Menopause• ED• Mammary hypoplasia• Micrognathia• Overbite/underbite• Acne• Circumcision

More Controversial• Nutritional deficiency• Precocious puberty• Psychiatric diagnoses

(e.g. social anxiety, ADHD, bipolar disorder)

• Hyperlipidemia• Pain• Abnormal test results

(e.g. Pap smears, PSA)

Did I lose anyone?

QUESTIONS?Email: sfeng@johnsonmemorial.org