Delayed orgasm and anorgasmia
2015; Elsevier BV; Volume: 104; Issue: 5 Linguagem: Inglês
10.1016/j.fertnstert.2015.09.029
ISSN1556-5653
AutoresLawrence C. Jenkins, John P. Mulhall,
Tópico(s)Genital Health and Disease
ResumoDelayed orgasm/anorgasmia defined as the persistent or recurrent difficulty, delay in, or absence of attaining orgasm after sufficient sexual stimulation, which causes personal distress. Delayed orgasm and anorgasmia are associated with significant sexual dissatisfaction. A focused medical history can shed light on the potential etiologies, which include medications, penile sensation loss, endocrinopathies, penile hyperstimulation, and psychological etiologies. Unfortunately, there are no excellent pharmacotherapies for delayed orgasm/anorgasmia, and treatment revolves largely around addressing potential causative factors and psychotherapy. Delayed orgasm/anorgasmia defined as the persistent or recurrent difficulty, delay in, or absence of attaining orgasm after sufficient sexual stimulation, which causes personal distress. Delayed orgasm and anorgasmia are associated with significant sexual dissatisfaction. A focused medical history can shed light on the potential etiologies, which include medications, penile sensation loss, endocrinopathies, penile hyperstimulation, and psychological etiologies. Unfortunately, there are no excellent pharmacotherapies for delayed orgasm/anorgasmia, and treatment revolves largely around addressing potential causative factors and psychotherapy. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/jenkinsl-delayed-orgasm-anorgasmia/ Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/jenkinsl-delayed-orgasm-anorgasmia/ Delayed orgasm (DO) and anorgasmia (AO) have been described as one end of a spectrum of orgasm timing disorders with the other end being premature ejaculation (1Corona G. Jannini E.A. Lotti F. Boddi V. de Vita G. Forti G. et al.Premature and delayed ejaculation: two ends of a single continuum influenced by hormonal milieu.Intern J Androl. 2011; 34: 41-48Crossref PubMed Scopus (97) Google Scholar). Delayed orgasm and anorgasmia are defined as the persistent or recurrent difficulty, delay in, or absence of attaining orgasm after sufficient sexual stimulation, which causes personal distress. Delayed orgasm has also been termed retarded orgasm, inhibited orgasm, retarded ejaculation, and/or inhibited ejaculation. We believe that DO is the correct term as some men fail to ejaculate for medical reasons but still experience orgasm (retroperitoneal surgery, radical prostatectomy). One of the major concerns with DO and in particular AO, young males or men with reproductive interest, is the failure to inseminate and therefore male factor infertility. Men with DO may develop anxiety and frustration, which may lead to other sexual problems such as erectile dysfunction and loss of sex drive. It is critically important to understand that orgasm is an entirely separate process from ejaculation, although they are designed to occur simultaneously. In the clinical setting, most men with failure to ejaculate (retrograde ejaculation, failure of emission both addressed elsewhere in this issue) experience orgasm (although a man with failure to ejaculate for medical reasons may also have DO or AO). However, men with AO will not ejaculate. The best definition is probably that of the World Health Organization 2nd Consultation on Sexual Dysfunction that defines DO as the persistent or recurrent difficulty, delay in, or absence of attaining orgasm after sufficient sexual stimulation, which causes personal distress (2McMahon C.G. Althof S.E. Waldinger M.D. Porst H. Dean J. Sharlip I.D. et al.An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine (ISSM) ad hoc committee for the definition of premature ejaculation.J Sex Med. 2008; 5: 1590-1606Crossref PubMed Scopus (314) Google Scholar). The International Consultation on Sexual Medicine defines AO as the perceived absence of orgasm, independent of the presence of ejaculation. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition, defines delayed orgasm as a marked delay in ejaculation or a marked infrequency or absence of ejaculation on almost all or all occasions (75%–100% of time) of partnered sexual activity without the individual desiring delay, persisting for at least 6 months and causing significant distress to the individual (3American Psychiatric Association, DSM-5 Task ForceDiagnostic and statistical manual of mental disorders: DSM-5. American Psychiatric Association Publishing, Arlington, VA2013Crossref Google Scholar). The sexual dysfunction is not explained by another nonsexual disorder, medication, or significant relation/life distress/stressors. Delayed orgasm is further classified as lifelong/acquired, generalized/situational, and mild/moderate/severe. An acquired dysfunction establishes that the patient previously had normal orgasm timing. Situational dysfunction implies the man has problems in a particular scenario or scenarios, yet functioning normally in others. There is no set time threshold for what defines DO. Time threshold for distress is dependent on the partners involved. Some men will reach orgasm with one partner in 15 minutes and have no distress, but with another partner it may cause severe distress because the partner may complain of pain with prolonged intercourse. A population-based survey established that the median intravaginal ejaculatory latency time (IELT) was 5.4 minutes and 2 SD above was approximately 22 minutes (4Waldinger M.D. Quinn P. Dilleen M. Mundayat R. Schweitzer D.H. Boolell M. A multinational population survey of intravaginal ejaculation latency time.J Sex Med. 2005; 2: 492-497Crossref PubMed Scopus (310) Google Scholar, 5McMahon C.G. Jannini E. Waldinger M. Rowland D. Standard operating procedures in the disorders of orgasm and ejaculation.J Sex Med. 2013; 10: 204-229Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 6Patrick D.L. Althof S.E. Pryor J.L. Rosen R. Rowland D.L. Ho K.F. et al.Premature ejaculation: an observational study of men and their partners.J Sex Med. 2005; 2: 358-367Crossref PubMed Scopus (340) Google Scholar). A provider with a patient complaining of IELT longer than 22 minutes will theoretically qualify him for the diagnosis of DO. One should differentiate between problems with of ejaculation and orgasm. Orgasm is a complex neurobiological process that comes as a result of sexual activity (physical sensation) and/or arousal (cognitive awareness). The physiology of ejaculation is discussed elsewhere. When ejaculation occurs, the brain processes the sensation of the pressure buildup within the posterior urethra (bladder neck and external urinary sphincter are closed contemporaneously) leading up to seminal fluid emission and the contraction of the periurethral musculature. This processing leads to the triggering of an orgasm. Advances in functional neuroimaging have been able to show the location of increased brain activity during orgasm (7Stoleru S. Fonteille V. Cornelis C. Joyal C. Moulier V. Functional neuroimaging studies of sexual arousal and orgasm in healthy men and women: a review and meta-analysis.Neurosci Biobehav Rev. 2012; 36: 1481-1509Crossref PubMed Scopus (206) Google Scholar). Positron emission tomography imaging has demonstrated that sexual stimulation leads to increased activity in the occipitotemporal, anterior cingulated, and insular cortices, as well as bilateral activation in the substantia nigra (8Georgiadis J.R. Reinders A.A. van der Graaf F.H. Paans A.M. Kortekaas R. Brain activation during human male ejaculation revisited.Neuroreport. 2007; 18: 553-557Crossref PubMed Scopus (41) Google Scholar). During orgasm there is a decrease in regional cerebral blood flow across the prefrontal cortex (right medial orbitofrontal, left lateral orbitofrontal, left dorsolateral) and in the left temporal lobe (fusiform gyrus, superior temporal gyrus), as well as increased activation in the left dentate cerebellar nucleus, left lateral midbrain, and right pons (8Georgiadis J.R. Reinders A.A. van der Graaf F.H. Paans A.M. Kortekaas R. Brain activation during human male ejaculation revisited.Neuroreport. 2007; 18: 553-557Crossref PubMed Scopus (41) Google Scholar, 9Georgiadis J.R. Reinders A.A. Paans A.M. Renken R. Kortekaas R. Men versus women on sexual brain function: prominent differences during tactile genital stimulation, but not during orgasm.Hum Brain Mapp. 2009; 30: 3089-3101Crossref PubMed Scopus (78) Google Scholar). The Diagnostic and Statistical Manual of Mental Disorders, 5th edition, states that only 25% of men routinely achieve orgasm in all sexual encounters. According to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, the prevalence remains constant until age 50 years and then the rate steadily increases with men in their 80s complaining twice as much as men less than age 59 years (3American Psychiatric Association, DSM-5 Task ForceDiagnostic and statistical manual of mental disorders: DSM-5. American Psychiatric Association Publishing, Arlington, VA2013Crossref Google Scholar). The increase with age is likely multifactorial and may be related to a combination of changes in penile sensitivity, increased prevalence of T deficiency, increased use of offending medications, decreased exercise tolerance, and reduced partner tolerance for prolonged sexual intercourse. In one study, the prevalence of primary DO was found to be 1.5 in 1,000 and secondary DO in men less than age 65 years was 3%–4% (10Nathan S.G. The epidemiology of the DSM-III psychosexual dysfunctions.J Sex Marital Ther. 1986; 12: 267-281Crossref PubMed Scopus (87) Google Scholar, 11Waldinger M.D. Schweitzer D.H. Retarded ejaculation in men: an overview of psychological and neurobiological insights.World J Urol. 2005; 23: 76-81Crossref PubMed Scopus (55) Google Scholar). Masters and Johnson only reported on 17 cases (12Masters W.H. Johnson V.E. Human sexual inadequacy. Churchill, London1970Google Scholar), Apfelbaum reported 34 cases (13Leiblum S.R. Rosen R. Principles and practice of sex therapy.3rd ed. Guilford Press, New York2000Google Scholar), and Kaplan reported 420 mU/L or 20 ng/mL) generally do not have an impact on sexual function; however, severe hyperprolactinemia (defined as >735 mU/L or 35 ng/mL) can have significant effects on sexual function, including erectile dysfunction and T production suppression (18Buvat J. Hyperprolactinemia and sexual function in men: a short review.Int J Impot Res. 2003; 15: 373-377Crossref PubMed Scopus (103) Google Scholar, 19Corona G. Effect of hyperprolactinemia in male patients consulting for sexual dysfunction.J Sex Med. 2007; 4: 1485-1493Crossref PubMed Scopus (91) Google Scholar, 21Corona G. Psycho-biological correlates of hypoactive sexual desire in patients with erectile dysfunction.Int J Impot Res. 2004; 16: 275-281Crossref PubMed Scopus (87) Google Scholar, 22Balercia G. Sexual symptoms in endocrine diseases: psychosomatic perspectives.Psychother Psychosom. 2007; 76: 134-140Crossref PubMed Scopus (56) Google Scholar). Prolactin secretion is positively influenced by PRL-releasing factors (thyroid-releasing hormone, oxytocin, vasopressin, and vasoactive intestinal peptide) (23Corona G. Jannini E.A. Vignozzi L. Rastrelli G. Maggi M. The hormonal control of ejaculation.Nat Rev Urol. 2012; 9: 508-519Crossref PubMed Scopus (117) Google Scholar). Serotonin is implicated in the control of PRL secretion through serotoninergic inputs from the dorsal raphe nucleus stimulating PRL-releasing factors in the paraventricular nucleus (24Van de Kar L.D. Bethea C.L. Pharmacological evidence that serotonergic stimulation of prolactin secretion is mediated via the dorsal raphe nucleus.Neuroendocrinology. 1982; 35: 225-230Crossref PubMed Scopus (103) Google Scholar). The SSRIs are therefore capable of causing hyperprolactinemia and lead to DO/AO (25Giuliano F. Neurophysiology of erection and ejaculation.J Sex Med. 2011; 8: 310-315Crossref PubMed Scopus (92) Google Scholar). Corona et al. (1Corona G. Jannini E.A. Lotti F. Boddi V. de Vita G. Forti G. et al.Premature and delayed ejaculation: two ends of a single continuum influenced by hormonal milieu.Intern J Androl. 2011; 34: 41-48Crossref PubMed Scopus (97) Google Scholar) identified relationships between ejaculation and PRL, TSH, and T levels. Knowing that DO and premature ejaculation represent two ends of a linear spectrum, it has been shown that PRL and TSH levels progressively increased from patients with premature ejaculation to those with DO, and the opposite was true for T. Some men obtain greater pleasure from masturbation than they do with sexual intercourse and may continue deep-rooted habits such as frequent masturbation or using idiosyncratic masturbation techniques. Studies have shown a correlation between DO and men with idiosyncratic masturbation practices (5McMahon C.G. Jannini E. Waldinger M. Rowland D. Standard operating procedures in the disorders of orgasm and ejaculation.J Sex Med. 2013; 10: 204-229Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 14Perelman M.A. Rowland D.L. Retarded ejaculation.World J Urol. 2006; 24: 645-652Crossref PubMed Scopus (57) Google Scholar). Also, with increasing frequency of masturbation the sensitivity of the penis can decline and lead to a vicious cycle where the man increases masturbation force to counteract the declining sensitivity, therefore leading to worsening DO. Vaginal intercourse or orogenital stimulation may not be able to replicate the stimulation achieved through idiosyncratic masturbation and this may result in reduced penile stimulation leading to difficulty achieving an orgasm (5McMahon C.G. Jannini E. Waldinger M. Rowland D. Standard operating procedures in the disorders of orgasm and ejaculation.J Sex Med. 2013; 10: 204-229Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 14Perelman M.A. Rowland D.L. Retarded ejaculation.World J Urol. 2006; 24: 645-652Crossref PubMed Scopus (57) Google Scholar, 26Rowland D. McMahon C.G. Abdo C. Chen J. Jannini E. Waldinger M.D. et al.Disorders of orgasm and ejaculation in men.J Sex Med. 2010; 7: 1668-1686Crossref PubMed Scopus (206) Google Scholar). Patients with DO have been shown to have higher masturbatory activity, decreased night-time emissions, and lower orgasm and intercourse satisfaction scores on the International Index of Erectile Function (IIEF), as well as higher anxiety and depression scores when compared with controls (27Abdel-Hamid I.A. Saleh el S. Primary lifelong delayed ejaculation: characteristics and response to bupropion.J Sex Med. 2011; 8: 1772-1779Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). In a study by Xia et al. (28Xia J.D. Han Y.F. Pan F. Zhou L.H. Chen Y. Dai Y.T. Clinical characteristics and penile afferent neuronal function in patients with primary delayed ejaculation.Andrology. 2013; 1: 787-792Crossref PubMed Scopus (18) Google Scholar), the investigators compared 24 patients with primary DO and 24 age-matched controls who had no sexual dysfunction complaints. They showed that patients with primary DO had significantly longer IELT (20 vs. 5.5 minutes), higher frequency of masturbation, lower nocturnal emissions, and higher rates of anxiety and depression. They also found that although patients with DO had normal glans sensation, they reported penile shaft hyposensitivity and hypoexcitability. The patients with DO were also found to more commonly use idiosyncratic masturbation methods. Penile sensation loss has been shown to increase with age (29Johnson R.D. Murray F.T. Reduced sensitivity of penile mechanoreceptors in aging rats with sexual dysfunction.Brain Res Bull. 1992; 28: 61-64Crossref PubMed Scopus (23) Google Scholar). In a literature review (13 studies) by Rowland (30Rowland D.L. Penile sensitivity in men: a composite of recent findings.Urology. 1998; 52: 1101-1105Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar), he plotted penile sensory thresholds as a function of age as well as sexual functional status. He found that penile sensation loss was more commonly present in those men with increased age and those with sexual dysfunctions. Lifelong DO has been associated with multiple psychological conditions. Some of these conditions include fear, anxiety, hostility, and relationship difficulties (31Munjack D.J. Kanno P.H. Retarded ejaculation: a review.Arch Sex Behav. 1979; 8: 139-150Crossref PubMed Scopus (42) Google Scholar, 32Shull G.R. Sprenkle D.H. Retarded ejaculation reconceptualization and implications for treatment.J Sex Marital Ther. 1980; 6: 234-246Crossref PubMed Scopus (31) Google Scholar). Fear and anxiety during sexual relations have been examined, and the most common triggers included hurting the woman, impregnating the woman, childhood sexual abuse, sexual trauma, repressive sexual education/religion, sexual anxiety, general anxiety, "spilling of seed," and conflict in men in their first sexual relationship after becoming widowed or divorced (11Waldinger M.D. Schweitzer D.H. Retarded ejaculation in men: an overview of psychological and neurobiological insights.World J Urol. 2005; 23: 76-81Crossref PubMed Scopus (55) Google Scholar). The man may also suffer from a lack in sexual arousal, thus inhibiting his ability to reach orgasm. The man may achieve an erection without reaching adequate arousal to proceed with intercourse, such as men who achieve an erection with the assistance of erectogenic medications. With the assistance of medication, men are more likely to get an erection without significant psychoemotional arousal or the necessary mental/physical stimulation needed to reach orgasm (33Perelman M.A. Regarding ejaculation, delayed and otherwise.J Androl. 2003; 24: 496PubMed Google Scholar, 34Nurnberg H.G. Hensley P.L. Gelenberg A.J. Fava M. Lauriello J. Paine S. Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial.JAMA. 2003; 289: 56-64Crossref PubMed Scopus (201) Google Scholar, 35Perelman M. Sildenafil, sex therapy, and retarded ejaculation.J Sex Educ Ther. 2001; 26: 13-21Crossref Scopus (29) Google Scholar). Delayed orgasm based on situational aspects (i.e., difficulties with a specific partner and not with another) is more likely to be due to a psychological etiology (36Rowland D.L. Psychophysiology of ejaculatory function and dysfunction.World J Urol. 2005; 23: 82-88Crossref PubMed Scopus (27) Google Scholar). One study (37Byun J.S. Lyu S.W. Seok H.H. Kim W.J. Shim S.H. Bak C.W. Sexual dysfunctions induced by stress of timed intercourse and medical treatment.BJU Intern. 2013; 111: E227-E234Crossref PubMed Scopus (13) Google Scholar) looked at stress and anxiety related to timed intercourse demands for fertility treatments and found DO developed in 6% of patients related to elevated anxiety levels. A novel study by Kirby et al. (38Kirby E.D. Geraghty A.C. Ubuka T. Bentley G.E. Kaufer D. Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats.Proc Natl Acad Sci U S A. 2009; 106: 11324-11329Crossref PubMed Scopus (269) Google Scholar) used a rat model to show how stress can suppress the hypothalamic-pituitary-gonadal axis, which is important in healthy normal sexual function. They showed that acute and chronic immobilization stress led to an increase in adrenal glucocorticoids causing an increase in gonadotropin inhibitory hormone, which suppresses the hypothalamic-pituitary-gonadal axis by inhibition of GnRH. There are numerous medications that have been implicated in the genesis of DO including antidepressants (especially SSRIs), antipsychotics, and opioids (3American Psychiatric Association, DSM-5 Task ForceDiagnostic and statistical manual of mental disorders: DSM-5. American Psychiatric Association Publishing, Arlington, VA2013Crossref Google Scholar). In a study by Corona et al. (39Corona G. Ricca V. Bandini E. Mannucci E. Lotti F. Boddi V. et al.Selective serotonin reuptake inhibitor-induced sexual dysfunction.J Sex Med. 2009; 6: 1259-1269Crossref PubMed Scopus (101) Google Scholar), approximately 2,000 male patients were evaluated for the sexual effects of antidepressant therapy. A sevenfold risk for DO was observed in patients taking SSRIs, and they had a twofold risk of low libido. In a study by Clayton et al. (40Clayton A.H. Croft H.A. Horrigan J.P. Wightman D.S. Krishen A. Richard N.E. et al.Bupropion extended release compared with escitalopram: effects on sexual functioning and antidepressant efficacy in 2 randomized, double-blind, placebo-controlled studies.J Clin Psychiatry. 2006; 67: 736-746Crossref PubMed Scopus (119) Google Scholar), the effects on sexual functioning and antidepressant efficacy of bupropion extended release was compared with escitalopram. The incidence of orgasm dysfunction and worsened sexual function at week 8 was statistically significantly higher in the escitalopram (30%) versus the bupropion (15%) and the escitalopram (30%) versus placebo (9%) groups, but not statistically significant in the bupropion (15%) versus placebo (9%) groups. Management should begin with a good medical/psychosexual history, social/religious history, medication list, and physical examination. Focusing on the major etiologic factors (as listed previously) is a useful starting point. Medication history should focus on SSRI agents and other psychotropic agents, and define the onset of the use of the medication as it pertains to the timing of onset of DO. Asking about penile sensitivity is a useful question, especially in men at risk for penile sensation loss such as diabetics. Symptoms and signs of endocrinopathies, such as T deficiency, hypothyroidism, and hyperprolactinemia, should be sought. Masturbatory style is another useful line of inquiry as frequent masturbation or idiosyncratic masturbatory styles may lead to DO. Defining relationship status, satisfaction, and the role external stressors may be playing in the DO genesis is also important. Furthermore, identifying the onset of the DO is critical, whether lifelong or acquired. Next, understanding whether the condition is generalized or situational is also critical to understanding the pathophysiology. Asking patients to describe a typical sexual encounter is often a useful ploy to unearth potential contributing factors. Defining the consistency of the problem, that is: "Does it happen all the time or only some of the time? with sexual intercourse and sexual outercourse with a partner and how this differs between partner-based relations and masturbation. For example, men who achieve orgasm with masturbation but have difficulty with partner-based relations often have one of two factors as causes—loss of penile sensitivity (overcome by vigorous masturbation) or psychological issues (interpersonal conflict, fear, anxiety, or hostility). Inquiring about how long a man attempts relations before stopping may also provide valuable insight into the problem. Some older men, due to inadequate exercise reserve of upper body strength, cease sexual relations sooner than they did when they were younger and thus interpret this as DO. Finally, asking about strategies or medications that have been tried previously for this problem will aid in plotting a course of treatment. The role of laboratory testing, such T and TSH levels, is optional and is applied depending on patient symptoms. If laboratory values are abnormal, endocrine function should be corrected. As shown by Carani et al. (15Carani C. Isidori A.M. Granata A. Carosa E. Maggi M. Lenzi A. et al.Multicenter study on the prevalence of sexual symptoms in male hypo- and hyperthyroid patients.J Clin Endocrinol Metab. 2005; 90: 6472-6479Crossref PubMed Scopus (270) Google Scholar), with correction of thyroid hormone levels, patients had significant improvements in DO. After thyroid hormone treatment and normalization of laboratory values, half of the hypothyroid patients reported that their DO improved, and IELT improved from 22–7 minutes. In patients complaining of loss of penile sensitivity, biothesiometry (Fig. 1) and/or pudendal somatosensory-evoked potential (SSEP) might be warranted (5McMahon C.G. Jannini E. Waldinger M. Rowland D. Standard operating procedures in the disorders of orgasm and ejaculation.J Sex Med. 2013; 10: 204-229Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). Biothesiometry examines the sensory threshold of vibratory tactile stimulation. Pudendal somatosensory-evoked potential evaluates the afferent activity from the dorsal nerve of the penis toward the brain. Sympathetic skin testing is another test that allows the evaluation of sympathetic efferent flow to the skin of the genitals. Last, sacral reflex arc testing examines the motor and sensory branches of the pudendal nerve and nerve roots S2, S3, and S4 (41Montorsi F. Basson R. Adaikan G. Becher E. Clayton A. Giuliano F. et al.Sexual medicine sexual dysfunctions in men and womenInternational consultation on urological diseases.2010 ed. International Society for Sexual Medicine, Paris2010Google Scholar). It is true that some men with DO/AO never have an etiology diagnosed that reflects our limited understanding of the physiology of orgasm and the pathophysiology of these conditions (Fig. 2). Therapy is focused on defining and treating any overt underlying causes often in conjunction with psychotherapy. Various lifestyle changes include steps to improve intimacy, reduce masturbation frequency, change of masturbation style, and decreasing alcohol consumption (5McMahon C.G. Jannini E. Waldinger M. Rowland D. Standard operating procedures in the disorders of orgasm and ejaculation.J Sex Med. 2013; 10: 204-229Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 11Waldinger M.D. Schweitzer D.H. Retarded ejaculation in men: an overview of psychological and neurobiological insights.World J Urol. 2005; 23: 76-81Crossref PubMed Scopus (55) Google Scholar). Once the organic
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