Male Sexual Dysfunction:

Evaluation,Treatment and the Role of Testosterone

UAPRN Georgia Conference

September 24, 2016

Elizabeth H. Burgess, MD

Learning Objectives

I.  3 Types of Male Sexual Dysfunction

II.  Focused H&P

III.  Choose labs

IV.  Primary vs. Secondary Hypogonadism

V.  Imaging

VI.  Treatment Options

VII.  Case Practice

3 Types of Male Sexual Dysfunction

u  Decreased libido

u  Erectile dysfunction

u  Ejaculatory dysfunction ( includes premature ejaculation, retrograde ejaculation)

u  Guideline on Male Sexual Dysfunction, European Association of Urology 2015. http://uroweb.org/wp-content/uploads/EAU-Guidelines-Male-Sexual-Dysfunction-2015-v2.pdf

3 questions

u  Libido

u  Morning erections

u  Erections partial or go away too fast?

Decreased libido

u  Psychological components

u  partner interactions or conflicts

u  stress, depression

u  Physical Components

u  systemic illness, sleep disorders

u  Medication side effects: especially SSRI’s, anti-HTN, anti-androgens, finasteride.

u  Alcoholism

u  Low testosterone

Erectile Dysfunction u  Erectile dysfunction – the inability to achieve and maintain an

erection sufficient for satisfactory sexual intercourse

u  Organic u  Vascular, neurologic, hormonal, drug related

u  Psychogenic u  Performance related issues, anxiety, depression, stress

u  Mixed

u  Affects up to 1/3 of adult men

u  Common in patients with HTN, ischemic heart disease and diabetes mellitus

Causes of Erectile Dysfunction – vary by onset

u  Neurologic - loss of spontaneous morning erections ( slow onset)

u  Vascular – loss of spontaneous erections (slow onset)

[CV disease, Diabetes, PVD...]

u  Psychogenic – (sudden onset)

u  Increased life stress

u  Performance anxiety in a new relationship

Causes of Erectile Dysfunction

u  Traumatic: after prostatectomy ( sudden onset )

u  Side effect of medications: thiazides, beta blockers, finasteride ( onset variable )

u  Hormonal – low testosterone ( slow onset )

u  Interpersonal conflict – rarely acknowledged

Ejaculation disorders

u  Premature ejaculation:

u  occurs within one minute of vaginal penetration and results in distress for the male. Treat with SSRI.

u  absent ejaculation:

u  side effect of antidepressants and alpha adrenergic antagonists like tamsulosin.

u  Retrograde ejaculation:

u  Bladder neck sphincter damage during prostate surgery.

u  Vacuum pump erection aids.

u  Present with infertility and azoospermia

3 questions

u  Libido

u  Morning erections

u  Erections partial or go away too fast?

History

u  Onset and duration –> sudden vs. slow onset

u  Relationship to new medication

u  Increased life stress

u  trauma

u  Presence of chronic diseases

u  SHIM – sexual health inventory for men

History

u  Symptoms of low testosterone

u  Low energy

u  fatigue

u  decreased libido

u  decreased muscle mass

u  decreased body hair

u  hot flashes

u  gynecomastia

u  Infertility

u  puberty? children?

Physical exam

u  General Physical – vascular or neurologic abnormalities, absence of testosterone effect.

u  Femoral pulses or bruits and peripheral pulses

u  Neurologic exam – monofilament testing in feet/hands, position sense, vibratory sense at the extremities

u  Hair growth pattern: Body hair, facial hair

u  body habitus – eunuchoid?

Physical Exam u  GU exam:

u  Penile plaques àPeyronie’s disease

u  micropenis

u  Testicles – small, soft, atrophic?

u  Gynecomastia

u  VF confrontation – bitemporal hemianopsia

Labs

u  CMP for liver and kidney function

u  TSH

u  Lipid profile to assess cardiac disease

u  Fasting glucose, A1C

Should we just screen for low testosterone? NO

u  Population screening is not cost effective.

u  Pursue case detection in groups that are high risk

u  Absent libido and spontaneous morning erections

u  Osteoporosis associated fractures

u  HIV associated weight loss

u  Those on chronic narcotics or high dose steroids for prolonged periods

u  Men with small atrophic testes on exam.

How often is low testosterone the problem?

u  20% of men in their 60s will have hypogonadism

u  30% of men in their 70s will have hypogonadism

u  Not all erectile dysfunction, decreased libido, loss of muscle mass, depression or decreased sense of well being is related to low testosterone.

u  Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: A Systemic Analysis. Mayo Clin Proc August 2015:90(8): 1104-1115

Labs: Testosterone testing

u  Serum total testosterone before 8am ( AACE before 10am)

u  If serum total testosterone is below normal on lab reference, confirm by repeating the total testosterone

u  Free testosterone if you suspect SHBG problem àSHBG decreased in obesity and increases with age

u  Check LH, if testosterone is confirmed as low. Consider prolactin, free t4 if testosterone <150

Imaging: http://www.bing.com/images/search?q=mri+picture+of+pituitary+macroadenoma&view=detailv2&id=36A2EF1459B801B85D2307EDD1E8759CE5C6531B&selectedindex=4&ccid=RaAkw4R3&simid=608030205750019560&thid=JN.BoR2WemaHt2Ruc625uB%2FJg&mode=overlay&first=1

u  If more than one pituitary hormone is low,

àMRI

Pituitary macroadenoma http://www.bing.com/images/search?q=mri+picture+of+pituitary+macroadenoma&view=detailv2&id=36A2EF1459B801B85D2307EDD1E8759CE5C6531B&selectedindex=4&ccid=RaAkw4R3&simid=608030205750019560&thid=JN.BoR2WemaHt2Ruc625uB%2FJg&mode=overlay&first=1

Etiology of low testosterone

u  If there is indication for checking testosterone, and low values found and confirmed, DETERMINE CAUSE

u  Not enough to find a low testosterone and just treat.

u  Need to give patient an explanation for why the testosterone is low.

Hypogonadism

Primary vs. Secondary

Both Primary and Secondary Hypogonadism cause

u  Loss of sperm production

u  Loss of testosterone production

u  Primary (testes): FSH and LH elevated, testosterone low

u  Secondary (pituitary or hypothalamus): FSH and LH low or inappropriately normal and testosterone low.

Hypothalamic Pituitary Axis

X X

X

Hypogonadism? u  Prevalence 4 to 35% in men with Erectile Dysfunction.

u  One study of 422 men with ED u  Hypogonadism 19%

u  Hypothyroidism (hypogonadotropic hypogonadism)

or hyperthyroidism (increased SHBG) in 6%

u  Hyperprolactinemia 4%

u  Drugs that raise prolactin inhibit fsh/lh and lead to hypogonadotropic hypogonadism

Common drugs that raise prolactin

u  Haloperidol, risperidone

u  Amitriptyline, sertraline, fluoxetine, paroxetine, buspirone, alprazolam

u  Metoclopramide

u  Verapamil

u  Morphine

u  Ranitidine, cimetidine

Ther Clin Risk Manag. 2007 Oct; 3(5):929-951

Evaluation and Treat

u  History

u  Physical Exam

u  Labs

u  Now what?

First case

u  50 yo male with BMI of 25 presents complaining of erectile dysfunction

u  Libido low, morning erections occur but not as often, + fatigue and low energy, erections for intercourse are partial

u  Thinks he has thyroid problems or low testosterone

u  Physical exam –> 1+ DP/PT pulses, o/w normal

u  GU: testes not soft, 20cc volume.

u  Labs drawn at 1:30pm

Labs

u  Testosterone 248mg/dl ( normal 300 to 1000) (other assays use 168-746ng/dl)

u  Tsh is 2.5 uIU/ml

u  Should we treat?

u  Remember time of day, confirm x 1 and if consistently low, check LH.

First case

u  Repeat testosterone was 400 ng/dl at 8am.

u  Trial of phosphodiesterase inhibitor given with adequate response

u  Meds reviewed and HCTZ changed to alternate agent.

Medications can cause Erectile Dysfunction

u  Most common drugs associated with ED are anti-HTN meds

u  Thiazides and Beta blockers

u  Chronic narcotics -cause suppression of FSH/LH

u  Side effects of finasteride/SSRI’s.

u  Sometimes better to adjust meds vs adding another…

FDA approved treatments

u  PDE inhibitors: if neurologic or vascular etiology suspected. Can help libido.

u  Sildenafil/Viagra, Vardenafil/Levitra, Tardenafil/Cialis ( longest acting ), Avanafil

u  Contraindicated with nitrates

u  Caution with alpha blockers – use low dose

u  Side effects of nasal congestion, priapism, vision /hearing changes

Sildenafil citrate is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE5) in smooth muscle, where PDE5 is responsible for degradation of cGMP. Sildenafil citrate increases cGMP within vascular smooth muscle cells resulting in relaxation and vasodilation. In patients with erectile dysfunction, sildenafil citrate enhances the effect of nitric oxide (NO) by inhibiting PDE5 in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil citrate causes increased levels of cGMP resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum www.medbullets.com/phosphodiesteraseinhibitorsmechanismofaction

If oral PDE inhibitor fails

u  Second line u  Alprostadil suppositories in urethral meatus

u  May cause burning discomfort

u  Third line u  Intracavernosal injections of alprostadil

u  Can be painful

u  Fourth line u  Penile implant

u  Erect aid vacuum pump – if pt’s can’t take meds.

ED and CV disease

u  Endothelial dysfunction – common pathway

u  Consider CV evaluation before initiating therapy for sexual dysfunction

u  Assess whether low, medium or high risk

u  Medium and High risk patients may need stress test/CV evaluation

u  Nitrates contraindicated with PDE inhibitors

Second case

u  Obese 70 yo male with BMI 48 presents with erectile dysfunction

u  Testosterone at 3pm 200ng/ml u  normal 300-1000ng/ml

u  Repeat at 8am was 180ng/ml

u  Repeat with free and total testosterone and LH

u  total testosterone 150 ( low)

u  free testosterone 90 ( normal ),

u  LH 6 ng/ml (normal).

u  WHY?

SHBG

u  Sex hormone binding globulin abnormalities occur for various reasons

u  Decreased in obesity ( makes a total testo seem low)

u  Increases with age ( makes a total testo seem normal)

u  Can increase with liver diseases like hepatitis C.

u  This patient had normal free testosterone and is not hypogonadal.

u  What else can happen to androgens in obese patients?

Obesity and Aromatization

Case 3 - Older Veteran

u  66 yr old found to have low testosterone level on evaluation for erectile dysfunction. Wife died several years before and he is interested in dating again.

u  total testosterone was 156 at 8:51 am

u  Repeat total testosterone was 117 at 9:23am

u  FSH 3.3 and LH 2.3 ng/ml ( low normal )

Case 3 continued

u  Repeat with total testosterone 145 (low) and free testosterone 22 (low)

u  Prolactin normal at 5.1

u  TFT’s normal

Case 3- continued

u  PMHx:

u  BPH and chronic prostatitis.

u  +sleep apnea and has CPAP but doesn’t use

u  MEDs:

u  Takes 40mg of oxycontin SR BID for back and knees. Prescribed for years.

u  takes finasteride and terazosin “If I miss a dose, I can’t pee.”

u  Social: fathered two children. Normal puberty.

Physical Exam

u  Bp 130/68, hr 87, temp 98.3, resp 16

u  BMI 32

u  VF intact

u  Mild gynecomastia ~3-4 cm bilaterally, nontender

u  GU: normal phallus, testes 12cc volume and soft, atrophic

Assessment and Plan

u  Hypogonadotropic hypogonadism

u  Physical exam c/w hypogonadism

u  Prolactin, TFTs, liver, kidney, blood sugar normal.

u  FSH and LH inappropriately low/normal for low total and free testosterone levels

u  MRI recommended

u  He declines. Can’t lie still b/c of back pain. Denies HA, n/v, VF cuts

Assessment

u  Hypogonadotropic Hypogonadism

u  Chronic narcotics likely playing a significant role.

u  Common cause of hypogonadotropic hypogonadism.

u  Testosterone?

Testosterone ? Endocrine Society Clinical Practice Guideline for Testosterone Replacement in Men 2010

Controversial in this patient for several reasons

u  Untreated sleep apnea –

u  BPH that requires 2 meds and is symptomatic if he forgets to take meds.

u  >65 and risk for increased CAD.

Critical Update of the 2010 Endocrine Society Clinical Practice Guideline for Male Hypogonadism Mayo Clinic Proc. August 2015:90(8):1104-1115

u  Reconfirmed: Only treat with clear hypogonadal symptoms and testosterone levels <200.

u  Contradindications to reconsider: Untreated sleep apnea and LUTS

u  Another look at CV disease and testosterone use in men over 65

u  Other groups that might benefit from testosterone: u  Patients with type 2 diabetes

u  Metabolic syndrome

u  Compensated CHF

Contraindication to reconsider: untreated sleep apnea

u  Untreated sleep apnea:

u  Hoyos et al RCT on 67 middle aged obese men. Treated with IM testosterone x 18 weeks. Only saw increased O2 desat at 7 weeks, not at final end point. No increase in apnea. (Clin Endocrinology (Oxf). 20012;77(4):599-607)

u  Hildreth et al RCT in healthy hypogonadal males, treated with Testosterone gel. No increase in Epworth Sleepiness Score or daytime hypoxemia. (JCEM 2013;98(5):1891-1900)

Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: A Systemic Analysis. Mayo Clin Proc August 2015:90(8): 1104-1115

Contraindication to reconsider: elevated LUTS score

u  LUTS score >19 on International Prostate Symptom Score questionnaire = contraindication to TRT in 2010 recommendations from Endocrine Society.

u  Severe LUTS has been an exclusion criterion

u  Tan et al RTC of 114 hypogonadal men treated with IM testosterone for 48 weeks. 14.9% had severe LUTS symptoms measured by IPSS. NO difference in symptoms between treated and placebo arms. Small improvement in LUTS symptoms in the treatment arm. ( p=0.54 ) (BJU Int. 2013;111(7):1130-1140)

u  Strict contraindication?

Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: A Systemic Analysis. Mayo Clin Proc August 2015:90(8): 1104-1115

Testosterone and CV Disease: MAYO 2015 Update

u  Most data is from large retrospective cohort studies

u  VA 8709 patients – increased CV outcomes in testosterone treated patients.

u  Finkle evaluated database of 55,593 men for acute MI within 90 days of filling a testosterone prescription. Found positive association in younger men with known heart disease and in older men.

u  Medicare database with 6355 men. Found men at highest risk for MI had a relative reduction in risk on testosterone

u  2015 FDA Safety Announcement: “possible increased MI and CVA risk with TRT”

u  use CAUTION

u  High quality trials are needed to address CV morbidity and mortality associated with TRT.

Contraindications to Testosterone replacement therapy ( TRT ) u  Breast cancer

u  Prostate cancer

u  Transgender female to male with + pregnancy

u  History of DVT or PE

Cancer and testosterone

u  Absolute contraindication in active breast and prostate cancer patients.

u  Testosterone is not thought to cause prostate cancer.

u  BUT, it can increase prostate and breast cancer growth

u  Discussions with Oncology and Urology

u  late relapses of prostate cancer are common with or without hormonal treatment

u  Concern about increased vascular thrombosis

u  Would this be higher in cancer patients?

u  BAD IDEA- even in those who are “cured”

Groups not addressed in 2010 guidelines: Type 2 DM and Metabolic Syndrome – Does T help insulin sensitivity?

u  Conflicting evidence on insulin sensitivity in Diabetics

u  BLAST study in UK = RCT 190 symptomatic hypogonadal men with type 2 DM treated with IM testosterone x 30 weeks

u  Modest improvement in a1c (-0.18)

u  No change in insulin sensitivity, insulin levels or inflammatory markers overall.

u  Testosterone treated group had improved BMI, weight, waist circumference, sexual function and symptoms of hypogonadism improved at 30 weeks.

Groups not addressed in 2010 guidelines:Type 2 DM and Metabolic Syndrome u  TIMES2 RCT with 220 symptomatic hypogonadal men

with type 2 DM or Metabolic Syndrome. Testo gel for 12 months.

u  Insulin sensitivity improved in first 6 months. BUT, no difference in a1c, fasting lipids, glucose levels or BMI.

u  HDL was significantly decreased

u  BLAST (+) and TIMES2 (-) are conflicting.

u  Men with type 2DM – data inconclusive.

Hypogonadal Metabolic Syndrome patients – Could they benefit from testosterone treatment?

u  MOSCOW trial: 184 hypogonadal men with metabolic syndrome, treated with IM testosterone x 30 weeks.

u  Lost weight ( -4.31 kg), decreased BMI ( -1.32kg/m2), decreased waist circumference by 6cm, decreased CRP to 19 for TRT vs. 38 for placebo.

u  Insulin sensitivity and lipid profile not significantly different at 30 weeks.

u  Men with metabolic syndrome – data suggests potential benefits.

u  Interesting, but needs more study.

Contraindication to testosterone: compensated CHF?

u  Often an exclusion criterion

u  No new data for decompensated CHF – NO TESTOSTERONE

u  Stout et al 41 hypogonadal men with stable CHF ( NYHA avg.score = 2.5 +/- 0.5 )

u  Improved O2 uptake

u  Improved leg strength

Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: A Systemic Analysis. Mayo Clin Proc August 2015:90(8): 1104-1115

Back to case 3:

u  Would you treat with testosterone?

Confirmed hypogonadal patients

u  Testosterone cypionate or enanthate u  200mg IM every 2 weeks

u  100mg IM weekly

u  Testosterone patch u  4mg patch, apply new patch daily to nonscrotal skin

u  Testosterone gel u  2 pumps to shoulders, arms, chest, back.

u  Cover with cloth, fully absorb.

u  Shower before coming into contact with another person if gel applied in last few hours.

Monitoring on testosterone

u  Digital prostate exam

u  CBC

u  LFTs

u  Lipids

u  PSA

u  Testosterone level

u  Baseline and 3 to 6 months after treatment starts and then annually

u  Monitor for improvement in symptoms

u  testosterone level – goal is mid normal range.

u  Injection – measure at midpoint between shots

u  Patch – measure 3 to 12 hours after application

u  Gel– check anytime once patient on treatment for a week.

Monitoring on testosterone

u  Secondary polycythemia most common complication of testosterone treatment

u  Check hematocrit at baseline and then 3 to 6 months after start, then annually.

u  Stop treatment if hct >54% and restart at lower dose once HCT normal. Evaluate for hypoxia and sleep apnea.

Case 3 – Older Veteran

u  Anything else? à Check a bone density

u  Results

u  Showed normal spine, hip and back t-score and low FRAX score.

u  Vitamin D ok

u  Recommended repeat bmd in 3-5 years.

Effects of Testosterone on Bone Density, Frailty and Muscle Strength

u  Improved spine BMD and hip but not in all studies. Overall + trend

u  Effects on risk of fracture in men with osteoporosis not studied.

u  Inconsistent benefits to muscle strength and physical function.

Case 4: Young veteran

u  32 yo male with h/o hypogonadism, treated since 2010.

u  HPI: returned from Afghanistan 4/1/2010 complaining of ED

u  No sex drive, couldn’t maintain an erection

u  Labs checked and told testosterone labs “messed up.”

Case 4 continued

u  No hx of TBI or exposure to IED blast

u  Puberty was a little later than friends around age 16 or 17.

u  Never fathered children. He and girlfriend weren’t using contraception. No pregnancies.

CASE 4

u  He had infertility workup in 2012 and was told his semen analysis had zero sperm.

u  He is not interested in fertility now.

u  Testosterone treatment fixed his libido and erections.

u  Viagra helps when injection is waning and dose due in a few days.

u  Most recent dose is testosterone 150mg IM weekly

Case 4

u  ROS: mild acne on back, worse in summer

u  Meds: no other significant meds.

u  Current labs: HCT 46.5

u  PE: VF intact

u  Chaperoned GU exam: testes 20cc volume, not soft, normal phallus

2 important points

u  Records didn’t show workup for why this 32 year old male is “hypogonadal.”

u  Before starting testosterone determine if the patient has confirmed hypogonadism and if it is primary or secondary

u  Explore fertility plans. Exogenous testosterone will suppress FSH and LH leading to leydig and sertoli cell dysfunction. This can lead to decreased sperm production. Can be permanent.

Case 4 evaluation

u  Hold testosterone. How long? Months?

u  Check fsh, lh, total testosterone, prolactin, free t4/tsh.

u  His testosterone was 129, LH low normal. Testosterone held a month.

u  MRI negative.

u  Semen analysis azoospermic – rare sperm seen. Should repeat and follow with post collection UA. If sperm present then he also has retrograde ejaculation or other obstructive process. SSRI or urologist.

u  Hold testosterone for 2 to 3 months and see if axis rebounds.

Summary u  3 types of male sexual dysfunction

u  3 questions: libido, AM erections, erections partial?

u  Determine etiology of sexual dysfunction

u  Confirm, don’t just treat low testosterone

u  Treatment might require removing or changing meds, psychology referrals

u  FDA approved treatments: PDE inhibitors, testosterone

u  Use caution, do no harm.

References

u  AACE/ACE Position Statement on the Association of Testosterone and Cardiovascular Risk. Endocrine Practice 2015;21(No. 9): 1066-1073

u  Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: A Systemic Analysis. Mayo Clin Proc August 2015:90(8): 1104-1115

u  Guideline on Male Sexual Dysfunction, European Association of Urology 2015. http://uroweb.org/wp-content/uploads/EAU-Guidelines-Male-Sexual-Dysfunction-2015-v2.pdf

u  Testosterone Therapy in Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline ( JCEM 95;2536-2559, 2010)

u  Up to Date: reviewed 8/1/2016: Overview of male sexual dysfunction; Clinical features and diagnosis of male hypogonadism; Treatment of male sexual dysfunction

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