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 scleraeNo thyromegaly. No neck vein engorgement. No carotid bruit.

Equal chest expansion. Clear breath sounds. No gynecomastia.No heaves or thrills. Apex beat and PMI 5th ICS LMCL. Good S1 and S2. No murmurs.Abdomen flabby, soft. No tenderness, masses or organomegaly.No edema or varicosities. Full pulses.Pubic hair and genitalia Tanner Stage V.

BP 130/80HR 80 RR 16Wt 88 kg Ht 1.77 cm BMI 28 kg/m2Waist circ 103 cmHip circ 100 cmWaist-hip ratio 1.03

The Case

FBS 181 mg/dL HbA1c 6.6%AST 192 (NV <47 u/L)Uric acid 295 mmol/LBUN 5.1 mmol/L Crea 76 Total cholesterol 208 mg/dLHDL 48 mg/dL LDL 124 mg/dLTriglyceride 179 mg/dL

The Case

Lab work from studyLH 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 11. The patient fulfills the NCEP-ATP III criteria for

Metabolic Syndrome as he hasa. elevated total cholesterol, low HDL, diabetes

and hypertensionb. elevated triglycerides, BP >130/85 mm Hg,

diabetes and abdominal obesityc. elevated total cholesterol, elevated LDL,

diabetes and abdominal obesityd. 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/m2Waist circ 103 cm Hip circ 100 cmWaist-hip ratio 1.03 FBS 181 mg/dL HbA1c 6.6%Total cholesterol 208 mg/dLHDL 48 mg/dL LDL 124 mg/dLTriglyceride 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 11. The patient fulfills the NCEP-ATP III criteria for

Metabolic Syndrome as he hasa. elevated total cholesterol, low HDL, diabetes

and hypertensionb. elevated triglycerides, BP >130/85 mm Hg,

diabetes and abdominal obesityc. elevated total cholesterol, elevated LDL,

diabetes and abdominal obesityd. elevated total cholesterol, low HDL,

hypertension and abdominal obesity

Question 22. All of the following are signs and/or symptoms

of androgen deficiency EXCEPTa. depressionb. lethargyc. weight lossd. 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 22. All of the following are signs and/or symptoms

of androgen deficiency EXCEPTa. depressionb. lethargyc. weight lossd. sleep disturbance

Question 22. All of the following are signs

and/or symptoms of androgen deficiency EXCEPTa. depressionb. lethargyc. weight lossd. sleep disturbance

Question 33. The patient should have been screened for

erectile dysfunction regardless of enrollment in the studya. Yesb. No

Erectile Function Domain 0 1 2 3 4 5How often were you able to get an erection during sexual activity?

X

When you had erections after stimulation, how often were your erections hard enough for penetration?

X

When you attempted sexual intercourse, how often were you able to penetrate (enter) your partner?

X

During sexual intercourse, how often were you able to maintain erection after you had penetrated (entered) your partner?

X

During sexual intercourse, how difficult is it to maintain your erection to completion of intercourse?

X

How do you rate your confidence that you could get and keep an erection?

X

Total score 11 = moderate EF score

International Index of Erectile Function

0 = No sexual activity1 = Almost never/never2 = A few times (much less than half the time)3 = Sometimes (about half the time)4 = Most times (much more than half the time)5 = Almost always/always

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

Feldiabetesan et al J Urol 1994;151:54-61Kaiser FE. Med Clin North Am 1999;83:1267-78

Cross-sectional survey in a community-based clinic541 men with diabetes

6% 52% 55-95%

20-24 y 55-59 y >60 y

~ 50% in an unselected

population (Massachusetts

Aging Male Survey)

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

Question 33. The patient should have been screened for

erectile dysfunction regardless of enrollment in the studya. Yesb. No

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

and in their secretory capacity, as well asby an age-related decrease in episodic andstimulated gonadotropin secretion (25).

The second hormonal system demon-strating age-related changes is the cir-culating levels of dehydroepiandrosterone(DHEA) and its sulphate (DHEAS), whichgradually decline with age, resulting in “ad-renopause” (26, 27). Adrenal secretion ofDHEA gradually decreases over time,whereas adrenocorticotropin (ACTH) se-cretion, which is physiologically linked toplasma cortisol levels, remains largely un-changed. The decline in DHEA(S) levels inboth sexes contrasts therefore with themaintenance of plasma cortisol levels andseems to be caused by a selective decrease inthe number of functional zona reticulariscells in the adrenal cortex rather than reg-ulated by a central (hypothalamic) pace-maker of aging (27).

The third endocrine system that gradu-ally declines in activity during aging is thegrowth hormone (GH)/insulin-like growthfactor I (IGF-I) axis (Fig. 2) (5, 28). Meanpulse amplitude, duration, and fraction ofGH secreted, but not pulse frequency, grad-ually decrease during aging. In parallel,there is a progressive fall in circulatingIGF-I levels in both sexes (28). There is no

evidence for a “peripheral” factor in thisprocess of “somatopause,” and its triggeringpacemaker seems mainly localized in thehypothalamus, because pituitary soma-totrops, even of the oldest old, can berestored to their youthful secretory capac-ity during treatment with GH-releasingpeptides.

We do not know whether the changesin gonadal function (menopause and an-dropause) are interrelated with the pro-cesses of adrenopause and somatopause,which occur in both sexes. In addition,functional correlates (such as muscle sizeand function, fat and bone mass, progres-sion of atherosclerosis, and changes incognitive function) have not been relatedto these changes in endocrine activity.However, a number of effects of normalaging closely resemble features of (isolated)hormonal deficiency (such as hypogonadismand GH deficiency), which in mid-adultpatients are successfully reversed by replace-ment therapy with the appropriate hormone(29). Although aging does not simply re-sult from a variety of hormone deficiencystates, medical intervention in the pro-cesses of meno-, andro-, adreno-, or so-matopause might successfully prevent ordelay some aspects of the aging process.

Menopause and Andropause

In most women, this period of decline inestrogens is accompanied by vasomotor reac-tions, depressed mood, and changes in skinand body composition (increase in body fatand decrease in muscle mass). In the subse-quent years, the loss of estrogens is followedby a high incidence of cardiovascular disease,loss of bone mass, and cognitive impairment(Fig. 3) (30). The average age of menopause(51.4 years) has not changed over time andseems to be largely determined by geneticfactors. Because life expectancy is increasing,the time a woman spends after menopauseconstitutes more than one third of her life.Long-term (5 to 10 years) hormone replace-ment with estrogens in combination withprogestins starting at menopause has manyadvantages (31). Apart from relieving hotflashes and mood changes, reducing skin andreproductive tract atrophy (such as drynessof the vagina and urinary incontinence), andpreventing changes in body composition, es-trogen/progestin replacement therapy delaysatherosclerosis, loss of bone mass, and loss ofcognitive function. Life expectancy seemsnot to be influenced by estrogen/progestinreplacement, but atherosclerosis and boneloss are considerably delayed (Table 1) (31).An exciting observation is the apparent de-lay in the onset of Alzheimer’s disease inwomen treated with hormone replacement(32). The mechanisms of these estrogen ef-fects on the aging brain are speculative atpresent (33).

There are, however, also importantnegative effects of estrogen/progestin re-placement therapy during menopause.The most compelling problem is the in-creased incidence of breast cancer (Table1) (34). Little data are available on theeffects of a yearly mammogram on morbid-ity and mortality of breast cancer patientsdiagnosed during or after hormone re-placement therapy. In addition, the in-convenience of irregular menstruationshas an effect on long-term compliancewith this treatment. [“Nonbleeding” estro-gen/progestins have recently been devel-oped, however (35)]. At present, the de-cision to start hormone replacement atmenopause should be based on the indi-vidual’s risk factors, her attitude towardhormonal treatment, and knowledge of itsrisks and benefits. Knowledge and educa-tion influence this decision; in a recentSwedish study, only 24% of women aged54 years but 72% of female general prac-titioners and 88% of female gynecologistswere on estrogen/progestin replacementtherapy (36).

A new development in the search foroptimalizing hormone replacement therapyduring menopause came from observations

Fig. 3. Changes occurring in the hormone levels of normal women (left) and men (right) during the agingprocess. Estrogen secretion throughout an individual normal woman’s life (expressed as urinary estro-gen excretion) is shown at the top left [after (22)], and the mean free T index (the ratio of serum total T tosex hormone–binding globulin levels) during the lifespan of healthy men is shown at the top right. In themiddle panels, serum DHEAS concentrations in 114 healthy women (left) and 163 healthy men (right) areshown [adapted from (26)]. In the lower panel, the course of serum IGF-I concentrations in 131 healthywomen (left) and 223 healthy men (right) during aging is shown [adapted from (28)]. Note the differencein the distribution of ages in the different panels.

ARTICLES

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Free T index = serum total T / SHBG

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

Prevalence of Metabolic Syndrome Increases with Age in Males

Study NPrevalence

in malesPrevalence

by age

NHANES III (US)8814 adults

>20 y24%

6.7% (20-29 y) 43.5% (60-69 y)

N. Trondelag Study (Norway)

10206 adults 20-89 y

26.8%13% (20-29 y)46% (80-89 y)

Urban Chinese (China)

2359 adults >40 y

36.8%35.3% (40-64 y)43.2% (>65 y)

Ford et al JAMA 2002:287:356-9Hildrum et al BMC Public Health 2007

Lin et al BMC Public Health 2007

Declining androgen levels associated with components of the Metabolic Syndrome

Obesity

Hypertension

Dyslipidemia

Impaired glucose tolerance

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

Low T is associated with insulin resistance; diabetic men have low T levels

Inverse correlation between T levels and SBP/DBP; ↑hypogonadal men with history of hypertension in HIM study

Positive correlation between plasma T levels and HDL-C; inverse correlation with triglycerides, total cholesterol and LDL-C

Lunenfeld B. The Aging Male 2007;10(2):53-6 Wu & von Eckardstein. Endocr Rev 2003;24(2):183-217

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

• For every 1 SD decrease in total T: adj RR 1.41 (95%CI, 1.06-1.87)

• Symptomatic androgen deficiency: RR 2.51 (95% CI 1.12-5.65)

Early warning sign for CV risk and opportunity for early 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 <8 nmol/L (230 ng/dL): usually benefit from T treatment

Total T 8-12 nmol/L: repeat total T with SHBG to calculate free T

Total T >12 nmol/L (350 ng/dL) does not require 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

The Case

Lab work from studyLH 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)

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


•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

Pathophysiology and factors complicating diabetic ED


Modifiable risk factors for ED


Risk Factor StrategySedentary lifestyle Increase physical activityDepression Treatment of depressionDiabetes Improved controlAlcohol Abstinence from alcoholTobacco Quit smoking/use of patchHypogonadism Testosterone replacementOverweight or obesity Weight loss

Question 44. The patient has low testosterone levels. Will

you start testosterone replacement for this patient?a. Yesb. Noc. It depends

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)

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)




•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




•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



Question 44. The patient has low testosterone levels. Will

you start testosterone replacement for this patient?a. Yesb. Noc. It depends

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)

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 DosageImplants Testosterone 200 mg Testosterone implants 200 mg 3-6 implants every 6 months

IntramuscularTestosterone enanthate 250 mg Testosterone depot 250 1 ampule every 2-3 weeks

Testosterone undecanoate Nebido 1 ampule every 10-14 weeks

Oral Testosterone undecanoate Andriol Testocaps 2-4 capsules at 40 mg/day

Transdermal

Testosterone patch Androderm 2x5 mg/day

TTS scrotal Testoderm 1 membrane/day

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



Historical overview of T preparations available for clinical use

walk test and also in mood (Pugh et al., 2004). No adverseeffects of testosterone on hematocrit or any other parameterwere observed. A longer term study is in progress to investigatethese findings further.

Current evidence suggests that testosterone acts as an arterialvasodilator. This is supported by the finding that vascular stiff-ness in aorta and radial arteries increases in men with prostatecancer treated with a GnRH analogue (Smith et al., 2001). Lab-oratory studies have shown that testosterone has a direct effect onvascular smooth muscle cells (Jones et al., 2003b) which isendothelium-independent, non-genomic (independent of the clas-sic androgen receptor) and mediated via a calcium channel block-ing effect (English et al., 2002; Jones et al., 2003a,c ). It hasrecently been demonstrated that testosterone is a selective andpotent inhibitor of vascular L-type calcium channels acting atconcentrations within the physiological range (Scragg et al.,2004).

Based on the currently available data, there is no convincingevidence of an adverse effect of testosterone replacementtherapy on coronary heart disease or chronic heart failure, andthere may be a role for testosterone in the treatment of cardio-vascular diseases in men.

Potential effects on the prostate

Testosterone replacement therapy increases prostate volume tothat of normal men (with a wide inter-individual variance)(Behre et al., 1994). The final size of the prostate achievedunder testosterone substitution is influenced by the androgenreceptor gene polymorphism. Hypogonadal men with fewerCAG nucleotide repeats in exon 1 of the gene attain larger pros-tate volumes than those with more CAG repeats (Zitzmann et al.,2003). In patients with pre-existing prostate enlargement, orurinary flow obstruction, testosterone replacement therapyshould be used with caution. However, it remains uncertainwhether testosterone substitution is of benefit or will worsen thesymptoms in this condition.

Concerns over the effects of testosterone replacement on pros-tate cancer stem from the fact that most prostate adenocarcino-mata are androgen-dependent in their early stages. The largemajority of patients harbouring foci of prostatic adenocarcinomaare not clinically detected, and, of those that are, the largemajority of patients do not die from this disease (Ruijter et al.,

1999). Concerns have therefore also been raised over whetherraising androgen levels in these patients might alter the pheno-type of an otherwise non-aggressive prostatic adenocarcinoma.To date, the most robust study of the correlation between serumtestosterone levels and the incidence of prostate cancer is a meta-analysis of three epidemiological studies (Shaneyfelt et al., 2000).This study concluded that individuals with a serum testosteroneconcentration in the upper quartile of the population distributionhave an increased risk of developing prostate cancer. However,this observation has limited relevance to the effects of increasinglow testosterone levels to within the normal range and a large,long-term study is required to resolve this issue. Screening forprostate cancer [using prostate specific antigen (PSA) monitoringand digital rectal examination] is recommended before initiatingtherapy and periodically throughout treatment in younger menand is mandatory in men over 45 years.

Treatment options

According to the World Health Organization Guidelines for Useof Androgens in Men (1992), the ideal testosterone replacementtherapy should offer: safety, efficacy, value for money, conven-ience, a good release profile, dosing flexibility, and effectivenormalization of testosterone levels.

The ideal testosterone therapy should also replace testosteroneto physiologic levels using natural (unmodified) testosterone.

A number of routes of delivery have been used in testosteronereplacement therapy over the years (Figure 4). Although thesetherapies have contributed significantly to alleviating the burdenof male hypogonadism, none of them fully satisfy the WHOdefinition of an ideal therapy (WHO, 1992). In the experience ofthe authors, the selection of different currently available testos-terone preparations, both at national and local hospital formularylevels, appears to be largely based on market forces (i.e. pricingand reimbursement issues) rather than differences in efficacy andsafety, or desire to offer patients a choice of treatment, despitethe long-term nature of treatment.

Implants

This is the oldest form of testosterone replacement therapy,available since the 1940s and still marketed in the UK. Betweenthree and six pellets of 200mg unmodified testosterone are

Figure 4. Different testosterone preparations and the years they became available for clinical use: 1940 ! subdermal testosterone pellet implants, 1954 !intramuscular testosterone enanthate, 1977 ! oral testosterone undecanoate, 1992 ! scrotal testosterone patch, 1995 and 1998 ! transdermal testosteronepatches, 2002 ! transdermal testosterone gels, 2004 ! buccal testosterone and intramuscular testosterone undecanoate.

E.Nieschlag et al.

414

1940 subdermal T pellet implants, 1954 IM T enanthate, 1977 oral T undecanoate, 1992 scrotal T patch, 1995 and 1998 transdermal T patches, 2002 transdermal T gels, 2004 buccal T and IM T 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) before 30-wk injection

Injection interval

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, steady state, and as warranted clinically

For i.m. T injection, measure serum T at the midpoint between injections

Free 5-21 ng/dL

% free 2.0-4.8%

Bioavailable T 92-420 ng/dL

DHT 30-85 ng/dLAs warranted clinically

LH 1.29-1.8 IU/l At 3-6 months

Indicated for hypergonadotropic hypogonadism. Failure to 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 55. If testosterone replacement is given for this

patient, all the following should be done at baseline EXCEPTa. Hemoglobin/hematocritb. ALT/ASTc. Breast examinationd. Creatinine

Potential risks of androgen therapy


Potential risk Comments

Cardiovascular disease Existing evidence suggests a neutral or possibly beneficial effect

Lipid alterations Most studies show no change with physiologic replacement doses

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

Fluid retention Rarely of clinical significance

BPH Rarely of clinical significance

Prostate cancer Controversial; unknown level of risk; requires long-term monitoring

Potential risks of androgen therapy


Potential risk CommentsAcne or oily skin Infrequent

Testicular atrophy or infertility

Common especially in young men, usually reversible with cessation of treatment

Erythrocytosis Wide range of risk, depending on mode of 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 yearly if stable and normalHematocrit 42-52%

Serum lipid panel (ATP III)

TC <200 mg/dLLDL-C <70-160 mg/dLHDL-C >40 mg/dLTG <350 mg/dL

Baseline, 6-12 mo of first year, then annually

ALT 13-40 U/L At baseline, 6-12 months, and as warranted clinicallyAST 19-48 U/L

Breast examination

Baseline

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.

Question 55. If testosterone replacement is given for this

patient, all the following should be done at baseline EXCEPTa. Hemoglobin/hematocritb. ALT/ASTc. Breast examinationd. Creatinine

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