Exam 2 - Men's Health

Lerning Objectives

• Discuss the Hypothalamic-Pituitary-Gonadal Axis

• Describe male hypogonadism, including primary vs secondary causes

• Review clinical manifestations of hypogonadism and the role of testosterone

• Compare and contrast the various products used to treat low testosterone

• Discuss erectile dysfunction, including causes and available options for management

• Discuss the assessment tool used to evaluate symptoms of patients with benign prostatic hyperplasia

What is the definition of male hypogonadism?

• Clinical syndrome that arises secondary to disruption of the hypothalamic-pituitary-gonadal axis at any level

• Results in diminished functional capacity of the testes

What are the two types of hypogonadism?

Primary and Secondary

What is primary hypogonadism?

Hypogonadism in which the testes are primarily affected:

• Characterized by:

  • Low serum testosterone concentrations

  • Impaired spermatogenesis

  • Increased gonadotropin concentrations

What are potential causes of primry hypogonadism?

• Testicular trauma

• Medications

  • Chemotherapy/Alkylating agents, e.g. cyclophosphamide

  • Ketoconazole

  • Spironolactone

• Radiation

• Genetic/Chromosomal abnormalities, e.g. Klinefelter’s syndrome(XXY)

• Infection, e.g. mumps-related orchitis

What is secondary hypogonadism?

• Hypogonadism in which the hypothalamus or pituitary gland primarily affected

• Characterized by:

  • Low serum testosterone levels

  • Reduced spermatogenesis

  • Low or inappropriately normal concentrations of gonadotropins

What are potential causes of secondary hypogonadism?

• Hyperprolactinemia

• Medications → decrease in GnRH synthesis

  • Mu opioid receptor agonists, e.g. morphine, methadone

• Genetic gonadotropin deficiencies, e.g. Kallman’s syndrome

• Poor nutrition/ starvation

What is seen in mixed hypogonadism?

• Hypogonadism characterized by:

  • Low serum testosterone

  • Variable LH

  • Variable FSH

• Causes include:

  • Cancer

  • Diabetes

  • Medications

  • Chronic glucocorticoids use

  • HIV/AIDS

  • COPD

  • CKD

  • Age-related Testosterone Deficiency (TD)

What are non-specific symptoms of hypogonadism?

• Fatigue

• Reduced muscle mass

• Depression

• Alopecia

• Sleep disturbances

• Decreased libido

• Decreased energy

• Erectile dysfunction

• Decreased motivation

• Infertility

What are clinical manifestations of pre-pubertal onset of hypogonadism?

Pre-pubertal onset

• Testes volume < 5 cm3

• Micropenis

• Decreased muscle mass

• Decreased bone mass

• Decreased libido

• Gynecomastia

• Decreased body hair

• High-pitched voice

• Small prostate

What are clinical manifestations of post-pubertal onset of hypogonadism?

Post-pubertal onset*

• Decreased testicular volume

• Decreased muscle mass

• Decreased bone mass

• Decreased libido

• Gynecomastia

• Hot flashes

• Decreased energy

• *Patients have normal skeletal proportions, penile length, voice, and prostate size

What do symptoms of hypogonadism depend on?

Symptoms vary depending on:

1) Age of onset (pre- vs post- pubertal)

2) Severity of testosterone deficiency

3) Androgen sensitivity of the individual

4) Previous use of testosterone replacement therapy

What is testosterone deficiency associated with?

Not necessarily a cause/effect, but:

• Obesity

• Insulin resistance

• CVD

• All-cause Mortality

• Osteopenia/ Osteoporosis

How is hypogonadism diagnosed?

1) Thorough history and physical exam, including DRE

2) Confirm presence of low testosterone on at least two occasions, and

3) Evaluate associated signs and symptoms via questionnaire:

• Androgen Deficiency in the Aging Male questionnaire

• Aging Males’ Symptoms scale

**Diagnosis should never be made solely on questionnaires alone:

What is the testosterone level needed for diagnosis of hypogonadism?

• T_total < 300 ng/dL

• T_free < 64 pg/mL

Total testosterone (T_total)

• 38% loosely bound to albumin (T_alb)

• 60% tightly bound to sex hormone binding globulin (T_SHBG)

• 0.5% - 2% circulates in free form (T_free) and is biologically active

How can LH and FSH be used to diagnose hypogonadism?

• If LH/FSH High → Primary hypogonadism

• If LH/FSH Low → Secondary hypogonadism

What are reasons for age-related testosterone deficiency?

Two reasons for this:

• Decreases in testosterone production

  • Concentration of free testosterone naturally declines with age

    (~ 2% per year)

• Increases in the production of Sex-Hormone Binding Globulin (SHBG)

  • T is tightly bound to SHBG

What can testosterone replacement therapy (TRT) be used for?

Treatment of clinical hypogonadism but not age-related low testosterone

What IM injectable products can be used for TRT?

IM injections

• Testosterone enanthate (Delatestryl)

• Testosterone cypionate (DEPO-Testosterone)

  • Same dosing but cheaper but cheaper than enanthate

  • Both IM testosterone enanthate and cypionate products exhibit variable PK’s which leads to fluctuations in mood, libido, and energy

• Testosterone undecanoate (Aveed):

  • 750mg IM initially, at week 4, then q10weeks thereafter

  • Pharmacokinetics/clinical response more predictable than with older IM products

  • Most expensive

What side effect can be seen in all injectable products?

ALL three injectable products may result in skin irritation and coughing fits immediately after injection

What is our SQ injection for TRT?

Testosterone enanthate (Xyosted):

What are advantages of using subcutaneous TRT?

• SQ injection reduces discomfort and simplifies home use

• Typically dosed once/week, providing consistent levels

• Dosing adjusted based on serum testosterone levels

Which testosterone gels can be used for TRT?

Testosterone transdermal gel

• Vogelxo 1% (generic): 4 pumps (12.5mg/pump actuation) applied once daily; $230 vs $70 for two gel pumps

• Vogelxo 1% (generic): 1 dose (50mg/ unit dose pack) applied once daily; $440 vs $90 for thirty packets

• Androgel 1.62% (generic): 1-4 pumps (20.25mg/pump actuation) applied once daily; $400 vs $40 for one gel pump

• Testim 1% (generic): 1 tube (50mg/tube) applied once daily; $580 vs $96 for thirty tubes

How should testosterone gels be applied?

• Applied to shoulders and upper arms

• Mimics daily circadian profile of testosterone delivery, mornings

• Potential for transfer to women/children

• High [DHT]; must wash hands

  • Can increase DHT production which can lead to (hair loss, acne, oily skin)

Which SQ product injects pellets?

Testopel - testosterone propionate pellets

• Can be painful, scarring

• 8.5% extrusion of pellets

• Possibility of infection

• A new insertion site is used each time

• Expensive $$$

What risk if associated with use of testosterone pellets?

Risk of supra-physiological testosterone levels

Which testosterone product is used intranasally?

Natesto - Nasal gel

• 11mg four times daily

• Prime pump before use

• Blow nose before use

• Place actuator inside one nostril and squeeze; press nostrils together and massage

• Do not blow nose for one hour

• May cause nasal discomfort, sinusitis, pharyngitis, URTI’s, or bronchitis

• $470 for one nasal gel pump (Expensive $$$)

Which oral testosterone products are there?

• Jatenzo

• Tlando

• Kyzatrex - Most affordable option

Which oral T products require dose titration?

Jatenzo and Kyzatrex

Tlando → Do titration required

What side effects are associated with oral T products?

• Headache, Nausea

• Worsening BPH

• Increased risk of VTE

• Increase in Hct

• Increase in blood pressure (black box) which may lead to increase in risk of heart attack or stroke

What are monitoring parameters for TRT?

• Things to monitor baseline, q3-6months, then annually

  • Serum testosterone levels; adjust dose accordingly to achieve 400- 700ng/mL

  • Complete Blood Count (Hgb & Hct)

  • PSA - Prostate specific antigen

  • DRE - Digital rectal exam

• Monitor at baseline, then annually

  • Bone density scan

• Periodically

  • LFTs

  • Lipids

• Adverse effects

  • Gynecomastia

  • Acne

  • Priapism

What are the clinical practice guidelines for TRT?

• TRT is not FDA-approved for Age-related Low Testosterone (ARLT)

• Clinicians may discuss possible initiation of TRT in men with ARLT who are:

  • Suffering from sexual dysfunction

  • Wish to improve performance prior auth.

• After initiation of TRT, symptom re-evaluation take place within 12 months; if sexual function does not improve → Discontinue

• Cost effectiveness of TRT: IM >> transdermal

• Clinical effectiveness/Hazards: IM = transdermal

What are absolute contraindications to TRT?

• Active or High-risk Prostate CA

• Prostatic nodules or indurations on DRE

• Unexplained elevated PSA levels (>4 ng/mL)

• Breast CA

What are relative contraindications to TRT?

• Erythrocytosis (increase in HCT by 50%)

• Severe Lower Urinary Tract Symptoms (LUTS) with Benign Prostatic Hypertrophy (BPH) and an International Prostate Symptom Score (IPSS) > 19

  • LUTS + BPH + IPSS > 19

• Unstable Congestive Heart Failure Class III or Class IV

• Severe, untreated Sleep Apnea

What are TRT’s effect on cardiovascular disease?

• It was thought that TRT increases risk of heart disease

• TOM” Trial stopped early because men randomized to TRT

  had an increased risk in CVE’s

• TRAVERSE Trial:

  • TRT is not linked to higher overall CV event rates in this population, but clinicians should weigh specific risks and monitor for thromboembolic and arrhythmic events

What is the effect of TRT on prostate health?

• Testosterone replacement therapy (TRT) can be considered in men with a history of low-risk prostate cancer, but careful monitoring and individualized assessment are essential.

• Current evidence indicates that TRT does not increase the risk of developing new prostate cancer or recurrence in men treated for low-risk disease

What should be prostate things monitored for patients taking TRT?

• Prostate-specific antigen (PSA); @ baseline, @ 3 mos, then annually thereafter

• Digital Rectal Exam (DRE): @ baseline, @ 3 mos, then annually thereafter

• Testosterone: @ baseline, @ 3 mos, then annually thereafter

When should a patient be referred to a urologist?

• Verified PSA >4 ng/mL

• Increase in PSA > 1.4ng/mL within any 12-month period of testosterone treatment

• PSA velocity >0.4ng/mL/year

• Detection of a prostatic abnormality on DRE

What is erectile dysfunction? What are the categories?

Erectile Dysfunction (ED): inability to achieve or sustain an erection suitable for intercourse

1) Psychological → stress, depression, schizophrenia

2) Hormonal → Elevated prolactin levels, use of anabolic steroids

3) Neurological → stroke, TBI, Parkinson’s

4) Vascular → characterized by PAD or endothelial dysfunction

• DM, Atherosclerosis, CAD, HTN, Sickle Cell anemia

What are risk factors for erectile dysfunction?

• DM

• CVD

• CKD

• Liver disease

• Chronic inflammatory diseases

• Recreational/ Illicit drug use (chronic EtOH, smoking history, marijuana, cocaine)

• Certain medications

Which medications can cause erectile dysfunction?

• Diuretics

• Anticholinergics

• Beta blockers

• H1 & H2 antagonists

• Antipsychotics

• Estrogens

• Antidepressants

• Ketoconazole

• Narcotics

• Corticosteroids

What is our first line option for treatment of ED?

• 1st Line - PDE₅ Inhibitors

• MOA: Work by enhancing the effects of nitric oxide

• Produces smooth muscle relaxation, thereby

• leading to an influx of blood into the corpus cavernosum

What do PDE5 inhibitors NOT do?

DO NOT heighten arousal, stimulation, or libido

What are side effects/AEs of using PDE5 inhibitors?

• SEs: Headache, nasal congestion, flushing, heartburn

• Serious AEs: Hypotension/syncope, priapism, changes in vision,

  hearing loss

PDE5 Inhibitors are contraindicated in..?

• Concurrent use with nitrates, use with caution in patients with underlying CVD

What is used locally to treat ED?

• Intra-cavernosal Injection

  • MOA: smooth muscle vasodilator

  • Inject 10mcg, 20 mcg, or 40mcg directly into corporeal bodies of penis

  • Side effects: Pain, Priapism, Fibrosis

  • Products: Alprostadil (Caverject, Edex), Phentolamine + papaverine (off-label use)

What topical product can be used for ED?

Eroxon (MED3000)

• First over-the-counter topical treatment for ED

• Fast-acting- works in less than 10 minutes

• Apply a pea-sized amount to the head of the penis; gel evaporates and cools the skin before gradually becoming warm → NO release → smooth muscle relaxation → increased blood flow

• Side effects: Nausea and HA in 1-3% of men

What are contraindications to vacuum constriction device?

Sickle Cell patients

Anticoagulation

What is a penile implant?

• Permanent treatment option for those who have tried oral options without success

• Higher patient and partner satisfaction; 70% effective

• May require replacement after 5-10 years

• Side Effects:

  • Pain

  • Infection

  • Erosion thru skin

What is BPH?

Benign Prostatic Hypertrophy (BPH)

• The most common benign tumor in men

• By age 50, up to 50% of men have histologically distinguished BPH

• Characterized by hyperplasia of the prostate tissue

• Results in pressure being placed on the bladder and the urethra

• Patient is unable to urinate or completely empty the bladde

W

What is the score used to score/evaluate lower urinary tract symptoms (LUTS)?

International Prostate Symptom Score (I-PSS)

• Score = 1-7 mild

• Score = 8-19 moderate

• Score = 20-35 severe

W

Which agents are used to treat BPH?

• Alpha-1 adrenergic blockers:

  • Mechanism: Antagonize the smooth muscle of the prostate and bladder

• 5- alpha reductase inhibitors (5-ARTI’s):

  • Selective inhibitor of Type 1 and Type 2 isoforms of 5-alpha reductase

  • Suppresses serum dihydrotestosterone levels by inhibiting conversion of testosterone to dihydrotestosterone

  • Leads to reduced prostate volume (size), improved

Which alpha-1 adrenergic blockers are used?

Non-selective agents- binds to all alpha-1 receptor subtypes (1a, 1b, 1c) • Doxazosin: 1-8mg po QHS; $26/ 30 tabs • Terazosin: 1-10mg po QHS; may increase up to 20mg; $21/ 30 caps • Alfuzosin ER (Uroxatral): 10mg po Qday; $73/ 30 tabs generic • Selective alpha-1 blocking agents- selective for receptor subtype 1a • Tamsulosin (Flomax): 0.4-0.8mg po Qday; $66/ 30 caps generic • Silodosin (Rapaflo): 8mg po Qday; $228/ 30 caps generic