Metabolic Syndrome and Erectile Dysfunction

Erectile Dysfunction and
Metabolic Syndrome
Iris Thiele Isip Tan MD (PhiSSAM)
Dennis Serrano MD (PUA)

The Case
•46/M on follow-up at Diabetes Clinic
•Known diabetic x 5 years
•Glimepiride 2 mg od and Metformin 500 mg bid
•Currently smoking
‣ 60-pack year smoking history

The Case
•RUQ pain unrelated to food or movement
3 months PTC
‣ Fatty liver changes on ultrasound
•Screened for erectile dysfunction for a study
‣ IIEF-5 score: 11

The Case
Pink conjunctivae, anicteric sclerae
No thyromegaly. No neck vein BP 130/80
engorgement. No carotid bruit.
HR 80
Equal chest expansion. Clear breath
sounds. No gynecomastia.
RR 16
Wt 88 kg
No heaves or thrills. Apex beat and PMI
5th ICS LMCL. Good S1 and S2. Ht 1.77 cm
No murmurs. BMI 28 kg/m2
Abdomen ﬂabby, soft. No tenderness, Waist circ 103 cm
masses or organomegaly.
Hip circ 100 cm
No edema or varicosities. Full pulses.
Waist-hip ratio 1.03
Pubic hair and genitalia Tanner Stage V.

The Case
FBS 181 mg/dL HbA1c 6.6%
AST 192 (NV <47 u/L)
Uric acid 295 mmol/L
BUN 5.1 mmol/L Crea 76
Total cholesterol 208 mg/dL
HDL 48 mg/dL LDL 124 mg/dL
Triglyceride 179 mg/dL

The Case
Lab work from study
LH 6.8 (NV 1.9-9.4 uIU/dL)
FSH 2.5 (NV 1.0-10.5 uIU/L)
Prolactin 526 (NV 90-500 nmol/L)
SHBG 51.8 (NV 7-81 nmol/L)
Total testosterone 2 (NV 2.8-5 nmol/L)
Free testosterone 0.00373 (NV 0.225 nmol/L)
Bioavailable testosterone 0.138 (NV 5.2 nmol/L)

What is the diagnosis?
Metabolic syndrome (Type 2 diabetes mellitus,
hypertension, obesity, dyslipidemia)
Fatty liver
Erectile dysfunction
Hypogonadotrophic hypogonadism

Question 1
1. The patient fulﬁlls the NCEP-ATP III criteria for
Metabolic Syndrome as he has
a. elevated total cholesterol, low HDL, diabetes
and hypertension
b. elevated triglycerides, BP >130/85 mm Hg,
diabetes and abdominal obesity
c. elevated total cholesterol, elevated LDL,
diabetes and abdominal obesity
d. elevated total cholesterol, low HDL,
hypertension and abdominal obesity

NCEP-ATP III (2001) deﬁnition
Metabolic Syndrome

Three or more of

• Central obesity (waist circ)
‣ >102 cm ( ) & >88 cm ( )

• TG >150 mg/dL
• HDL <40 ( ) & <50 ( ) mg/dL

• BP >130/>85 mm Hg
• FPG >110 mg/dL

The Case
BP 130/80
Wt 88 kg Ht 1.77 cm BMI 28 kg/m2
Waist circ 103 cm Hip circ 100 cm
Waist-hip ratio 1.03
FBS 181 mg/dL HbA1c 6.6%
Total cholesterol 208 mg/dL
HDL 48 mg/dL LDL 124 mg/dL
Triglyceride 179 mg/dL

IDF deﬁnition
Metabolic Syndrome

Central obesity (waist circ)
‣ >90 cm ( ) & >80 cm ( )

PLUS any two of
• TG >150 mg/dL
• HDL <40 ( ) & <50 ( ) mg/dL

• SBP >130 mm Hg or
DBP >85 mm Hg or on treatment
• FPG >100 mg/dL or pre-existing
IFG or IGT

Metabolic Syndrome
predicts CV mortality

Question 2
2. All of the following are signs and/or symptoms
of androgen deﬁciency EXCEPT
a. depression
b. lethargy
c. weight loss
d. sleep disturbance

Signs/Symptoms of
Androgen Deﬁciency
‣ Loss of libido
‣ Depression (current use of
antidepressants)
‣ Erectile dysfunction
‣ Lethargy
‣ Inability to concentrate
‣ Sleep disturbance
‣ Irritability
‣ Depressed mood

Kupelian et al JCEM 2006;91:843-50

Late-onset
Hypogonadism (LOH)
‣ Age-associated testosterone
deﬁciency syndrome (TDS)
‣ Clinical and biochemical syndrome
associated with advancing age
‣ Characterized by symptoms and a
deﬁciency in serum T levels (below
young healthy adult male reference
range)

ISA, ISSAM, EAU, EAA and ASA recommendations: investigation,
treatment and monitoring of late-onset hypogonadism in males.
The Aging Male March 2009;12(1):5-12

Suggestive of T deﬁciency
‣ Low libido
‣ Erectile dysfunction
‣ Decreased muscle mass and strength
‣ Increased body fat
‣ Decreased bone mineral density and
osteoporosis
‣ Decreased vitality and depressed
mood


Use of Questionnaires
•Not recommended for the
diagnosis of hypogonadism
because of low speciﬁcity
‣ Aging Male Symptom Score
‣ Androgen Deﬁciency in Aging Men


Question 2
2. All of the following are signs
and/or symptoms of androgen
deﬁciency EXCEPT
a. depression
b. lethargy
c. weight loss
d. sleep disturbance

Question 3
3. The patient should have been screened for
erectile dysfunction regardless of enrollment in
the study
a. Yes
b. No

International Index of Erectile Function
Erectile Function Domain 0 1 2 3 4 5
How often were you able to get an X
erection during sexual activity?
When you had erections after stimulation, X
how often were your erections hard
enough for penetration?
When you attempted sexual intercourse, X
how often were you able to penetrate 0 = No sexual activity
(enter) your partner? 1 = Almost never/never
X
During sexual intercourse, how often 2 = A few times (much less than half the time)
were you able to maintain erection after 3 = Sometimes (about half the time)
you had penetrated (entered) your 4 = Most times (much more than half the time)
partner? 5 = Almost always/always
During sexual intercourse, how difﬁcult is X
it to maintain your erection to completion
of intercourse?
How do you rate your conﬁdence that X
you could get and keep an erection?
Total score 11 = moderate EF score

ED in Diabetes
•35-75% of men with diabetes have ED

•Compared to age-matched control subjects, men with
diabetes develop ED ~5-10 years earlier

Romeo et al J Urol 2000;163:788-91

Prevalence of ED in diabetes
increases with age
Cross-sectional survey in a ~ 50
pop %i
community-based clinic n an
ulat
541 men with diabetes Agin ion unsele
gM (Ma cted
ale ssa
Sur chu
vey sett
6% 52% 55-95% ) s

20-24 y 55-59 y >60 y
Feldiabetesan et al J Urol 1994;151:54-61
Kaiser FE. Med Clin North Am 1999;83:1267-78

ED in Diabetes
•Correlated with HbA1c

•Presence of peripheral neuropathy increases risk of ED

‣ Underlying autonomic neuropathy

‣ Almost 100% of patients with diabetic neuropathy have ED

Romeo et al J Urol 2000;163:788-91

Evaluation of ED

?
•Medication history
‣ Antihypertensives: B-blockers and thiazide diuretics
‣ Acting on CNS: TCA, SSRI, phenothiazines,
butyrophenones, atypical antidepressants
‣ Affecting endocrine: anti-androgens, GnRH agonists and
antagonists, estrogens, cimetidine, metoclopramide, ﬁbric
acid derivatives, alcohol, marijuana

Theti et al Clinical Diabetes 2005;23(3):105-13

Evaluation of ED
•Vascular disease
‣ Doppler studies of penile blood ﬂow
‣ Pharmacodynamic testing using vasoactive compounds
‣ Pudendal angiography and cavernosometry
•Psychosocial Assessment
‣ Combine with nocturnal penile tumescence test
‣ Marital counseling


Evaluation of ED
•Hormonal status
‣ LH, FSH, prolactin
‣ Testosterone level
‣ Ferritin (to evaluate for hemochromatosis)
•Autonomic neuropathy
‣ ECG (R-R variability), heart rate variability
‣ Orthostatic blood pressure readings
‣ Tilt table testing


Gradual Decline of T in Aging Males

Free T index = serum total T / SHBG

Lamberts et al. Science 1997;278:419-24

Prevalence of Metabolic Syndrome
Increases with Age in Males

Prevalence Prevalence
Study N
in males by age
8814 adults 6.7% (20-29 y)
NHANES III (US) 24%
>20 y 43.5% (60-69 y)
N. Trondelag 10206 adults 13% (20-29 y)
26.8%
Study (Norway) 20-89 y 46% (80-89 y)
Urban Chinese 2359 adults 35.3% (40-64 y)
36.8%
(China) >40 y 43.2% (>65 y)
Ford et al JAMA 2002:287:356-9
Hildrum et al BMC Public Health 2007
Lin et al BMC Public Health 2007

Declining androgen levels associated with
components of the Metabolic Syndrome

Inverse correlation between plasma T levels and
Obesity BMI, WC, WHR and amount of visceral fat

Positive correlation between plasma T levels
Dyslipidemia and HDL-C; inverse correlation with
triglycerides, total cholesterol and LDL-C
Inverse correlation between T levels and
Hypertension SBP/DBP; ↑hypogonadal men with history
of hypertension in HIM study

Impaired glucose Low T is associated with insulin
tolerance resistance; diabetic men have low T levels
Wu & von Eckardstein. Endocr Rev 2003;24(2):183-217
Lunenfeld B. The Aging Male 2007;10(2):53-6

Low T: A Marker of Metabolic Syndrome?

•Low total T and symptomatic
androgen deﬁciency increased
risk for metabolic syndrome in
non-obese men (BMI<25) over
time Early warning
• For every 1 SD decrease in total T: sign for CV risk
adj RR 1.41 (95%CI, 1.06-1.87) and opportunity
• Symptomatic androgen deﬁciency: for early
RR 2.51 (95% CI 1.12-5.65)
intervention in
non-obese men
Kupelian et al JCEM 2006:91:843-850

No recommendation to
screen men with
symptoms of T deﬁciency
for metabolic syndrome

No recommendation to
screen men with metabolic
syndrome for T deﬁciency

2009 Uniﬁed ISA, ISSAM, EAU, EAA and ASA
Recommendations for Late-onset Hypogonadism

Recommendation 8

•Serum T should be measured in men with type 2
diabetes mellitus with symptoms suggestive of T
deﬁciency (Level 2b, Grade A)


The Case
Lab work from study

SHBG 51.8 (NV 7-81 nmol/L)
Total testosterone 2 (NV 2.8-5 nmol/L)
Free testosterone 0.00373 (NV 0.225 nmol/L)
Bioavailable testosterone 0.138 (NV 5.2 nmol/L)

Laboratory diagnosis of LOH in males

Obtain serum sample for total T between 0700 and 1100 h

Total T >12
Total T <8 nmol/L Total T 8-12 nmol/L:
nmol/L (350
(230 ng/dL): repeat total T with
ng/dL) does
usually beneﬁt SHBG to calculate
not require
from T treatment free T
substitution
Consider
treatment if free T
below 225 pmol/L
(65 pg/mL)


Algorithm for suspected hypogonadism

Lunenfeld & Nieschlag,The Aging Male 2007;10(3):139-153

Hypogonatrophic hypogonadism

•Common in obese men and those with type 2 diabetes

‣ Attributed to ↑ levels of estrone and estradiol produced by
aromatase enzyme in adipose tissue from adrenal
(androstenedione) and testicular (testosterone) androgen

‣ Aging also associated with progressive decline in androgens


Nitric oxide (NO) and erection


Pathophysiology and factors
complicating diabetic ED
•Reduced nitric oxide (NO)
‣ Advanced glycation end products → increase in reactive
oxidizing substances and reduced NO production
‣ Failed neural signal transmission to and from the spinal cord
due to diabetic neuropathy and reduced production of
neuronal NO synthase → reduced levels of neuronal NO
release to cavernosal smooth muscle
‣ Endothelial dysfunction of the sinusoidal endothelial cells →
decrease in NO release and impaired vasodilatation


Pathophysiology and factors
complicating diabetic ED
• Increasing age and hyperglycemia → glycation of elastic
ﬁbers → failure of relaxation of the corpora cavernosa
• Peripheral vascular disease → reduced arterial and
arteriolar inﬂow
•Hypogonadotrophic hypogonadism
•Multiple drug regimens
•Dyslipidemia


Modiﬁable risk factors for ED

Risk Factor Strategy
Sedentary lifestyle Increase physical activity
Depression Treatment of depression
Diabetes Improved control
Alcohol Abstinence from alcohol
Tobacco Quit smoking/use of patch
Hypogonadism Testosterone replacement
Overweight or obesity Weight loss


Question 4
4. The patient has low testosterone levels. Will
you start testosterone replacement for this
patient?
a. Yes
b. No Total testosterone
c. It depends 2 (NV 2.8-5 nmol/L)
Free testosterone
0.00373 (NV 0.225 nmol/L)
Bioavailable testosterone
0.138 (NV 5.2 nmol/L)

Who should receive T replacement?

•Reserved for those who are androgen
deﬁcient, especially if use of a PDE-5
inhibitor is contemplated

‣ Neuronal NO production is androgen
dependent

‣ PDE-5 inhibitors require the presence of NO
to be effective



•Men with erectile dysfunction and/or
diminished libido and documented T
deﬁciency are candidates for T therapy
(Level 2a, grade A)

‣ An inadequate response to T treatment
requires reassessment of the causal
mechanisms responsible for the ED



•Evidence suggesting therapeutic
synergism with combined use of T and
PDE-5 inhibitors in hypogonadal or
borderline eugonadal men (Level 1b, grade B)

‣ Consider combination treatment in
hypogonadal patients with ED failing to
respond to either treatment alone

‣ Unclear whether men with hypogonadism and
ED should be treated initially with PDE-5-I, T
or both


•Premature to recommend T treatment for
metabolic syndrome or type 2 diabetes
mellitus in the absence of laboratory and
other clinical evidence of hypogonadism

‣ T treatment for traditional hypogonadal
symptoms may have other unproven beneﬁts
on their metabolic status (Level 2a, grade B)


Testosterone treatment and CV events

Wide conﬁdence interval: consistent with 1-fold
decrease and a 4-fold increase in odds of CV events in
patients using testosterone
Haddad et al Mayo Clin Proc 2007;82(1):29-39

Who should NOT receive T replacement?
•Contraindicated in men with breast or prostate CA
(Level 3, grade A)

•Relatively contraindicated in men at high risk of
developing prostate CA
‣ Unclear whether localized low-grade (Gleason score <7)
prostate cancer represents a relative or absolute
contraindication for treatment (Level 4, grade C)


Who should NOT receive T
replacement?

•Men with signiﬁcant erythrocytosis
(Hct >52%) (Level 3, grade A)
•Untreated signiﬁcant obstructive
sleep apnea (Level 3, grade B)
•Untreated severe congestive heart
failure (Level 3, grade B)
•Resolve co-morbid conditions prior
to T treatment


Who should NOT receive
T replacement?

•Aging is NOT a
contraindication to initiate T
treatment (Level 2a, grade A)
‣ Individual assessment of co-
morbidities (as possible
causes of symptoms) and
potential risks vs beneﬁts of T
treatment


Recommendations for androgen therapy

•Preparations of natural testosterone should be used
‣ 17-α-alkylated androgen preparations i.e. 17α-
methyltestosterone are obsolete because of potential liver
toxicity (Level 2a, grade A)
‣ Non-testosterone androgen precursor preparations (i.e.
DHEA, DHEA-S, androstenediol, androstenedione) are not
recommended (Level 1b, grade A)


Recommendations for androgen therapy

•Not enough evidence to recommend anti-estrogens and
aromatase inhibitors which ↑ endogenous T levels (Level
2b, grade B)
•Selective androgen receptor modulators are under
development but not yet clinically available
‣ Non-aromatizable and risks of long-term use unclear


Testosterone delivery systems

•Currently available preparations of T are safe and
effective (Level 1b, grade A)
‣ Intramuscular, subdermal, transdermal, oral and buccal
Route Generic name Trade name Dosage
Implants Testosterone 200 mg Testosterone implants 200 mg 3-6 implants every 6 months
Testosterone enanthate 250 mg Testosterone depot 250 1 ampule every 2-3 weeks
Intramuscular
Testosterone undecanoate Nebido 1 ampule every 10-14 weeks
Oral Testosterone undecanoate Andriol Testocaps 2-4 capsules at 40 mg/day
Testosterone patch Androderm 2x5 mg/day
TTS scrotal Testoderm 1 membrane/day
Transdermal
Testosterone gel 25 or 50 mg Testogel Androptop gel 50-100 mg/day
Testosterone gel 50 mg Testim 50-100 mg/day
Buccal Testosterone 30 mg Striant 1 tablet twice daily
Lunenfeld and Nieschlag The Aging Male 2007 10(3):139-53 The Aging Male March 2009;12(1):5-12

not die from this disease (Ruijter et al., three and six pellets of 200 mg unmo

Historical overview of T preparations
available for clinical use

1940 subdermal T pellet implants, 1954 IM T enanthate, 1977 oral T undecanoate,
one preparations and the years they became available for clinical use: 1940 ¼ subdermal testostero
1992 scrotal T patch, 1995 and 1998 transdermal T patches, 2002 transdermal T gels,
nanthate, 1977 ¼ oral testosterone undecanoate, 1992 ¼ scrotal testosterone patch, 1995 and 1998
2004 buccal T and IM T undecanoate
testosterone gels, 2004 ¼ buccal testosterone and intramuscular testosterone undecanoate.

Nieschlag et al Hormone Reprod Update 2004, 10(5):409-19

Oral testosterone undecanoate

•Safe and effective, free of liver toxicity
‣ Circumvents the ﬁrst passage through the liver
•Brings serum T within the physiological range
•Liposoluble
‣ 120-200 mg daily taken with meals
‣ Extremely variable absorption and bioavailability; inﬂuenced
by amount of simultaneously ingested fat

Morales and Lunenfeld The Aging Male 2002;5:74-86

IM testosterone undecanoate

•Single injection of 1000
mg T undecanoate
normalize serum T levels
for about 3 months
•Free from supra-
physiological peaks
‣ Maintains very stable
serum testosterone levels
within normal range for an
extended period of time

Jockenhovel F. The Aging Male 2003;6:200-206


•Sufﬁcient knowledge and adequate understanding of
pharmacokinetics and advantages/drawbacks of each
preparation
‣ Selection of preparation should be a joint decision of an
informed physician and patient



•Short-acting preparations may be preferred over long-
acting depot preparations in the initial treatment of
patients with LOH (Level 4, Grade C)
‣ Possible development of an adverse event during treatment
(especially elevated hematocrit or prostate carcinoma)
requires rapid discontinuation of T substitution


Goals of treatment for T replacement

•Restore normal serum testosterone levels into the
physiologic range
•Restore metabolic parameters to the eugonadal state
•Increase muscle mass, strength,and function
•Maintain BMD and reduce fracture risk
•Improve neuropsychological function (cognition and
mood)
•Improve libido and sexual functioning
•Enhance quality of life

Lunenfeld and Nieschlang The Aging Male 2007 10(3):139-53

Recommended standard (initial regimen) for
i.m. testosterone undecanoate therapy

Total serum testosterone (nmol/L)
Injection interval
before 30-wk injection
10-15 12 weeks
<10 10 weeks
>15 14 weeks

Morales et al The Aging Male 2006, 9(4):221-7

Monitoring efﬁcacy of T replacement

Parameter Reference range Frequencya Comments
Serum testosterone
Total 300-1050 ng/dL
At baseline, For i.m. T injection,
Free 5-21 ng/dL steady state, and measure serum T at the
% free 2.0-4.8% as warranted midpoint between
clinically injections
Bioavailable T 92-420 ng/dL
As warranted
DHT 30-85 ng/dL
clinically
Indicated for
hypergonadotropic
hypogonadism. Failure to
LH 1.29-1.8 IU/l At 3-6 months suppress to normal range
indicates inadequate
replacement
a Monitor clinical response and side effects at 3- to 4- month intervals
during the ﬁrst year of therapy unless otherwise designated.

A Seftel. Int J Impot Res 2007;19(1):2-24

For how long?

•Discontinue T replacement if clinical manifestations do
not improve within a reasonable time interval
‣ 3-6 months: for libido and sexual function, muscle function,
and improved body fat
‣ Longer interval for bone mineral density
•Further investigation for other causes of symptoms is
then mandatory (Level 1b, Grade A).


Question 5
5. If testosterone replacement is given for this
patient, all the following should be done at
baseline EXCEPT
a. Hemoglobin/hematocrit
b. ALT/AST
c. Breast examination
d. Creatinine

Potential risks of androgen therapy

Potential risk Comments
Existing evidence suggests a neutral or possibly
Cardiovascular disease beneficial effect
Most studies show no change with physiologic
Lipid alterations replacement doses

Wide range of risk, depending on mode of
Erythrocytosis administration (up to 44% with i.m.); requires monitoring

Fluid retention Rarely of clinical significance
BPH Rarely of clinical significance
Controversial; unknown level of risk; requires long-term
Prostate cancer monitoring


Potential risks of androgen therapy

Potential risk Comments
Acne or oily skin Infrequent
Testicular atrophy or Common especially in young men, usually reversible
infertility with cessation of treatment
Wide range of risk, depending on mode of
Erythrocytosis administration (up to 44% with i.m.); requires monitoring
Sleep apnea Infrequent
Gynecomastia Rare, usually reversible
Skin reactions Rare with injections


Monitoring for safety

Parameter Reference range Frequency
Hemoglobin 13-18 g/dL Every 6 months x first 18 months then
Hematocrit 42-52% yearly if stable and normal
TC <200 mg/dL
Serum lipid panel LDL-C <70-160 mg/dL Baseline, 6-12 mo of first year, then
(ATP III) HDL-C >40 mg/dL annually
TG <350 mg/dL
ALT 13-40 U/L At baseline, 6-12 months, and as
AST 19-48 U/L warranted clinically
Breast
Baseline
examination
Sleep apnea Baseline and as needed clinically

a Monitor clinical response and side effects at 3- to 4- month intervals
during the first year of therapy unless otherwise designated.


Thank You
http://www.endocrine-witch.info

Metabolic Syndrome and Erectile Dysfunction

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