Androgens are essential for the maintenance of libido, and they also control the initiation, maintenance, and termination of penile erection through a variety of mechanisms at both the central and peripheral levels. Androgen deficiency not only leads to decreased libido, but also causes structural damage to the penis and significant changes in erection-related active substances, such as decreased smooth muscle content of the penile corpus cavernosum, increased connective tissue, and deposition of fat cells under the white membrane. When the penis is erect, these changes in the cavernous tissues can lead to venous leakage due to incomplete venous occlusion and erectile dysfunction. Testosterone supplementation in patients with hypogonadal erectile dysfunction can have a good therapeutic effect. Close observation is needed during testosterone replacement therapy to avoid adverse effects. Androgens and penile erectile function 1. Androgens regulate penile erectile function Androgens regulate penile erection at both central and peripheral levels. Previous studies have found that androgens affect sexual desire and have limited effects on penile erection induced by sexual stimulation. Earlier studies found that spontaneous erections such as nocturnal penile erections and sexual fantasy-induced erections are testosterone-dependent, whereas penile erections induced by sexual stimulation (e.g., visual and auditory stimulation) are less testosterone-dependent. It was hypothesized that the neural pathways mediating nocturnal erections and sexually stimulated erections may be inconsistent. However, Carani et al. showed that testosterone influences important indices such as duration, maximum hardness and speed of weakness of sexually stimulated-induced erection. Nevertheless, the above observations do not change the generally accepted view that the primary target of androgens is libido and that their effects on the penis are indirectly exerted by influencing sexual desire. Previous experience has pointed out that only normal low levels of testosterone are required for the maintenance of male sexual function, and thus testosterone was considered ineffective in the treatment of erectile dysfunction (ED), especially as the use of phosphodiesterase type 5 (PDE5) inhibitors seemed to reinforce this point. However, a number of recent studies offer hope for testosterone treatment of ED in older men: 1. Older men may require higher levels of testosterone than younger men to maintain normal sexual function. Serum testosterone levels to maintain libido vary from person to person, with older men requiring higher levels of testosterone for libido and erectile function than younger male patients; 2. PDE5 inhibitors do not provide adequate erections in all patients, and testosterone significantly increases the effectiveness of this class of drugs; 3. There are androgen receptors in the adult penile corpus cavernosum, and testosterone upregulates PDE5 synthesis and can increase arterial blood flow to the penis. The results of new experimental animal studies found that testosterone has an effect on penile tissue and its erectile mechanism. Testosterone deficiency can damage the anatomical structure of erectile tissue and its physiological function, and testosterone supplementation can reverse the lesion. The quality of penile erection (hardness and maintenance time) depends on the balanced relationship between diastolic factors such as NO and cGMP and contractile factors such as norepinephrine (NE) and PDE5. If NO dominates, the penis is erect: 1. If PDE5 dominates, the penis is weak. Most ED occurs as a direct result of decreased NO or/and increased PDE5, i.e. NO/PDE5 negative balance. 2. The effect of androgens on the protein expression and enzyme activity of endothelium-derived and neurogenic NOS 3. The effect of androgens on the protein expression and enzyme activity of PDE5 4. Effects of androgens on ion channels in smooth muscle cells of the penile corpus cavernosum. 5. Effects of androgens on the structure and function of smooth muscle cells of the penile corpus cavernosum. ED is a multifactorial disease, and the causes of ED, such as vascular, neurological and endocrine, have been understood in detail. The cavernous body of the penis is mainly composed of trabecular smooth muscle cells and extra-cellular matrix (ECM), which is the structural basis of penile erection. Androgens play an important role in maintaining normal cavernous tissue structure, and androgen deficiency can lead to the occurrence of ED through the following mechanisms. 1, changes in cavernous smooth muscle cell content and ultrastructure. 2, increase in cavernous ECM. 3, deposition of submacular adipocytes in the cavernous body. 4, cavernous tissue NOS expression is down-regulated and RhoA/Rho kinase is increased. Diagnosis, treatment and monitoring of androgen-deficient ED Diagnosis: Mandatory items 1, physical examination: including height, weight, blood pressure, heart rate, liver and prostate palpation, testicular volume, acne, gynecomastia feminization; 2, serum hormone measurements: LH?FSH and T; 3, clinical blood biochemistry: urea nitrogen? muscle liver? electrolytes? Blood esters? Lipoproteins; liver function (bilirubin? Alkaline phosphatase, AST, ALT, transpeptidase. Albumin); 4. Hematological indicators: hemoglobin? Erythrocytes? White blood cells? Platelets? Urinalysis: urine protein? Urine glucose? Sediment microscopy; 6. Sexual function records: frequency of erection? Number of sexual intercourse? The number of ejaculation, etc.? Optional items 1.Serum hormone measurement: free T? E2; 2.Full set of blood lipids; 3.Semen analysis; 4.B ultrasound transrectal measurement of prostate volume; 5.Uroflowmetry measurement of urine flow rate and urine flow index; 6.Serum PSA measurement; 7.Quantitative bone mineral density measurement; 8.Lean body mass/body fat measurement; 9.Psychological testing of emotion and behavior; Treatment and monitoring Primary or secondary hypogonadism due to various causes Patients with hypogonadism due to various causes of primary or secondary hypogonadism are often combined with ED, and androgen therapy can enhance libido and restore normal erectile function. Erectile function did not improve in patients given sildenafil (50 mg) or apomorphine (3 mg) alone, whereas after 6 months of testosterone supplementation (5 mg/d) followed by the same dose of sildenafil or apomorphine, patients’ nocturnal erections (NPT), various parameters of penile color Doppler ultrasound (CDU), and visually stimulated induced erections returned to normal. Although these are only preliminary findings at this time and further studies are needed, however, combination therapy should be considered in patients with ED with hypogonadism who do not respond to any of the individual treatments? However, should PDE5 inhibitors be initiated in men with hypogonadism with ED? Testosterone or a combination of both needs to be further explored? Testosterone production in men gradually decreases with age, with approximately 30% of men between the ages of 60 and 70 experiencing a decrease in serum free testosterone levels. In middle-aged and older men, symptoms associated with lower testosterone levels, such as fatigue, depression, muscle weakness, and hypogonadism, are called late onset hypogonadism (LOH), which is essentially due to hypogonadism, and ED is one of its main manifestations. Isidori et al. conducted a Meta-analysis of the past 30 years of studies on the efficacy of testosterone replacement therapy on sexual function in adult men (weighted mean age 57.5 years) and showed that the effect of testosterone replacement therapy on improving erectile function was related to serum testosterone levels. Patients with testosterone levels <7 nmol/L had significantly better libido and erectile function after testosterone replacement therapy, and the frequency, hardness, and satisfaction with intercourse of erections improved; at testosterone levels >10 nmol/L, patients had increased erection frequency and libido, but no significant increase in erectile hardness; and at testosterone levels >12 nmol/L, patients had improved erectile function compared with The difference was not significant when comparing placebo, suggesting that the efficacy of testosterone treatment for ED depends on the testosterone level. Testosterone supplementation enhances the response to PDE5 inhibitors and significantly improves the International Index of Erectile Function (IIEF) scores in patients with LOH who have varying degrees of reduced free testosterone levels. The initial 3 months of testosterone supplementation is a trial treatment period. If symptoms improve significantly after exogenous testosterone supplementation, suggesting that symptoms are related to lower testosterone levels, can long-term treatment continue? If there is no significant improvement in symptoms, should treatment be discontinued and the cause of the disease re-examined? ED caused by venous leakage due to venous occlusion insufficiency is often treated with the help of surgery, however, the long term results of surgery are not satisfactory. The results of animal studies have shown that testosterone deficiency often leads to venous occlusion insufficiency due to changes in cavernous tissue structure, suggesting that testosterone supplementation can help restore erectile function in patients with venous ED. Recently, Yassin et al. reported a patient whose ED due to venous leakage was cured by testosterone supplementation. The patient suffered from severe ED for 3.5 years, had a severe venous leak confirmed by cavernous venography, and was given testosterone replacement therapy because of a reduced serum testosterone level (6.25 nmol/L, normal reference range: 13.88 to 29.84 nmol/L). After 9 weeks of testosterone supplementation the patient felt an improvement in erectile function, and after 12 weeks the patient agreed to undergo another penile cavernous angiography due to significant improvement in erectile function, which revealed the disappearance of venous leakage. A German study found that 12 hypogonadal men with low plasma testosterone and moderate to severe ED, who were treated with oral PDE5 inhibitors did not improve erectile function and had varying degrees of cavernous vein occlusion dysfunction on penile cavernosography? In patients treated with intramuscular testosterone undecanoate for 12 to 20 weeks, erectile function improved significantly in 5 of 12 patients and libido was also significantly increased, suggesting that testosterone may improve erectile function in hypogonadal patients by restoring veno-occlusive function? Although the reported cases are limited, it provides a new idea for the treatment of venous ED, and more patients need to be observed and studied in the future. IV. Safety of androgen therapy Current concerns about the possible adverse consequences of exogenous testosterone supplementation are mainly focused on benign prostatic hyperplasia (BPH) and prostate cancer (PCa). The prostate is an androgen-dependent organ, and the development of BPH and the growth of PCa are closely related to testosterone. However, there is no evidence that testosterone supplementation leads to the development of BPH and PCa. El-Sakka et al [34] observed PSA levels in 187 patients over 45 years of age with hypogonadism with ED treated with testosterone replacement and found that the difference between PSA levels after 1 year of medication and before medication was not significant (P>0.05). Calof et al [35] performed a Meta-analysis of studies related to adverse effects of testosterone replacement therapy in middle-aged and elderly men and showed that the most common adverse effect of testosterone replacement was elevated hematocrit, and although the incidence of prostate events (including PCa, PSA >4 g/L and prostate biopsy) increased numerically, the difference was not significant when compared with placebo. Nevertheless, testosterone supplementation in patients with symptoms of lower urinary tract obstruction requires caution, and testosterone therapy is contraindicated in patients suspected of having PCa. Regular testing of complete blood cell analysis, blood PSA and rectal examination of the prostate during testosterone replacement is necessary. Testosterone replacement therapy is safe as long as attention is paid to regular follow-up and observation of the patient.