MALE AND FEMALE SEXUAL FUNCTION AND DYSFUNCTION; ANDROLOGY

Re: Functional and Taxonomic Dysbiosis of the Gut, Urine, and Semen
Microbiomes in Male Infertility
S. D. Lundy, N. Sangwan, N. V. Parekh, M. N. Panner Selvam, S. Gupta, P. McCaffrey,
K. Bessoff, A. Vala, A. Agarwal, E. S. Sabanegh, S. C. Vij and C. Eng
Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio Genomic Medicine Institute, Lerner Research
Institute, Cleveland Clinic, Cleveland, Ohio, Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio,
Vastbiome, Millbrae, California, and Department of Genetics and Genome Sciences and Germline High Risk Cancer Focus Group, Case Comprehensive
Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
Eur Urol 2021; 79: 826e836.

Editorial Comment: Humans carry many microbial passengers: they in fact outnumber human
cells by about 10 to 1. Investigators now have the molecular and computational tools to assess our
little hitchhikers in health and disease, and these authors did just that with 25 men with primary
infertility and 12 healthy men with proven paternity. They collected rectal swabs, semen, urine and
controls. With these kinds of studies, like the epigenome, researchers seek patterns that are similar
in subjects with disease and that are different from those who are healthy. In this study, the investigators did find a microbial fingerprint in the semen that was somewhat similar to that in the
urine and that somewhat distinguished infertile from fertile men. Interestingly, vasectomy appeared
to alter the microbiome, indicating that the testis or epididmyis likely contributed to it. With
increasingly sophisticated tools, we’re finding that our microbial tourists play an important role in
disease, and that includes infertility.
Craig Niederberger, MD

Male and Female Sexual Function and Dysfunction; Andrology

Re: Sperm Count and Hypogonadism as Markers of General
Male Health
A. Ferlin, A. Garolla, M. Ghezzi, R. Selice, P. Palego, N. Caretta, A. Di Mambro, U. Valente,
M. De Rocco Ponce, S. Dipresa, L. Sartori, M. Plebani and C. Foresta
Unit of Endocrinology and Metabolism, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy, Unit of Andrology and

Reproductive Medicine, Department of Medicine, University of Padova, Padova, Italy, Department of Medicine, Clinica Medica I, University of Padova,
Padova, Italy, and Unit of Laboratory Medicine, Department of Medicine, University of Padova, Padova, Italy
Eur Urol Focus 2021; 7: 205e213.

Editorial Comment: The authors tested the provocative hypothesis as to whether semen quality
and reproductive function could represent a marker of general male health in a retrospective study of
5,177 individuals from a prospectively collected database of 11,516 males of infertile couples who had
semen analysis in a tertiary university center. Data included reproductive hormones, testis ultrasound, and biochemical determinations for glucose and lipid metabolism. The average patient age
was 31.7Ỉ7.9 years.
Men with a low sperm count (<39 million/ejaculate) are at a high risk of hypogonadism (OR 12.2,
95% confidence interval [CI] 10.2e14.6) and have higher body mass index, waist circumference,
systolic pressure, low-density lipoprotein cholesterol, triglycerides, and homeostatic model assessment index; lower high-density lipoprotein cholesterol; and a higher prevalence of metabolic syndrome (OR 1.246, 95 CI 1.005e1.545). All data are worse in men with hypogonadism, but a low sperm
count per se is associated with a poor metabolic parameter. Men with hypogonadism have lower bone
mineral density and 51% prevalence of osteoporosis/osteopenia.

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Please note that this is a young patient cohort. Azoospermic patients are more likely to experience
worse metabolic parameters such as blood pressure, body mass index etc, and lower sperm counts.
Interesting data.

Suggested Reading
Krzastek SC, Sharma D, Abdullah N et al: Long-term safety and efficacy of clomiphene citrate for the treatment of hypogonadism. J Urol 2019; 202: 1029.


Re: Testosterone Treatment to Prevent or Revert Type 2 Diabetes in Men
Enrolled in a Lifestyle Programme (T4DM): A Randomised, Double-Blind,
Placebo-Controlled, 2-Year, Phase 3b Trial
G. Wittert, K. Bracken, K. P. Robledo, M. Grossmann, B. B. Yeap, D. J. Handelsman,
B. Stuckey, A. Conway, W. Inder, R. McLachlan, C. Allan, D. Jesudason, M. Ng Tang Fui,
W. Hague, A. Jenkins, M. Daniel, V. Gebski and A. Keech
Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, South Australia, Australia, South Australian Health and
Medical Research Institute, Adelaide, South Australia, Australia, NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South
Wales, Australia, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia, Department of Endocrinology, Austin Health,
Melbourne, Victoria, Australia, Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Western Australia, Australia, Medical
School, University of Western Australia, Perth, Western Australia, Australia, ANZAC Research Institute, Concord Hospital, University of Sydney,
Sydney, New South Wales, Australia, Medical School, University of Western Australia, Perth, Western Australia, Australia, Keogh Institute for
Medical Research, Perth, Western Australia, Australia, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Western
Australia, Australia, Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane, Queensland, Australia, Faculty of
Medicine, The University of Queensland, Brisbane, Queensland, Australia, Hudson Institute of Medical Research and Monash University,
Clayton, Victoria, Australia, Department of Endocrinology, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia, Department of
Medicine, University of Melbourne, Melbourne, Victoria, Australia, and Health Research Institute, University of Canberra, Canberra, Australian
Capital Territory, Australia
Lancet Diabetes Endocrinol 2021; 9: 32e45.

Editorial Comment: Men who are overweight or obese frequently have low serum testosterone
concentrations, which are associated with increased risk of type 2 diabetes. The authors aimed to
determine whether testosterone treatment prevents progression to or reverses early type 2 diabetes,
beyond the effects of a community-based lifestyle program.
The study was termed “testosterone treatment to prevent or revert type 2 diabetes in men enrolled
in a lifestyle program” (T4DM). The study of 19,022 men took place between February 5, 2013 and
February 27, 2017. It was a randomized, double-blind, placebo-controlled, 2-year, phase 3b trial done
at 6 Australian tertiary care centers. Men aged 50e74 years with a waist circumference of 95 cm or
higher, a serum testosterone concentration of 14.0 nmol/L or lower but without pathological hypogonadism, and impaired glucose tolerance (oral glucose tolerance test 2-hour glucose 7.8e11.0 mmol/L)

or newly diagnosed type 2 diabetes (provided oral glucose tolerance test 2-hour glucose 15.0 mmol/L)
were enrolled in a lifestyle program and randomly assigned (1:1) to receive an intramuscular injection
of testosterone undecanoate (1,000 mg) or placebo at baseline, 6 weeks, and then every 3 months for 2
years.
Testosterone treatment for 2 years reduced the proportion of participants with type 2 diabetes
beyond the effects of a lifestyle program. Increases in hematocrit might be treatment limiting.
Longer-term durability, safety, and cardiovascular effects of the intervention remain to be further
investigated. Timely data.

Suggested Reading
Mulhall JP, Trost LW, Brannigan RE et al: Evaluation and management of testosterone deficiency: AUA guideline. J Urol 2018; 200: 423.

Copyright © 2021 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.


MALE AND FEMALE SEXUAL FUNCTION AND DYSFUNCTION; ANDROLOGY

Re: Transdermal Testosterone Attenuates Drug-Induced Lengthening of Both
Early and Late Ventricular Repolarization in Older Men
E. Tomaselli Muensterman, H. A. Jaynes, K. M. Sowinski, B. R. Overholser, C. Shen,
R. J. Kovacs and J. E. Tisdale
College of Pharmacy, Purdue University, Indianapolis, Indiana, Division of Clinical Pharmacology, School of Medicine, Indiana University, Indianapolis,
Indiana, The Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, and Krannert Institute of Cardiology, School of Medicine, Indiana University, Indianapolis, Indiana
Clin Pharmacol Ther 2021; 109: 1499e1504.

Editorial Comment: The authors have previously reported that transdermal testosterone attenuates drug-induced QT interval lengthening in older men. However, it is unknown whether this is due
to modulation of early ventricular repolarization, late repolarization, or both. In a secondary analysis
of a prospective, randomized, double-blind, placebo-controlled 3-way crossover study, the authors
determined if transdermal testosterone and oral progesterone attenuate drug-induced lengthening of
early and late ventricular repolarization, represented by the electrocardiographic measurements.

Male volunteers !65 years of age (14) were randomized to receive transdermal testosterone
100 mg, oral progesterone 400 mg, or matching transdermal/oral placebo daily for 7 days. On the
morning following the seventh day, subjects received intravenous ibutilide 0.003 mg/kg, after which
electrocardiograms were performed serially.
Transdermal testosterone attenuates drug-induced lengthening of both early and late ventricular
repolarization in older men. Important data.

Re: Testosterone Ameliorates Age-Related Brain Mitochondrial Dysfunction
W. Yan, T. Zhang, Y. Kang, G. Zhang, X. Ji, X. Feng and G. Shi
Department of Neurobiology, Hebei Medical University, Shijiazhuang, China, Neuroscience Research Center, Hebei Medical University, Shijiazhuang,
China, Hebei Laboratory Animal Center, Hebei Medical University, Shijiazhuang, China, and Hebei Key Laboratory of Forensic Medicine, Department of
Forensic Medicine, Hebei Medical University, Shijiazhuang, China
Aging (Albany NY) 2021; 13: 16229e16247.

Editorial Comment: Brain mitochondrial dysfunction and reduced testosterone levels are common
features of aging in men. Although evidence suggests that the 2 phenomena are interrelated, it is
unclear whether testosterone supplementation ameliorates mitochondrial dysfunction in the aging
male brain.
The authors show that testosterone supplementation significantly alleviates exploratory behavioral deficits and oxidative damage in the substantia nigra and hippocampus of aging male rats.
These effects were consistent with improved mitochondrial function, reflected by testosteroneinduced increases in mitochondrial membrane potential, antioxidant enzyme (GSH-PX, catalase,
and Mn-SOD) expression/activity, and mitochondrial respiratory complex activities in both brain
regions. This is an interesting laboratory study that has clinical application.

Re: Intralesional Low-Dose Methylprednisolone for the Treatment of Active
Phase Peyronie’s Disease: A Single-Centre, Preliminary Prospective
Non-Randomised Study
I. Ure and A. Ozen
Department of Urology, Faculty of Medicine, Osmangazi University, Eskisehir, Turkey
Int J Clin Pract 2021; 75: e13754.


Editorial Comment: The authors aimed to evaluate the effect of intralesional low-dose methylprednisolone treatment on patients in the active phase of Peyronie’s disease.
Forty-eight patients suffering from Peyronie’s disease active phase symptoms were included in the
study. Methylprednisolone was administered intralesionally for 8 weeks, once per week, at a dose of

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40 mg. Methylprednisolone was injected into the plaque. The plaque that caused maximal curvature
was selected for injection. Patients were evaluated before and after treatment for plaque size, angle of
curvature, and erectile dysfunction according to the International Index of Erectile Function-5 and
Peyronie’s Disease Questionnaire.
The mean age of the patients was 61.1 years (range 43e78). The mean duration of the symptoms was
3.4 months (range 0e9). The average plaque size before treatment was 13.6 mm (range 7.1e16.8), and
after treatment this value decreased to 10.8 mm (4.3e14.6, p <0.025). The average scores of Peyronie’s
Disease Questionnaire elements symptom severity, penile pain, and bother/discomfort were 12.3, 19.1,
and 6.2, respectively, before the treatment. These scores were decreased to 8.9, 9.6, and 4.4, respectively, after treatment. All subgroups of Peyronie’s Disease Questionnaire scores were significantly
improved after treatment (p[0.001, p <0.001, p[0.045, respectively). No adverse events were
observed during or after treatment. Interesting study.

Suggested Reading
Kuja-Halkola R, Henningsohn L, D'Onofrio BM et al: Mental disorders in Peyronie's disease: a Swedish cohort study of 3.5 million men. J Urol 2021; 205: 864.

Allen D. Seftel, MD


Pediatric Urology

Re: Does Renal Function Remain Stable after Puberty in Children Who
Underwent Ureteral Reimplantation Due to Ureterovesical Junction
Obstruction?
B. B. Neeman, J. Jaber, S. Kocherov, A. Farkas and B. Chertin
Department of Urology and Pediatric Urology, Shaare Zedek Medical Center, Faculty of Medicine, Hebrew University, Jerusalem, Israel
Eur J Pediatr Surg 2021; 31: 187e190.

Editorial Comment: The authors share a series of 21 children with mean age of surgery at 14.3
months (range: 3 to 60 months) who underwent open reimplantation for ureterovesical junction
obstruction with followup into adulthood. Indications for surgery included hydronephrosis and
decreased relative renal function on MAG3 renal scan. Reimplantation resulted in increased relative
renal function not only in the short-term but also remained stable after puberty in all 21 patients.
Relative renal function improvement following surgery for ureterovesical junction obstruction
appears to be stable long-term.

Re: Pyeloplasty Is a Safe and Effective Surgical Approach for Low Functioning
Kidneys with Ureteropelvic Junction Obstruction
D. K. Bowen, S. Mittal, A. Aghababian, S. Eftekharzadeh, L. Dinardo, J. Weaver, C. Long,
A. Shukla and A. K. Srinivasan
Department of Urology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, Division of Urology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, and Division of Urology, Hospital of the University of Pennsylvania, Perelman Center for Advanced Care, Philadelphia, Pennsylvania
J Pediatr Urol 2021; 17: 233.e1e233.e7.

Editorial Comment: The authors share a large series of 364 children with ureteropelvic junction
obstruction in whom 8 children had affected kidneys with 0% to 10% relative renal function, 24 with
greater than 10% to 20% relative renal function and 332 with greater than 20% function. Following
robotic pyeloplasty there were no differences in 30-day postoperative complications, overall success

Copyright © 2021 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.