Male Sexual Dysfunctions and Treatments

Alexander W. Pastuszak, MD, PhDAssistant ProfessorDivision of Urology

Department of SurgeryUniversity of Utah School of Medicine

ISSM / SMSNA Sexual Health SymposiumNovember 24, 2019

Nairobi, Kenya

Disclosures

• Endo Pharmaceuticals – speaker, advisor, research / fellowship support

• Bayer AG – speaker

• Antares Pharmaceuticals – advisor

• Woven Health – founder and leadership position

Objectives• To present an overview of male sexual dysfunctions including

hypogonadism, erectile dysfunction, ejaculatory dysfunction, and Peyronie’s disease

• To discuss the role of testosterone in sexual function, and the diagnosis and management of hypogonadism (low testosterone)

• To examine ejaculatory dysfunction and its treatments

• To briefly discuss erectile dysfunction and (some) treatment

• To briefly present Peyronie’s disease

Hypogonadism

http://www.melbourneurology.net.au/patient-information/benign-prostate-enlargement-bph

Testosterone Has Critical Roles in Sexual Function

Testosterone’s Role in Sexual Function

• Testosterone is one of the main factors in male (and female) libido

• The chemical mechanism for normal erections is testosterone dependent• Men with low testosterone have a diminished response to

Viagra-like drugs

• Testosterone is likely important in regulating ejaculatory function

Definition of Clinical “Hypogonadism”

A disease complex of:

1. Low testosterone

(<300ng/dl)

2. Specific and non-

specific symptoms

Hypogonadal Symptoms

More Specific- Decreased libido

- Erectile dysfunction

- Delayed puberty

- Gynecomastia

- Breast tenderness

- Loss of axillary / pubic hair

- Small / shrinking testes

- Infertility

- Low bone mineral density

- Hot flushes / sweats

Less Specific- Low energy / motivation

- Decreased muscle strength

- Increased fat mass

- Depressed mood

- Poor concentration

- Poor memory

- Insomnia

- Decreased work

performance

J Clin Endocrinol Metab. 2010; 95:6.

Higher Centers

GnRHHypothalamus

Anterior

Pituitary

Sertoli Cells Leydig Cell

Germinal

Epithelium

FSH LH+ +

Inhibin

--

-

Male Hypothalamic-

Pituitary-Gonadal

Axis

Testosterone

Estrogen

Aromatase

Causes of Hypogonadism

Primary Hypogonadism- Testicular failure

- Cryptorchidism

- Bilateral torsion

- Orchitis

- Orchiectomy

- Klinefelter’s

- Chemotherapy

- Other toxins

Secondary Hypogonadism- Pituitary-hypothalamic injury

- Tumors

- Trauma

- Radiation

- Hemochromatosis

- Kallmann syndrome

- Inflammation

- Medications

- HIV/AIDS

- Obesity

Cause Unknown → Idiopathic Hypogonadism → 90% of cases

Incidence• 500,000 men diagnosed annually in the U.S.

Prevalence• Population-based studies (Europe and U.S.) → 2.1-12.8%

• Community-based studies (U.S.)→ 9.5-31.2%

• Few data beyond U.S. and Europe…

• Increases with age

• Varies with definition of hypogonadism

Journal of Hormones. 2014; http://dx.doi.org/10.1155/2014/190347.

N Engl J Med. 2004; 350:482.

Prevalence of Low Testosterone13.8 Million Men in the U.S.

Hypogonadism TreatmentTestosterone Therapy - Formulations• Transdermal gels / creams / patches

• Injections

• Subcutaneous pellets

• Intranasal gel

• Buccal

• (Orals)

Non-Testosterone Therapies• Human chorionic gonadotropin (HCG)

• Clomiphene citrate

• Anastrozole & other aromatase inhibitors

Benefits• Symptomatic Improvement

• Serum T levels

• Sexual function

• Bone / muscle mass

• Sleep

• Others

Risks• Erythrocytosis

• Infertility (when used alone)

• Testicular atrophy

• Local reactions

• Gynecomastia

• Cardiovascular risk(?)

Monitoring While on Therapy

Endocrine Society Recommendations• Initial evaluation 3-6 months after treatment initiation, then annually

• Baseline Hct, then at 3-6 months, then annually

• If elevated, stop T therapy until decreases or perform therapeutic

phlebotomy

• Repeat bone mineral density evaluation 1-2 years after therapy

initiation

• Men >40 years old with baseline PSA >0.6 ng/mL → DRE, PSA before

starting therapy, then at 3-6 months, then annually

J Clin Endocrinol Metab. 2010; 95: 2536.

Summary

• Hypogonadism affects many men

• Various definitions of hypogonadism exist, impacting diagnosis and treatment

• Treatment of hypogonadism primarily consists of testosterone therapy, though non-testosterone therapies are available

• Proper diagnosis and monitoring are essential during treatment

Ejaculatory Dysfunction

Ejaculation – The ProcessSeparate event from erection!

Thus, can occur in the ABSENCE of erection!

Sensory input - glans (S2-4)

(Dorsal Nerve)

Emission

Sympathetic input (T12-L1)

Periurethral muscle contraction

Vas deferens contraction

SV, prostate contraction

Bladder neck contraction

Bulbocavernosus / spongiosus

contraction

Projectile ejaculation

Expulsion

Somatic input (S1-3)

Transl Androl Urol. 2018; 7: 686.

Neurochemistry of Sexual Function

Effects of Sex Steroids in the Brain

Normal Hormonal FunctionTestosterone• AR ubiquitous → including pelvic floor

• High T = PE; Low T = DE in some men

• T levels vary in men with DE

Thyroid Hormone• Similar to T levels in effect → high thyroid = PE; low thyroid = DE

Prolactin

• May be surrogate of serotonergic activity• Suppressed during orgasm → spikes after (refractory period?)

• High Prl → low T and PE

Oxytocin

• Surges during ejaculation, orgasm, and detumescence

• Stimulates ejaculation, paternal nurturing, sexual desire, and long-term

romantic bonds

Other Determinants of Ejaculatory FunctionIELT Determinants: • Genetics

• Neurophysiology

• Behaviors

• Psychosocial variables

• Cultural influences

Somatic Considerations• Aging – decreased orgasm intensity

• Neurologic disorders (i.e. MS, DM)

• Endocrine disorders (i.e. T, Prl, thyroid)

• Medications

Premature Ejaculation (PE)Prevalence→ 3-75% due to DIFFERENCES IN DEFINITIONS

DSM-5 Definition• “The persistent or recurrent pattern of ejaculation occurring during

partnered sexual activity within about one minute following vaginal penetration and before the individual wishes it”

• Present in 75-100% of sexual encounters, causes distress, lasts at least 6 months, and can’t be explained by another disorder

Intravaginal Ejaculatory Latency Time (IELT)1,2

• Defined by 2 multinational population-based studies• Average → 5.7 minutes• Lifelong PE → mean IELT - 2 SD = ~1 minute• Acquired PE – ISSM Expert Consensus → IELT <3 minutes = PE

1. JAMA. 1999; 281: 537.

2. J Am Geriatr Soc. 2001; 49: 436.

Premature Ejaculation TreatmentFirst-Line Therapies• Daily SSRIs• On demand clomipramine, dapoxetine• Tramadol• Topical penile anesthetics

Other Therapies• Behavioral therapies

Alternative Therapies (Insufficient Evidence for Efficacy)• Testosterone therapy• Intracavernosal injection (ICI)• Oxytocin antagonists• Herbal medicines

Dapoxetine is the only

approved treatment for PE

Delayed Ejaculation (DE) / AnorgasmiaPrevalence → 1-4%3 – ALSO depends on DEFINITION USED

DSM-5 Definition

• The persistent or recurrent delay, difficulty, or absence of orgasm after sufficient sexual stimulation that causes personal distress

Intravaginal Ejaculatory Latency Time (IELT)1,2

• Normal (median) → 5.4 minutes (0.55-44.1 minutes)• DE → mean IELT + 2 SD = 22-25 minutes

1. J Sex Med. 2010; 7: 2947.

2. World J Urol. 2005; 23: 76

3. Transl Androl Urol. 2016; 5: 549.

Delayed Ejaculation Treatment

Therapies• Behavioral therapy

• Pharmacotherapies → very limited evidence • Testosterone – maybe???• Others…

Overall, few therapies with any evidence of efficacy for the treatment of delayed ejaculation!!

There are no approved therapies

for treatment of DE

Treatment of SSRI-Induced DE• Use when SSRI is likely cause of DE

• Can also switch to different SSRI in same class

• DE treatment with meds up to 70% effective (based on small studies)

Drug PRN Dosage Daily Dosage

Cyproheptadine 4-12 mg (3-4h prior to sex) --

Bethanechol 20 mg (1-2 hours prior to sex) --

Amantadine100-400 mg (for 2 days prior

to sex)75-100 mg BID / TID

Bupropion -- 75 mg BID / TID

Buspirone -- 5-15 mg BID

Loratadine -- 10 mg Daily

Sex Med Rev. 2016; 4: 167.

Andrology. 2015; 3: 626.

Treatment of DE – No SSRIDrug PRN Dosage Daily Dosage

Oxytocin 24 IU intranasal / SL during sex --

Pseudoephedrine 60-120 mg (120-150 min prior to sex) --

Ephedrine 15-60mg (1 hour prior to sex) --

Midodrine 5-40mg Daily (30-120 min prior to sex) --

Apomorphine0.5-1.5mg intranasal (20 min prior to

sex)--

Yohimbine -- 5.4 mg TID

Cabergoline -- 0.25-2 mg BIW

Reboxetine -- 4-8 mg

Imipramine -- 25-75 mg Daily

Sex Med Rev. 2016; 4: 167.

Summary• Orgasmic function is dependent on interplay of numerous

neurohormonal and physical factors

• Norepinephrine, serotonin, dopamine, and prolactin are the primary neurohormones involved

• The causes of PE and DE are not well established

• DE/anorgasmia can be caused by many meds, in particular SSRIs

• Treatment should include psychosexual and medical therapy

• Medical therapies are poorly studied and not FDA approved

Erectile Dysfunction

Erectile Dysfunction (ED)

• Definition: “. . .the consistent or recurrent inability of a man to attain and/or maintain a penile erection sufficient for sexual activity”

Prevalence of ED:Massachusetts Male Aging Study

Feldman HA, et al. J Urol. 1994;151:54-61.

Feldman HA, et al. J Urol. 1994;151:54-61.

Men aged 40 to 70 years (N = 1290)

Shared Risk Factors:ED and Cardiovascular Disease (CVD)

• Hypertension

•Diabetes

•Dyslipidemia

•Depression

• Smoking

• Obesity

• Sedentary Lifestyle

Int J Clin Pract. 1999;53:445-451

Am J Cardiol. 2000;86:1210-1213

Prev Med. 2000;30:328-338.

ED may be the first sign of

underlying CVD!

Erectile

Dysfunction

- Vascular

- Arterial Insufficiency

- Venous Leak

- Endocrine

- Neurologic

- Trauma

Organic

Psychogenic

Iatrogenic

- Prior surgery

-Prostate

-Retroperitoneal

- Medications

Anatomic

-Peyronie’s Disease

-Phimosis

-Marital conflicts

-Guilt

-Performance anxiety

Diagnosis• Laboratory testing

• Testosterone / Free Testosterone

• Hb A1c

• Cholesterol

• Ultrasound (Penile duplex)• PSV < 30 ml/sec (arterial insufficiency)

• EDV > 5 ml/sec (venous leak)

• Physical examination• Penile plaques

• Testicular atrophy

Treatment Options

• Medical (hormonal): Androgens / Testosterone

• Oral therapy: PDE Inhibitors

• ICI therapy: Caverject, Trimix

• Intraurethral Rx: MUSE

• Vacuum Constriction Device

• Penile Prosthesis

5*

Medical Therapy of ED

Sildenafil (Viagra): April 1998

Vardenafil (Levitra): August 2003

Tadalafil (Cialis): November 2003

Udenafil (Zydena): 2005…

Avanafil (Stendra): April 2012

First-Line Treatment for ED:How PDE5 Inhibitors Work

Nitric

OxideGuanylate

Cyclase

PDE5

GMP

GTPcGMP

Smooth Muscle

Relaxation

Erection

*Nonadrenergic, noncholinergic nerve.Boolell. Br J Urol. 1996;78:257-261; Burnett. J Urol. 1997;157:320-324; Heaton. Neurosci Biobehav Rev. 2000;24:561-569.

NANC* Neurons

Endothelial Cells

Summary

• Erectile dysfunction is a common problem

• There is a strong relationship between CVD and ED

• Nearly every man can be successfully treated for ED using a number of therapies: • PDE5 inhibitors / hormone therapy

• Intracavernosal injections

• VED

• Penile prosthesis

Peyronie’sDisease

https://www.aaurology.com/for-patients/our-blog/

Peyronie’s Disease (PD) - Definition

An acquired penile abnormality characterized by fibrosis of the tunica albuginea, which may be accompanied by:

• Pain

• Deformity

• Erectile Dysfunction (ED)

• Penile shortening

• Psychological distress

https://www.auanet.org/education/guidelines/peyronies-disease.cfm

Prevalence of PD

• Prevalence rates have been underestimated

• Overall, 0.5-20.3% of men have PD (≈9%)

https://www.auanet.org/education/guidelines/peyronies-disease.cfm

Dibenedetti DB, et al. Adv Urol.; 2011: 282503.

• Trauma/micro-trauma

• Abnormal wound healing: • Collagen deposition

• Fibrosis

• Calcification

• Peyronie’s (penile) plaque

Photo courtesy of Dr. Hatzichristodolou

HOW DOES PD HAPPEN?

Psychological Impact of PDOften overlooked or underestimated…

• 77% → negative psychological effect

• 48% → clinically significant depression

• 26% → severe depression

• 81% → emotional problems associated with loss of penile length and the ability to have intercourse

• 54% → relationship problems

Nelson CJ, et al. J Sex Med. 2008;5:1985–1990.

Smith JF, et al. J Sex Med. 2008, 5(9): 2179-84.

Nelson C.J, Mulhall JP. J Sex Med 2013, 10(3): 653-60.

Treatment Options for PD

•Oral medications

• Intralesional injection therapy

• Surgery

• Penile traction therapy

• (Shockwave therapy)

Summary• Peyronie’s disease is an abnormal penile curvature / deformity

resulting from fibrous plaque formation in the tunica albuginea

• Peyronie’s disease is more prevalent than previously thought

• PD is highly treatable through a number of options, including injections, traction therapy, and surgery

• There are a number of male sexual dysfunctions

• Male sexual dysfunctions are interrelated and men often present with multiple (i.e. low libido and ED, etc.)

• Male sexual dysfunctions are overall highly treatable

THANK YOU!

@utahurology @apastuszwww.utahmenshealth.com