Erectile Dysfunction

Number: 0007

Table Of Contents

Applicable CPT / HCPCS / ICD-10 Codes


Aetna considers the diagnosis and treatment of erectile dysfunction (ED; impotence) medically necessary according to the criteria outlined below.

  1. Diagnosis

    Aetna considers the following diagnostic workup of erectile dysfunction medically necessary:

    • Comprehensive history and physical examination (including medical and sexual history and psychosocial evaluation)
    • Duplexscan (Doppler and ultrasound) in conjunction with intracorporeal papaverine
    • Dynamic infusion cavernosometry and cavernosography only for members who are to undergo re-vascularization procedures and meet medical necessity criteria for penile re-vascularization (see below)
    • Pharmacological response test for erectile dysfunction (using vasoactive drugs, e.g., papaverine HCl, phentolamine mesylate, prostaglandin E1)
    • Pudendal arteriography (angiography) only for members who are to undergo penile re-vascularization and meet the medical necessity criteria for penile revascularization (see below).

    Aetna considers the following laboratory tests medically necessary for the diagnosis of erectile dysfunction:

    • Biothesiometry (Note: Biothesiometry is considered an integral part of the comprehensive history and physical examination.)
    • Blood glucose
    • Complete blood count
    • Creatinine
    • Hepatic panel
    • Lipid profile
    • Prostate specific antigen
    • Serum testosterone

      Tests for evaluation of pituitary dysfunction (e.g., measurement of luteinizing hormone, follicle-stimulating hormone, and prolactin levels) if serum testosterone level is below normal

    • Thyroid function studies
    • Urinalysis.

    Note: Routine nocturnal penile tumescence (NPT) and/or rigidity testing has no proven value.  Nocturnal penile tumescence testing using the postage stamp test or the snap gauge test is rarely medically necessary; it is considered medically necessary where clinical evaluation, including history and physical examination, is unable to distinguish psychogenic from organic impotence and any identified medical factors have been corrected.  Nocturnal penile tumescence testing using the RigiScan is considered medically necessary only where NPT testing is indicated, and the results of postage stamp or snap gauge testing are equivocal or inconclusive.

    Aetna considers the following workup / laboratory tests for the diagnosis of erectile dysfunction experimental and investigational because their effectiveness has not been established:

    • Angiotensin-converting enzyme insertion/deletion polymorphism testing (for determining erectile dysfunction susceptibility)
    • Cavermap cavernous nerves electrical stimulation with penile plethysmography (also referred to as cavernosal nerve mapping).  This policy is based upon an assessment by the Centers for Medicare and Medicaid Services (CMS, 2006)
    • Corpora cavernosal electromyography
    • Dorsal nerve conduction latencies
    • Endothelial nitric oxide synthase polymorphism (4 VNTR, G894T, and T786C) testing for estimating risk of erectile dysfunction
    • Evoked potential measurements (including stimulus evoked response for measurement of bulbocavernosus reflex latency)
    • Iron binding capacity
    • Measurement of serum melatonin levels 
    • Measurement of serum vitamin D levels 
    • Penile plethysmography
    • Prostatic acid phosphatase
    • Shear wave elastography
    • The use of serum biomarkers (e.g., E-selectin, endothelial progenitor cells, endothelial micro-particles, homocysteine, interleukin-10, malondialdehyde, nitric oxide, and ratio of tumor necrosis factor-alpha to IL-10) for the development and/or progression of ED.
  2. Treatments

    Aetna considers the following therapies for the treatment of erectile dysfunction medically necessary:

    1. Injectable Medications

      Aetna considers self-administered injectable medications for the treatment of erectile dysfunction medically necessary.Footnotes*  Medically necessary self-administered medications for erectile dysfunction include:

      1. Injections into the corpus cavernosa to cause an erection (papaverine, alprostadil, phentolamine) and,
      2. Medicated Urethral System for Erection (MUSE) method of treatment for erectile dysfunction that involves inserting medication through a small catheter into the urethra.

      Titrating doses of injectable impotence medications that are administered in a physician's office and the accompanying office visits are considered medically necessary.  This includes in office titrating doses of papaverine, alprostadil (prostaglandin E1 or Caverject) and phentolamine.  Except for phentolamine, which is not generally used alone, these drugs can be used alone or in combination.  The drug MUSE, a pellet from of alprostadil, is also used as an alternative to alprostadil injections.

      Diagnostic injections of impotence medications by the treating physician are also considered medically necessary.

      Footnotes*Note: Coverage of injectable medications is subject to the terms of the member’s benefit plan.  Please check benefit plan descriptions for details.

    2. Oral and Transdermal Medications

      Aetna considers exogenous testosterone replacement therapy, including transdermal preparations, experimental and investigational for the treatment of non-hypogonadal impotence because its effectiveness in non-hypogonadal impotence has not been established.  (See CPB 0345 - Implantable Hormone Pellets.)

      Aetna considers topical cream or gel containing vasodilators, such as verapamil cream, experimental and investigational for the treatment of erectile dysfunction because their effectiveness for this indication has not been established.

      Note: Many Aetna pharmacy benefit plans exclude coverage of drugs for lifestyle enhancement or performance.  Please check benefit plan descriptions for details.  Under these plans, sildenafil citrate (Viagra), vardenafil hydrochloride (Levitra) and tadalafil (Cialis) are covered only when required by state regulation or when a plan sponsor has elected an optional rider under the pharmacy plan, or, for indemnity or PPO plans without a separate pharmacy benefit, when the plan sponsor has added optional coverage under the medical plan. 

    3. External Devices

      Aetna considers the external penile vacuum pump device medically necessary durable medical equipment (DME) when it is prescribed by a physician as an alternative to other therapies for erectile dysfunction.  External penile pumps are considered experimental and investigational for other indications including for the prevention of erectile dysfunction following prostatectomy because their effectiveness for these indications has not been established.

    4. Implantable Devices

      Aetna considers implantation of semi-rigid penile prostheses or inflatable penile prostheses (implantable penile pumps) medically necessary for members with documented physiologic erectile dysfunction when all of the following criteria are met

      1. Absence of active alcohol or substance abuse; and
      2. Absence of drug-induced impotence related to: anabolic steroids, anticholinergics, antidepressants, antipsychotics or central nervous system depressants; and
      3. Absence of untreated depression or psychiatric illness; and
      4. Nonsurgical methods have proven ineffective or are contraindicated; and
      5. Normal prolactin and thyroid hormone levelsFootnotes2**and
      6. Normal serum testosterone levels (low testosterone suggests treatable endocrine cause of impotence)Footnotes2** and
      7. History of organic disease including any one or more of the following:
        1. Documented injury to perineum/genitalia; or
        2. Major pelvic trauma affecting bladder and/or anal and/or erection control; or
        3. Major vascular surgery involving aorta or femoral blood vessels; or
        4. Neurological disease (eg, diabetic neuropathy); or
        5. Peyronie’s disease; or
        6. Renal failure; or
        7. Secondary to spinal cord injury; or
        8. Status-post prostate, bladder, bowel or spinal surgery; or
        9. Vascular insufficiency or venous incompetence documented by dynamic infusion cavernosometry and cavernosography (DICC); or
        10. Venous leak of the penis.

      Footnotes2**Note: For individuals who have a surgical, radiation, or traumatic cause for their disease, the selection criteria of "normal prolactin and thyroid hormone levels" and  "normal serum testosterone levels" do not have to be met for implantation of semi-rigid penile prostheses or inflatable penile prostheses.

      Removal of a penile implant is considered medically necessary for infected prosthesis, intractable pain, mechanical failure, or urinary obstruction.  

      Reimplantation of a penile implant is considered medically necessary for persons who meet medical necessity criteria above for a penile implant and whose prior prosthesis was removed for medically necessary indications.

      Implantable penile prostheses are considered experimental and investigational for other indications because their effectiveness for indications other than the one listed above has not been established.

      Note: Some traditional medical plans exclude coverage of charges for the treatment of sexual dysfunction. Under these plans, procedures for treatment of impotence would be excluded from coverage. Please check benefit plan descriptions.

    5. Surgical Re-Vascularization

      Aetna considers penile re-vascularization for vasculogenic erectile dysfunction medically necessary only in men less than 55 years old who meet all of the following criteria:

      1. A focal blockage of arterial inflow is demonstrated by duplex Doppler ultrasonography or arteriography; and 
      2. Diagnostic work-up reveals normal corporeal venous function; and 
      3. Member is not actively smoking; and 
      4. Member is not diabetic and has no evidence of systemic vascular occlusive disease; and 
      5. The erectile dysfunction is the direct result of an arterial injury caused by blunt trauma to the pelvis and/or perineum.

      Penile re-vascularization is considered experimental and investigational for other indications because its effectiveness for indications other than the one listed above has not been established.  Consistent with clinical guidelines of the American Urological Association, Aetna considers arterial reconstructive procedures, dorsal vein arterialization procedures, or penile venous occlusive surgery (e.g., venous ligation, dorsal vein ligation) in men with erectile dysfunction secondary to arteriosclerotic occlusive disease experimental and investigational because such procedures have not been proven to be effective.

    6. Experimental and Investigational Treatments for Erectile Dysfunction

      Aetna considers the following treatments experimental and investigational for erectile dysfunction because their effectiveness has not been established:

      1. Acupuncture
      2. Acoustical wave therapy (Alpha Wave SwissWave Protocol)
      3. Botulinum toxin
      4. Endovascular treatment (e.g., angioplasty and drug-eluting stent placement for the treatment of vasculogenic ED)
      5. Epalrestat
      6. Extracorporeal shock wave therapy (ESWT)
      7. Gene therapy
      8. Pelvic floor muscle training (for ED following radical prostatectomy)
      9. Percutaneous electrostimulation of the perineum
      10. Platelet-rich plasma injection
      11. Statins
      12. Stem cell therapy (including adipose-derived stem cells and mesenchymal stem cells)
      13. Tacrolimus.

      Aetna considers genetic polymorphism testing experimental and investigational for the evaluation of response to phosphodiesterase 5 (PDE5) inhibitors in members with erectile dysfunction.

    7. Peyronie's Disease

      1. Plaque Excisions and Venous Graft Patching

        Aetna considers surgical correction of Peyronie’s disease (e.g., plaque excisions and venous graft patching, tunica plication, Nesbit tuck procedure) medically necessary for the treatment of members with Peyronie's disease for 12 or more months with significant morbidity who have failed conservative medical treatment.  Surgical correction of Peyronie's disease is considered experimental and investigational when criteria are not met.

      2. Extracorporeal Shock Wave Therapy (ESWT)

        Aetna considers ESWT experimental and investigational for Peyronie’s disease because of a lack of evidence from prospective randomized controlled clinical studies of the effectiveness of ESWT for this indication. 

      3. Interferon Alpha

        For interferon alpha for Peyronie’s disease, see CPB 0404 - Interferons.

      4. Verapamil Iontophoresis or Nicardipine/Verapamil Intra-Lesional Injection

        Aetna considers iontophoresis or intra-lesional injection of nicardipine or verapamil experimental and investigational for Peyronie’s disease because of a lack of evidence from prospective randomized controlled clinical studies of the effectiveness of this approach for this indication.

      5. Testosterone Injection

        Aetna considers testosterone injection experimental and investigational for Peyronie’s disease because of a lack of evidence from prospective randomized controlled clinical studies of the effectiveness of this approach for this indication.

      6. Xiaflex - Criteria for Initial Approval

        Aetna considers Xiaflex (collagenase clostridium histolyticum) medically necessary for the treatment of Peyronie’s disease when all of the following criteria are met:  

        1. The member has stable Peyronie’s disease without clinical changes (e.g., worsening curvature) for at least three months; and
        2. The member has a palpable plaque and curvature deformity of at least 30 degrees and less than 90 degrees prior to initiating Xiaflex therapy; and
        3. The member has intact erectile function (with or without medication); and
        4. The member is 18 years of age or older; and 
        5. The member will receive a maximum of one treatment course with a maximum of 8 injections total, including any injections the member has received for any previous treatment; and
        6. The medication will be administered by a healthcare provider experienced in the treatment of urological disease and who has completed the Xiaflex REMS program requirements.

        Aetna considers Xiaflex as experimental and investigational for all other indications except for Dupuytren's contracture, see CPB 0800 - Dupuytren's Contracture Treatments.

      7. Xiaflex - Continuation of Therapy

        Aetna considers continuation of Xiaflex (collagenase clostridium histolyticum) therapy medically necessary for the treatment of Peyronie's disease when all of the following criteria are met:

        1. The member meets all initial selection criteria; and
        2. The member has curvature deformity of at least 15 degrees at the time of the continuation request; and
        3. The member has received less than 8 injections total, including any injections the member has received for any previous treatment; and
        4. The medication will be administered by a healthcare provider experienced in the treatment of urological disease.

Dosage and Administration

Peyronie’s Disease

Collagenase clostridium histolyticum is available as Xiaflex for intralesional injection as single-use glass vials containing 0.9 mg of collagenase clostridium histolyticum as a sterile, lyophilized powder for reconstitution. Sterile diluent for reconstitution is provided in the package in a single-use glass vial containing 3 mL of 0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride.

  • Xiaflex should be administered by a healthcare provider experienced in the treatment of male urological diseases.
  • The dose of Xiaflex is 0.58 mg per injection administered into a Peyronie’s plaque.
  • A treatment course consists of a maximum of 4 treatment cycles.
  • Each treatment cycle consists of two Xiaflex injection procedures and one penile modeling procedure.
  • The second Xiaflex injection procedure is performed 1 to 3 days after the first.
  • The penile modeling procedure is performed 1 to 3 days after the second injection of the treatment cycle.
  • The interval between treatment cycles is approximately 6 weeks. The treatment course therefore, consists of a maximum of 8 injection procedures and 4 modeling procedures.
  • If the curvature deformity is less than 15 degrees after the first, second or third treatment cycle, or if the healthcare provider determines that further treatment is not clinically indicated, then the subsequent treatment cycles should not be administered.
  • The safety of more than one treatment course of Xiaflex is not known.

Source: Endo Pharmaceuticals, 2021


CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

37788 Penile revascularization, artery, with or without vein graft
54110 - 54112 Excision of penile plaque (Peyronie disease)
54200 - 54205 Injection procedure for Peyronie disease
54230 Injection procedure for corpora cavernosography
54231 Dynamic cavernosometry, including intracavernosal injection of vasoactive drugs (e.g., papaverine, phentolamine)
54235 Injection of corpora cavernosa with pharmacologic agent(s) (e.g., papaverine, phentolamine)
54400 - 54417 Penile prosthesis procedures
74445 Corpora cavernosography, radiological supervision and interpretation
78012 Thyroid uptake, single or multiple quantitative measurement(s) (including stimulation, suppression, or discharge, when performed)
80061 Lipid panel
80076 Hepatic function panel
81000 - 81003 Urinalysis, by dip stick or tablet reagent for bilirubin, glucose, hemoglobin, ketones, leukocytes, nitrite, pH, protein, specific gravity, urobilinogen, any number of these constituents
82565 Creatinine; blood
82947 Glucose; quantitative, blood (except reagent strip)
83001 - 83002 Gonadotropin; follicle stimulating hormone (FSH), and luteinizing hormone (LH)
83727 Luteinizing releasing factor (LRH)
84146 Prolactin
84152 - 84154 Prostate specific antigen (PSA)
84402 - 84403 Testosterone; free or total
84410 Testosterone; bioavailable, direct measurement (eg, differential precipitation)
84443 Thyroid stimulating hormone (TSH)
84479 Thyroid hormone (T3 or T4) uptake or thyroid hormone binding ratio (THBR)
85025 - 85027 Blood count; complete (CBC), automated
93975 - 93976 Duplex scan of arterial inflow and venous outflow of abdominal, pelvic, scrotal contents and/or retroperitoneal organs
93980 - 93981 Duplex scan of arterial inflow and venous outflow of penile vessels

CPT codes not covered for indications listed in the CPB:

Gene therapy, pelvic floor muscle training, endovascular treatments for like angioplasty, drug-eluting stent placement, genetic polymorphism testing for evaluation of the response to phosphodiesterase 5 inhibitors - no specific code:

0019T Extracorporeal shock wave involving musculoskeletal system, not otherwise specified, low energy
0038U Vitamin D, 25 hydroxy D2 and D3, by LC-MS/MS, serum microsample, quantitative
0101T Extracorporeal shock wave involving musculoskeletal system, not otherwise specified, high energy
0232T Injection(s), platelet rich plasma, any site, including image guidance, harvesting and preparation when performed
11900 Injection, intralesional; up to and including 7 lesions [intra-lesional injection of nicardipin]
11901     more than 7 lesions [intra-lesional injection of nicardipin]
37790 Penile venous occlusive procedure
38240 Hematopoietic progenitor cell (HCP); allogeneic transplantation per donor
38241     autologous transplantation
38242 Allogeneic lymphocyte infusions
51792 Stimulus evoked response (e.g., measurement of bulbocavernosus reflex latency time)
54240 Penile plethysmography
54250 Nocturnal penile tumescence and/or rigidity test
64565 Percutaneous implantation of neurostimulator electrodes; neuromuscular
64580 Incision for implantation of neurostimulator electrodes; neuromuscular
64585 Revision or removal of peripheral neurostimulator electrodes
64590 Insertion or replacement of peripheral or gastric neurostimulator pulse generator or receiver, direct or inductive coupling
64595 Revision or removal of peripheral or gastric neurostimulator pulse generator or receiver
76981 Ultrasound, elastography; parenchyma (eg, organ) [shear wave]
80197 Tacrolimus
82306 Vitamin D; 25 hydroxy, includes fraction(s), if performed
83090 Homocysteine
83550 Iron binding capacity
84066 Phosphatase, acid; prostatic
91200 Liver elastography, mechanically induced shear wave (eg, vibration), without imaging, with interpretation and report
95907 - 95913 Nerve conduction studies
95925 - 95927 Short-latency somatosensory evoked potential study, stimulation of any/all peripheral nerves or skin sites, recording from the central nervous system
97014 Application of a modality to 1 or more areas; electrical stimulation (unattended)
97032 Application of a modality to one or more areas; iontophoresis, each 15 minutes
97810 - 97814 Acupuncture

Other CPT codes related to the CPB:

96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular

HCPCS codes covered if selection criteria are met:

C1813 Prosthesis, penile, inflatable
C2622 Prosthesis, penile, non-inflatable
J0270 Injection, alprostadil, 1.25 mcg (code may be used for Medicare when drug administered under the direct supervision of a physician, not for use when drug is self-administered)
J0275 Alprostadil urethral suppository (code may be used for Medicare when drug administered under the direct supervision of a physician, not for use when drug is self-administered)
J0775 Injection, collagenase, clostridium histolyticum, 0.01 mg
J2440 Injection, papaverine HCl, up to 60 mg
J2760 Injection, phentolamine mesylate, up to 5 mg
L7900 Male vacuum erection system
L7902 Tension ring, for vacuum erection device, any type, replacement only, each

HCPCS codes not covered for indications listed in the CPB:

Serum biomarkers, Epalrestat - no specific code :

J0585 Injection, onabotulinumtoxinA, 1 unit
J0586 Injection, abobotulinumtoxinA, 5 units
J0587 Injection, rimabotulinumtoxinB, 100 units
J0588 Injection, incobotulinumtoxinA, 1 unit
J1071 Injection, testosterone cypionate, 1mg
J3121 Injection, testosterone enanthate, 1mg
J3145 Injection, testosterone undecanoate, 1 mg
J7503 Tacrolimus, extended release, (envarsus xr), oral, 0.25 mg
J7507 Tacrolimus, immediate release, oral, 1 mg
J7508 Tacrolimus, extended release, (astagraf xl), oral, 0.1 mg
J7525 Tacrolimus, parenteral, 5 mg
J9213 Injection, interferon alpha-2A, recombinant, 3 million units
J9214 Injection, interferon alpha-2B, recombinant, 1 million units
J9215 Injection, interferon alpha-N3, (human leukocyte derived), 250,000 IU
S0090 Sildenafil citrate, 25 mg

ICD-10 codes covered if selection criteria are met:

N48.6 Induration of penis plastica [Peyronie's disease]
N52.01 - N52.1, N52.31 - N52.39 Male erectile dysfunction [impotence of organic origin] [not covered for serum melatonin]

ICD-10 codes not covered for indications listed in the CPB:

F12.23 Cannabis dependence with withdrawal
F12.93 Cannabis use, unspecified with withdrawal
F52.0 Hypoactive sexual desire disorder
F52.1, F52.8 Psychosexual dysfunction and other specified psychosexual dysfunctions
F52.21 Male erectile disorder [psychogenic impotence]
F52.32 Male orgasmic disorder
F52.4 Premature ejaculation
F53.3 Abuse of steroids or hormones
N52.2 Drug-induced erectile dysfunction
N52.8 - N52.9 Other and unspecified male erectile dysfunction
R37 Sexual dysfunction, unspecified

Collagenase clostridium histolyticum (Xiaflex):

HCPCS codes covered if selection criteria are met:

J0775 Injection, collagenase, clostridium histolyticum, 0.01 mg

ICD-10 codes covered if selection criteria are met:

N52.01 - N52.1 Male erectile dysfunction
N52.31 - N52.39 Postprocedural erectile dysfunction


This policy is supported by guidelines from the American Urological Association.

Researchers have been examining less invasive alternatives to surgery for Peyronie's disease.  A number of studies have examined the effectiveness of transdermal administration of verapamil as a treatment for Peyronie's disease.  One study found a non-significant improvement in penile curvature with transdermal administration of verapamil (Greenfield et al, 2007).  Greenfield et al (2007) stated that while surgery remains the gold standard of therapy to correct the acquired curvature of Peyronie's disease, the search for a less invasive therapy continues.  Transdermal drug delivery was proposed to be superior to oral or injection therapy because it bypasses hepatic metabolism and minimizes the pain of injection.  After electromotive drug administration with verapamil tunica albuginea specimens were demonstrated to contain detectable levels of the drug.  Due to varying success with verapamil as injectable therapy for Peyronie's disease, these researchers performed a double-blind, placebo controlled trial to determine the effectiveness of verapamil delivered through electromotive drug administration.  A total of 42 men with Peyronie's disease volunteered to participate in this study, which was approved by the authors' institutional review board.  A genito-urinary examination was performed on all patients, including plaque location, stretched penile length, objective measurement of curvature after papaverine injection and duplex ultrasound.  Each subject was randomized to receive 10 mg verapamil in 4 cc saline or 4 cc saline via electromotive drug administration.  A Mini-Physionizer (Physion, Mirandola, Italy) device was used at a power of 2.4 mA for 20 minutes.  Treatments were performed 2 times weekly for 3 months.  After 3 months each patient was re-evaluated with physical examination and duplex ultrasound by a technician blinded to the treatment received.  A modified erectile dysfunction index of treatment satisfaction questionnaire was also completed by each patient.  A total of 23 patients were randomized to the verapamil treatment group (group 1) and 19 were randomized to the saline group (group 2).  There were no significant differences between patient groups with respect to patient age, disease duration or pretreatment curvature.  In group 1, 15 patients (65 %) had measured improvement (mean 9.1 degrees, range 5 to 30), 5 (22 %) had no change and in 3 (13 %) the condition worsened.  In group 2, 11 patients (58 %) had measured improvement (mean 7.6 degrees, range 5 to 30), 7 (37 %) showed no change and in 1 (5 %) the condition worsened.  To better evaluate effectiveness the total number of patients experiencing significant improvement (20 degrees or greater) was calculated and compared.  Seven patients (30 %) in group 1 and 4 (21 %) in group 2 achieved this criterion.  The authors found that, although a greater percent of patients treated with verapamil in the electromotive drug administration protocol had a measured decrease in curvature, the results were not statistically significant.  The authors stated that further research is needed to determine whether electric current may have a role in the treatment of Peyronie's disease as well as if verapamil delivered via electromotive drug administration may have a role as effective treatment.

Cabello Benavente et al (2005) reported on a small, uncontrolled study of the effects of transdermal iontophoresis with verapamil and dexamethasone in patients with early Peyronie's disease, finding effects on pain, but limited effects on curvature.  These researchers treated 10 patients with Peyronie's disease of less than 1 year of evolution twice-weekly during 6 consecutive weeks using iontophoresis with a Miniphysionizer dispositive.  This device generates a 2-mA electric current during 20 mins that triggers the transdermal penetration of medication.  In every session dexamethasone 8 mg and verapamil 5 mg were administered inside a small self-adhesive receptacle on the penile skin overlying the fibrosis plaque.  To evaluate the efficacy, penile curvature was measured by Kelami's test, while the plaque size was assessed by penile ultrasound.  Other parameters like pain, erectile function and ability for vaginal intercourse were recorded using questionnaires.  Safety parameters were also assessed during treatment.  No improvement or progression in penile curvature was evidenced in any of the patients.  The hardness of the plaque was reduced in 5 patients, becoming impalpable in 2 of them.  Decrease in plaque volume was observed by penile ultrasound in 6.  Pain improved in 8 patients, disappearing in 6 of them.  One patient recovered his erectile function at the end of the treatment; whereas 3 referred that their ability for intercourse enhanced while 2 reported that treatment improved their sexual life in general.  These researchers didn't record any significantly side effects, except for a transitory and slight dermal redness on the site of electrode placement.  The authors concluded that transdermal iontophoresis had an effect on pain control in early stages of Peyronie's disease, but efficacy in reducing penile curvature seems to be limited.  They stated that controlled clinical trials are needed, and perhaps reviewing indications in order to obtain more relevant clinical effects.

Shirazi et al (2009) assessed the effect of intra-lesional verapamil on the treatment of Peyronie's disease.  This randomized study involved 80 patients.  First, they were divided into 2 groups -- the 1st group (case: 40 patients) received intra-lesional verapamil and the 2nd group (control: 40 patients) local saline injection.  They were followed about 24 weeks and evaluated for the size of plaques, plaque softening, reduction of pain and amelioration of penile deformity and erectile dysfunction (ED) (estimated by the International Index of Erectile Function) before and after treatment.  Reduction of plaque size was seen in 17.5 % of the case group and 12.8 % of the control group (p = 0.755).  Pain was reduced in 30 % of the case group and 28.2 % of the control group (p = 0.99).  Curvature was decreased in 17.5 % of the case group and 23.1 % the control group (p = 0.586).  Plaque softening was seen in 30 % of the case group compared with 25.6 % improvement in the control group (p = 0.803).  Also these investigators found 5 % and 2.6 % improvement in sexual dysfunction in the case and control groups, respectively (p = 0.985).  The authors concluded that although in some studies verapamil has been found to be effective in the treatment of Peyronie's disease, these researchers did not find any improvement in comparison with the control group.  They stated that larger scale studies are warranted to assess the effect of this drug on the treatment of Peyronie's disease.

Heidari et al (2010) evaluated the effect of intra-lesional injection of verapamil in Peyronie's plaque with confirmed lesion.  This randomized clinical trial was performed between March 2005 and March 2006 on 16 patients with Peyronie's disease.  Performing a comprehensive physical examination, the genitalia of the patients were checked to confirm the diagnosis and reject other sexual disorders.  Besides, parameters such as penis curving, lesion size were measured.  Then, based on the 10-point visual analog scale, sexual satisfaction of patients and their wives were recorded in a questionnaire.  Patients got intra-lesional verapamil every 14 days and were treated for 6 months.  After that, the parameters were assessed and data collected was analyzed using paired t-test.  P-value < 0.05 was considered statistically significant.  On average, lesion size and penis curving decreased 30 %.  Almost 20 % of patients and their wives were satisfied with the outcome of the treatment.  No significant side effect was seen during the treatment.  The authors concluded that injection of calcium channel blockers are effective for treatment of the Peyronie's disease; however, more studies with more patients are needed.

Early studies suggested a potential benefit on neurogenic ED (NED) from percutaneous electrostimulation of the perineum, although additional studies are needed.  Shafik et al (2008) examined the hypothesis that percutaneous perineal stimulation evokes erection in patients with NED.  Percutaneous electro-stimulation of the perineum (PESP) with synchronous intra-corporeal pressure (ICP) recording was performed in 28 healthy volunteers (age of 36.3 +/- 7.4 years) and 18 patients (age of 36.6 +/- 6.8 years) with complete NED.  Current was delivered in a sine wave summation fashion.  Average maximal voltages and number of stimulations delivered per session were 15 to 18 volts and 15 to 25 stimulations, respectively.  Percutaneous perineal electro-stimulation of healthy volunteers resulted in an increase in ICP (p < 0.0001), which returned to the basal value upon cessation of stimulation.  The latent period recorded was 2.5 +/- 0.2 seconds.  Results were reproducible on repeated PESP in the same subject but with an increase of the latent period.  Patients with NED recorded an ICP increase that was lower (p < 0.05) and a latent period that was longer (p < 0.0001) than those of healthy volunteers.  The authors concluded that PESP resulted in ICP increase in the healthy volunteers and patients with NED.  The ICP was significantly higher and latent period shorter in the healthy volunteers than in patients with NED.  They noted that PESP may be of value in the treatment of patients with NED, provided that further studies are carried out to reproduce these results.

There is reliable evidence that oral phosphodiesterase-5 (PDE-5) inhibitors (e.g., sildenafil, vardenafil, tadalafil, mirodenafil, and udenafil) improve erectile functioning in men with ED.  However, there is a lack of reliable evidence of the efficacy of hormonal treatments and the value of hormone testing for ED.

The American College of Physicians (ACP) developed guidelines on hormonal testing and pharmacological treatments of ED (Qaseem et al, 2009).  Current drug therapies include PDE-5 inhibitors as well as hormonal treatment.  The ACP recommended
  1. clinicians initiate therapy with a PDE-5 inhibitor in men who seek treatment for erectile dysfunction and who do not have a contra-indication to PDE-5 inhibitor use, and
  2. clinicians base the choice of a specific PDE-5 inhibitor on the individual preferences of men with erectile dysfunction, including ease of use, cost of medication, and adverse effects profile. 

The ACP did not recommend for or against routine use of hormonal blood tests or hormonal treatment in the management of patients with ED.

In a systematic review and meta-analysis, Tsertsvadze and colleagues (2009) evaluated the efficacy and harms of oral PDE-5 inhibitors and hormonal treatments for ED and assessed the effect of measuring serum hormone levels on treatment outcomes for ED.  The authors concluded that oral PDE-5 inhibitors improved erectile functioning and had similar safety and efficacy profiles.  However, results on the efficacy of hormonal treatments and the value of hormone testing in men with ED were inconclusive.  The authors selected randomized, controlled trials (RCTs) of oral PDE-5 inhibitors and hormonal treatment for ED, and observational studies reporting measurement of serum hormone levels, prevalence of hormonal abnormalities, or both in men with ED.  Two independent reviewers abstracted data on study, participant, and treatment characteristics; efficacy and harms outcomes; and prevalence of hormonal abnormalities.  Data, primarily from short-term trials (less than or equal to 12 weeks), indicate that PDE-5 inhibitors were more effective than placebo in improving sexual intercourse success (69.0 % versus 35.0 %).  The proportion of men with improved erections was significantly greater among those treated with PDE-5 inhibitors (range of 67.0 % to 89.0 %) than with placebo (range of 27.0 % to 35.0 %).  The PDE-5 inhibitors were associated with increased risk for any adverse events compared with placebo (e.g., relative risk with sildenafil, 1.72 [95 % confidence interval (CI): 1.53 to 1.93]).  In 4 head-to-head RCTs comparing sildenafil, vardenafil, and tadalafil, improvement of ED and adverse events did not differ among treatments.  Results from 15 RCTs evaluating hormonal treatment of ED were inconsistent on whether treatment improved outcomes.  Evidence was insufficient regarding whether men with ED had a higher prevalence of hypo-gonadism than men without ED. 

There is insufficient evidence of the effectiveness of acupuncture for the treatment of ED.  In a systematic review, Lee et al (2009) found insufficient evidence for the use of acupuncture in the treatment of ED.  Systematic searches were conducted in 15 electronic databases, with no language restrictions.  Hand-searches included conference proceedings and the authors' files.  All clinical studies of acupuncture as a treatment for ED were considered for inclusion, and their methodological quality was assessed using the Jadad score.  Of the 4 studies included, 1 RCT showed beneficial effects of acupuncture compared with sham acupuncture in terms of response rate, while another RCT found no effects of acupuncture.  The remaining 2 studies were uncontrolled clinical trials.  Collectively, these data showed that RCTs of acupuncture for ED are feasible but scarce.  Most investigations had methodological flaws (e.g., inadequate study design, poor reporting of results, small sample size, and publication without appropriate peer review process).  The authors concluded that the evidence is insufficient to suggest that acupuncture is an effective intervention for treating ED.  They stated that further research is needed to examine if there are specific benefits of acupuncture for men with ED.

Other treatments for ED include inflatable penile prostheses, and vacuum erectile devices, and vascular surgery.  Hellstrom and colleagues (2010) provided state-of-the-art knowledge regarding the treatment of ED by implant, mechanical device, and vascular surgery, representing the opinions of 7 experts from 5 countries developed in a consensus process over a 2-year period.  The inflatable penile prosthesis (IPP) is indicated for the treatment of patients with organic ED after failure or rejection of other treatment options.  Comparisons between the IPP and other forms of ED therapy generally reveal a higher satisfaction rate in men with ED who chose the prosthesis.  Organic ED responds well to vacuum erection device (VED) therapy, especially among men with a sub-optimal response to intra-cavernosal pharmacotherapy.  After radical prostatectomy, VED therapy combined with PDE-5 therapy improved sexual satisfaction in patients dissatisfied with VED alone.  Penile re-vascularization surgery seems most successful in young men with absence of venous leakage and isolated stenosis of the internal pudendal artery following perineal or pelvic trauma.  Currently, surgery to limit venous leakage is not recommended.  The authors stated that more research is needed in the area of re-vascularization surgery, in particular, venous outflow surgery.

Hilz and Marthol (2003) stated that neurogenic, particularly autonomic disorders, frequently contribute to the etiology and pathophysiology of ED.  Parasympathetic and sympathetic outflow mediates erection.  Non-cholinergic, non-adrenergic neurotransmitters induce activation of cyclic monophosphates, leading to relaxation of smooth muscles of the corpora cavernosa and by this to tumescence and rigidity, i.e., erection.  The diagnosis of neurologic causes of ED requires a detailed history and neurologic examination.  Conventional neurophysiological procedures evaluate the function of rapidly conducting, thickly myelinated nerve fibers only.  Therefore, techniques such as sphincter ani externus electromyography, latency measurements of the pudendal nerve or bulbocavernosus reflex studies frequently do not contribute to the diagnostic process.  The evaluation of small nerve fibers that are essential for erection, for example by means of psychophysical quantitative thermo-testing, might improve the diagnosis of neurogenic causes of ED.  In addition, the assessment of heart rate variability at rest, during metronomic breathing, Valsalva maneuver, and active standing might be helpful to identify an autonomic neuropathy as the cause of ED.

Hamdan and Al-Matubsi (2009) noted that ED etiology is multi-factorial, including endocrine, neurological, vascular, systemic disease, local penile disorders, nutrition, psychogenic factors, and drug-related.  This study was performed to compare the relevant comprehensive biochemical parameters as well as the clinical characteristics in diabetic ED and healthy control subjects and to assess the occurrence of penile neuropathy in diabetic patients and thus the relationship between ED and diabetes.  A total of 56 patients accepted to undergo assessment for penile vasculature using intracavernosal injection and color Doppler ultrasonography.  Of the 56 diabetic patients, 38 patients were found with normal blood flow and thus they were considered as the diabetic-ED group, whereas, ED diabetic patients with an arteriogenic component were excluded.  These patients with an age range between 17 and 58 years, complaining of ED, with duration of diabetic illness ranging from 2 to 15 years.  The control group comprised of 30 healthy subject aged between 19 and 55 years.  Peripheral venous levels of testosterone, prolactin, follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), malondialdehyde and glycosylated hemoglobin (HbA(1)c) were obtained in all subjects.  Valsalva maneuver and neurophysiological tests were also determined.  Testosterone, prolactin, FSH, LH, and TSH hormones of the diabetic patients were not significantly different from those of the control group.  Diabetic patients with ED have higher HbA(1)c and oxidative stress levels while the R-R ratio was significantly decreased.  Bulbocavernosus reflex latency was significantly prolonged, whereas its amplitude, the conduction velocity and amplitude of dorsal nerve of penis were significantly reduced in the diabetic patients.  The authors concluded that although ED is a multi-factorial disorder, yet, the present study revealed that in ED patients without arteriogenic ED a neurogenic component is present.  Furthermore, the complex effect of the Valsalva maneuver on cardiovascular function is the basis of its usefulness as a measure of autonomic function.  Thus, it can be of value in the diagnosis of ED although these hypotheses require follow-up in a large study cohort.

In an open-label, single-arm, prospective study, Gruenwald and colleagues (2012) noted that low-intensity extracorporeal shock wave therapy (LI-ESWT) has been reported as an effective treatment in men with mild and moderate ED.  These investigators determined the effectiveness of LI-ESWT in severe ED patients who were poor responders to PDE-5 inhibitor (PDE5i) therapy.  Patients with an erection hardness score (EHS) less than or equal to 2 at baseline were included in this study.  The protocol comprised 2 treatment sessions per week for 3 weeks, which were repeated after a 3-week no-treatment interval.  Patients were followed at 1 month (FU1), and only then an active PDE5i medication was provided for an additional month until final follow-up visit (FU2).  At each treatment session, LI-ESWT was applied on the penile shaft and crus at 5 different anatomical sites (300 shocks, 0.09 mJ/mm(2) intensity at 120 shocks/min).  Each subject underwent a full baseline assessment of erectile function using validated questionnaires and objective penile hemodynamic testing before and after LI-ESWT.  Outcome measures used were changes in the International Index of Erectile Function-erectile function domain (IIEF-ED) scores, the EHS measurement, and the 3 parameters of penile hemodynamics and endothelial function.  A total of 29 men (mean age of 61.3 years) completed the study.  Their mean IIEF-ED scores increased from 8.8 +/- 1 (baseline) to 12.3 +/- 1 at FU1 (p = 0.035).  At FU2 (on active PDE5i treatment), their IIEF-ED further increased to 18.8 +/- 1 (p < 0.0001), and 72.4 % (p < 0.0001) reached an EHS of greater than or equal to 3 (allowing full sexual intercourse).  A significant improvement (p = 0.0001) in penile hemodynamics was detected after treatment and this improvement significantly correlated with increases in the IIEF-ED (p < 0.05).  No noteworthy adverse events were reported.  The authors concluded that penile LI-ESWT is a new modality that has the potential to treat a subgroup of severe ED patients.  Moreover, they stated that these preliminary data need to be confirmed by multi-center sham control studies in a larger group of ED patients with long-term follow-up.

Zhang et al (2013) stated that several studies have reported the influence of the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene on ED susceptibility, but the results remain controversial.  These investigators performed a meta-analysis using data published to derive a more precise estimation of the relationship,.  A total of 6 case-control studies, including 1,039 cases and 927 controls, were selected.  The pooled odds ratios (ORs) and respective 95 % CIs were calculated by comparing the carriers of D-allele with the wild homozygotes (ID + DD versus II).  Comparisons of other genetic models were also performed (ID + II versus DD, DD versus II, DI versus II and D versus I).  In the overall analysis, no significant association between the polymorphism and ED risk was observed (OR = 1.07, 95 % CI: 0.84 to 1.37, p = 0.575 for ID + DD versus II).  In the subgroup analysis by ethnic, no significant association was detected among Asian, Latino and European for the comparison of ID + DD versus II (Asian: OR = 1.27, 95 % CI: 0.89 to 1.81; Latino: OR = 0.76, 95 % CI: 0.46 to 1.27; European: OR = 1.06, 95 % CI: 0.67 to 1.66).  Results from other comparative genetic models also indicated the lack of associations between this polymorphism and ED risk.  The authors concluded that this meta-analysis indicated that the ACE I/D polymorphism might not contribute to the risk of ED.

Xu and colleagues (2013) evaluated the effect of continuous positive airway pressure (CPAP) on ED in patients with obstructive sleep apnea syndrome (OSAS).  These investigators searched Cochrane Library, PubMed, China Academic Journal Full-Text Database, Chinese Biomedical Literature Database, Wanfang Resource Database and Chinese Journal Full-Text Database for clinical trials on the effect of CPAP on ED in OSAS patients.  They identified the trials according to inclusion and exclusion criteria, evaluated their quality, and then extracted valid data for meta-analysis.  These researchers included 4 articles, 3 in English and 1 in Chinese, involving 77 cases of OSAS with ED.  Meta-analysis revealed no statistically significant heterogeneity among different studies (p = 0.80; I2 = 0 %), and therefore the fixed effect model was used for the analysis, which showed a significant increase in the IIEF-5 score after CPAP treatment (WMD = 4.19, 95 % CI: 3.01 to 5.36, p < 0.001).  The authors concluded that the existing evidence from clinical trials showed that the CPAP therapy can significantly improve ED in OSAS patients.  Moreover, they stated that its effectiveness has to be verified by RCTs of higher quality and larger sample size.

In a placebo-controlled, prospective, randomized, single-blind clinical trial, Hatzichristodoulou and colleagues (2013) examined the effectiveness of ESWT in the treatment of patients with Peyronie's disease.  Subjects (n = 102) were randomly assigned (n = 51) to each group (ESWT or placebo).  All patients were given 6 weekly treatments.  Patients in the ESWT-group received 2,000 shock waves per session, using the Piezoson 100 lithotripter (Richard Wolf, Knittlingen, Germany).  Patients in the placebo-group were treated with interposition of a plastic membrane, which prevented any transmission of shock waves.  Primary end-point was decrease of pain between baseline and after 4 weeks follow-up.  Secondary end-points were changes in deviation, plaque size, and sexual function.  Pain was assessed by a visual analog scale (VAS).  Deviation was measured by a goniometer after artificial erection using Alprostadil (Viridal®, Schwarz Pharma, Monheim, Germany).  Plaque size was measured with a ruler and sexual function assessed by a scale regarding the ability to perform sexual intercourse.  Overall, only 45 patients experienced pain at baseline.  In the subgroup analysis of these patients, pain decreased in 17/20 (85.0 %) patients in the ESWT group and 12/25 (48.0 %) patients in the placebo group (p = 0.013, relative risk [RR] = 0.29, 95 % CI: 0.09 to 0.87).  Penile deviation was not reduced by ESWT (p = 0.66) but worsened in 20/50 (40 %) and 12/49 (24.5 %) patients of the ESWT and placebo-group, respectively (p = 0.133).  Plaque size reduction was not different between the 2 groups (p = 0.33).  Additional, plaque size increased in 5 patients (10.9 %) of the ESWT group only.  An improvement in sexual function could not be verified (p = 0.126, RR = 0.46).  The authors concluded that despite some potential benefit of ESWT in regard to pain reduction, it should be emphasized that pain usually resolves spontaneously with time.  Moreover, they stated that given this and the fact that deviation may worsen with ESWT, this treatment cannot be recommended.

Jordan et al (2014) stated that Peyronie's disease (PD) is often physically and psychologically devastating for patients, and the goal of treatment is to improve symptoms and sexual function without adding treatment-related morbidity.  The potential for treatment-related morbidity after more invasive interventions (e.g. surgery) creates a need for effective minimally invasive treatments.  These investigators examined the available literature using levels of evidence to determine the reported support for each treatment.  Most available minimally invasive treatments lack critical support for effectiveness due to the absence of RCTs or non-significant results after RCTs.  Iontophoresis, oral therapies (e.g., vitamin E, potassium para-aminobenzoate, tamoxifen, carnitine, and colchicine), ESWT, and intra-lesional injection with verapamil or nicardipine have shown mixed or negative results.  Treatments that have decreased penile curvature deformity in Level 1 or Level 2 evidence-based, placebo-controlled studies include intra-lesional injection with interferon α-2b or collagenase clostridium histolyticum.

Cai et al (2014) evaluated the effect of statins for ED.  These investigators performed a systematic review of the literature using the Cochrane Library, Embase and PubMed from the inception of each database to June 2013.  Only RCTs comparing treatment for ED with statins were identified.  Placebo RCTs with the IIEF as the outcome measure were eligible for meta-analysis.  A total of 7 RCTs including 2 statins with a total of 586 patients strictly met selection criteria for systematic review and 5 of them qualified for the meta-analysis.  A meta-analysis using a random effects model showed that statins were associated with a significant increase in IIEF-5 scores (mean difference (MD): 3.27; 95 % CI:1.51 to 5.02; p < 0.01) and an overall improvement of lipid profiles including total cholesterol (MD: -1.08; 95 % CI: -1.68 to -0.48; p < 0.01), low-density lipoprotein (LDL) cholesterol (MD: -1.43; 95 % CI: -2.07 to -0.79; p < 0.01), high-density lipoprotein (HDL) cholesterol (MD: 0.24; 95 % CI: 0.13 to 0.35; p < 0.01) and triglycerides (TGs) (MD: -0.55; 95 % CI: -0.61 to -0.48; p < 0.01).  The authors concluded that the findings of this study revealed positive consequences of these lipid-lowering drugs on erectile function, especially for non-responders to PDE5is.  However, it has been reported that statin therapy may reduce levels of testosterone and aggravate symptoms of ED.  They stated that larger, well-designed RCTs are needed to investigate the double-edged role of statins in the treatment of ED.

Furthermore, an UpToDate review on “Treatment of male sexual dysfunction” (Cunningham and Seftel, 2014) does not mention nicardipine and statins as therapeutic options.

Acoustical Wave Therapy (Alpha Wave SwissWave Protocol)

Alpha Wave’s SwissWave Protocol (acoustical wave therapy) uses a Swiss-made medical device cleared by the FDA for use on the human body as a massage device for soft tissue repair and improved blood flow, among other uses.  However, there is a lack of evidence regarding the effectiveness of Alpha Wave (acoustical wave therapy) for the treatment of ED.

Adipose-Derived Regenerative Cells (ADRC) Therapy for the Treatment of Erectile Dysfunction

In an open-label, phase-I clinical trial, Haahr and colleagues (2018) examined the safety of adipose-derived regenerative cells (ADRC) therapy in the treatment of ED.  A total of 21 patients with ED after radical prostatectomy (RP), with no signs of recovery using conventional therapy, received a single intra-cavernous injection of autologous ADRC and were followed for 1 year; 6 men were incontinent, and 15 were continent at inclusion.  The primary (safety of ADRC therapy) and secondary end-points (sexual function) were evaluated at 1, 3, 6, and 12 months after ADRC injection by registration of AEs and validated questionnaires using the IIEF-5 and EHS.  No serious adverse events (SAEs) occurred, but 8 reversible minor events related to the liposuction were noted; 8 out of 15 (53 %) patients in the continent group reported erectile function sufficient for intercourse at 12 months.  Baseline median IIEF-5 scores (6.0; inter-quartile range [IQR] 3) were unchanged 1 month after the treatment, but significantly increased after 6 to 7 (IQR 17).  This effect was sustained at 12 months (median of 8; IQR 14).  These researchers did not see any improvements in erectile function in the group of incontinent men or among men with ED prior to RP.  The authors concluded that intra-cavernous injection of ADRC was safe in this phase-I clinical trial with a 12 month follow-up.  These preliminary findings need to be further investigated in phase-II/III clinical trials.

Botulinum Toxin for the Treatment of Erectile Dysfunction

Ghanem and colleagues (2018) noted that botulinum toxin type A (BoNT-A) has been used to treat several striated and smooth muscle disorders.  During the past year, human and animal studies conducted in Egypt and Canada by 2 different groups of investigators have suggested a possible role for the intra-cavernosal injection of BoNT-A in the treatment of ED.  These investigators discussed BoNT-A and its current medical uses, the rationale for its new potential use in the treatment of ED, and the available evidence and concerns.  They performed a literature search; and this review was based on the available studies presented at the European Society for Sexual Medicine, Sexual Medicine Society of North America, and International Society for Sexual Medicine meetings in 2016 by the 2 groups.  Main outcome measures were sinusoidal diameter, penile color Doppler study, Erection Hardness Score, Sexual Health Inventory for Men questionnaire, and Sexual Encounter Profile questions 2 and 3.  Two human studies conducted by the authors and 2 animal studies (1 from the authors' group and 1 from Canada) were reviewed.  These findings appeared to suggest generally favorable outcomes with the use of BoNT-A in the treatment of ED.  The authors concluded that BoNT-A could be a potential therapy for ED.  Moreover, they stated that in addition to the findings of the 3 pilot studies, larger multi-center trials are needed to further explore the true therapeutic efficacy and clinical safety of BoNT-A in the treatment of ED.

Collagenase Clostridium Histolyticum Injection

U.S. Food and Drug Administration (FDA)-Approved Indications

  • Xiaflex (collagenase clostridium histolyticum) is indicated for the treatment of adult patients with Dupuytren’s contracture with a palpable cord.
  • Xiaflex (collagenase clostridium histolyticum) is indicated for the treatment of adult men with Peyronie’s disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy. 

Collagenases are proteinases that hydrolyze collagen in its native triple helical conformation under physiological conditions, resulting in lysis of collagen deposits. The signs and symptoms of Peyronie’s disease have been found to be caused by a collagen plaque. Injection of collagenase clostridium histolyticum into a Peyronie’s plaque, which is comprised mostly of collagen, may result in enzymatic disruption of the plaque. Following this disruption of the plaque, penile curvature deformity are reduced (Endo Pharmaceuticals, 2021).

Jordan (2008) evaluated the safety and effectiveness of intra-lesional clostridial collagenase injection therapy in a series of patients with Peyronie's disease.  A total of 25 patients aged 21 to 75 years who were referred to a single institution with a well-defined Peyronie's disease plaque were treated with three intra-lesional injections of clostridial collagenase 10,000 units in a small volume (0.25 cm(3) per injection) administered over 7 to 10 days, with a repeat treatment (i.e., 3 injections of collagenase 10,000 units/25 cm(3) injection over 7 to 10 days) at 3 months.  Primary efficacy measures were changes from baseline in the deviation angle and plaque size.  Secondary efficacy end-points were patient responses to a Peyronie's disease questionnaire and improvement according to the investigators' global evaluation of change.  The primary efficacy measures were change in deviation angle and change in plaque size.  Secondary end-points were patient questionnaire responses and improvement according to the investigators' global evaluation of change.  Significant decreases from baseline were achieved in the mean deviation angle at months 3 (p = 0.0001) and 6 (p = 0.0012), plaque width at months 3 (p = 0.0052), 6 (p = 0.0239), and 9 (p = 0.0484), and plaque length at months 3 (p = 0.0018) and 6 (p = 0.0483).  More than 50 % of patients in this series considered themselves "very much improved" or "much improved" at all time-points in the study, and the drug was generally well-tolerated.  The authors concluded that the benefits of intra-lesional clostridial collagenase injections in this trial lent support to prior studies supporting its use in the management of Peyronie's disease.  Moreover, they noted that a double-blind, placebo-controlled study is currently under development.

In a phase IIb, double-blind, randomized, placebo-controlled study, Gelbard and colleagues (2012) examined the safety and effectiveness of collagenase Clostridium histolyticum and assessed a patient reported outcome questionnaire.  A total of 147 subjects were randomized into 4 groups to receive collagenase C. histolyticum or placebo (3:1) with or without penile plaque modeling (1:1).  Per treatment cycle 2 injections of collagenase C. histolyticum (0.58 mg) were given 24 to 72 hours apart.  Subjects received up to 3 cycles at 6-week intervals.  When designated, investigator modeling was done 24 to 72 hours after the second injection of each cycle.  These researchers evaluated penile curvature by goniometer measurement, patient reported outcomes and adverse event profiles.  After collagenase C. histolyticum treatment significant improvements in penile curvature (29.7 % versus 11.0 %, p = 0.001) and patient reported outcome symptom bother scores (p = 0.05) were observed compared to placebo.  In modeled subjects 32.4 % improvement in penile curvature was observed in those on collagenase C. histolyticum compared to 2.5 % worsening of curvature in those on placebo (p < 0.001).  Those treated with collagenase C. histolyticum who underwent modeling also showed improved Peyronie disease symptom bother scores (p = 0.004).  In subjects without modeling there were minimal differences between the active and placebo cohorts.  Most adverse events in the collagenase C. histolyticum group occurred at the injection site and were mild or moderate in severity.  No treatment related serious adverse events were reported.  The authors concluded that collagenase C. histolyticum treatment was well-tolerated.  Moreover, they noted significant improvement in penile curvature and patient reported outcome symptom bother scores, suggesting that this may be a safe, non-surgical alternative for Peyronie disease.

Gelbard et al (2013) stated that IMPRESS (Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies) I and II examined the clinical safety and effectiveness of collagenase C. histolyticum intra-lesional injections in subjects with Peyronie disease.  Co-primary outcomes in these identical phase III randomized, double-blind, placebo controlled studies included the percent change in the penile curvature abnormality and the change in the Peyronie disease questionnaire symptom bother score from baseline to 52 weeks.  IMPRESS I and II examined collagenase C. histolyticum intra-lesional injections in 417 and 415 subjects, respectively, through a maximum of 4 treatment cycles, each separated by 6 weeks.  Men received up to 8 injections of 0.58 mg collagenase C. histolyticum that are 2 injections per cycle separated by approximately 24 to 72 hours with the second injection of each followed 24 to 72 hours later by penile plaque modeling.  Men were stratified by baseline penile curvature (30 to 60 versus 61 to 90 degrees) and randomized to collagenase C. histolyticum or placebo 2:1 in favor of the former.  Post hoc meta-analysis of IMPRESS I and II data revealed that men treated with collagenase C. histolyticum showed a mean 34 % improvement in penile curvature, representing a mean ± SD -17.0 ± 14.8 degree change per subject, compared with a mean 18.2 % improvement in placebo treated men, representing a mean -9.3 ± 13.6 degree change per subject (p <0.0001).  The mean change in Peyronie disease symptom bother score was significantly improved in treated men versus men on placebo (-2.8 ± 3.8 versus -1.8 ± 3.5, p = 0.0037).  Three serious adverse events (corporeal rupture) were surgically repaired.  The authors concluded that IMPRESS I and II supported the clinical safety and effectiveness of collagenase C. histolyticum for the physical and psychological aspects of Peyronie disease.

On December 6, 2013, the FDA approved Xiaflex (collagenase clostridium histolyticum) as the first FDA-approved medicine for the treatment of Peyronie’s disease.  A treatment course for Peyronie’s disease consists of a maximum of 4 treatment cycles.  Each treatment cycle consists of 2 Xiaflex injection procedures (in which Xiaflex is injected directly into the collagen-containing structure of the penis) and 1 penile modeling procedure performed by the health care professional.  The safety and effectiveness of Xiaflex for the treatment of Peyronie’s disease were established in 2 randomized double-blind, placebo-controlled studies in 832 men with Peyronie’s disease with penile curvature deformity of at least 30 degrees.  Participants were given up to 4 treatment cycles of Xiaflex or placebo and were then followed 52 weeks.  Xiaflex treatment significantly reduced penile curvature deformity and related bothersome effects compared with placebo.  The most common adverse reactions associated with use of Xiaflex for Peyronie’s disease include penile hematoma, penile swelling and penile pain.

According to the FDA, when prescribed for the treatment of Peyronie’s disease, Xiaflex is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) because of the risks of serious adverse reactions, including penile fracture (rupture of one of the penile bodies within the penile shaft, also known as corporal rupture) and other serious penile injury.  Xiaflex for the treatment of Peyronie’s disease should be administered by a health care professional who is experienced in the treatment of male urological diseases.  The REMS requires participating health care professionals to be certified within the program by enrolling and completing training in the administration of Xiaflex treatment for Peyronie’s disease.  The REMS also requires health care facilities to be certified within the program and ensure that Xiaflex is dispensed only for use by certified health care professionals. The most frequently reported adverse drug reactions (25% or more) of patients treated with Xiaflex and at an incidence greater than placebo were penile hematoma, penile swelling, and penile pain.

Endovascular Treatment of Vasculogenic Erectile Dysfunction

Kim and colleagues (2015) stated that the treatment of ED has been a fascination involving multiple medical specialties over the past century with urologic, cardiac and surgical experts all contributing knowledge toward this multi-factorial disease.  With the well-described association between ED and cardiovascular disease, angiography has been utilized to identify vasculogenic impotence.  Given the success of endovascular drug-eluting stent (DES) placement for the treatment of coronary artery disease, there has been interest in using this same technology for the treatment of vasculogenic ED.  For men with inflow stenosis, DES placement to bypass arterial lesions has recently been reported with a high technical success rate.  Comparatively, endovascular embolization as an approach to correct veno-occlusive dysfunction (VOD) has produced astonishing procedural success rates as well.  However, after a thorough literature review, arterial intervention is only recommended for younger patients with isolated vascular injuries, typically from previous traumatic experiences.  Short-term functional outcomes were less than optimal with long-term results yet to be determined.  The authors concluded that endovascular intervention with angioplasty and DES placement offers hope for men with ED from focal arterial lesions resulting from blunt trauma.  However, long-term data are needed to evaluate its efficacy fully.  Although hemodynamically feasible, the pathophysiology of ED is commonly multi-factorial, even in such isolated lesions.  Whereas coronary and peripheral vasculature are often amenable to luminal diameter increases that result in long-term patency, the penile anatomy is co-dependent on surrounding anatomy for successful tumescence.  Furthermore, when endothelial dysfunction, microvascular changes or structural defects that result in corporeal VOD (CVOD),  accompany arterial inflow stenosis, isolated therapy with endovascular stent placement becomes less effective.  The hope for a less invasive method to treat ED in select populations may be possible in the future, but its time is not right now.

In a systematic review and meta-analysis, Doppalapudi and associates (2019) examined the safety and efficacy of endovascular therapy in the treatment of the 2 most common etiologies of vasculogenic ED : VOD and arterial insufficiency (AI).  PubMed, Web of Science, ScienceDirect, and Scopus databases were searched for published English literature regarding endovascular ED treatments.  Case series (n greater than or equal to 3) were included.  Multiple data points were obtained, including demographic data, etiology, diagnosis method, imaging studies, treatment approach, technical success, clinical success, complications, and follow-up.  A total of 16 relevant articles were obtained and a total of 212 patients with VOD and 162 with AI were identified.  The VOD cohort were treated either percutaneously (60.4 %; n = 128) or after surgical exposure of the deep dorsal vein (33.5 %, n = 71), or it was unspecified (6.1 %; n = 13).  The most common embolic used was n-butyl cyanoacrylate (51.9 %; n = 109).  Meta-analysis found an overall clinical success rate of 59.8 % in VOD patients.  Complications occurred in 5.2 % of patients (n = 11), with 9 considered to be mild and 2 considered to be severe.  The AI cohort contained 162 patients most commonly treated via stenting of the internal pudendal artery (40.1 %; n = 65).  Meta-analysis found an overall clinical success rate of 63.2 % in AI patients.  Complications occurred in 4.9 % of patients (n = 8), with 4 considered to be mild and 4 considered to be severe.  The authors concluded that endovascular therapy for medically refractory ED was safe and may provide a treatment alternative to more invasive surgical management; however, conclusions are limited by the heterogeneity of clinical success definitions among the included studies.

Epalrestat for the Treatment of Erectile Dysfunction

Yang and associates (2019) stated that epalrestat, an aldose reductase inhibitor (ARI), was adopted to improve the function of peripheral nerves in diabetic patients.  These researchers examined if epalrestat could restore the erectile function of diabetic ED using a rat model.  From June 2016, a total of 24 rats were given streptozocin (STZ) to induce the diabetic rat model, and epalrestat was administered to 10 diabetic ED (DED) rats.  Intra-cavernous pressure (ICP) and mean systemic arterial pressure (MAP), levels of aldose reductase (AR), nerve growth factor (NGF), neuronal NOS (nNOS), alpha-smooth muscle antigen (α-SMA), and von Willebrand factor (vWF) in the corpus cavernosum were analyzed.  These investigators discovered that epalrestat acted on cavernous tissue and partly restored erectile function; NGF and nNOS levels in the corpora were increased after treatment with epalrestat.  The authors also found that the content of α-SMA-positive smooth muscle cells and vWF-positive endothelial cells in the corpora cavernosum were reduced.  They concluded that epalrestat might improve erectile function by increasing the up-regulation of NGF and nNOS to restore the function of the dorsal nerve of the penis.  These preliminary findings need to be further investigated.

Extracorporeal Shock Wave Therapy / Low-Intensity Shock Wave Therapy

Zou and colleagues (2017) noted that the role of LI-ESWT in ED is not clearly determined.  These investigators examined the short-term safety and effectiveness of LI-ESWT for ED patients.  Relevant studies were searched in Medline, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), WANFANG and VIP databases.  Effective rate in terms of IIEF-Erectile Function Domain (IIEF-EF) and EHS at about 1 month after LI-ESWT was extracted from eligible studies for meta-analysis to calculate RR of effective treatment in ED patients treated by LI-ESWT compared to those receiving sham-treatment.  A total of 15 studies were included in the review, of which 4 RCTs were for meta-analysis.  Effective treatment was 8.31 [95 % CI: 3.88 to 17.78] times more effective in the LI-ESWT group (n = 176) than in the sham-treatment group (n = 101) at about 1 month after the intervention in terms of EHS, while it was 2.50 (95 % CI: 0.74 to 8.45) times more in the treatment group (n = 121) than in the control group (n = 89) in terms of IIEF-EF; 9-week protocol with energy density of 0.09 mJ/mm2 and 1,500 pluses appeared to have better therapeutic effect than 5-week protocol.  No significant adverse event (AE) was reported.  The authors concluded that LI-ESWT, as a non-invasive treatment, has potential short-term therapeutic effect on patients with organic ED irrespective of sensitivity to PDE5is.  Moreover, they stated that owing to the limited number and quality of the studies, more large-scale, well-designed and long-term follow-up time studies are needed to confirm this analysis.

In a double-blinded, sham-controlled, randomized clinical trial, Fojecki and associates (2017) evaluated the treatment outcome of linear Li-ESWT (LLi-ESWT) for ED.  Men with ED (n = 126) and a score lower than 25 points on the IIEF-EF were included.  Subjects were allocated to receive LLi-ESWT once-weekly for 5 weeks or sham treatment once-weekly for 5 weeks.  After a 4-week break, the 2 groups received active treatment once-weekly for 5 weeks.  Subjects completed the IIEF, EHS, Sexual Quality of Life-Men, and the Erectile Dysfunction Inventory of Treatment Satisfaction at baseline, after 9 weeks, and after 18 weeks.  The primary outcome measurement was an increase of at least 5 points on the IIEF-EF score.  The secondary outcome measurement was an increased EHS score to at least 3 in men with a score no higher than 2 at baseline.  Data were analyzed by linear and logistic regression.  Mean IIEF-EF scores were 11.5 at baseline (95 % CI: 9.8 to 13.2), 13.0 after 5 sessions (95 % CI: 11.0 to 15.0), and 12.6 after 10 sessions (95 % CI: 11.0 to 14.2) in the sham group and correspondingly 10.9 (95 % CI: 9.1 to 12.7), 13.1 (95 % CI: 9.3 to 13.4), and 11.8 (95 % CI: 10.1 to 13.4) in the ESWT group.  Success rates based on IIEF-EF score were 38.3 % in the sham group and 37.9 % in the ESWT group (OR = 0.95, 95 % CI: 0.4 to -2.02, p = 0.902).  Success rates based on EHS score were 6.7 % in the sham group and 3.5 % in the ESWT group (OR = 0.44, 95 % CI: 0.08 to 2.61, p = 0.369).  The authors concluded that no clinically relevant effect of LLi-ESWT on ED was found. 

In a systematic review and meta-analysis, Man and Li (2018) evaluated the effectiveness of LI-ESWT for the treatment of ED.  These researchers carried out a comprehensive search of the PubMed, Cochrane Register and Embase databases to March 2017 for RCTs reporting on patients with ED treated with LI- ESWT.  The IIEF and the EHS were the most commonly used tools to evaluate the effectiveness of LI-ESWT.  There were 9 studies including 637 patients from 2005 to 2017.  The meta-analysis revealed that LI-ESWT could significantly improve IIEF (MD: 2.54; 95 % CI: 0.83 to 4.25; p = 0. 004) and EHS (risk difference [RD]: 0.16; 95 % CI: 0.03 to 0.28; p = 0.01)).  Therapeutic efficacy could last at least 3 months (MD: 4.15; 95 % CI: 1.40 to 6.90; p = 0.003).  Lower energy density (0.09mj/mm2, MD: 4.14; 95 % CI: 0.87 to 7.42; p = 0.01) increased number of pulses (3,000 pulses per treatment, MD: 5.11; 95 % CI: 3.18 to 7.05, p < 0.0001) and shorter total treatment courses (less than 6 weeks, MD: 3.73; 95 % CI: 0.54 to 6.93; p = 0.02) resulted in better therapeutic efficacy.  The authors concluded that the findings of these studies suggested that LI-ESWT could significantly improve the IIEF and EHS of ED patients.  Moreover, they stated that the publication of robust evidence from additional RCTs and longer-term follow-up would provide more confidence regarding use of LI-ESWT for ED patients.

In a systematic review, Brunckhorst and colleagues (2019) examined the efficacy of low-intensity shockwave therapy (LISWT) as a treatment modality for vasculogenic ED, focusing on the long-term outcomes at over 6 months following treatment.  These researchers carried out a systematic literature search using Medline and Scopus databases from 2010 to September 2018.  Outcome measures extracted for long-term efficacy included IIEF scores and EHS.  Subgroup analysis for LISWT effectiveness included age, PDE5i responsiveness, presence of vascular co-morbidities and smoking status.  The search identified 11 studies, representing a total of 799 patients; 9 studies found a significant improvement in erectile function after LISWT at 6-month follow-up (median IIEF-EF improvement in 5.3 at 6 months).  However, of 5 studies assessing erectile function at 12 months; 2 identified a plateauing of results, with three a deterioration (IIEF-EF score changes of - 2 to 0.1 from 6 months).  Erectile function did, however, remain above baseline results in all of these studies.  Subgroup analysis revealed increasing age to reduce the response to LISWT treatment.  While ED severity, PDE5i responsiveness and co-morbidities potentially influence effectiveness, results were still inconsistent.  The authors concluded that LISWT may be a safe and acceptable potential ED treatment with demonstrated benefits at 6 months.  There is some question regarding efficacy deterioration beyond this, but there is still a demonstrated benefit observed even at 12 months post treatment.  However, these researchers stated that quality of evidence remains low with larger multi-institutional studies needed, standardizing confounders such as shock wave administration and oral medication use.

Sokolakis and associates (2019) noted that despite recent promising clinical results, the underlying mechanism of action of low-intensity ESWT (LI-ESWT) for ED is mostly unclear and currently under investigation.  These investigators examined the evidence regarding the basic science behind LI-ESWT for ED, discussed and proposed a putative mechanism of action, addressed the limitations, and implied insights for further investigation in the field.  Using Cochrane's methodologic recommendations on scoping studies and systematic reviews, these researchers conducted a systematic scoping review of the literature on experimental research regarding LI-ESWT for ED and other pathologic conditions.  The initial systematic search was carried between January and November 2017, with 2 additional searches in April and August 2018.  All studies that applied shockwave treatment at an energy flux density greater than 0.25 mJ/mm2 were excluded from the final analysis.  These investigators primarily aimed to clarify the biological responses in erectile tissue after LI-ESWT that could lead to improvement in erectile function.  A total of 59 publications were selected for inclusion in this study; 15 experimental research articles were identified on LI-ESWT for ED and 44 on LI-ESWT for other pathologic conditions.  LI-ESWT for ED appeared to improve erectile function possibly through stimulation of mechano-sensors, inducing the activation of neo-angiogenesis processes, recruitment and activation of progenitor cells, improving microcirculation, nerve regeneration, remodeling of erectile tissue, and reducing inflammatory and cellular stress responses.  The authors concluded that LI-ESWT for ED, based on current experimental studies, appeared to improve erectile function by inducing angiogenesis and reversing pathologic processes in erectile tissue.  These studies provided preliminary insights, but no definitive answers, and many questions remain unanswered regarding the mechanism of action, as well as the ideal treatment protocol.  These researchers stated that a common limitation in all these studies was the heterogeneity of the shockwave treatment application and protocol.  Moreover, they noted that improving the understanding of the mechanism of action of LI-ESWT for ED could aid in improving study designs, as well as suggest new avenues of investigation.

Ladegaard et al (2021) noted that previous studies have indicated that Li-ESWT may improve male ED of vascular etiology.  In a prospective, randomized, placebo-controlled study, these researchers examined penile rehabilitation of Li-ESWT in men with ED following robotic nerve-sparing radical prostatectomy (RARP).  This trial included men with ED following nerve-sparing RP with a score of less than 22 in the IIEF-5 questionnaire.  Subjects were divided into an active A (n = 20) and a placebo/sham B group (n = 18).  They were randomized consecutively upon study entry.  Each study arm had 1 treatment a week for 5 weeks.  Sexual outcomes were assessed by international validated questionnaires, EHS and IIEF-5 at baseline and at 4 and 12 weeks after treatment.  A total of 38 (n = 38) subjects were enrolled; there were no dropouts.  A significant increase was observed in IIEF-5 and EHS in group A at both 4 and 12 weeks.  At 12 weeks, the mean IIEF-5 score had increased by 3.45 points (p = 0.026), while the mean EHS score had increased by 0.5 points (p = 0.019).  The authors concluded that this randomized study showed that Li-ESWT for ED in men who had undergone RP might be safe and effective; however, further and more robust research is needed before Li-ESWT can be characterized as a reliable treatment modality.  These researchers stated that future research should focus on which patient subgroups can benefit from Li-ESWT.  They stated that international multi-center studies must be carried out in a suitable study population with narrowly defined inclusion criteria.

Sandoval-Salinas and colleagues (2021) noted that radial waves are used in the treatment of ED; however, they are different than focal waves, and their mechanism of action or effect on improving this condition is unclear.  In a systematic review, these researchers examined the effect of radial waves at the cellular level and their effectiveness at the clinical level for the treatment of ED.  They carried out electronic database searches and manual searches to identify clinical trials or cohort studies examining the effectiveness of radial waves in men with ED and pre-clinical trials in animal models or cell cultures in which the production of nitric oxide (NO) or endothelial growth factor (EGF) was evaluated.  Study quality was assessed, and data were extracted from each study.  A narrative synthesis of the results was conducted given the high heterogeneity between the selected studies.  Main outcomes measures included NO production, EGF expression, and changes in the EHS as well as the IIEF Questionnaire score.  A total of 4 studies in animal models and 1 randomized clinical trial in men with ED and kidney transplantation were identified that met the selection criteria.  Pre-clinical studies in animals suggested that radial waves increased cellular apoptosis in penile tissue, while vascular EGF (VEGF) expression increased in brain tissue.  In men with ED, no differences were found between radial wave therapy and placebo therapy in the mean IIEF score (15.6 ± 6.1 versus 16.6 ± 5.4 at 1 month after treatment), EHS (2.5 ± 0.85 versus 2.4 ± 0.7 at 1 month after treatment), or penile Doppler parameters.  The authors concluded that no quality evidence was found to support the use of radial pressure waves in humans for the treatment of ED.  In animal models and at the cellular level, the results were contradictory; these investigators stated that more research is needed.

The Canadian Urological Association’s guideline on “Erectile dysfunction” (Domes et al, 2021) recommended against the use of low-intensity shockwave therapy for patients with ED (low levels of certainty in evidence).

Gene Therapy for Erectile Dysfunction

Gur and co-workers (2018) noted that ED is a common health problem in approximately 50 % of men of advanced age (40 to 70 years old).  Recent attention related gene therapy to ED cases; this received much interest to further progress gene therapy for the treatment of ED.  These investigators analyzed key challenges and emphasized primary areas, including mostly pre-clinical and few clinical trials, cellular target(s), and different viral vectors/nanoparticles for gene delivery in ED.  While over-expression of target genes can be silenced by RNA interference (RNAi), down-regulation of these mechanisms has been implicated in ED.  Although many patients with ED show high efficacy with PDE5i, this therapy is insufficient in 30 to 40 % of patients.  Although several pre-clinical studies for ED treatment provided promising results, gene therapy has not shown promise in clinical practice, due to technical limitations of gene therapy to clinical translation and the ED pathogenesis.  Developments in small RNA, such as siRNA, approaches for ED may lead to significant management for ED.  Also, siRNA delivery into the corpus cavernosum appears to be a challenging issue and awaits further development.  The authors concluded that further investigation on several safety concerns of gene therapy, gene acquisition, preparation, and delivery are needed before any widespread application of gene therapy is used in ED.

Genetic Polymorphism on the Response to PDE5 Inhibitors

Mostafa and colleagues (2020) noted that several treatment strategies are nowadays available for ED patients.  Currently, oral PDE5i is the 1st-line treatment for ED.  However, they are effective in all treated cases with variable non-responsiveness.  Many factors have been listed for this behavior, but the possibility of gene polymorphisms as an underlying cause has not been systematically examined.  In a systematic review, these investigators examined the possible involvement of gene polymorphisms affecting the response to PDE5Is in men with ED.  They carried out a systematic review based on a search of all relevant articles in various electronic sites such as PubMed, Medline Medical Subject Headings, Cochrane Library, Science Direct, Scopus, Embase, CINAHL, and Egyptian Knowledge Bank data-bases.  Keywords used for relevant associations were sexual health, genes, variants, erectile dysfunction, polymorphisms, PDE5Is, and cavernous tissues.  Several studies have been performed to determine the contribution of different encoded genes to ascertain the association between different genotypes and ED men who were non-responders for PDE5Is.  A total of 11 studies were selected for this review.  In these studies, 6 examined eNOS genetic polymorphism with variable outcomes.  Only 1 study was conducted for each of the following genetic polymorphisms: phosphodiesterase 5A, G-protein β3 subunit, angiotensin converting enzyme, dimethylarginine dimethylaminohydrolase, arginase, and vascular endothelial growth factor with variable results.  The authors concluded that despite the relative shortage of available studies and the varied methodologies used, most of the research articles demonstrated a significant association between genetic polymorphism and the response to PDE5Is, especially for endothelial nitric oxide synthase polymorphism.  The limited number of studies that examined the possible effect of genetic polymorphism and the response to PDE5Is were challenged by many factors, especially for the definition of responders and non-responders.  This should be a motivating factor for researchers to perform further studies with a standardized methodology to address the influence of genetic variations on the response to PDE5Is.

Measurement of Platelet Indices

Yang and Muzepper (2019) stated that elevated platelet levels have been postulated to be associated with cardiovascular diseases, conditions closely linked to ED.  In a systematic review and meta-analysis, these researchers evaluated the platelet indices, which including platelet count (PLT), mean platelet volume (MPV) and platelet distribution width (PDW) in subjects with ED compared to controls in an attempt to clarify the possible role of platelet indices in the pathogenesis of ED.  These investigators initially screened the candidate studies observing the possible association between platelet indices and ED following literature search of database Cochrane Library, PubMed, Embase and Medline, and thus included the studies based on the pre-defined inclusion and exclusion criteria.  Two independent investigators extracted the related information on article data and outcome measures from the qualified studies, and a meta-analysis was performed using Stata 12.0 software.  Subgroup analyses were conducted by the different ED etiology obtained from the eligible studies.  The SMD and the corresponding 95 % CIs were applied to estimate the outcome measures.  A total of 14 articles were qualified in this meta-analysis with a total of 1,595 cases and 987 controls included.  Pooled estimate was in favor of increased MPV levels in subjects with ED with a SMD of 0.651 fl (95 % CI: 0.567 to 0.735, p = 0.000).  Subgroup analysis showed that vasculogenic ED had a higher MPV levels than controls as well (SMD [95 % CI]: 1.026 [0.823 to 1.228], p = 0.000).  However, pooled analysis based on PLT and PDW levels has produced inconsistent results and not strong evidence on platelet level and ED correlation.  The authors concluded that vasculogenic ED patients had a higher MPV level in this analysis.  However, the results need further interpretation with caution and more high-quality studies are needed.

Measurement of Serum Melatonin Levels for the Diagnosis of Erectile Dysfunction

Bozkurt and associates (2018) noted that melatonin is a hormone secreted from the pineal gland and has anti-oxidative and anti-inflammatory effects.  Oxidative stress is considered as an important factor in the etiology of ED, and in many experimental models, positive results have been obtained with melatonin treatment.  These investigators measured serum melatonin levels in ED patients and examined the possible relationship between ED and melatonin levels.  A total of 62 patients diagnosed with mild, moderate or severe ED according to the IIEF-5 and 22 healthy individuals were included in the study.  The serum melatonin levels, anthropometric data, and other biochemical and hormonal parameters of all the subjects were recorded.  Detailed anamnesis was also obtained in terms of diabetes, hypertension, cardiovascular diseases, smoking status, and alcohol use.  The serum melatonin level was found 34.2 ± 13.3 ng/dL in the mild ED group, 33.3 ± 14.7 ng/dL in the moderate ED group, 34.8 ± 17.2 ng/dL in the severe ED group, and 44.6 ± 16.5 ng/dL in the control group.  The serum melatonin levels were significantly lower in all ED groups compared to the control group (p = 0.019).  There was no significant difference in the serum melatonin levels between the 3 ED groups.  Diabetes, hypertension, cardiovascular diseases, smoking and alcohol use were not significantly different between the ED groups (p > 0.05).  The authors considered that if their findings are supported by further studies with larger populations, the measurement of the serum melatonin level may have a future role in the diagnosis and treatment of ED.

The authors stated that this was the first study evaluating serum melatonin level as a causative factor in this patient group.  A low serum melatonin level may result in an inadequate erection by preventing sufficient antioxidant capacity.  There is a need for additional studies to determine the exact role of melatonin deficiency in ED patients.  The drawbacks of this study were the absence of Doppler ultrasound findings, the lack of a treatment group and follow-up data on melatonin levels and the small sample size (n = 62).  They stated that future studies may evaluate the association or a possible correlation between serum melatonin levels and Doppler ultrasound parameters of erectile function.

Measurement of Serum Vitamin D Levels

Wei and colleagues (2019) noted that suboptimal levels of serum vitamin D levels have been implied to be associated with cardiovascular diseases and endothelial dysfunction, conditions closely associated with ED.  In a systematic review and meta-analysis, these researchers examined serum vitamin D levels in subjects with ED compared to controls and the 5-item version of the IIEF (IIEF-5) score in subjects with vitamin D deficiency compared to those without vitamin D deficiency in order to elucidate the role of vitamin D in the pathogenesis of ED.  Studies evaluating the possible association between vitamin D levels and ED were initially screened and thus included following electronic literature search of database Cochrane Library, PubMed, Embase and Medline.  Essential article information including outcome measures was extracted from the qualified studies by 2 independent authors, and STATA 12.0 software was used conducted the meta-analysis.  Subgroup analyses were conducted by vitamin D detection methods and sample size.  The SMD as well as the 95 % CIs was applied to estimate the outcome measures.  A total of 7 articles were included in this meta-analysis with a total of 4,132 subjects.  Pooled estimate was in favor of increased vitamin D levels in subjects without ED with a SMD of 3.027 ng/ml, 95 % CI: 2.290 to 3.314, p = 0.000.  However, subgroup analysis showed an opposite trend, after 1 study with a sample size over 1,000 that could possibly influence the weight balance was excluded, with a SMD of 0.267, 95 % CI: -0.052 to 0.585, p = 0.101.  These investigators also identified about 0.320 higher in IIEF-5 score (95 % CI: 0.146 to 0.494, p = 0.000) in subjects without vitamin D deficiency versus with vitamin D deficiency.  Nevertheless, subgroup analysis based on vitamin D detection methods obtained differential results (radioimmunoassay subgroup, SMD (95 % CI): 0.573 (0.275 to 0.870), p = 0.000; immunoassay subgroup, SMD (95 % CI): 0.189 (-0.025 to 0.404), p = 0.084).  The authors concluded that findings from the present meta-analysis did not provide a strong relationship between vitamin D and the risk of ED.  However, the results should be interpreted with caution and more high quality studies are needed.

Nitric Oxide Synthase Polymorphisms

Liu and colleagues (2015) stated that ED is a frequent disorder in men and has a serious impact on the quality of the patient's life.  Recent studies have examined the relationship between endothelial nitric oxide synthase (eNOS) polymorphisms and ED.  However, the results remain inconclusive.  The present study aimed to offer an actual view of estimating the correlation between eNOS polymorphisms and ED.  These investigators performed a meta-analysis to estimate the association between eNOS polymorphisms and ED risk.  Databases employed for data mining until December 1, 2014 included PubMed, Web of Science, and the Chinese National Knowledge Infrastructure.  Two study investigators independently conducted a literature search and data extraction.  Odds ratios with 95 % CIs for the risk were calculated by using a random effects model or fixed effects model.  A total of 20 studies in 13 publications increased ED risk in allele contrast, dominant, heterozygote, and homozygote models (allele contrast: OR = 1.514, 95 % CI were included in the meta-analysis.  In the overall comparison, the eNOS G984T polymorphism was associated with an [CI]: 1.019 to 2.248).  For 4 VNTR polymorphisms, the overall analysis showed a significant association between homozygote comparison and recessive genetic model (homozygote comparison: OR = 1.917, CI: 1.073 to 3.424).  The eNOS T786C polymorphism increased ED risk in allele contrast, homozygote, and recessive models (allele contrast: OR = 1.588, CI: 1.316 to 1.915).  Significant heterogeneity was mainly observed in studies on the G894T polymorphism.  No publication bias was detected in all of the variants.  The authors concluded that the eNOS polymorphisms G894T, 4 VNTR, and T786C were associated with an increased risk for ED.  However, they stated that these results are still preliminary; further studies based on different confounders and using a large population size should be conducted to generate more accurate and reliable conclusions.

Dai and associates (2015) noted that the gene encoding eNOS is an interesting candidate gene for understanding the physiopathology of ED.  However, an association between eNOS G894T polymorphism and ED risk is uncertain and should be updated.  Therefore, a meta-analysis of the current literature was necessary to clarify this relationship.  These investigators searched PubMed and China National Knowledge Infrastructure (CNKI) (last search updated on December 12, 2013) using “nitric oxide synthase”, “polymorphism or variant”, “genotype”, and “ED” as keywords.  They also searched reference lists of studies corresponding to the inclusion criteria for the meta-analysis.  These studies involved the total number of 1,445 ED men and 1,459 healthy control men subjects.  Odds ratio and 95 % CIs were used to evaluate this relationship.  Statistical analysis was performed with STATA10.0.  In the overall analysis, significantly decreased associations between ED risk and eNOS G894T polymorphism were found.  Moreover, in the subgroup analysis based on ethnicity, similar significant associations were detected in both Caucasians (such as GG+GT versus TT: OR 0.92, 95 % CI: 0.86 to 0.97) and Asians (such as GG+GT versus TT: OR 0.24, 95 % CI: 0.07 to 0.85).  The Egger's test did not reveal the presence of a publication bias.  The authors concluded that their investigations demonstrated that eNOS G894T polymorphism might protect men against ED risk.  Moreover, they stated that further studies based on larger sample size and gene-environment interactions should be conducted.

Pelvic Floor Muscle Training for Erectile Dysfunction Following Radical Prostatectomy

Wong and colleagues (2020) summarized current evidence regarding the effectiveness of pelvic floor muscle training in the management of ED following RP and provided recommendations for future research.  These investigators carried out an electronic search for relevant research studies using PubMed, Embase, CINAHL, Medline, and PEDro.  Quality of selected trials was evaluated by 2 independent reviewers using the Modified Downs and Black Checklist; disagreements were resolved by consensus.  The main outcome measure was IIEF-5.  A total of 9 studies of various study design were included in this review.  Most studies showed improvements in ED with pelvic floor muscle training; however, lack of methodological rigor for several studies and variability among training protocols limited interpretation of results.  The authors concluded that further well-powered and rigorously designed RCTs are needed to examine the effect of pelvic floor muscle training on ED following RP.

Serum Biomarkers of Erectile Dysfunction

Patel and colleagues (2017) stated that ED is a common complication in patients with diabetes mellitus (DM).  However, the utility of serum biomarkers as clinical surrogates for the development and/or progression of ED is unknown.  These investigators summarized the current literature for serum biomarkers for ED in DM and emphasized areas for future research.  Main outcome measures were human subject data demonstrating the utility of serum markers for the development and progression of ED in patients with DM.  These researchers performed a systematic PubMed-Medline search in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement using Medical Subject Headings (MeSH) for articles published from January 1, 2000 through December 31, 2016 of serum biomarkers for development or progression of ED in patients with DM using erectile dysfunction [MeSH] AND (biomarkers [MeSH] or inflammation mediators [MeSH] or intercellular signaling peptides and proteins [MeSH] or cell adhesion molecules [MeSH]).  A thorough review of these studies was completed.  Of the 327 abstracts screened, 12 full-text studies were assessed and 1 study was excluded.  A total of 11 studies assessing serum biomarkers for ED in patients with DM were included in this review.  The most studied serum biomarkers for ED in men with DM included endothelial dysfunction markers such as serum E-selectin, endothelial progenitor cells, and endothelial micro-particles and specific markers of inflammation such as interleukin (IL)-10, ratio of tumor necrosis factor-alpha (TNF-α) to IL-10, and reactive oxygen species such as nitric oxide and malondialdehyde.  The authors concluded that serum biomarkers for ED in men with DM are very limited.  They stated that future longitudinal studies with uniform patient characteristics are needed to evaluate the potential clinical use of serum biomarkers in men with DM for the development and progression of ED.

Shear Wave Elastography for the Diagnosis of Erectile Dysfunction

Cui and colleagues (2018) examined the effect of shear wave elastography (SWE) on the measurement of rigidity changes of penile erection in venogenic ED and in rigidity alterations of corpus cavernosum penis with age in normal population.  The study was a prospective analysis of 81 patients referred to the department of urology with complaints of ED as well as 35 healthy volunteers; SWE was performed on the corpus cavernosum penis (CCP) in the flaccid state of healthy group.  The patients were divided into venogenic ED (31 patients) and non-vascular ED (neither arterial insufficiency nor venogenic dysfunction) (36 patients) by performing color Doppler ultrasonography in association with intra-cavernous injection (ICI).  SWE measurements were performed in CCP in the flaccid state, after 15 to 20 mins and 25 to 30 mins of ICI in both patients groups.  Differences between groups were compared.  Age was significantly negatively associated with SWE values of CCP among the 3 groups (healthy group: r = -0.584, p < 0.05; venogenic ED group: r = -0.468, p < 0.05; non-vascular ED group: r = -0.539, p < 0.05).  There was no significant difference between the SWE values of the 3 groups in the flaccid state (p > 0.05). The mean SWE values of CCP were significantly lower in the erectile state (15 to 20 mins after ICI) compared with the flaccid state in 2 patients groups (p < 0.05).  The mean SWE values of CCP after ICI increased with time (from 15 to 20 mins to 25 to 30 mins) in patients with venogenic ED (p < 0.05), while the SWE values of CCP after ICI did not statistically significantly differ with time in patients with non-vascular ED (p > 0.05).  The authors concluded that SWE is expected to be a promising approach in terms of the etiological diagnosis of ED and the quantitative evaluation of alternations of penile structures with age.

Stem Cell Therapy

There is emerging interest in the use of adipose-derived stem cells for treatment of Peyronie's disease.  Adipose-derived stem cells (ADSCs) are a somatic stem cell population contained in fat tissue that possess the ability for self-renewal, differentiation into one or more phenotypes, and functional regeneration of damaged tissue, which may benefit the recovery of erectile function.  Lin et al (2009) reviewed available evidence concerning ADSCs availability, differentiation into functional cells, and the potential of these cells for the treatment of ED.  These researchers examined data from 1964 to 2008 that were associated with the definition, characterization, differentiation, and application of ADSCs, as well as other kinds of stem cells for stem cell-based therapies of erectile dysfunction.  They noted that ADSCs are para-vascularly localized in the adipose tissue.  Under specific induction medium conditions, these cells differentiated into neuron-like cells, smooth muscle cells, and endothelium in-vitro.  The insulin-like growth factor/insulin-like growth factor receptor pathway participates in neuronal differentiation while the fibroblast growth factor 2 pathway is involved in endothelium differentiation.  In a preliminary in-vivo experiment, the ADSCs functionally recovered the damaged erectile function.  However, the underlying mechanism needs to be further examined.  The authors concluded that ADSCs are a potential source for stem cell-based therapies, which imply the possibility of an effective clinical therapy for ED in the near future.

Lin et al (2012) noted that current therapeutic options for ED are less effective for patients having cavernous nerve (CN) injury or diabetes mellitus-related ED.  These 2 types of ED are thus the main focus of past and current stem cell therapy (SCT) studies.  In a total of 16 studies so far, rats were exclusively used as disease models and SCs were mostly derived from bone marrow, adipose tissue, or skeletal muscle.  For tracking, SCs were labeled with LacZ, green fluorescent protein, 4',6-diamidino-2-phenylindole, DiI, bromodeoxyuridine, or 5-ethynyl-2-deoxyuridine, some of which might have led to data misinterpretation.  Stem cell transplantation was done exclusively by intra-cavernous (IC) injection, which has been recently shown to have systemic effects.  Functional assessment was done exclusively by measuring increases of IC pressure during electro-stimulation of CN.  Histological assessment usually focused on endothelial, smooth muscle, and CN contents in the penis.  In general, favorable outcomes have been obtained in all trials so far, although whether SCs had differentiated into specific cell lineages remains controversial.  Recent studies have shown that intra-cavernously injected SCs rapidly escaped the penis and homed into bone marrow.  This could perhaps explain why intra-cavernously injected SCs had systemic anti-diabetic effects and prolonged anti-ED effects.  The authors stated that these hypotheses and the differentiation-versus-paracrine debate require further investigation.

Lokeshwar and colleagues (2020) stated that novel therapeutic modalities have been proposed for the treatment and management of ED; and SCT is the injection of mesenchymal stem cells or stromal vascular fractions from adipose and other tissue sources.  Although SCT has been studied and reported in multiple rodent trials, few human clinical trials exist.  These researchers provided a systematic review of SCT for the treatment of ED with an emphasis on data from peer-reviewed human studies.  They carried out a systematic review assessing SCT for ED in human studies using PubMed-Medline and Scopus databases.  Literature search was performed using key words such as "Clinical Trials of SCT for ED", "Stromal Vascular Fraction Treatment for ED" and "SCT for ED".  Systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.  The main outcomes measure was the safety and efficacy of SCT for ED in humans.  A total of 5 studies specific to SCT for ED treatment were included; 61 patients were included in these phase-I and phase-II clinical trials and follow-up periods ranged from 6 to 62 months.  End-points of the studies included safety, tolerability, and efficacy of SCT for ED.  The majority of the studies demonstrated improvement in erectile function due to SCT in patients, including improvements in penile vascular flow, IIEF-15 items, and EHS scores.  All of the studies reported that there were no serious AEs for patients.  Limitations of the studies included small cohort sizes, and only 1 contained a sham arm.  The authors concluded that the 5 completed human clinical trials showed promise for SCT as a restorative therapy for the treatment of ED.  However, although promising, there still exists very limited data for the use of SCT for ED in humans.  With the expansion of clinics offering SCT for ED, it is imperative that SCT is further examined for safety, efficacy, and standardization.

Tacrolimus for the Treatment of Erectile Dysfunction

Mulhall and colleagues (2018) noted that RP is associated with ED, largely mediated through cavernous nerve injury.  There are robust pre-clinical data supporting a potential role for neuro-modulatory agents in this patient population.  In a randomized, double-blind trial, these investigators examined tacrolimus in improving erectile function recovery rates after RP.  They compared tacrolimus 2 to 3 mg daily and placebo in men undergoing RP.  Patients had localized prostate cancer and excellent baseline erectile function, underwent bilateral nerve-sparing RP, and were followed-up for at least 18 months after RP.  Patients received study drug for 27 weeks and completed the IIEF-erectile function domain (EFD) questionnaire at baseline and serially after surgery.  Main outcome measure was the IIEF-EFD score.  Data were available for 124 patients (59 tacrolimus, 65 placebo); mean age was 54.6 ± 6.2 years.  No patient experienced permanent creatinine or potassium elevation.  At baseline, mean EFD scores were 28.6 ± 2.1 (tacrolimus group) and 29 ± 1.5 (placebo group).  By week 5, mean EFD scores had dropped to 8 ± 9.4 (tacrolimus) and 9 ± 10.7 (placebo).  At 18 months, mean EFD scores were 16.0 ± 11.3 (tacrolimus) and 20.2 ± 9.0 (placebo) (p = 0.09).  Tacrolimus failed to meet significance (hazard ratio [HR] = 0.83; p = 0.50), with no difference in percentage of patients achieving normal spontaneous erectile function (EFD score greater than or equal to 24); time to normalization of EFD score (greater than or equal to 24); percentage of patients capable of intercourse in response to PDE5i; and time to achieve response to PDE5i.  The authors concluded that despite positive animal data, oral tacrolimus as used in this trial failed to improve erectile function after nerve sparing RP.  These researchers stated that this study was limited by a high attrition rate; its strengths included a randomized, placebo controlled design, extensive patient monitoring, use of medication diaries and a validated instrument as the primary outcome measure.

Use of Serum Homocysteine Levels as Biomarkers for the Development and/or Progression of Erectile Dysfunction

Sansone and colleagues (2018) noted that elevated levels of serum homocysteine (Hcy) have been associated with cardiovascular diseases and endothelial dysfunction, conditions closely associated with ED.  In a meta-analysis, these investigators examined serum Hcy levels in subjects with ED compared to controls in order to clarify the role of Hcy in the pathogenesis of ED.  Medline, Embase, and the Cochrane Library were searched for publications investigating the possible association between ED and Hcy.  Results were restricted by language, but no time restriction was applied.  Standardized mean difference (SMD) was obtained by random effect models.  A total of 9 studies were included in the analysis with a total of 1,320 subjects (489 subjects with ED; 831 subjects without ED).  Pooled estimate was in favor of increased Hcy in subjects with ED with a SMD of 1.00, 95 % CI: 0.65 to 1.35, p < 0.0001.  Subgroup analysis based on prevalence of diabetes showed significantly higher SMD in subjects without diabetes (1.34 (95 % CI: 1.08 to 1.60)) compared to subjects with diabetes (0.68 (95 % CI: 0.39 to 0.97), p < 0.0025 versus subgroup without diabetes).  The authors concluded that findings from this meta-analysis suggested that increased levels of serum Hcy were more often observed in subjects with ED.  They stated that based on existing literature on this topic, a causative role for hyperhomocysteinemia as an independent risk factor for ED could be postulated, although confirmation would require interventional studies aimed to decrease serum Hcy levels considering erectile function as primary outcome.  These researchers stated that actually, only in rat model of hyperhomocysteinemia has been observed an improvement in erectile function after being treated with a demethylation agent.  These investigators also reported significantly higher levels of Hcy in subjects without diabetes, compared to diabetic men.  They noted that while one could assume that this is further proof of a multi-factorial pathogenesis for ED, it is also a clear indication that future research in this field should examine the possible association with other known risk factors such as smoking habit and obesity in order to adequately address the possible effects of different variates.

The authors stated that this study has several drawbacks, most notably the small number of studies (n = 9) involved and the lack of a clear definition of ED.  A single study assessed presence of ED by means of a single question (“How would you describe your ability to get and keep an erection that is adequate for satisfactory intercourse?”).  The remaining studies used validated questionnaires: in detail, 4studies used the IIEF and 4 studies used the IIEF-5.  However, most studies did not report separate measurements of serum Hcy based on the degree of severity of ED.

Platelet-Rich Plasma Injections for the Treatment of Erectile Dysfunction

Epifanova and associates (2020) stated that platelet-rich plasma (PRP) found its use in treating different conditions and diseases, because concentrated plasma PRP consists of many growth factors.  Their interaction with surrounding cells, intracellular matrix, and mediators at the site of injection leads to tissue regeneration.  Angiogenic, vasculogenic, and regenerative effects of PRP may be used for the treatment of patients with ED and Peyronie's disease (PD).  These investigators presented a current data review of pre-clinical and clinical studies on the use of PRP for the treatment of ED and PD.  Up-to-date literature on PRP use for ED and PD treatment was analyzed.  The search was based on PubMed, Cochrane Library, databases, with the following key words: "platelet-rich plasma" and/or "erectile dysfunction" and/or "Peyronie's disease" and/or "sexual dysfunction".  The main outcome measures for pre-clinical trials on ED were erectile function, assessed with intra-cavernous pressure, and pathologic analysis of penile tissue.  The main outcome measures for clinical trials on ED included penile duplex Doppler ultrasound (US) scanning and validated questionnaires.  The main outcome measures on PD were pathologic analysis of penile tissue for pre-clinical trials, as well as penile duplex Doppler US scanning, penile curvature angle measuring, and validated questionnaires for clinical trials.  A total of 4 pre-clinical and 6 clinical trials were described and analyzed in this article.  Drawbacks for both pre-clinical and clinical trials included small groups, short follow-up periods, a lack of control groups or groups with placebo, and the lack of quality and quantity analysis of PRP.  The authors concluded that available data showed the lack of adverse reactions with PRP treatment.  The studies that these researchers found were limited by small groups. This is why the data on safety and effectiveness should be taken carefully.  However, it is important to mention that PRP therapy has the potential for treating male sexual dysfunction and may be useful in andrology.

Alkandari and colleagues (2021) noted that ED and PD are debilitating medical conditions affecting patients' quality of life (QOL); and PRP injections are one of the various emerging approaches proposed to treat these medical conditions.  In a systematic review, these researchers examined the evidence of the potential role of PRP injections in ED and PD.  They carried out a systematic review according to the PRISMA statement using the following databases in November 2019: The National Library of Medicine (PubMed), Ovid Medline, Cochrane, Scopus, Embase, and Embase classic.  The search was performed using keywords drawn from studies on the use of PRP in ED and PD in clinical as well as pre-clinical studies.  A total of 18 articles met the inclusion criteria for review, including 12 studies on the use of PRP in humans and 6 on the use of PRP in rats; 10 studies reported on the effectiveness of PRP in ED exclusively, 7 in PD exclusively and 1 in both conditions.  In humans, 6 and 3 studies showed promising results in PD and ED, respectively.  No major complications were noted.  Unwanted minor side effects were noted by studies reporting on PD, including mild penile bruising, ecchymosis, hematomas as well as transient hypotension noted in 2 out of 90 patients.  The authors concluded that PRP injections for the treatment of ED may be promising, but no recommendation can be made because of scarce evidence.  These researchers stated that safety and effectiveness of PRP injections in the treatment of ED and PD require further pre-clinical and clinical studies with standardized protocols to gain an adequate insight into its potential implications.  Patients should be offered to be part of such trials to better understand PRP potential.


The above policy is based on the following references:

  1. Akin-Olugbade Y, Mulhall JP. The medical management of Peyronie's disease. Nat Clin Pract Urol. 2007;4(2):95-103.
  2. Aldridge J, Measham F. Sildenafil (Viagra) is used as a recreational drug in England. BMJ. 1999;318(7184):669.
  3. Alkandari MH, Touma N, Carrier S. Platelet-rich plasma injections for erectile dysfunction and Peyronie's disease: A systematic review of evidence. Sex Med Rev. 2021 Jul 1 [Online ahead of print].
  4. American Academy of Neurology. Assessment: Neurological evaluation of male sexual dysfunction. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 1995;45(12):2287-2292.
  5. American Association of Clinical Endocrinologists (AACE) Male Sexual Dysfunction Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of male sexual dysfunction: A couple's problem--2003 update. Endocr Pract. 2003;9(1):77-95.
  6. Babaei AR, Safarinejad MR, Kolahi AA. Penile revascularization for erectile dysfunction: A systematic review and meta-analysis of effectiveness and complications. Urol J. 2009;6(1):1-7.
  7. Balhara YP, Sarkar S, Gupta R. Phosphodiesterase-5 inhibitors for erectile dysfunction in patients with diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials.
  8. Basar MM, Atan A, Tekdogan UY. New concept parameters of RigiScan in differentiation of vascular erectile dysfunction: Is it a useful test? Int J Urol. 2001;8(12):686-691.
  9. Bemelmans BL, Hendrikx LB, Koldewijn EL, et al. Comparison of biothesiometry and neuro-urophysiological investigations for the clinical evaluation of patients with erectile dysfunction. J Urol. 1995;153(5):1483-1486.
  10. Benevides MD, Carson CC. Intraurethral application of alprostadil in patients with failed inflatable penile prosthesis. J Urol. 2000;163(3):785-787.
  11. Bennett AH, Carpenter AJ. An improved vasoactive drug combination for a pharmacologic erection program (PEP). J Urol. 1991;146(6):1564-1565.
  12. Bozkurt A, Karabakan M, Aktas BK, et al. Low serum melatonin levels are associated with erectile dysfunction. Int Braz J Urol. 2018;44(4):794-799.
  13. Brake M, Loertzer H, Horsch R, Keller H. Treatment of Peyronie's disease with local interferon-alpha 2b. BJU Int. 2001;87(7):654-657.
  14. Broderick GA, Allen GA, McClure RD. Vacuum tumescence devices: The role of papaverine in the selection of patients. J Urol. 1991;145(2):284-286.
  15. Broderick GA. Evidence based assessment of erectile dysfunction. Int J Impot Res. 1998;10 Suppl 2:S64-S73; discussion S77-S79.
  16. Brunckhorst O, Wells L, Teeling F, et al. A systematic review of the long-term efficacy of low-intensity shockwave therapy for vasculogenic erectile dysfunction. Int Urol Nephrol. 2019;51(5):773-781.
  17. Burls A, Clark W, Gold L, Simpson S. Sildenafil: An oral drug for the treatment of male erectile dysfunction. Birmingham, UK: West Midlands Health Technology Assessment Collaboration, Department of Public Health and Epidemiology, University of Birmingham; 1998.
  18. Cabello Benavente R, Moncada Iribarren I, de Palacio Espana A, et al. Transdermal iontophoresis with dexamethasone and verapamil for Peyronie's disease. Actas Urol Esp. 2005;29(10):955-960.
  19. Cai X, Tian Y, Wu T, et al. The role of statins in erectile dysfunction: A systematic review and meta-analysis. Asian J Androl. 2014;16(3):461-466.
  20. Capogrosso P, Montorsi F, Salonia A. Phase I and phase II clinical trials for the treatment of male sexual dysfunction - a systematic review of the literature. Expert Opin Investig Drugs. 2018;27(7):583-593.
  21. Centers for Medicare and Medicaid Services (CMS). Decision memo for cavernous nerves electrical stimulation with penile plethysmography (CAG-00311N). Medicare Coverage Database. Baltimore, MD: CMS; August 24, 2006. Available at: Accessed September 18, 2006.
  22. Cheitlin MD, Hutter AM Jr, Brindis RG, et al. ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. J Am Coll Cardiol. 1999;33(1):273-282.
  23. Chen J, Greenstein A, Sofer M, Matzkin H. Rigiscan versus snap gauge band measurements: Is the extra cost justifiable? Int J Impot Res. 1999;11(6):315-318.
  24. Cui A, Xu L, Mu J, et al. The role of shear wave elastography on evaluation of the rigidity changes of corpus cavernosum penis in venogenic erectile dysfunction. Eur J Radiol. 2018;103:1-5.
  25. Cunningham GR, Seftel AD. Treatment of male sexual dysfunction. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed September 2014.
  26. Da Ros CT, Teloken C, Antonini CC, et al. Long-term results of penile vein ligation for erectile dysfunction due to cavernovenous disease. Tech Urol. 2000;6(3):172-174.
  27. Dai F, Zhu L, Mi Y, Feng N. An updated meta-analysis of the effects of the endothelial nitric oxide synthase gene G894T polymorphism and erectile dysfunction risk. Cell Biochem Biophys. 2015;72(3):821-828.
  28. Dall'era JE, Mills JN, Koul HK, Meacham RB. Penile rehabilitation after radical prostatectomy: Important therapy or wishful thinking? Rev Urol. 2006;8(4):209-215.
  29. Dang G, Matern R, Bivalacqua TJ, et al. Intralesional interferon-alpha-2B injections for the treatment of Peyronie's disease. South Med J. 2004;97(1):42-46.
  30. DeForge D, Blackmer J, Moher D, et al. Sexuality and reproductive health following spinal cord injury. Evidence Report/Technology Assessment No. 109. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ) 2004.
  31. Delodovici ML, Fowler CJ. Clinical value of the pudendal somatosensory evoked potential. Electroencephalogr Clin Neurophysiol. 1995;96(6):509-515.
  32. Domes T, Najafabadi BT, Roberts M, et al. Canadian Urological Association guideline: Erectile dysfunction. Can Urol Assoc J. 2021;15(10):310-322.
  33. Doppalapudi SK, Wajswol E, Shukla PA, et al. Endovascular therapy for vasculogenic erectile dysfunction: A systematic review and meta-analysis of arterial and venous therapies. J Vasc Interv Radiol. 2019;30(8):1251-1258.
  34. Dorey G. Conservative treatment of erectile dysfunction 2: Clinical trials. Br J Nursing, 2000;9(12):755-762.
  35. Endo Pharmaceuticals, Inc. Xiaflex (collagenase clostridium histolyticum) for injection, intralesional use. Prescribing Information. Malvern, PA: Endo Pharmaceuticals; revised December 2021.
  36. Ensign C. First-line therapies for erectile dysfunction. JAAPA. 2001;14(10):17-20.
  37. Epifanova MV, Gvasalia BR, Durashov MA, Artemenko SA. Platelet-rich plasma therapy for male sexual dysfunction: Myth or reality? Sex Med Rev. 2020;8(1):106-113.
  38. Fink H, Wilt T, Mac Donald R, et al. Sildenafil for erectile dysfunction (Protocol). Cochrane Database Syst Rev. 2006;(2):CD001424. 
  39. Fink HA, MacDonald R, Rutks IR, et al. Sildenafil for male erectile dysfunction. A systematic review and meta-analysis. Arch Intern Med. 2002;162:1349-1360.
  40. Fojecki GL, Tiessen S, Osther PJ. Effect of low-energy linear shockwave therapy on erectile dysfunction -- A double-blinded, sham-controlled, randomized clinical trial. J Sex Med. 2017;14(1):106-112.
  41. Gelbard M, Goldstein I, Hellstrom WJ, et al. Clinical efficacy, safety and tolerability of collagenase clostridium histolyticum for the treatment of peyronie disease in 2 large double-blind, randomized, placebo controlled phase 3 studies. J Urol. 2013;190(1):199-207.
  42. Gelbard M, Lipshultz LI, Tursi J, et al. Phase 2b study of the clinical efficacy and safety of collagenase Clostridium histolyticum in patients with Peyronie disease. J Urol. 2012;187(6):2268-2274.
  43. Ghanem H, Raheem AA, AbdelRahman IFS, et al. Botulinum neurotoxin and its potential role in the treatment of erectile dysfunction. Sex Med Rev. 2018;6(1):135-142.
  44. Golubinski AJ, Sikorski A. Usefulness of power Doppler ultrasonography in evaluating erectile dysfunction. BJU Int. 2002;89(7):779-782.
  45. Greenfield JM, Shah SJ, Levine LA. Verapamil versus saline in electromotive drug administration for Peyronie's disease: A double-blind, placebo controlled trial. J Urol. 2007;177(3):972-975.
  46. Gruenwald I, Appel B, Vardi Y. et al. Low-intensity extracorporeal shock wave therapy -- a novel effective treatment for erectile dysfunction in severe ED patients who respond poorly to PDE5 inhibitor therapy. J Sex Med. 2012;9(1):259-264.
  47. Gur S, Abdel-Mageed AB, Sikka SC, et al. Destination penis? Erectile dysfunction as possible future indication of therapeutic gene delivery. Curr Gene Ther. 2018;18(4):225-239.
  48. Haahr MK, Jensen CH, Toyserkani NM, et al. A 12-month follow-up after a single intracavernous injection of autologous adipose-derived regenerative cells in patients with erectile dysfunction following radical prostatectomy: An open-label phase I clinical trial. Urology. 2018;121:203.e6-203.e13.
  49. Hamdan FB, Al-Matubsi HY. Assessment of erectile dysfunction in diabetic patients. Int J Androl. 2009;32(2):176-185.
  50. Handelsman H. Diagnosis and treatment of impotence. Health Technol Assess Rep. 1990;(2):1-23.
  51. Hatzichristodoulou G, Meisner C, Gschwend JE, et al. Extracorporeal shock wave therapy in Peyronie's disease: Results of a placebo-controlled, prospective, randomized, single-blind study. J Sex Med. 2013;10(11):2815-2821.
  52. Hatzichristou DG, Pescatori ES. Current treatments and emerging therapeutic approaches in male erectile dysfunction. BJU Int. 2001;88(Suppl 3):11-17.
  53. Hauck EW, Altinkilic BM, Ludwig M, et al. Extracorporal shock wave therapy in the treatment of Peyronie's disease. First results of a case-controlled approach. Eur Urol. 2000;38(6):663-669; discussion 670.
  54. Hauck EW, Mueller UO, Bschleipfer T, et al. Extracorporeal shock wave therapy for Peyronie's disease: Exploratory meta-analysis of clinical trials. J Urol. 2004;171(2 Pt 1):740-745.
  55. Hauri D. A critical review of penile revascularization procedures. Urol Int. 1998;60(3):133-146.
  56. Heidari M, Nejadi JR, Ghate A, et al. Evaluation of intralesional injection of verapamil in treatment of Peyronie's disease. J Pak Med Assoc. 2010;60(4):291-293.
  57. Heidelbaugh JJ. Management of erectile dysfunction. Am Fam Physician. 2010;81(3):305-312.
  58. Hellstrom WJ, Montague DK, Moncada I, et al. Implants, mechanical devices, and vascular surgery for erectile dysfunction. J Sex Med. 2010;7(1 Pt 2):501-523.
  59. Hilz MJ, Marthol H. Erectile dysfunction -- value of neurophysiologic diagnostic procedures. Urologe A. 2003;42(10):1345-1350.
  60. Hultling C, Giuliano F, Quirk F, et al. Quality of life in patients with spinal cord injury receiving Viagra (sildenafil citrate) for the treatment of erectile dysfunction. Spinal Cord. 2000;38(6):363-370.
  61. Hurst LC, Badalamente MA, Hentz VR, et al. Injectable collagenase clostridium histolyticum for Dupuytren's contracture. N Engl J Med. 2009;361(10):968-979.
  62. Husain J, Lynn NN, Jones DK, et al. Extracorporeal shock wave therapy in the management of Peyronie's disease: Initial experience. BJU Int. 2000;86(4):466-468. Indian J Endocrinol Metab. 2015;19(4):451-461.
  63. Isidori A, Aversa A, Fabbri A. Erectile dysfunction. Recenti Prog Med. 1999;90(7-8):396-402.
  64. Jain P, Rademaker AW, McVary KT. Testosterone supplementation for erectile dysfunction: Results of a meta-analysis. J Urol. 2000;164(2):371-375.
  65. Jain S, Bhojwani A, Terry TR. The role of penile prosthetic surgery in the modern management of erectile dysfunction. Postgrad Med J. 2000;76:22-25.
  66. Janssen T, Sarramon JP, Rischmann P, et al. Microsurgical arterio-arterial and arterio-venous penile revascularization in patients with pure arteriogenic impotence. Br J Urol. 1994;73(5):561-565.
  67. Jordan GH, Carson CC, Lipshultz LI. Minimally invasive treatment of Peyronie's disease: Evidence-based progress. BJU Int. 2014;114(1):16-24.
  68. Jordan GH. Erectile function and dysfunction. Postgrad Med. 1999;105(2):131-134, 137-138, 143-144 passim.
  69. Jordan GH. The use of intralesional clostridial collagenase injection therapy for Peyronie's disease: A prospective, single-center, non-placebo-controlled study. J Sex Med. 2008;5(1):180-187.
  70. Kedia S, Zippe CD, Agarwal A, et al. Treatment of erectile dysfunction with sildenafil citrate (Viagra) after radiation therapy for prostate cancer. Urology. 1999;54(2):308-312.
  71. Kendirci M, Bejma J, Hellstrom WJ. Update on erectile dysfunction in prostate cancer patients. Curr Opin Urol. 2006;16(3):186-195.
  72. Kessler WO. Nocturnal penile tumescence. Urol Clin North Am. 1988;15(1):81-86.
  73. Kim ED, Owen RC, White GS, et al. Endovascular treatment of vasculogenic erectile dysfunction. Asian J Androl. 2015;17(1):40-43.
  74. Kiyota H, Ohishi Y, Asano K, et al. Extracorporeal shock wave treatment for Peyronie's disease using EDAP LT-02; preliminary results. Int J Urol. 2002;9(2):110-113.
  75. Krane RJ, Goldstein I, Saenz de Tejada I. Impotence. N Engl J Med. 1989;321(24):1648-1659.
  76. Kunelius P, Lukkarinen O. Intracavernous self-injection of prostaglandin E1 in the treatment of erectile dysfunction. Int J Impot Res. 1999;11(1):21-24.
  77. Lacy GL 2nd, Adams DM, Hellstrom WJ. Intralesional interferon-alpha-2b for the treatment of Peyronie's disease. Int J Impot Res. 2002;14(5):336-339.
  78. Ladegaard PBJ, Mortensen J, Skov-Jeppesen SM, Lund L. Erectile dysfunction. A prospective randomized placebo-controlled study evaluating the effect of low-intensity extracorporeal shockwave therapy (LI-ESWT) in men with erectile dysfunction following radical prostatectomy. Sex Med. 2021;9(3):100338.
  79. Lakin M. The evaluation and nonsurgical management of impotence. Semin Nephrol. 1994;14(6):544-550.
  80. Laumann L, Zimmerman J. Peyronie disease. eMedicine Dermatology Topic 851. Omaha, NE:; updated May 13, 2003. Available at: Accessed August 13, 2003.
  81. Lebret T, Loison G, Herve JM, et al. Extracorporeal shock wave therapy in the treatment of Peyronie's disease: Experience with standard lithotriptor (siemens-multiline). Urology. 2002;59(5):657-661.
  82. Lee MS, Shin BC, Ernst E. Acupuncture for treating erectile dysfunction: A systematic review. BJU Int. 2009;104(3):366-370.
  83. Licht MR. Use of oral sildenafil (Viagra) in the treatment of erectile dysfunction. Compr Ther. 1999;25(2):90-94.
  84. Lin CS, Xin ZC, Wang Z, et al. Stem cell therapy for erectile dysfunction: A critical review. Stem Cells Dev. 2012;21(3):343-351.
  85. Lin G, Banie L, Ning H, et al. Potential of adipose-derived stem cells for treatment of erectile dysfunction. J Sex Med. 2009;6 Suppl 3:320-327.
  86. Liu C, Lu K, Tao T, et al. Endothelial nitric oxide synthase polymorphisms and erectile dysfunction: A meta-analysis. J Sex Med. 2015;12(6):1319-1328. 
  87. Lizza E. Peyronie disease. eMedicine Urology Topic 3422. Omaha, NE:; updated November 15, 2002. Available at: Accessed August 13, 2003.
  88. Lizza EF, Rosen RC. Definition and classification of erectile dysfunction: Report of the Nomenclature Committee of the International Society of Impotence Research. Int J Impot Res. 1999;11(3):141-143.
  89. Lokeshwar SD, Patel P, Shah SM, Ramasamy R. A systematic review of human trials using stem cell therapy for erectile dysfunction. Sex Med Rev. 2020;8(1):122-130.
  90. Man L, Li G. Low-intensity extracorporeal shock wave therapy for erectile dysfunction: A systematic review and meta-analysis. Urology. 2018 Sep;119:97-103.
  91. Mangır N, Turkeri L. Stem cell therapies in post-prostatectomy erectile dysfunction: A critical review. Can J Urol. 2017;24(1):8609-8619.
  92. Manikandan R, Islam W, Srinivasan V, Evans CM. Evaluation of extracorporeal shock wave therapy in Peyronie's disease. Urology. 2002;60(5):795-800.
  93. Manning M, Junemann KP, Scheepe JR, et al. Long-term followup and selection criteria for penile revascularization in erectile failure. J Urol. 1998;160(5):1680-1684.
  94. Martin DJ, Badwan K, Parker M, Mulhall JP. Transdermal application of verapamil gel to the penile shaft fails to infiltrate the tunica albuginea. J Urol. 2002;168(6):2483-2485.
  95. Matthew AG, Goldman A, Trachtenberg J, et al. Sexual dysfunction after radical prostatectomy: Prevalence, treatments, restricted use of treatments and distress. J Urol. 2005;174(6):2105-2110.
  96. Matthews LA, Herbener TE, Seftel AD. Impotence associated with blunt pelvic and perineal trauma: Penile revascularization as a treatment option. Semin Urol. 1995;13(1):66-72.
  97. McMahon CG, Touma K. Predictive value of patient history and correlation of nocturnal penile tumescence, colour duplex Doppler ultrasonography and dynamic cavernosometry and cavernosography in the evaluation of erectile dysfunction. Int J Impot Res. 1999;11(1):47-51.
  98. Merino GA. Penile prosthesis implantation in the treatment of erectile dysfunction [summary]. INF2005/02. Santiago de Compostela, Spain: Galician Agency for Health Technology Assessment (AVALIA-T); 2005.
  99. Miles CL, Candy B, Jones L, et al. Interventions for sexual dysfunction following treatments for cancer. Cochrane Database Syst Rev. 2007;(4):CD005540.
  100. Mizuno I, Fuse H, Fujiuchi Y. Snap-Gauge band compared to RigiScan Plus in a nocturnal penile tumescence study for evaluation of erectile dysfunction. Urol Int. 2003;71(1):96-99.
  101. Monatague DK, Jarow JP, Broderick GA, et al. Erectile Dysfunction Guideline Update Panel. The management of erectile dysfunction: An update. Linthicum, MD: American Urological Association (AUA); June 2005. J Urol. 2005;174(1):230-239. 
  102. Monatague DK, Jarow JP, Broderick GA, et al.; Erectile Dysfunction Guideline Update Panel. The management of erectile dysfunction: An update. Linthicum, MD: American Urological Association (AUA); revised May 2006. Available at: Accessed January 8, 2007.
  103. Montague DK. Clinical guidelines panel on erectile dysfunction: Summary report on the treatment of organic erectile dysfunction. The American Urological Association. J Urol. 1996;156(6):2007-2011.
  104. Montorsi F, Salonia A, Zanoni M, et al. Current status of local penile therapy. Int J Impot Res. 2002;14(Suppl 1):S70-S81.
  105. Moore RA, Derry S, McQuay HJ. Indirect comparison of interventions using published randomised trials: systematic review of PDE-5 inhibitors for erectile dysfunction. BMC Urology. 2005;5(18).
  106. Morales A, Gingell C, Collins M, et al. Clinical safety of oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction. Int J Impot Res. 1998;10(2):69-73; discussion 73-74.
  107. Mostafa T, Hassan A, Alghobary MF, Abdelrahman SH. Effect of genetic polymorphism on the response to PDE5 inhibitors in patients with erectile dysfunction: A systematic review and a critical appraisal. Sex Med Rev. 2020;8(4):573-585.
  108. Motiwala HG, Patel DD, Joshi SP, et al. Experience with penile venous surgery. Urol Int. 1993;51(1):9-14.
  109. Mulhall JP, Klein EA, Slawin K, et al. A randomized, double-blind, placebo-controlled trial to assess the utility of tacrolimus (FK506) for the prevention of erectile dysfunction following bilateral nerve-sparing radical prostatectomy. J Sex Med. 2018;15(9):1293-1299.
  110. National Institute for Clinical Excellence (NICE). Extracorporeal shockwave therapy (ESWT) for Peyronie's disease. Interventional Procedures Consultation Document. London, UK: NICE; August 2003. 
  111. National Institute for Clinical Excellence (NICE). Interventional procedures overview of extracorporeal shock wave therapy for Peyronie's disease. IPP Procedure No. 182. London, UK: NICE; March 2003. 
  112. Nehra A, Alterowitz R, Culkin DJ, et al. Peyronie’s Disease: AUA Guideline. J Urol. 2015;194(3):745-753.
  113. Nehra A, Barrett DM, Moreland RB. Pharmacotherapeutic advances in the treatment of erectile dysfunction. Mayo Clin Proc. 1999;74(7):709-721.
  114. No authors listed. American Urological Association issues treatment guidelines for erectile dysfunction. Am Fam Physician. 1997;55(5):1967-1968, 1973.
  115. No authors listed. Diagnostic and Therapeutic Technology Assessment. Penile implants for erectile impotence. JAMA. 1988;260(7):997-1000.
  116. No authors listed. Diagnostic and Therapeutic Technology Assessment. Intracavernous pharmacotherapy for impotence: Papaverine and phentolamine. JAMA. 1990;264(6):752-754.
  117. No authors listed. Impotence. NIH Consens Statement. 1992;10(4):1-33.
  118. No authors listed. NIH Consensus Development Panel on Impotence. JAMA. 1993;270(1):83-90.
  119. No authors listed. Testosterone for erectile dysfunction. Bandolier Knowledge Library. Oxford, UK: Bandolier; 2001. Available at: Accessed August 28, 2003.
  120. Nurnberg HG, Hensley PL, Gelenberg AJ, et al. Treatment of antidepressant-associated sexual dysfunction with sildenafil: A randomized controlled trial. JAMA. 2003;289(1):56-64.
  121. Patel DP, Craig JR Jr., Myers JB, et al. Serum biomarkers of erectile dysfunction in diabetes mellitus: A systematic review of current literature. Sex Med Rev. 2017;5(3):339-348.
  122. Pickard RS, Powell PH, Schofield IS. The clinical application of dorsal penile nerve cerebral-evoked response recording in the investigation of impotence. Br J Urol. 1994;74(2):231-235.
  123. Qaseem A, Snow V, Denberg TD, et al; Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Hormonal testing and pharmacologic treatment of erectile dysfunction: A clinical practice guideline from the American College of Physicians. Ann Intern Med. 2009;151(9):639-649.
  124. Rao DS, Donatucci CF. Vasculogenic impotence. Arterial and venous surgery. Urol Clin North Am. 2001;28(2):309-319.
  125. Rolo F, Requixa A. Erectile dysfunction. Its diagnosis and treatment. Acta Med Port. 1999;12(1-3):35-38.
  126. Sadovsky R, Dunn M, Grobe BM. Erectile dysfunction: The primary care practitioner's view. Am J Manag Care. 1999;5(3):333-341; quiz 342-343.
  127. Saenz Calvo A, Conde Olasagasti J L, Imaz Iglesia I, Hernandez Torres A. Effectiveness and safety of penile prosthesis. IPE-98/15 (Public report). Madrid, Spain: Agencia de Evaluacion de Tecnologias Sanitarias (AETS); 1998.
  128. Sakamoto H, Shimada M, Yoshida H. Hemodynamic evaluation of the penile arterial system in patients with erectile dysfunction using power Doppler imaging. Urology. 2002;60(3):480-484.
  129. Sandoval-Salinas C, Saffon JP, Corredor HA, et al. Are radial pressure waves effective in treating erectile dysfunction? A systematic review of preclinical and clinical studies. Sex Med. 2021;9(4):100393.
  130. Sansone A, Cignarelli A, Sansone M, et al. Serum homocysteine levels in men with and without erectile dysfunction: A systematic review and meta-analysis. Int J Endocrinol. 2018;2018:7424792.
  131. Sarramon JP, Bertrand N, Malavaud B, et al. Microrevascularisation of the penis in vascular impotence. Int J Impot Res. 1997;9(3):127-133.
  132. Sasso F, Gulino G, Falabella R, et al. Peyronie's disease: Lights and shadows. Urol Int. 2007;78(1):1-9.
  133. Schmid DM, Schurch B, Hauri D. Sildenafil in the treatment of sexual dysfunction in spinal cord-injured male patients. Eur Urol. 2000;38(2):184-193.
  134. Schroeder-Printzen I, Hauck EW, Weidner W. New aspects in Peyronie's disease--a mini-review. Andrologia. 1999;31 Suppl 1:31-5.
  135. Setter SM, Baker DE, Campbell RK, et al. Sildenafil (Viagra) for the treatment of erectile dysfunction in men with diabetes. Diabetes Educ. 1999;25(1):79-80, 83-84, 87 passim.
  136. Shafik A, Shafik AA, Shafik IA, El Sibai O. Percutaneous perineal electrostimulation induces erection: Clinical significance in patients with spinal cord injury and erectile dysfunction. J Spinal Cord Med. 2008;31(1):40-43.
  137. Sharaby JS, Benet AE, Melman A. Penile revascularization. Urol Clin North Am. 1995;22(4):821-832.
  138. Sharlip ID. Evaluation and nonsurgical management of erectile dysfunction. Urol Clin North Am. 1998;25(4):647-659, ix.
  139. Shirazi M, Haghpanah AR, Badiee M, et al. Effect of intralesional verapamil for treatment of Peyronie's disease: A randomized single-blind, placebo-controlled study. Int Urol Nephrol. 2009;41(3):467-471.
  140. Shmueli J, Israilov S, Segenreich E, et al. Progressive treatment of erectile dysfunction with intracorporeal injections of different combinations of vasoactive agents. Int J Impot Res. 1999;11(1):15-19.
  141. Shokeir AA, Alserafi MA, Mutabagani H. Intracavernosal versus intraurethral alprostadil: A prospective randomized study. BJU Int. 1999;83(7):812-815.
  142. Sica GS, Sileri P, Riccardelli F, et al. Revascularization of the corpora cavernosa in vasculogenic impotence. Minerva Urol Nefrol. 1999;51(2):129-134.
  143. Sokolakis I, Dimitriadis F, Teo P, et al. The basic science behind low-intensity extracorporeal shockwave therapy for erectile dysfunction: A systematic scoping review of pre-clinical studies. J Sex Med. 2019;16(2):168-194.
  144. Speel TG, van Langen H, Wijkstra H, Meuleman EJ. Penile duplex pharmaco-ultrasonography revisited: Revalidation of the parameters of the cavernous arterial response. J Urol. 2003;169(1):216-220.
  145. Stewart C, Hogan S. Evidence based review of medicines for sexual dysfunction in men: A report commissioned by the New Zealand Accident Compensation Corporation (ACC). NZHTA Report. Christchurch, New Zealand: New Zealand Health Technology Assessment (NZHTA); 2004;7(4).
  146. Swedish Council on Technology Assessment in Health Care (SBU). Viagra for impotence - early assessment briefs (ALERT). Stockholm, Sweden: SBU; 1999.
  147. Tharyan P, Gopalakrishanan G. Erectile dysfunction. In: BMJ Clinical Evidence. London, UK: BMJ Publishing Group; August 2005.
  148. The Process of Care Consensus Panel. The process of care model for evaluation and treatment of erectile dysfunction. Int J Impot Res. 1999;11(2):59-74.
  149. Trottmann M, Marcon J, Pompe S, et al. Conservative therapy of erectile dysfunction. Urologe A. 2015;54(5):668-675.
  150. Tsertsvadze A, Fink HA, Yazdi F, et al. Oral phosphodiesterase-5 inhibitors and hormonal treatments for erectile dysfunction: A systematic review and meta-analysis. Ann Intern Med. 2009;151(9):650-661.
  151. U.S. Department of Veteran's Affairs, Veteran's Health Administration, Pharmacy Benefits Management Strategic Healthcare Group and the Medical Advisory Panel. The primary care management of erectile dysfunction. Pub. No. 99-0014. Washington, DC: Department of Veterans Affairs; June 1999.
  152. U.S. Department of Veteran's Affairs, Veteran's Health Administration, Office of Research and Development, Health Services Research and Development Service, Management Decision and Research Center (MDRC), Technology Assessment Program. Treatment options for male erectile dysfunction: A systematic review of published studies of effectiveness. Technology Assessment Program, Report No. 11. MTA98-016. Boston, MA: MDRC; January 1999.
  153. U.S. Food and Drug Administration (FDA). FDA approves first drug treatment for Peyronie’s disease. FDA News. Silver Spring, MD: FDA; December 6, 2013.  
  154. Urciuoli R, Cantisani TA, CarliniI M, et al. Prostaglandin E1 for treatment of erectile dysfunction. Cochrane Database Syst Rev. 2004;(2):CD001784.
  155. Vardi M, Nini A. Phosphodiesterase inhibitors for erectile dysfunction in patients with diabetes mellitus. Cochrane Database Syst Rev. 2007;(1):CD002187.
  156. Webber R. Erectile dysfunction. In: Clinical Evidence. London, UK: BMJ Publishing Group, Ltd.; August 2003.
  157. Wei Y, Chen P, Chen Q, Zhu H. Serum vitamin D levels and erectile dysfunction: A systematic review and meta-analysis. Andrologia. 2019;51(3):e13211.
  158. Wespes E, Amar E, Hatzichristou D, et al. EAU Guidelines on erectile dysfunction: An update. Eur Urol. 2006;49(5):806-815.
  159. Wespes E, Amar E, Hatzichristou D, et al. Guidelines on erectile dysfunction. Eur Urol. 2002;41(1):1-5.
  160. Wierman ME. Advances in the diagnosis and management of impotence. Dis Mon. 1999;45(1):1-20.
  161. Wong C, Louie DR, Beach C. A systematic review of pelvic floor muscle training for erectile dysfunction after prostatectomy and recommendations to guide further research. J Sex Med. 2020;17(4):737-748.
  162. Xin ZC, Xu Y, Lin G, et al. Recruiting endogenous stem cells: A novel therapeutic approach for erectile dysfunction. Asian J Androl. 2016;18(1):10-15.
  163. Xu J, Huang P, Song B, Chen JM. Effect of continuous positive airway pressure on erectile dysfunction in patients with obstructive sleep apnea syndrome: A meta-analysis. Zhonghua Nan Ke Xue. 2013;19(1):77-81.
  164. Yang BB, Hong ZW, Zhang Z, et al. Epalrestat, an aldose reductase inhibitor, restores erectile function in streptozocin-induced diabetic rats. Int J Impot Res. 2019;31(2):97-104.
  165. Yang G, Muzepper M. Platelet indices and erectile dysfunction: A systematic review and meta-analysis. Andrologia. 2019;51(5):e13248.
  166. Yao HX, Ma FZ, Tan YY, Liu LY. Endothelial nitric oxide synthase gene polymorphisms and risk of erectile dysfunction: An updated meta-analysis of genetic association studies. Int J Surg. 2018;54(Pt A):141-148.
  167. Zhang T, Li WL, He XF, et al. The insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene and erectile dysfunction risk: A meta-analysis. Andrology. 2013;1(2):274-280.
  168. Zou ZJ, Tang LY, Liu ZH, et al. Short-term efficacy and safety of low-intensity extracorporeal shock wave therapy in erectile dysfunction: A systematic review and meta-analysis. Int Braz J Urol. 2017;43(5):805-821.