Improving Erectile Function and Quality of Life in Hypogonadal Euglycemic and Diabetic Men with Refractory Erectile Dysfunction

1. Introduction

Erectile dysfunction (ED) is estimated to affect nearly one in ten adult men, with rates increasing disproportionally with age [1]. Among men with ED, those with moderate to severe disease, defined by erections insufficient for penetrative intercourse, represent the subgroup with the greatest functional impairment and the fewest therapeutic options [2]. The combined prevalence of moderate to severe ED was 22% in men aged 40-49 and rose to 49% in men aged 70–79 [3]. The burden of ED falls disproportionately on men with type 2 diabetes mellitus (T2DM), in whom overall ED prevalence reaches 66% and the odds of ED are approximately 3.5 times those of non-diabetic controls [1,4]. Among diabetic men with ED, more than half have moderate to severe disease [4,5].

ED is a multifactorial systemic condition, with hormonal, metabolic, neuromuscular, and neurovascular, and psychological components [6,7]. Despite this multidimensional biology, most treatment protocols target only one or two contributing factors. The lack of a comprehensive approach may explain the failure to achieve satisfactory restoration of erectile function in men with moderate to severe ED. To address this gap, we developed an integrated approach that combines physical and pharmacologic treatments to target the major contributors to ED in parallel. We focused on hypogonadal men, with and without T2DM, because these patients are profoundly affected by ED and often respond incompletely to oral pharmacotherapy. Shockwave therapy promotes angiogenesis, restores nitric oxide synthase activity, and supports cavernous nerve regeneration [8], and produces limited improvements in erectile function [7]. Class IV laser therapy and therapeutic ultrasound act through related regenerative pathways, increasing nitric oxide availability, neovascularization, and smooth muscle content while reducing cavernosal fibrosis in diabetic models [9,10]. Structured neuromuscular exercise targeting the lumbopelvic complex can strengthen the muscles responsible for penile rigidity, support the spinal reflex pathways that coordinate erection and ejaculation, and address the musculoskeletal deconditioning common in men with ED [11,12]. Testosterone supports erectile function by upregulating neuronal and endothelial nitric oxide synthase (nNOS/eNOS), maintaining trabecular smooth muscle integrity, enhancing penile blood flow through endothelium-dependent and endothelium-independent vascular mechanisms, and modulating central sexual desire pathways [13,14]. Tadalafil is a phosphodiesterase type 5 inhibitor (PDE5i) that improves erectile function by prolonging nitric oxide-mediated smooth muscle relaxation, increasing penile blood flow, and improving underlying endothelial dysfunction [4,6]. Men with T2DM additionally received tirzepatide to address the metabolic drivers of their disease, because glycemic control and GLP-1-based therapy are associated with improved erectile function in diabetes [15]. Psychological factors, including avoidance, performance anxiety, partner withdrawal, and intimacy hesitancy, can also contribute to ED [6,16], and our program included counseling targeting these factors. In this case series, we report the outcomes of 71 hypogonadal men with moderate to severe ED refractory to oral PDE5is treated with this protocol. We evaluated erectile function, sexual quality of life, body composition, grip strength, and metabolic and inflammatory markers before and after approximately 3-4 months of outpatient care, comparing euglycemic and diabetic men.

2. Materials and Methods

2.1. Participants, Procedures, and Outcome Measures

Seventy-one men evaluated and treated for erectile dysfunction at a single outpatient clinic comprised this retrospective case series. The study followed the principles of the Declaration of Helsinki. Because the case series used de-identified data generated during routine clinical care, formal IRB approval was not obtained. Observations occurred over a period of 3 to 4 months beginning at treatment initiation. Men were included if they had moderate to severe erectile dysfunction of at least twelve months duration defined as an Erection Hardness Scale (EHS) ≤ 2 [17], were refractory to maximum dose oral PDE5i medications, had a positive Androgen Deficiency in the Aging Male (ADAM) screening questionnaire [18], and had biochemical hypogonadism, defined as a morning serum total testosterone < 400 ng/dL measured by immunoassay. This threshold reflects the symptom-driven approach to testosterone deficiency endorsed by the International Consultations on Sexual Medicine, which recognizes a typical ceiling of 350 ng/dL for starting testosterone therapy, but also a gray zone between 200 and 400 ng/dL within which the effect of testosterone on sexual function may not be maximal and treatment may be considered based on clinical presentation [19,20]. In this case series, the positive ADAM screening questionnaire and moderate to severe ED provided the clinical rationale for testosterone therapy in the gray zone. We stratified the cohort by glycemic status using hemoglobin A1c (HbA1c), with euglycemia defined as HbA1c <5.7% and T2DM defined as HbA1c ≥6.5%. Body composition was determined using an InBody 270 system (InBody, Cerritos, CA). Grip strength was measured in the dominant hand using a Jamar digital dynamometer (Patterson Medical, Warrenville, IL), with the best value of three trials used in the analysis.

Men were excluded if they were currently taking medication to treat T2DM or had a history of penile or pelvic trauma, prostate-specific antigen (PSA) ≥4.0 ng/mL, polycythemia, active infection, malignancy, Peyronie’s disease, or neurologic disease affecting pelvic or sexual function. We also excluded men with uncontrolled endocrine disease other than T2DM, cardiovascular disease, or psychiatric disease independently capable of producing sexual dysfunction, as well as those with incomplete baseline or follow-up data or inability to complete the treatment course.

Patient-reported outcomes were collected at treatment initiation and completion. The PROMIS Global Health 10 was used to assess general physical and mental health outcomes [21]. The Arizona Sexual Experience Scale (ASEX) was used to quantify sex drive, arousal, ability to obtain and maintain an erection, ability to orgasm, and satisfaction with orgasm [22].

2.2. Treatment Interventions

Patients underwent treatment sessions of four synergistic modalities, including radial pressure wave shockwave therapy (RPW), class IV (CIV) laser therapy, therapeutic ultrasound, and therapeutic exercises, modified from previous studies [12,23,24,25]. Oral tadalafil 5 mg daily was also prescribed to support pelvic and penile vascular function [26]. Testosterone cypionate was delivered intramuscularly at a starting dose of 100mg weekly, with dose adjustment during the treatment period based on symptoms. Follow-up labs were performed approximately 12 weeks after the start of treatment, and 3-4 days after the last testosterone injection. Men with T2DM were prescribed tirzepatide (Mounjaro) at 2.5 mg weekly for the first four weeks, 5 mg weekly for the next four weeks, and either 5 mg or 7.5 mg weekly thereafter based on tolerance. Treatment sessions occurred one to two times per week. Patients were generally encouraged to continue treatment until they were satisfied with overall erectile function, typically defined by return of the ability to engage in penetrative intercourse and a plateau in symptom improvement.

RPW (Intelect RPW 2, Enovis, Wilmington, DE) delivered 2000-3000 pulses at a frequency of 12-14 Hz, with intensity adjusted to just below the maximum tolerated comfort level. Class IV laser therapy (REMY Medical Laser, Cherry Hill, NJ) applied 700-800 J to tissue at 810 nm and 980 nm wavelengths. Therapeutic ultrasound (CX2, Richmar, Clayton, MO) was delivered at a frequency of 3Mhz with energy output of 1.0-1.2 W/cm2 and a 100% duty cycle for 5-8 minutes. These modalities were delivered to the dorsal and lateral aspects of the penis to target the corpora cavernosa. Therapeutic exercises were based on individual patient assessment, followed standard neuromuscular and progressive overload principles, and targeted abdominal, lumbopelvic, and proximal limb musculature. Exercises included bicycle crunches, body blade rotations, Bulgarian split-squats, cat-cow, Copenhagen plank, dead bugs, double leg raise, glute bridge, isometric adduction, leg press, Pallof press, pelvic floor muscle isometrics, pelvic tilts, quadruped rocking, reverse deadlifts, reverse lunges, Russian twists, side-lying abduction, single leg bridge, squats, step-downs, supine march, and Swiss ball routines. A Neubie direct current stimulator (NeuFit, Austin, TX) was used to facilitate muscle contractions in patients with neuromuscular inhibition. Proprioceptive neuromuscular facilitation stretching was applied to patients with limited range of motion. Manual therapy and dry needling (SERIN, Boston, MA) were applied as needed to treat comorbid musculoskeletal disorders. Patients were instructed to perform prescribed exercises and stretching at home 2-3 times weekly.

Counseling was provided to address psychological contributors to erectile dysfunction, set expectations during the rehabilitation period, and manage performance-related anxiety during the initial return to sexual activity [27]. Goals included reducing avoidance-driven deconditioning, limiting catastrophizing, supporting relationship health, and restoring satisfying sexual function. Men were encouraged to participate in a six-stage protocol to progressively prepare for penetrative intercourse based on EHS stage (Table 1) [27,28,29,30]. Single patients received additional coaching on dating hesitancy, normalization of performance anxiety after dysfunction, graded exposure to dating situations, partner communication, expectation setting, and management of performance-related anxiety [31].

2.3. Statistics

Differences in age were tested using two-tailed Welch unpaired t-tests (α=0.05), and differences in symptom duration and total treatment sessions were tested using two-tailed Mann-Whitney U tests (α=0.05). Treatment effects on body composition, hand grip strength, PROMIS-10 scores, HS-CRP, serum testosterone, and hemoglobin A1c were tested using two-way mixed-design ANOVAs (α=0.05), with diabetes status as the between-subjects factor and time as the within-subjects factor. These analyses were followed by paired t-tests and Welch unpaired t-tests for within-subject and between-group pairwise contrasts, respectively. Treatment effects on EHS and ASEX were tested using two-tailed Wilcoxon signed-rank tests (α=0.05) for within-subject contrasts and two-tailed Mann-Whitney U tests (α=0.05) for between-group contrasts. A Sidak correction for multiple comparisons was applied across the six pairwise contrasts within each outcome. Spearman ρ analysis was performed to evaluate associations between baseline EHS, post-treatment EHS, and total treatment sessions. Analyses were performed using Python 3.12 (Python Software Foundation, Wilmington, DE). Values in the text are median (IQR).

3. Results

Seventy-one men met the inclusion criteria, including 38 euglycemic and 33 with T2DM (Table 2). The groups were similar in age. Men with T2DM had lived with erectile dysfunction for a median of 12 months longer than euglycemic men before presenting and required 42% more treatment sessions to reach satisfactory penile function.

Men with T2DM had higher hs-CRP than euglycemic men by a median of 1.25 mg/L (Figure 1A), lower serum testosterone by 66 ng/dL (Figure 1B), and higher hemoglobin A1c by 3.7 percentage points (Figure 1C). All men with T2DM began in the diabetic range, and all euglycemic men began in the normal range. After treatment, these differences narrowed or disappeared. hs-CRP fell by a median of 2.2 mg/L in men with T2DM and 0.7 mg/L in euglycemic men, a three-fold steeper decline that eliminated the baseline difference between groups (Figure 1A). Serum testosterone, drawn 3 to 4 days after the weekly injection, rose to the upper-normal range in both groups, and the groups no longer differed (Figure 1B). Hemoglobin A1c was unchanged in euglycemic men but fell by 2.8 percentage points in men with T2DM, from 9.2% to 6.2%, narrowing the between-group gap from 3.7 to 0.8 points (Figure 1C). Of the 33 men with T2DM, 19 (58%) moved from the diabetic to the prediabetic range, and the remaining 14 ended at a lower hemoglobin A1c than they began (Figure 1C).

Both groups lost fat and gained strength, with larger changes in men with T2DM (Figure 2). At baseline, men with T2DM had a median 7.5 kg greater body fat mass and 4.5 kg lower grip strength than euglycemic men. After treatment, BMI decreased approximately twice as much in men with T2DM as in euglycemic men (Figure 2A), and body fat mass fell by a median of 5.4 kg, more than double the 2.3 kg lost by euglycemic men (Figure 2B). Skeletal muscle mass increased by a median of 2.7 kg in men with T2DM and 1.8 kg in euglycemic men (Figure 2C). Grip strength increased by a median of 6.4 kg in men with T2DM and 2.3 kg in euglycemic men, and the two groups no longer differed after treatment (Figure 2D).

Self-reported health and sexual function improved in both groups (Figure 3). Men with T2DM again had worse baseline values, with PROMIS-10 Physical Health scores a median of 5.4 points lower and Mental Health scores 7.3 points lower than euglycemic men. After treatment, both PROMIS-10 subscales improved, and the euglycemic and diabetic groups no longer differed (Figure 3A). ASEX scores improved by a median of 6 points in both groups, and the groups no longer differed after treatment (Figure 3B). Before treatment, no man scored above an EHS of 2, the threshold below which erections are insufficient for penetration, and men with T2DM began a median of one point lower than euglycemic men (Figure 3C). After treatment, every man scored 3 or 4, a median increase of 2 points in each group, with treatment restoring the ability to engage in penetrative intercourse. Among euglycemic men, 26 of 38 (68%) reached EHS 4 and the remaining 12 (32%) reached EHS 3. Among men with T2DM, 19 of 33 (58%) reached EHS 4 and the remaining 14 (42%) reached EHS 3 (Figure 3C). Total treatment sessions were unrelated to post-treatment EHS in either group (ρ=0.00, P=1.00 in euglycemic men; ρ=0.10, P=0.59 in men with T2DM). Instead, sessions were inversely correlated with baseline EHS (ρ = -0.46 in euglycemic men, ρ = -0.76 in men with T2DM, both P<0.05), indicating that men who began with more severe ED received more sessions and that all men were able to return to penetrative intercourse regardless of the number of sessions required.

4. Discussion

This retrospective case series demonstrates that a multimodal treatment protocol combining physical therapies, daily tadalafil, testosterone replacement, and tirzepatide for men with T2DM, restored the ability to engage in penetrative intercourse in all 71 men with PDE5i-refractory ED over a 3-4 month treatment period. Every man improved from an EHS ≤2 to an EHS ≥3, with 68% of euglycemic men and 58% of men with T2DM reaching the maximum score of 4. The odds of successful sexual intercourse at EHS 3 are 41.9 times those at EHS 2 [32], and a 1-point change on the EHS is considered the minimally clinically important difference [7]. Although not every man achieved a fully rigid erection (EHS 4), restoration of penetrative function after inability to penetrate represents a clinically meaningful outcome. These results are also notable because each individual component of the protocol, when studied in isolation, has produced only modest and often clinically insufficient improvements in this population [4,6,7,10,12,13,14] .

The magnitude of erectile function improvement observed here exceeds what has been reported for any single modality in PDE5i-refractory men. The most recent Cochrane review of low-intensity shockwave therapy found only a small improvement in erectile function with low-certainty evidence, and a subsequent meta-analysis concluded that most trials failed to achieve the minimally clinically important difference on the IIEF [7,33]. Testosterone replacement produces a standardized mean difference of 0.16-0.32 on erectile function scores, with the effect further attenuated in men with diabetes and obesity [34,35]. A meta-analysis of 44 studies found that combination therapy with PDE5i plus a second pharmacologic or physical agent modestly improved erectile function compared with monotherapy, with larger effects in monotherapy-resistant ED [36]. However, these combination approaches did not approach universal restoration of penetrative function. The present protocol differs from prior combination strategies by layering distinct modalities and interventions that target complementary tissue-level mechanisms, including neovascularization, corporal smooth muscle remodeling, and neuromuscular facilitation, while also optimizing the hormonal, vascular, metabolic, and psychological environment required for successful erectile function.

The rationale for each physical modality rests on distinct but convergent biological mechanisms. Shockwave therapy induces neovascularization through cavitation-mediated shear stress on endothelial membranes, upregulating VEGF, eNOS, and progenitor cell recruitment [37,38]. The 12-14 Hz radial pressure wave protocol used in this study exceeds the 2-8 Hz repetition rates reported in prior ED shockwave literature [7,33]. This higher frequency was intended to generate sustained calcium-calmodulin-dependent eNOS activation rather than discrete, isolated calcium transients at lower frequencies, while also creating a denser cavitation field with more uniformly distributed microshear forces across the cavernosal endothelium. Therapeutic ultrasound has been used to promote favorable cavernosal remodeling in Peyronie’s disease, and translational models have demonstrated improved vascular function, cavernosal healing, and nerve regeneration [10,25]. Laser photobiomodulation at near-infrared wavelengths activates mitochondrial cytochrome c oxidase, increasing ATP production and nitric oxide release, while preclinical models of diabetic ED demonstrate that combined red and near-infrared light restores intracavernosal pressure to 90% of normal levels through enhanced neurovascular regeneration [9,39]. Structured neuromuscular exercise targeting the lumbopelvic complex addresses musculoskeletal contributors to erectile dysfunction that are frequently underemphasized in urologic care. The ischiocavernosus muscles generate suprasystolic intracavernosal pressures that convert an erect penis to a rigid one, and ischiocavernosus atrophy has been directly linked to reduced penile rigidity [40,41,42]. Pelvic floor muscle training strengthens these muscles and has been shown to increase intracavernosal pressure, improve erectile function scores, and restore normal function in approximately 40% of men with ED [11,41]. Beyond the pelvic floor itself, erection and ejaculation are coordinated by spinal reflex circuits spanning the thoracolumbar (T11-L2) and sacral (S2-S4) segments, with supraspinal modulation from the hypothalamus and brainstem [41,43]. The broader lumbopelvic exercise program used in this protocol, targeting abdominal, hip, and proximal limb musculature in addition to the pelvic floor, was designed to optimize the neuromuscular environment supporting these spinal reflex pathways while addressing the deconditioning and musculoskeletal dysfunction commonly present in this population [44,45]. Daily tadalafil 5 mg provides tonic cGMP-mediated smooth muscle relaxation and has been shown to improve endothelial function as measured by brachial artery flow-mediated dilation, with potential disease-modifying effects beyond acute symptom relief [6,46]. Testosterone replacement in hypogonadal men modulates nearly every component involved in erectile function, from pelvic ganglia to cavernosal smooth muscle and endothelium, while also restoring orgasmic function through enhancement of the bulbospongiosus reflex arc that coordinates the rhythmic perineal contractions producing orgasm [13,47] . Androgen deficiency promotes apoptosis of cavernosal endothelial and smooth muscle cells and downregulates PDE5 expression, which may explain why PDE5i monotherapy fails in untreated hypogonadism and why restoring physiologic testosterone levels can rescue both erectile and orgasmic responsiveness [48]. The counseling approach used in this case series is supported by evidence that psychosocial interventions, particularly those incorporating performance anxiety reduction, cognitive restructuring, and graded sexual exposure, improve erectile function outcomes and reduce treatment dropout when combined with medical therapy [16]. By combining these modalities, the protocol simultaneously addresses vascular, neural, structural, muscular, and psychological deficits that contribute to refractory ED.

Men with T2DM presented with more severe disease at baseline, including lower EHS, longer symptom duration, higher hs-CRP, lower testosterone, and greater adiposity, and required 42% more treatment sessions to reach satisfactory function. Despite this greater disease burden, the T2DM group achieved comparable post-treatment erectile function, with between-group differences in EHS, ASEX, and PROMIS-10 scores eliminated after treatment. The addition of tirzepatide in the T2DM group produced a 2.8 percentage-point reduction in HbA1c, from 9.2% to 6.2%, with 58% of men transitioning from the diabetic to the prediabetic range. This glycemic improvement is consistent with previous studies in which tirzepatide reduced HbA1c by 1.87-2.07 percentage points at the 5 mg dose and achieved normoglycemia in 31-52% of participants [49]. The three-fold steeper decline in hs-CRP observed in the T2DM group (2.2 vs. 0.7 mg/L) aligns with a meta-analysis demonstrating that tirzepatide reduces hs-CRP by approximately 33% relative to placebo, with rapid onset within 4 weeks suggesting a direct anti-inflammatory effect independent of weight loss [15,50]. The magnitude of hs-CRP reduction was likely greater in this study than in previous reports because of the synergistic contributions of testosterone therapy, resistance exercise, and tadalafil, all of which have been shown to decrease systemic inflammation in isolation [51,52,53]. Because systemic inflammation impairs nitric oxide bioavailability and accelerates corporal fibrosis, key pathogenic mechanisms in diabetic ED, the reduction in inflammatory burden may have been a critical enabler of the erectile function gains observed in the T2DM group [54,55].

A notable finding was that men with T2DM gained skeletal muscle mass (median 2.7 kg) and grip strength (median 6.4 kg) despite concurrent weight loss, a pattern that runs counter to the expected trajectory with incretin-based therapy alone. Tirzepatide is associated with reductions in muscle volume that are broadly proportional to total weight loss, and 25% to 39% of total weight lost with GLP-1 receptor agonists is estimated to be fat-free mass [56,57]. The concurrent use of testosterone replacement and progressive resistance exercise in this protocol appears to have prevented the expected muscle loss and reversed it, producing net muscle gain alongside fat loss. This finding is consistent with evidence that resistance training can reduce lean mass loss by 50-95% during caloric restriction and with the known anabolic effects of testosterone on skeletal muscle protein synthesis [58,59]. The combination of tirzepatide for metabolic optimization, testosterone for anabolic support in appropriate patients, and structured exercise for mechanical loading may represent a practical strategy to address the muscle mass concern that has emerged as a central limitation of incretin-based weight loss therapies [56,60].

Several limitations of this study should be considered. As a retrospective case series without a control group, causal inference is not possible, and the observed improvements cannot be attributed to any individual component of the multimodal protocol. The absence of randomization and blinding introduces the possibility of placebo effect, selection bias, and regression to the mean. The treatment protocol was individualized in terms of session frequency and exercise prescription, which limits reproducibility. The EHS, while validated, clinically meaningful, and easily administered in the clinical setting, is a single-item ordinal measure that provides less granularity than other erectile function outcomes. The T2DM group received tirzepatide in addition to the other interventions, confounding the comparison between groups and preventing isolation of the contribution of tirzepatide to erectile function outcomes specifically. Testosterone levels were measured 3-4 days after injection, which captures mid-cycle values for weekly injections but does not reflect peak concentrations.

5. Conclusions

This case series suggests that a multimodal treatment approach combining therapies designed to address the multiple causes of ED, including hormonal, metabolic, neuromuscular, and neurovascular, and psychological components, restored penetrative erectile function in euglycemic and diabetic patients (Figure 4). Men with T2DM, despite presenting with greater disease severity, achieved equivalent post-treatment sexual function while simultaneously experiencing clinically meaningful improvements in glycemic control, systemic inflammation, body composition, and grip strength. The concurrent use of testosterone therapy and progressive resistance exercise appeared to counteract the muscle mass loss typically associated with incretin-based therapy, producing net gains in skeletal muscle mass and strength. These findings support the concept that refractory ED, particularly in the setting of diabetes and hypogonadism, may require simultaneous intervention across multiple pathophysiologic domains rather than sequential escalation of single modality treatments. In addition, testosterone therapy and resistance exercise in appropriately selected patients receiving incretin-based therapy may help preserve or increase skeletal muscle mass. Prospective controlled trials are needed to confirm these observations, identify the relative contribution of each treatment component, and determine the long-term durability of these outcomes.