Management of Persistent Erectile Dysfunction after COVID-19 Infection: An 18-Month Follow-Up Case Report
Abstract
:1. Introduction
2. Patients and Methods
3. Results
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Wiersinga, W.J.; Rhodes, A.; Cheng, A.C.; Peacock, S.J.; Prescott, H.C. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA 2020, 324, 782–793. [Google Scholar] [CrossRef] [PubMed]
- Chen, N.; Zhou, M.; Dong, X.; Qu, J.; Gong, F.; Han, Y.; Qiu, Y.; Wang, J.; Liu, Y.; Wei, Y.; et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020, 395, 507–513. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bernard, I.; Limonta, D.; Mahal, L.K.; Hobman, T.C. Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19. Viruses 2020, 13, 29. [Google Scholar] [CrossRef] [PubMed]
- Harrison, A.G.; Lin, T.; Wang, P. Mechanisms of SARS-CoV-2 Transmission and Pathogenesis. Trends Immunol. 2020, 41, 1100–1115. [Google Scholar] [CrossRef]
- La Vignera, S.; Cannarella, R.; Condorelli, R.A.; Torre, F.; Aversa, A.; Calogero, A.E. Sex-Specific SARS-CoV-2 Mortality: Among Hormone-Modulated ACE2 Expression, Risk of Venous Thromboembolism and Hypovitaminosis D. Int. J. Mol. Sci. 2020, 21, 2948. [Google Scholar] [CrossRef]
- Oran, D.P.; Topol, E.J. Prevalence of Asymptomatic SARS-CoV-2 Infection: A Narrative Review. Ann. Intern. Med. 2020, 173, 362–367. [Google Scholar] [CrossRef]
- Crocerossa, F.; Visser, W.; Carbonara, U.; Falagario, U.G.; Pandolfo, S.D.; Loizzo, D.; Imbimbo, C.; Klausner, A.P.; Porpiglia, F.; Damiano, R.; et al. The impact the COVID-19 pandemic on urology literature: A bibliometric analysis. Cent. Eur. J. Urol. 2022, 75, 102–109. [Google Scholar] [CrossRef]
- Sansone, A.; Mollaioli, D.; Ciocca, G.; Limoncin, E.; Colonnello, E.; Vena, W.; Jannini, E.A. Addressing male sexual and reproductive health in the wake of COVID-19 outbreak. J. Endocrinol. Invest. 2021, 44, 223–231. [Google Scholar] [CrossRef]
- Hu, B.; Ruan, Y.; Liu, K.; Wei, X.; Wu, Y.; Feng, H.; Deng, Z.; Liu, J.; Wang, T. A Mid-to-Long Term Comprehensive Evaluation of Psychological Distress and Erectile Function in COVID-19 Recovered Patients. J. Sex Med. 2021, 18, 1863–1871. [Google Scholar] [CrossRef]
- Vaccaro, M.G.; Izzo, G.; Sarica, A.; La Vignera, S.; Aversa, A. Cluster Analysis Method Reveals Gender Attitudes in Sociosexual Orientation of a Southern Italy Population During the COVID-19 Lockdown. Sex Res. Social Policy 2022, 24, 1–14. [Google Scholar] [CrossRef]
- Salonia, A.; Bettocchi, C.; Boeri, L.; Capogrosso, P.; Carvalho, J.; Cilesiz, N.C.; Cocci, A.; Corona, G.; Dimitropoulos, K.; Gül, M.; et al. European Association of Urology Guidelines on Sexual and Reproductive Health-2021 Update: Male Sexual Dysfunction. Eur. Urol. 2021, 80, 333–357. [Google Scholar] [CrossRef]
- Yafi, F.A.; Jenkins, L.; Albersen, M.; Corona, G.; Isidori, A.M.; Goldfarb, S.; Maggi, M.; Nelson, C.J.; Parish, S.; Salonia, A.; et al. Erectile dysfunction. Nat. Rev. Dis. Prim. 2016, 2, 16003. [Google Scholar] [CrossRef] [Green Version]
- Sansone, A.; Mollaioli, D.; Ciocca, G.; Colonnello, E.; Limoncin, E.; Balercia, G.; Jannini, E.A. “Mask up to keep it up”: Preliminary evidence of the association between erectile dysfunction and COVID-19. Andrology 2021, 9, 1053–1059. [Google Scholar] [CrossRef]
- Kresch, E.; Achua, J.; Saltzman, R.; Khodamoradi, K.; Arora, H.; Ibrahim, E.; Kryvenko, O.N.; Almeida, V.W.; Firdaus, F.; Hare, J.M.; et al. COVID-19 Endothelial Dysfunction Can Cause Erectile Dysfunction: Histopathological, Immunohistochemical, and Ultrastructural Study of the Human Penis. World J. Mens Health 2021, 39, 466–469. [Google Scholar] [CrossRef]
- Kaynar, M.; Gomes, A.L.Q.; Sokolakis, I.; Gül, M. Tip of the iceberg: Erectile dysfunction and COVID-19. Int. J. Impot. Res. 2022, 34, 152–157. [Google Scholar] [CrossRef]
- Pizzol, D.; Shin, J.I.; Trott, M.; Ilie, P.C.; Ippoliti, S.; Carrie, A.M.; Ghayda, R.A.; Lozano, J.M.O.; Muyor, J.M.; Butler, L.; et al. Social environmental impact of COVID-19 and erectile dysfunction: An explorative review. J. Endocrinol. Invest. 2022, 45, 483–487. [Google Scholar] [CrossRef]
- Adeyemi, D.H.; Odetayo, A.F.; Hamed, M.A.; Akhigbe, R.E. Impact of COVID 19 on erectile function. Aging Male 2022, 25, 202–216. [Google Scholar] [CrossRef]
- Jannini, E.A.; McCabe, M.P.; Salonia, A.; Montorsi, F.; Sachs, B.D. Organic vs. psychogenic? The Manichean diagnosis in sexual medicine. J. Sex. Med. 2010, 7, 1726–1733. [Google Scholar] [CrossRef]
- De Leonardis, F.; Colalillo, G.; Finazzi Agrò, E.; Miano, R.; Fuschi, A.; Asimakopoulos, A.D. Endothelial Dysfunction, Erectile Deficit and Cardiovascular Disease: An Overview of the Pathogenetic Links. Biomedicines 2022, 10, 1848. [Google Scholar] [CrossRef]
- Barthelmes, J.; Nägele, M.P.; Ludovici, V.; Ruschitzka, F.; Sudano, I.; Flammer, A.J. Endothelial dysfunction in cardiovascular disease and Flammer syndrome—Similarities and differences. EPMA J. 2017, 8, 99–109. [Google Scholar] [CrossRef]
- Neumann, P.; Gertzberg, N.; Johnson, A. TNF-alpha induces a decrease in eNOS promoter activity. Am. J. Physiol. Lung Cell. Mol. Physiol. 2004, 286, L452–L459. [Google Scholar] [CrossRef] [PubMed]
- Ma, L.; Xie, W.; Li, D.; Shi, L.; Mao, Y.; Xiong, Y.; Zhang, Y.; Zhang, M. Effect of SARS-CoV-2 infection upon male gonadal function: A single center-based study. medRxiv 2020. [Google Scholar] [CrossRef] [Green Version]
- Okçelik, S. COVID-19 pneumonia causes lower testosterone levels. Andrologia 2021, 53, e13909. [Google Scholar] [CrossRef] [PubMed]
- Magadum, A.; Kishore, R. Cardiovascular Manifestations of COVID-19 Infection. Cells 2020, 9, 2508. [Google Scholar] [CrossRef] [PubMed]
- Graney, B.A.; Wamboldt, F.S.; Baird, S.; Churney, T.; Fier, K.; Korn, M.; McCormick, M.; Vierzba, T.; Swigris, J.J. Looking ahead and behind at supplemental oxygen: A qualitative study of patients with pulmonary fibrosis. Heart Lung 2017, 46, 387–393. [Google Scholar] [CrossRef]
- Sansone, A.; Mollaioli, D.; Limoncin, E.; Ciocca, G.; Bắc, N.H.; Cao, T.N.; Hou, G.; Yuan, J.; Zitzmann, M.; Giraldi, A.; et al. The Sexual Long COVID (SLC): Erectile Dysfunction as a Biomarker of Systemic Complications for COVID-19 Long Haulers. Sex Med. Rev. 2022, 10, 271–285. [Google Scholar] [CrossRef]
- Romano, L.; Pellegrino, R.; Sciorio, C.; Barone, B.; Gravina, A.G.; Santonastaso, A.; Mucherino, C.; Astretto, S.; Napolitano, L.; Aveta, A.; et al. Erectile and sexual dysfunction in male and female patients with celiac disease: A cross-sectional observational study. Andrology 2022, 10, 910–918. [Google Scholar] [CrossRef]
- Apolone, G.; Mosconi, P. The Italian SF-36 Health Survey: Translation, validation and norming. J. Clin. Epidemiol. 1998, 51, 1025–1036. [Google Scholar] [CrossRef]
- Cappelleri, J.C.; Rosen, R.C.; Smith, M.D.; Mishra, A.; Osterloh, I.H. Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology 1999, 54, 346–351. [Google Scholar] [CrossRef]
- Rosen, R.C.; Cappelleri, J.C.; Smith, M.D.; Lipsky, J.; Peña, B.M. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int. J. Impot. Res. 1999, 11, 319–326. [Google Scholar] [CrossRef]
- Steidle, C.P.; McCullough, A.R.; Kaminetsky, J.C.; Crowley, A.R.; Siegel, R.L.; Deriesthal, H.; Tseng, L.J. Early sildenafil dose optimization and personalized instruction improves the frequency, flexibility, and success of sexual intercourse in men with erectile dysfunction. Int. J. Impot. Res. 2007, 19, 154–160. [Google Scholar] [CrossRef] [Green Version]
- Aversa, A.; Crafa, A.; Alessandra Greco, E.; Chiefari, E.; Brunetti, A.; La Vignera, S. The Penile Duplex Ultrasound: How and when to perform it? Andrology 2021, 9, 1457–1466. [Google Scholar] [CrossRef]
- Vena, W.; Vaccalluzzo, L.; Morenghi, E.; D’Agostino, C.; Perri, A.; Giammusso, B.; Lania, A.G.; Aversa, A.; Pizzocaro, A. Low-intensity shockwave treatment (liswt) improves penile rigidity in eugonadal subjects with erectile dysfunction: A pilot study. Minerva Endocrinol. 2021. [Google Scholar] [CrossRef]
- Groff, D.; Sun, A.; Ssentongo, A.E.; Ba, D.M.; Parsons, N.; Poudel, G.R.; Lekoubou, A.; Oh, J.S.; Ericson, J.E.; Ssentongo, P.; et al. Short-term and Long-term Rates of Postacute Sequelae of SARS-CoV-2 Infection: A Systematic Review. JAMA Netw. Open 2021, 4, e2128568. [Google Scholar] [CrossRef]
- Moncada, I.; Martinez-Salamanca, J.; Ruiz-Castañe, E.; Romero, J. Combination therapy for erectile dysfunction involving a PDE5 inhibitor and alprostadil. Int. J. Impot. Res. 2018, 30, 203–208. [Google Scholar] [CrossRef]
- McMahon, C.N.; Smith, C.J.; Shabsigh, R. Treating erectile dysfunction when PDE5 inhibitors fail. BMJ Clin. Res. Ed. 2006, 332, 589–592. [Google Scholar] [CrossRef] [Green Version]
- Herrero, A.; Marcos, M.; Galindo, P.; Miralles, J.M.; Corrales, J.J. Clinical and biochemical correlates of male hypogonadism in type 2 diabetes. Andrology 2018, 6, 58–63. [Google Scholar] [CrossRef] [Green Version]
- Aversa, A.; Basciani, S.; Visca, P.; Arizzi, M.; Gnessi, L.; Frajese, G.; Fabbri, A. Platelet-derived growth factor (PDGF) and PDGF receptors in rat corpus cavernosum: Changes in expression after transient in vivo hypoxia. J. Endocrinol. 2001, 170, 395–402. [Google Scholar] [CrossRef] [Green Version]
- Hellstrom, W.J.; Elhilali, M.; Homering, M.; Taylor, T.; Gittleman, M. Vardenafil in patients with erectile dysfunction: Achieving treatment optimization. J. Androl. 2005, 26, 604–609. [Google Scholar] [CrossRef]
- Albersen, M.; Mwamukonda, K.B.; Shindel, A.W.; Lue, T.F. Evaluation and treatment of erectile dysfunction. Med. Clin. North Am. 2011, 95, 201–212. [Google Scholar] [CrossRef]
- Hackett, G.; Kirby, M.; Wylie, K.; Heald, A.; Ossei-Gerning, N.; Edwards, D.; Muneer, A. British Society for Sexual Medicine Guidelines on the Management of Erectile Dysfunction in Men-2017. J. Sex Med. 2018, 15, 430–457. [Google Scholar] [CrossRef] [PubMed]
- Eardley, I.; Cartledge, J. Tadalafil (Cialis) for men with erectile dysfunction. Int. J. Clin. Pract. 2002, 56, 300–304. [Google Scholar] [PubMed]
- Porst, H.; Padma-Nathan, H.; Giuliano, F.; Anglin, G.; Varanese, L.; Rosen, R. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: A randomized controlled trial. Urology 2003, 62, 121–125. [Google Scholar] [CrossRef] [PubMed]
- Li, H.J.; Bai, W.J.; Dai, Y.T.; Xu, W.P.; Wang, C.N.; Li, H.Z. An analysis of treatment preferences and sexual quality of life outcomes in female partners of Chinese men with erectile dysfunction. Asian J. Androl. 2016, 18, 773–779. [Google Scholar] [CrossRef]
- McMahon, C. Efficacy and safety of daily tadalafil in men with erectile dysfunction previously unresponsive to on-demand tadalafil. J. Sex. Med. 2004, 1, 292–300. [Google Scholar] [CrossRef]
- Albersen, M.; Joniau, S.; Claes, H.; Van Poppel, H. Preclinical Evidence for the Benefits of Penile Rehabilitation Therapy following Nerve-Sparing Radical Prostatectomy. Adv. Urol. 2008, 2008, 594868. [Google Scholar] [CrossRef] [Green Version]
- Aversa, A.; Greco, E.; Bruzziches, R.; Pili, M.; Rosano, G.; Spera, G. Relationship between chronic tadalafil administration and improvement of endothelial function in men with erectile dysfunction: A pilot study. Int. J. Impot. Res. 2007, 19, 200–207. [Google Scholar] [CrossRef]
- Frairia, R.; Berta, L. Biological effects of extracorporeal shock waves on fibroblasts. A review. Muscles Ligaments Tendons J. 2011, 1, 138–147. [Google Scholar]
- Pons, S.; Fodil, S.; Azoulay, E.; Zafrani, L. The vascular endothelium: The cornerstone of organ dysfunction in severe SARS-CoV-2 infection. Crit. Care 2020, 24, 353. [Google Scholar] [CrossRef]
- Smilowitz, N.R.; Kunichoff, D.; Garshick, M.; Shah, B.; Pillinger, M.; Hochman, J.S.; Berger, J.S. C-reactive protein and clinical outcomes in patients with COVID-19. Eur. Heart J. 2021, 42, 2270–2279. [Google Scholar] [CrossRef]
- Willems, L.H.; Nagy, M.; Ten Cate, H.; Spronk, H.M.H.; Groh, L.A.; Leentjens, J.; Janssen, N.A.F.; Netea, M.G.; Thijssen, D.H.J.; Hannink, G.; et al. Sustained inflammation, coagulation activation and elevated endothelin-1 levels without macrovascular dysfunction at 3 months after COVID-19. Thromb. Res. 2022, 209, 106–114. [Google Scholar] [CrossRef]
- Perri, A.; Bossio, S.; Rago, V.; Greco, E.A.; Lofaro, D.; Aversa, A. NLRP3-inflammasome activation in male reproductive system diseases. Minerva Endocrinol. 2022, 14, 5323. [Google Scholar] [CrossRef]
- Bikdeli, B.; Madhavan, M.V.; Jimenez, D.; Chuich, T.; Dreyfus, I.; Driggin, E.; Nigoghossian, C.; Ageno, W.; Madjid, M.; Guo, Y.; et al. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review. J. Am. Coll. Cardiol. 2020, 75, 2950–2973. [Google Scholar] [CrossRef]
- Harirugsakul, K.; Wainipitapong, S.; Phannajit, J.; Paitoonpong, L.; Tantiwongse, K. Erectile dysfunction after COVID-19 recovery: A follow-up study. PLoS ONE 2022, 17, e0276429. [Google Scholar] [CrossRef]
- Ottaviano, G.; Zuccarello, D.; Frasson, G.; Scarpa, B.; Nardello, E.; Foresta, C.; Marioni, G.; Staffieri, A. Olfactory sensitivity and sexual desire in young adult and elderly men: An introductory investigation. Am. J. Rhinol. Allergy 2013, 27, 157–161. [Google Scholar] [CrossRef]
- Siegel, J.K.; Kung, S.Y.; Wroblewski, K.E.; Kern, D.W.; McClintock, M.K.; Pinto, J.M. Olfaction Is Associated With Sexual Motivation and Satisfaction in Older Men and Women. J. Sex. Med. 2021, 18, 295–302. [Google Scholar] [CrossRef]
- Bertolo, R.; Cipriani, C.; Bove, P. Anosmia and ageusia: A piece of the puzzle in the etiology of COVID-19-related transitory erectile dysfunction. J. Endocrinol. Invest. 2021, 44, 1123–1124. [Google Scholar] [CrossRef]
- Crafa, A.; Cannarella, R.; Condorelli, R.A.; La Vignera, S.; Calogero, A.E. Is There an Association Between Vitamin D Deficiency and Erectile Dysfunction? A Systematic Review and Meta-Analysis. Nutrients 2020, 12, 1411. [Google Scholar] [CrossRef]
- Crafa, A.; Cannarella, R.; Condorelli, R.A.; Mongioì, L.M.; Barbagallo, F.; Aversa, A.; La Vignera, S.; Calogero, A.E. Influence of 25-hydroxy-cholecalciferol levels on SARS-CoV-2 infection and COVID-19 severity: A systematic review and meta-analysis. Eclinical Med. 2021, 37, 100967. [Google Scholar] [CrossRef]
- Mirhosseini, N.; Rainsbury, J.; Kimball, S.M. Vitamin D Supplementation, Serum 25(OH)D Concentrations and Cardiovascular Disease Risk Factors: A Systematic Review and Meta-Analysis. Front. Cardiovasc. Med. 2018, 5, 87. [Google Scholar] [CrossRef] [Green Version]
- Jamali, N.; Sorenson, C.M.; Sheibani, N. Vitamin D and regulation of vascular cell function. Am. J. Physiol. -Heart Circ. Physiol. 2018, 314, H753–H765. [Google Scholar] [CrossRef]
- Rastogi, A.; Bhansali, A.; Khare, N.; Suri, V.; Yaddanapudi, N.; Sachdeva, N.; Puri, G.D.; Malhotra, P. Short term, high-dose vitamin D supplementation for COVID-19 disease: A randomised, placebo-controlled, study (SHADE study). Postgrad. Med. J. 2022, 98, 87–90. [Google Scholar] [CrossRef]
- Krajewska, M.; Witkowska-Sędek, E.; Rumińska, M.; Stelmaszczyk-Emmel, A.; Sobol, M.; Majcher, A.; Pyrżak, B. Vitamin D Effects on Selected Anti-Inflammatory and Pro-Inflammatory Markers of Obesity-Related Chronic Inflammation. Front. Endocrinol. 2022, 13, 920340. [Google Scholar] [CrossRef]
- Yang, C.-Y.; Leung, P.S.C.; Adamopoulos, I.E.; Gershwin, M.E. The Implication of Vitamin D and Autoimmunity: A Comprehensive Review. Clin. Rev. Allergy Immunol. 2013, 45, 217–226. [Google Scholar] [CrossRef]
- Zhang, J.; Shi, W.; Zou, M.; Zeng, Q.; Feng, Y.; Luo, Z.; Gan, H. Prevalence and risk factors of erectile dysfunction in COVID-19 patients: A systematic review and meta-analysis. J. Endocrinol. Investig. 2022, 1–10. [Google Scholar] [CrossRef] [PubMed]
Hormone | Normal Range (Age Related) | T0 | T1 (6 Months) | T2 (12 Months) | T3 (18 Months) |
---|---|---|---|---|---|
Total Testosterone | 13–33 nmol/L | 21.1 | 19.9 | 19.8 | 20.2 |
Free Testosterone | 0.17–0.66 nmol/L | 0.65 | 0.60 | 0.60 | 0.62 |
Luteinizing Hormone (LH) | 1.8–12.0 mUI/mL | 6.3 | 7.1 | 6.9 | 7.6 |
Follicle-stimulating Hormone (FSH) | 1.4–15.4 UI/L | 7.2 | 6.3 | 6.2 | 6.7 |
Estradiol | 10–45 pg/mL | 12.0 | 13.2 | 12.7 | 13.2 |
Sex-hormon binding-globulin (SHBG) | 10–57 nmol/L | 15.0 | 16.2 | 15.9 | 15.4 |
Vitamin D | 30–150 ng/dL | 14.2 | 23.2 | 33.4 | 47.2 |
Marker | Normal Range | T0 | T1 (6 Months) | T2 (12 Months) | T3 (18 Months) |
---|---|---|---|---|---|
Endothelin-1 | 0.87–1.61 pg/ml | 1.8 | 1.6 | 1.2 | 1.0 |
C-Reactive Protein (CRP) | <5.0 mg/L | 8.8 | 6.2 | <5.0 | <5.0 |
Questionnaire | Normal Scores (%) | T0 | T1 (6 Months) | T2 (12 Months) | T3 (18 Months) | |
---|---|---|---|---|---|---|
SF-36 | Vitality | 100 | 70 | 70 | 80 | 85 |
Social functioning | 100 | 37.5 | 62.5 | 100 | 100 | |
Role-emotional | 100 | 100 | 100 | 100 | 100 | |
Mental Health | 100 | 72 | 76 | 88 | 96 | |
Physical functioning | 100 | 90 | 95 | 100 | 100 | |
Role-Physical | 100 | 75 | 100 | 100 | 100 | |
Bodily pain | 100 | 77,5 | 77,5 | 100 | 100 | |
General Health | 100 | 65 | 70 | 75 | 90 | |
IEEF-5 | ≥22 | 13 | 17 | 20 | 23 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Iuliano, S.; Seminara, G.; Zagari, M.C.; Di Luigi, L.; Aversa, A. Management of Persistent Erectile Dysfunction after COVID-19 Infection: An 18-Month Follow-Up Case Report. Sexes 2023, 4, 55-64. https://doi.org/10.3390/sexes4010006
Iuliano S, Seminara G, Zagari MC, Di Luigi L, Aversa A. Management of Persistent Erectile Dysfunction after COVID-19 Infection: An 18-Month Follow-Up Case Report. Sexes. 2023; 4(1):55-64. https://doi.org/10.3390/sexes4010006
Chicago/Turabian StyleIuliano, Stefano, Giuseppe Seminara, Maria Carmela Zagari, Luigi Di Luigi, and Antonio Aversa. 2023. "Management of Persistent Erectile Dysfunction after COVID-19 Infection: An 18-Month Follow-Up Case Report" Sexes 4, no. 1: 55-64. https://doi.org/10.3390/sexes4010006