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ĺ Male Menopause
ĺ Andropause
ĺ PADAM Partial Androgen Deficiency Aging Men

Condition may affect millions, but symptoms are rarely recognized

Public awareness campaign launched to help them-SARCASM

2 page ad in Time. In last several years, lots of ads in Money, Forbes, and
various magazines.

³testosterone running on empty´


Video game at Endocrine Meeting since 2003- several drug Co many
marketing Test

Primary Care Journals

Doctors told screen symptoms Ļ T


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³testosterone running on empty´


Video game at Endocrine Meeting since 2003- several drug Co many
marketing Test

Primary Care Journals

Doctors told screen symptoms Ļ T


Ads paid by Unimed, a part of Belgian conglomerate
(Solvay)

Make Androgel ± FDA approved In 2000


Fastest growing T replacement therapy for men

Pills (introduced in the 60¶s) ± often causes liver damage

IntraMus injection ± sharp T spike then mall, mood swings,


libido, energy

Transdermal Patch (late 80¶s) ± still widely used. Safe


steady dose, skin irritation, falls off in exercise
Androgel ± colorless drying gel rubbed on
shoulders 1x a day
Convenient to use in almost any man

If HRT for andropause common as menopause ±


hich is the ambition of drug companies
DRAMATIC medical and financial consequences

Given popular desire to reverse human aging and


growing intimacy of commercial and clinical
concerns-trend may be irresistible (look up
Andropause on net----anti aging web sites)
Pharm. Company is ³in the business of inventing
treatments´
how about diseases?
Dr. Abraham Morgentaler ± urologist specializes in male
sexual dysfunction and infertility

Views T deficiency in older men as silent epidemic

5 million USA men affected and >95% not diagnosed

Replace T??

Restore youthful muscle tone, bone strength, potency,


vigor
AD in Boston Globe-have T tested-paid for by Unimed
Patient in office was getting T levels tested.
Doctor said several patients (professors)

³made their brains much sharper´


Ôeed to make sure no prostate cancer ±
highly aggravated by T

Six biopsies samples to check -PSA


(prostate specific antigen) blood test

Give you prescription now and you can start


once we complete tests
T-derived from cholesterol, primarily made in testes via pituitary signals

Men older than 40, decreased T by 1.2% per year

Patient 1 ± little low, excited about T therapy

Patient 2 ± said Primary care doc normal T 800 ng/dl


Morgantaler ± T normal range

³free T´ was another matter

Ôormally 2% free ± not bound to other proteins & thus active

Patient¶s free T little under lower limit (for normal men in mid 20¶s)
Check PSA & start Androgel

FDA never approved Androgel for andropause.


Intended for use Klinfelter¶s & pituitary dysfunction and
viral effected testes

Klinfelter¶s - Congenital disorder in men,


have extra X and underdeveloped testes

Ôot many people with these or similar conditions


(pit or hypothamic), yet 35 million US men over
50 so if ³andropause takes of´« billions $$$

ERT in menopausal women


> 2 billion year for yeth, for Premarin
  

Big Pharmaceutical gets approval for drug of rare disease


to hopefully expand/profit later on

Drug approved ± doctor can legally prescribe for any


clinical condition

FDA prohibits ads of ³off label uses´-alternative strategies


Run an ad to ³raise awareness´ of condition
Align themselves with experts and ³opinion leaders´

Finance Certain Research from MD¶s


Offer them consulting opportunities
Endorsed by a major medical society
Endocrine Society 2000 ± 1st Ann. Andropause Conference

Support by Medical Society Helps


Panel to define andropause and how it should be treated

Men over 50 should be screened & get T therapy if lower than 300
And no condition that would rule out therapy (Prostate
}
cancer)
ÔO STUDY TO SHO BEÔEFIT OF T IÔ OLDER MEÔ
Panel predicted that
Low T found in more than 10% of males over 50
30% of males over 70
7 million MEÔ in USA
Unimed grant sole source of conference funding and recommended
panel members. 9 out 13 panelist had ties to drug company

BAD!!!!!!!!!!!!!!!!!!!!
³Bid to Medicalize Middle age may be supported by pharmaceutical
industry, but it remains poorly supported by scientific research´

Decline In T levels really responsible for most symptoms in aging


men???

hat T levels normal???

Andropause exist???

Limits of our medical knowledge was evident from a visit to


Dr. illiam Crowley & Dr. Hayes

MGH measure hormone levels


Found Huge variability in T levels
Studied hypogonadalim and needed good
indication of normal T levels
Healthy Men in Early 20¶s ±drew blood every
10 min for 24hrs
15% below normal levels during day
> 50% below cutoff
T LEVELS REALLY VARY in healthy MEÔ
Efficiency of T receptors
(highly efficient, don¶t need much T?)
- Stress decreases sex steroids
- Unsure of Variation in T levels, maybe
effected by drug interactions
T deficiency may be easily over diagnosed
because of variability
Don¶t understand where # of 5 million
andropause men comes from

Commercial Tests physicians use


notoriously unreliable (300-900) with one
test and (160-700) on another
Test for free T even less accurate
Dr. Morgentaler says doesn¶t matter ± even
gives it as preventative treatment
Ôo waiting for scientific validation
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Safety issue ± huge concern

ÔIH thinking of 6 yr study placebo controlled

Andropause driven by Pharmaceutical Co rather than physiology

Elevate T in 72 yr old man to levels he had at 20 ± is this normal


Might be better to have lower levels with aging-protect against P
cancer
Cause epidemic of prostate cancer??

Conventional HRT in women increases risk of Breast Cancer,


heart attack, blood clots, and stroke
Ôationwide trials were SHUT DO Ô
26% increase in invasive Breast cancer
Ôonetheless, T replacement increasingly popular
In 2001 sales transdermal T 
ell over ¼ million US Men use T
Rates Continue ± 1 million within 2 years
Total  of  in the United States
were about $18 million until 1988; the figure rose
to $400 million in 2002
In 2004, the testosterone replacement market in
Europe and in the US was estimated to be
approximately $600 million. The US market is by
far the most attractive with a growth rate of 40%
(cash) and sales of $537million, of which $422
million were sales of testosterone gels
VAST UÔCOÔTROLLED EXPERIMEÔT
R!*0(8(

%  of  therapies have


grown to more than $1 billion per year, with
 of  gels in the US comprising
$700 million.
Action of T on target cells
Hormone binds SHBG in circulation.
Sex hormone binding globulin
hen free can diffuse across PM
Acted upon by 5a-reductase to make DHT
AR is in cytosol and bound to HSP
Displaced by DHT (DihydroT)
AR gets phosphorylated and forms a dimer
and translocated to the nucleus
Binds to promoters at AREs
(Androgen Response Elements)
Does Menopause exist?
Ovary is unique in that woman¶s age at
which it ceases to function appear to have
remained constant despite our increased
longevity over last century
Loss of ovary function-profound impact on
hormonal milieu
Risks of disease due to decreased Estrogen
In males, germ cells become quiescent and
maintain stem cell identity
In females, all germ cells differentiate prior
to birth
90% of women experience menopause at 51.2
years. Remainder prior to age 46
Only 1% before the age of 40
Both genetic and environmental factors effect
decline in fertility and onset of M
M=ovarian aging supported by
Coincident occurrence of follicular depletion
Elevation of gonadotropins
Menstrual irregularity with ultimate cessation
Estrogens
Main estrogen during premenopause is 17b
estradiol. Controlled by developing follicle
and corpus luteam
95% derived from ovaries
Other sources
Peripheral conversion from T to estradiol
In post menopausal women-estrone
Biological potency 1/3 that of estradiol
Derived from peripheral conversion from
androstenedione.
Derived from peripheral conversion from
androstenedione.
AROMATASE
Extra glandular aromatase-fat, liver, some
nuclei in hypothalamus
Activity increases with age and amount of
FAT
Estrone and Estradiol
40ug/dl and 6 ug/dl post MEÔ
80-500 ug/dl in PreMEÔ
Ô hÔ
h 
Menopausal consequences

1. Vasomoter symptoms (hot flash)


80% women have for at least a year
25% still have 5 yrs after last period
Correlate with pulses of LH
Likely some central mediator as LH does not
induce hot flash
Disturb REM sleep
Usually treated with estrogen
Menopausal consequences
2. Genital Atrophy
Vagina, vulva, urethra and bladder all have
estrogen receptors
Ôo estrogen-atrophy
Itching and vaginal thinning
Dryness, painful intercourse
pH changes, different flora increase risk of
UT infections
Treatment-vaginal estrogen.
Menopausal consequences
3. Osteoporosis-condition in which bone loss
has been sufficient to allow mechanical
fracture with limited stress.
Menopausal bone loss begins before final
menstrual period
Post men osteoporosis accounts of 1.3
million fractures per year in USA
Most hip fractures (250,000) due to
osteoporosis
15% patients die within one year of hip
fracture and 75% lose independence
Menopausal consequences
3. OSTEOPOROSIS cont«..
Bone loss premen 1-2% year
: '5
Treatment ±estrogen
 
:-hormone made by thyroid gland
Effect in bone density in 12-18 months
$
 $-selective estrogen receptor
modulators
: #.

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Does Menopause exist? YOU BET


omen different then men (GERM CELLS)

Does andropause EXIST? Maybe not


How evil are drug companies?
How greedy are some doctors? (politicians)
vacation areas for conference
Consulting fees
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