Ejaculatory dysfunction in men with diabetes mellitus

Table 1 Ejaculatory behavior in diabetic animals

Ref.	Animal model	Effects observed on ejaculatory function	Type of treatment and response
Sach et al[31], 1982	STZ-induced diabetic rats	No sexual performance difference between diabetic and control rats.
Clark[32], 1995	STZ-induced diabetic rats	No sexual performance difference between diabetic and control rats.
Scarano et al[33], 2006	STZ-induced diabetic rats	No sexual performance differences in EL after 15 d.
Steger et al[34], 1990	STZ-induced diabetic rats	Prolonged EL (DE or AE)	Delayed insulin replacement (4 wk) cannot prevent ejaculatory dysfunction.
Murray et al[35], 1992	Diabetic BB/WOR rats	Prolonged EL (DE or AE) after 28 wk
McVary et al[36], 1997	Diabetic BB/WOR rats	Prolonged EL (DE or AE) after 40 wk, reduced number of ejaculations.
		No differences regarding serum testosterone, FSH, and LH.
Ebiko et al[37], 2006	STZ-induced diabetic rats	Deteriorated spontaneous seminal emission after 5 wk.	Early insulin replacement can prevent ejaculatory dysfunction.
		In 15 and 30 wk, occurrence of SSE was almost completely suppressed.
Yonezawa et al[38], 2009	Streptozotocin (STZ)-induced diabetic rats	Deteriorated spontaneous seminal emission after 5 wk.	Early insulin replacement can prevent ejaculatory dysfunction. Once dysfunction occurs, insulin cannot restore it.
		Decreased ejaculated semen and decreased seminal vesicle fluid.
Suresh et al[39], 2012	STZ-induced diabetic rats	Prolonged EL suggesting DE. -Low serum testosterone.	Mucuna pruriens showed recovery of EL.
De et al[40], 2016	STZ-induced diabetic rats	Prolonged EL suggesting DE. -Low serum testosterone.	l-Norvaline (arginase inhibitor) reduced EL.
Shi et al[41], 2017	STZ-induced diabetic rats	Prolonged EL suggesting DE.	Lycium barbarum polysaccharide reduced EL.
Li et al[42], 2019	STZ-induced diabetic rats	Prolonged EL at 62 d suggesting DE.	No effect of vitexin (herb) on EL.
Lert-Amornpat et al[43], 2016	STZ-induced diabetic rats	Lack of copulatory behavior suggesting AE.	Kaempferia parviflora (herb) showed recovery of EL.
Fernández-Collazo et al[44], 1970	Rats with subtotal pancreatectomy	They did not AE.
Hassan et al[45], 1993	STZ-induced diabetic rats	Rats exhibited AE in diabetics. -Low serum testosterone.	Sabeluzole treatment was beneficial to correct dysfunction.
Pontes et al[46], 2011	STZ-induced diabetic rats	Lack of the sperms ejaculated into the uterus. -Low serum testosterone.	Testosterone supplement did not restore ejaculatory function.
Ghaheri et al[47], 2018	STZ-induced diabetic rats	Shorten EL after 28 d suggesting PE.	Stevia Bertoni extract improved EL.
Minaz et al[48], 2019	STZ-induced diabetic rats	Shorten EL after 8 wk suggesting PE. -Low serum testosterone.	Inhibition of soluble epoxide hydrolase prolonged EL.

AE: Anejaculation; DE: Delayed ejaculation; EL: Ejaculation latency; FSH: Follicle stimulating hormone; LH: Luteinizing hormone; PE: Premature ejaculation; STZ: Streptozotocin.

Table 2 Possible pathophysiological mechanisms underlying ejaculatory dysfunctions in diabetes mellitus (animal studies)

Ref.	Postulated mechanisms	Possible ejaculatory dysfunction
McVary et al[36], Yagihashi et al[49]	Pathologic changes in the nerve supply of seminal tract due to accumulation of AGE increased ROS (sympathetic neuropathy)	Prolongation of EL
Tomlinson et al[50], Longhurst et al[51]	Decreased number of synapses in thoracic ganglia	Reduction of the numbers of ejaculations
Kaschube et al[52], Kamata et al[53]	Axonopathy in postganglionic sympathetic fibers	Disturbed the emission phase
Güneş et al[54], Tsounapi et al[55]	Neuropathic changes in hypogastric nerve and motor pudendal nerve fibers	Disruption of the ejection phase
Tomlinson et al[50], Longhurst et al[51], Kaschube et al[52], Kamata et al[53], Güneş et al[54]	Hypersensitivity (supersensitivity) of seminal tract smooth muscles to exogenous noradrenaline	Reduction of EL
Sakai et al[56], Sakai et al[57]	Hyperactivity of Ca channels in smooth muscles	Reduction of EL
Ebiko et al[37], Yonezawa et al[38]Yagihashi et al[49], Torimoto et al[60]	Sympathetic neuropathy and external urethral sphincter relaxation dysfunction	Disruption of bladder neck closure
		Disruption of AE
Sandrini et al[61], Abraham et al[62]	Changes in serotonergic transmission	Reduction or prolongation of EL
Seethalakshmi et al[71], Wolfe et al[72]	Impaired hypothalamic or pituitary signaling	Decreased sexual performance
Oksanen et al[73], Sudha et al[74]	Deficiency of gonadotropic hormones or blockade of their actions	Decreased sexual performance
Ballester et al[75], Neirijnck et al[76]	Decrease in number and function of Leydig cells	Decreased sexual performance
Neirijnck et al[76]	Defective testicular steroidogenesis	Decreased sexual performance
Kühn-Velten et al[64], Anderson et al[65], Ricci et al[66], Murray et al[67], Cameron et al[68], Ohta et al[69], Nakane et al[70]	Reduced serum levels of LH and testosterone (T)	Decreased sexual performance
McVary et al[36], Minaz et al[48], Steger et al[85], Al-Roujayee et al[86], Kashif et al[87]	Reduced libido	Decreased sexual performance, decreased mount frequency, and reduced EL
Hassan et al[45], Steger et al[77]	Reduced reproductive organ weight	Exact Effects on ejaculation still unknown

AGE: Advanced glycation end products; Ca: Calcium; DE: Delayed ejaculation; EL: Ejaculation latency; FSH: Follicle stimulating hormone; LH: Luteinizing hormone; PE: Premature ejaculation; ROS: Reactive oxygen species; STZ: Streptozotocin; T: Testosterone.

Table 3 Possible pathophysiological mechanisms underlying ejaculatory dysfunctions in diabetes mellitus (human studies)

Ref.	Possible cause	Outcome
Premature ejaculation
Culha et al[88]	Anxiety	Among PE patients with DM, 15% had anxiety
Culha et al[88], Khan et al[89]	Depression	Among PE patients with DM, 16.9% had depression
		Depression score Significantly higher among diabetic-related PE patients
Khan et al[89], Malavige et al[90]	Genetic and racial factors	Long tri-nucleotide repeats of the androgen receptor are related to the lowest IELT (PE)
		Asian men reported higher diabetic PE than European counterparts
El-Sakka[91]	Diabetic condition, duration of MD	> 10 yr of diabetes were 2.7 times as likely to report diabetic-related PE
	Poor glycemic control	Poor glycemic control were 9.6 times as likely to report PE
El-Sakka[91], Majzoub et al[92]	Having diabetic-related -erectile dysfunction (ED) and Cardiovascular diseases	Significant association between PE and cardiovascular diseases
Malavige et al[93], Malavige et al[90]		ED showed a significantly higher incidence of PE
Olamoyegun et al[94]		ED was strongly associated with PE odds ratio = 4.4
El-Sakka[91]	Having diabetic –related neuropathy	It is not associated with PE
Khan et al[89]	Total serum testosterone	Significantly higher among type 2 diabetic-related PE patients
Owiredu et al[95]		It correlates negatively with short IELT among type 2 DM
Bellastella et al[96]		No significant difference in type 1 diabetes
Delayed ejaculation and anejaculation
Corona et al[97]	Depression	Severe depressive symptoms are associated with ejaculatory problems in DM
Ellenberg et al[25] , La Vignera et al[27] , Dinulovic et al[98]	Progressive autonomic neuropathy of the sympathetic nerves	Denervation leads to weak or loss of VD and SV peristaltic movements
Dunsmuir et al[99], Condorelli et al[100]		Abnormal inflammatory responses lead to alteration of the VD and SV peristaltic movements
La Vignera et al[101] , Pop-Busui et al[102]		Delayed /poor emission
		Absent emission
Haddad et al[26], Culver et al[103]	Calcification of vas deferens and seminal vesicles	Loss of their ability to contract as the smooth muscle is replaced by fibrotic, calcified tissue
Tsuno et al[104]		Delayed/poor emission
Hylmarova et al[29] , Corona et al[81]	Hypogonadism	No association between serum testosterone levels and ejaculation time in men self-reporting DE including diabetic patients
Paduch et al[82], Gianatti et al[105]
Morgentaler et al[106]		T replacement is not associated with improvement in DE or AE
Burke et al[107], Corona et al[108]	Low sexual desire	DM is significantly associated with low sexual desire
Corona et al[109]		DE and AE are associated with low sexual desire
Retrograde ejaculation
Klebanow et al[110]	Diabetic neuropathy (T10-L3)	Intact vasal and seminal vesicle contraction but incomplete simultaneous bladder neck closure leads to partial RE
Greene et al[111]		Intact vasal and seminal vesicle contraction and simultaneous complete lack of bladder neck closure leads to complete RE
Koyanagi[112]	External urethral sphincter relaxation dysfunction (triple parasympathetic-sympathetic-somatic innervation)	Lack of active external urethral sphincter relaxation leads to disruption of antegrade ejaculation
Cao et al[113]

AE: Anejaculation; DE: Delayed ejaculation; DM: Diabetes Mellitus; EL: Ejaculation latency; ED: Erectile dysfunction; PE: Premature ejaculation; SV: Seminal vesicle; VD: Vas deferens.

Table 4 Assessment steps in the evaluation of diabetes mellitus-related ejaculatory dysfunctions

History
Asking about the period from vaginal intromission to ejaculation (intravaginal ejaculatory latency time).
Is the patient unable to advance his ejaculatory response?
Is the patient or his partner distressed or bothered by the situation?
Is the symptom occurring since the first sexual experience or occurring after a period of normal ejaculatory performance?
Onset and duration of the symptom.
Is the symptom occurring on every/almost every attempt and with every partner?
Presence or absence of premonitory ejaculatory sensation.
The duration of thrusting before the suspension of intercourse.
Reasons for delay of intercourse (e.g., fatigue, loss of erection, a sense of ejaculatory futility, or partner request).
Presence of post-coital self- or partner-assisted masturbation.
Psychogenic anejaculation/anorgasmia can be suspected when there is a history of nocturnal emission.
Patient's ability to get an erection, relax, sustain, and heighten sexual arousal.
Exclude anorgasmia by asking about lack of orgasm.
Whether orgasm is present but there is a lack of external ejaculation that may indicate retrograde ejaculate.
Feeling before ejaculation/orgasm: The inadequate combination of “friction and fantasy” may exacerbate DE.
Intercourse frequency.
Presence of other sexual dysfunctions such as ED (ability to initiate or maintain an erection), low libido.
Other symptoms of hypogonadism (such as lack of energy, depressed mood).
Masturbation habits
The life events/circumstances related to the complaint.
Sexual communication abilities.
Paraphilic inclinations/interests (may be related to DE and anejaculation).
Cultural or religious beliefs (if any).
History of a psychiatric disorder (may be the etiologic factor).
History of previous treatment for this symptom.
History of neurologic disorders, spinal cord injury, medical diseases, trauma, abdominal/pelvic operations, drug intake, or pelvic radiotherapy.
History of pelvic or testicular pain (may indicate inflammation).
History of dysuria, burning micturition, or any urinary symptom (indicate inflammation).
Clinical examination
Signs of diabetic complications and co-morbidities.
Signs of hypogonadism.
Rule out systemic disorders that contribute to ejaculation dysfunction as neurological impairment, endocrine/ urological diseases.
Examination for secondary sexual characteristics, penile and testicular abnormalities.
Examination of the epididymis, and vas deferens on each side.
PR examination to determine the prostate size, anal sphincter tone, and quality of the bulbocavernosus reflex.
The cremasteric reflex: measures intact L1-2 spinal segments, also mediating emission and psychogenic erection.
Perineal reflexes (bulbocavernosus and anal reflex) mediated by sacral segments, also mediating reflex erection (for intact S2–4 pathway).
Examination of pinprick and temperature sensations in the saddle area (perineal) and glans penis for healthy sacral cord segments.
Inability to feel testicular squeeze: measures the integrity of T11 to T12 spinal nerves via the sympathetic nervous system.
Examination of lower abdominal cutaneous reflex: measures intact Th11-12.
Penile biothesiometry.
Investigations
Blood levels of glucose, HbA1c, serum testosterone, thyrotropin, and prolactin to exclude other endocrine disorders.
Post-masturbation first-void urine if we suspect retrograde ejaculation to search for spermatozoa and fructose content to confirm retrograde ejaculate
Microbiological examination of expressed prostatic secretion and urine to verify or exclude associated genital infections.
Urine cytology to exclude bladder cancer
Serum prostate-specific antigen to exclude prostate cancer
Neurophysiologic investigations (bulbocavernosus evoked response and dorsal nerve somatosensory evoked-potentials): If there is clinical evidence of neurologic lesions. These tests are little used in clinical practice and usually do not affect management.
Trans-rectal ultrasound examination if we suspect ejaculatory duct obstruction, prostatic or seminal vesicle abnormalities or stones.
CT or MRI scans to assess pelvic anatomy if we suspect major pelvic lesions.

CT: Computed tomography; MRI: Magnetic resonance imaging.

Table 5 Studies involving medical treatment for reversal of diabetic retrograde ejaculation

Ref.	Dosage	Ejaculation after	n	No. of successes	Ejaculate volume (ml)	Sperm count (106/m)	Sperm motility (%)
Brompheniramine
Andaloro et al[152]	16 mg/d p.o.	12 h	1	1	Unclear	Unclear	Unclear
Budd[153]	16 mg/d p.o.	3 d	1	1	Unclear	Unclear	Unclear
Chlorpheniramine + phenylpropanalamine
Stewart et al[154]	50 mg/d p.o.	Unclear	1	1	4.5	Normal	Normal
Ephedrine
Gilja et al[155]	50 mg/d p.o.	4 wk	17	3	Unclear	Unclear	Unclear
Arafa et al[156]	120 mg twice/d	14 d	23	11	Unclear	Unclear	Unclear
Shoshany et al[157]	60 mg/6 h the day before test + 2 doses on test day	At the test	6	4	1.5	Unclear	17.8
Imipramine
Brooks et al[158]	75 mg/d p.o.	1 wk	2	2	3	1.72	33
Okada et al[159]	25-150 mg/d	Unclear	7	3	Unclear	Unclear	Unclear
Gilja et al[155]	75 mg/d p.o.	4 wk	14	2	Unclear	Unclear	Unclear
Eppel et al[160]	50 mg/d p.o.	5 d	3	3	8	20	50
Arafa et al[156]	50 mg/d p.o	14 d	23	10	Unclear	Unclear	Unclear
Imramine + pseudoepherine
Arafa et al[156]	50 + 120 mg/d	14 d	23	16	Unclear	Unclear	Unclear
Amoxapine
Hibi et al[161]	50 mg/d	1 mo	1	1	0.2	213	53

Table 6 Semen parameters of studies recovering sperms from alkalized urine in diabetic premature ejaculation patients

Ref.	Medium installed	Post-masturbatory retrieval	No. of patients	Total sperm count (106)	Total sperm motility (%)	Pregnancies
Brassesco et al[163]	NaHCO3 4 g	Voiding	3	91	28	3
Templeton et al[162]	NaHCO3	Voiding	1	Unclear	2–21	0
Shangold et al[164]	NaHCO3 1.6 g	Voiding	1	30–240	0	5