|Year : 2015 | Volume
| Issue : 2 | Page : 212-216
Testosterone and benign prostatic hyperplasia
Thomas R Jarvis, Bilal Chughtai, Steven A Kaplan
Department of Urology, Weill Cornell Medical College, New York, USA
|Date of Submission||21-Jul-2014|
|Date of Decision||28-Aug-2014|
|Date of Acceptance||01-Sep-2014|
|Date of Web Publication||21-Oct-2014|
Department of Urology, Weill Cornell Medical College, New York
Source of Support: None, Conflict of Interest: None
The use of testosterone to treat the symptoms of late-onset hypogonadal men has increased recently due to patient and physician awareness. However, concerns regarding the effect of testosterone on the prostate, in particular any possible effect on the risk of prostate cancer have prompted further research in this regard. Surprisingly, numerous retrospective or small, randomized trials have pointed to a possible improvement in male lower urinary tract symptoms (LUTS) in patients treated with testosterone. The exact mechanism of this improvement is still debated but may have a close relationship to metabolic syndrome. For the clinician, the results of these studies are promising but do not constitute high levels of evidence. A thorough clinical examination (including history, examination and laboratory testing of testosterone) should be undertaken before considering the diagnosis of late-onset hypogonadism or instigating treatment for it. Warnings still remain on the testosterone supplement product labels regarding the risk of urinary retention and worsening LUTS, and these should be explained to patients.
Keywords: benign prostatic hyperplasia; lower urinary tract symptoms; metabolic syndrome X; testosterone; urinary bladder neck obstruction
|How to cite this article:|
Jarvis TR, Chughtai B, Kaplan SA. Testosterone and benign prostatic hyperplasia. Asian J Androl 2015;17:212-6
| Introduction|| |
With an increasing population of aging males, who are living longer and healthier lives, solutions are being sought (and money made) for what were once considered common problems of senescence. Testosterone, inexorably and emotionally linked to male development and sustainment, has come into the spotlight. New proponents champion its replacement in aging men as the panacea of "the andropause", while more traditional skeptics worry about under-investigated harms.
Urologists have known of testosterone's importance in prostate development and pathology for some time, but only more recently have we begun to better understand its effects on lower urinary tract symptoms (LUTS); and more importantly, that these symptoms are not always entirely due to bladder outlet obstruction (BOO).
Our understanding of the link between testosterone, benign prostatic hyperplasia (BPH), BOO, and LUTS is slowly improving through research. However, studies that allow clinicians to uphold the vigorous standards of evidence-based medicine in the use of testosterone for LUTS have not yet been forthcoming.
| The Prostate and Testosterone|| |
Natural history of benign prostatic hyperplasia
The prostate is small at birth (1.5 g) and remains so until early puberty when it increases in size via an androgen-dependent pubescent growth phase  from 10 g to an average of 20 g (±6 g) in young adults. , After this initial growth and remodeling phase, which involves the entire prostate gland (peripheral, central and transitional zones), there is a second selective growth phase of the transitional zone that occurs in approximately 50% of men by age 50, and 90% of men older than 80 years. This growth is pathologically recognized as BPH and clinically noted as benign prostatic enlargement (BPE) or benign prostatic obstruction/BOO. It is thought that the normal interactions between the epithelial and fibromuscular stromal components of the transitional zone prostate tissue are altered leading to a reduced epithelial/stromal ratio and thus micronodular remodeling that characterizes BPH.
Testosterone and benign prostatic hyperplasia
It has long been recognized that the volume of the prostate increases with age in normal men due to BPH but not in their untreated hypogonadal counterparts. This has been clearly demonstrated in animal studies, in which testosterone replacement for younger castrated dogs permits the development of BPH. Furthermore, after initial regression of BPH in older castrated dogs, BPH was restored following testosterone replacement. 
Similarly, in human patients with primary hypogonadism, testosterone replacement allows the development of normal prostatic growth and BPH.  It is also well-known that in men with diseases of the prostate (such as prostate cancer or BPH), castration or androgen deprivation treatments leads to decrease prostate size and improvement in urinary function in some patients. 
Exactly how testosterone influences BPH is less clear. In a simplified model, an androgen receptor (AR) on prostatic cells is activated inducing growth. This then leads to the AR-dependent transcription of specific target genes resulting in the production and secretion of peptide growth factors, including insulin-like growth factor 1, epidermal growth factor, fibroblast growth factor-related proteins, such as keratinocyte growth factor. 
Wilson  hypothesized that it was dihydrotestosterone (DHT), the highly biologically active metabolite converted from testosterone in the prostate by the isoenzymes 5a-reductase type 1 (5AR1) and type 2 (5AR2), which was responsible for activating the AR. This local effect can be reversed clinically by blockade of 5AR1 and/or 5AR2 by 5a-reductase inhibitors (such as finasteride or dutasteride), which reduce prostate volume by approximately 25%.  Such medications are now used commonly in urological practice and often lead to improvement in voiding symptoms in men with BOO secondary to BPH/BPE.
Effect of aging
Serum testosterone has been shown to decrease in men with age by approximately 2%-3% annually.  The prevalence of hypogonadism (often defined as serum testosterone < 300 ng dl−1 ) ranges from 6%  to as high as 38%  in some primary practice settings.
The process of BPH, however, continues as men age and despite the fact their serum testosterone decreases. Liu et al.  demonstrated that in a group of older males (mean age 59.8 years) that there was not a significant correlation of serum testosterone levels (total, free or bioavailable) with either prostate volume or International Prostate Symptom Score (IPSS). This is difficult to explain: Isaacs and Coffey  argue that aging results in an increase in intra-prostatic DHT levels associated with BPH in both animal and human studies. However, Marks et al.  recently disputed this concept when finding no evidence of increased intra-prostatic DHT with testosterone replacement therapy (TRT) in a small, randomized control trial (RCT).
Benign prostatic hyperplasia is often thought of as the main cause of worsening LUTS as men age.  Although it remains unclear whether there is a close association between aging, hypogonadism and LUTS. While Favilla et al.  were able to demonstrate an association between LUTS and serum levels of total testosterone in the study of 122 men with symptomatic BPH, they did not find a similar association with BPH/BPE and testosterone.
| Traditional Thinking Regarding Testosterone Replacement Therapy And Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms|| |
To this day, there are warning labels on the available testosterone supplements regarding the risk of BPH and urinary retention. These are empirical concerns based on historical studies, which noted that androgens lead to prostatic growth in the post-pubescent male as described in the previous paragraph. In the late-onset hypogonadal male, the addition of testosterone (even to return levels to a "normal" range) was hypothesized by extrapolation to increase prostatic size and thus worsened of LUTS secondary to BOO. Indeed, in eugonadal men, studies have demonstrated that the prostate can increase in volume by approximately 12%  with the addition of testosterone, which is thought may be enough to decompensate a significantly obstructed bladder.
Current clinical guidelines reflect these concerns to varying degrees. ,, The European Association of Urology guidelines  warn that androgen deprivation therapy (ADT) is contraindicated in men with severe LUTS (IPSS > 21). They note, however, that this assertion is not supported by strong clinical evidence and that once a man's LUTS is appropriately treated there is no longer a contraindication to TRT.
Despite these long-standing warnings, there has been an increase in the use TRT to treat late-onset hypogonadal males for a variety of symptoms and conditions of older age (decreased libido, fatigue, erectile dysfunction, etc.).  Arising more from concerns of other adverse events from this treatment, in particular possible increase the risk of prostate cancer,  a whole body of literature regarding prostate characteristics in late-onset hypogonadal men being treated with TRT was born and is now in early development.
| Testosterone Replacement Therapy and Benign Prostatic Hyperplasia/Benign Prostatic Enlargement|| |
There seems to be little doubt that the treatment with testosterone of a young hypogonadal male leads to significant growth of the prostate. This was reported in hypogonadal males with primary hypogonadism who have significant growth in prostate volume with TRT.  Thirteen men between 25 and 32 years old with Klinefelter's syndrome were treated intramuscular testosterone and found to have an increased in prostate size from 9.3 to 19.0 ml, compared with no change in the control volume of 18.7 ml (P ≤ 0.001). Similarly, Behre et al.  demonstrated increased prostate volume and prostate-specific antigen (PSA) levels in hypogonadal men to those seen in aged-matched normal men after treatment with TRT.
Most studies, however, have shown no effect of exogenous androgens on PSA or prostate volume for older hypogonadal males.  In an RCT of 44 late-onset hypogonadal men, Marks et al.  found that those treated with TRT did not have a significant increase in prostate tissue levels of testosterone or DHT, despite having significantly increased levels of serum testosterone. More recent evidence from placebo-controlled studies of hypogonadal men receiving androgen therapy, indicate that the differences between those men receiving testosterone and those on placebo were insignificant in regards to prostate volume, PSA and BOO. 
These findings are echoed by Jin et al.  who studied 71 aged matched hypogonadal patients. For younger hypogonadal patients, the zonal and total prostate volumes (TPVs) were significantly smaller than their aged matched eugonadal colleges whether they were treated with TRT or not. However, from mid-life, central, peripheral and TPV increased with age among healthy controls and men with androgen deficiency regardless of TRT. This demonstrated age is a more important determinant of prostate growth than ambient testosterone concentrations maintained in the physiological range for older men.
Through a retrospective review of publications from 1941 to 2008, Morgentaler and Traish  have theorized a "saturation model" to explain the lack of effect of TRT on prostate volume or PSA in these men. They argue that the prostate is relatively insensitive to changes in androgen concentration at normal levels or in mild hypogonadism because the AR is saturated by androgens and therefore maximal androgen-AR binding is achieved. Conversely, the prostate is very sensitive to changes in androgen levels when testosterone is low (such as castration or androgen ablation). As expected, a similar curvilinear relationship between serum testosterone and PSA has been demonstrated by Rastrelli et al.  with PSA initially increasing, then plateauing in the low hypogonadal range (8 nmol l− ), with no further increase for higher levels of androgens.
These concepts are an important, direct challenge to those traditional safety concerns regarding TRT and BPH outlined above.
There are also numerous other competing theories for the development of BPH in older men that do not rely on the direct action of testosterone, such as the aromatization of androgens to estrogens, which then bind to estrogen receptors in the bladder and prostate.  Supporting this concept was a study of men over 40 with LUTS (IPSS > 7) by Schatzl et al.  that showed increasing estrogens correlated closely to prostate volume, while increasing serum testosterone did not.
Another concept is an inflammatory cause of BPH, which has been known to directly or indirectly contribute to prostate enlargement since described by Kohnen and Drach  in 1979. The exact molecular mechanisms of are beyond the scope of this review, however have been clinically revealed in the medical therapy of prostatic symptoms study. Here, men in the placebo arm whose baseline prostate biopsies demonstrate inflammation were significantly more likely to experience BPH progression and a higher rate of acute urinary retention or BPH-related surgery.  This was similarly demonstrated in a similar analysis of the data of the REDUCE trial. 
Finally, Vignozzi et al.  have more recently hypothesized that BPH is a more complex "metabolic" condition, brought about by an initial insult (likely to be an infection) and perpetuated by poor metabolism (in particular features associated with metabolic syndrome, such as dyslipidemia, hypercholesterolemia and hyperinsulinemia) and/or endocrine abnormalities (hypogonadism and hyperestrogenism). This "multi-hit" scenario leads to the overproduction of growth factors, which lead to prostate remodeling and BPE. The theory attempts to reconcile many of the concepts above, but remains to be fully tested.
| Testosterone Replacement Therapy and Lower Urinary Tract Symptoms|| |
Lower urinary tract symptoms in men are traditionally considered the ultimate clinical expression of BPH/BPE due to BOO. Nonetheless, LUTS are a set of subjective and objective symptoms, the causes of which are multifactorial and generally not disease specific. In fact, the natural history of LUTS is complex, and symptoms can wax and wane with time even without any treatment. 
Although there is no double-blinded RCTs to date, current studies seem to demonstrate that either TRT does not worsen LUTS or that it may, in fact, improve symptoms. This is not a new concept; as early as 1939, Walther and Willoughby  used testosterone to treat 15 men with "BPH" with the improvement in their LUTS over 2 years; although this treatment seemed to have been dismissed or forgotten for some time.
A recent retrospective review of a prospective database by Pearl et al.  demonstrated a lack of any relationship between IPSS and ADT in 120 men with a median follow-up of 1 year. In fact, there were just as many men who had improvement of their LUTS (change in IPSS > 3) as who had worsening of LUTS. Furthermore, the duration of treatment did not have any effect on IPSS.
These findings correlate with a prospective, observational registry study by Yassin et al.  of 261 hypogonadal men, in which TRT was associated with a significant improvement in LUTS, even when corrected for phosphodiesterase type 5 inhibitors (PDE5I) use and amount of weight loss. The mean IPSS decreased from 10.35 to 6.58, (P ≤ 0.05) with a median follow-up of 42.3 months.
Ko et al.  investigated a small subset of 17 patients receiving TRT with moderate LUTS and a Q max > 10 ml s−1 , who were not taking any BPH medication, and found that their IPSS was significantly improved (both voiding and storage components) although mean change was minimal (IPSS 9 to IPSS 7, P = 0.028). There was no change in Q max or post void residual (PVR).
Shigehara et al.  completed a randomized study of 52 patients with BPH and LUTS and showed that treatment with TRT significantly decreased the IPSS from baseline (15.7 ± 8.7 vs 12.5 ± 9.5; P < 0.05) at 1 year. There was also a significant improvement in Q max , but not in PVR.
| Metabolic Syndrome, Lower Urinary Tract Symptoms and Testosterone Replacement Therapy|| |
There is an increased understanding of links between metabolic syndrome and LUTS. Park et al.  investigated a group of 1224 otherwise healthy police officers, 29% of whom were diagnosed with metabolic syndrome. When compared with those without metabolic syndrome (and corrected for age and serum testosterone), they had a worse IPSS, larger TPV, and larger PVR volume.
Similarly, Kwon et al.  studied risk factors associated with BPH progression (TPV of > 31 cm 3 , PSA level of > 1.6 ng ml−1 , Q max < 10.6 ml s−1 , or PVR of > 39 ml) in men with moderate to severe LUTS and demonstrated a significant association with the increasing number of components of metabolic syndrome. These concepts are reinforced by other studies that demonstrate that in obese men (body mass index [BMI] >25), only age, increasing total testosterone and sex score were related to their worsening LUTS. 
Furthermore, in men with Klinefelter's syndrome (primary hypogonadism) treated with testosterone to eugonadal levels, only men with a waist circumference > 94 cm had a significant increase in prostate size;  the implication being that visceral obesity (one of the most significant components of metabolic syndrome) is associated with prostate volume and influences prostate growth during TRT.
An intimate relationship between metabolic syndrome, hypogonadism, and LUTS has also been demonstrated in animal models. Vignozzi et al.  showed the presence of prostate and bladder inflammation in rabbits with metabolic syndrome; this inflammation was exacerbated when the rabbits were made hypogonadal and returned to baseline when they were treated with testosterone. This hypothesis of inflammation induced LUTS is also argued to be a mechanism for improvement of LUTS with PDE5I. 
The concept, therefore, that treatment with TRT of hypogonadal males with metabolic syndrome might lead to improvement/stabilization of their LUTS, appears to be confirmed in recent work by Francomano et al.  They published data in which 20 obese, hypogonadal men with metabolic syndrome were treated with TRT and followed for 5 years. Compared to matched controls, there was no difference between the two groups in terms of IPSS, Q max , PVR or prostate size. In fact, the TRT group (with moderate baseline LUTS) had stable LUTS throughout the period and had fewer episodes of prostatitis (P < 0.01) than the untreated group. There was also an improvement in components of the patient's metabolic syndrome (such as BMI, waist circumference, hemoglobin A1c [HbA1c], insulin sensitivity, and lipid profile) as well as inflammatory markers and C-reactive protein. They concluded that TRT was safe in this group of men, and hypothesize that TRT mitigates the pro-inflammatory factors associated with metabolic syndrome.
| Quality of Life and Testosterone Replacement Therapy|| |
The presence of BPH is known to substantially reduce the quality-of-life.  The treatment of hypogonadal males with testosterone has also been shown to improve health-related quality-of-life,  primarily due to improved erectile function and muscle/joint pain. Unfortunately, in a short term study by Takao et al.  there was no difference in quality of life indices or LUTS in 21 men treated with TRT after 3 months.
| Patient Assessment|| |
The possibility of a significant relationship between testosterone, testosterone replacement and LUTS/BPH mandate the urologist consider these factors when patients are being investigated for LUTS.
The focused history should enquire for symptoms of hypogonadism, as well as symptoms that may reveal the presence of metabolic syndrome. The physical examination should make note of the patient's BMI and physical signs of hypogonadism. Obesity in patients with LUTS was found to be significantly prevalent in men with low testosterone.  Investigations to be performed, aside from the usual LUTS workup, may include serum testosterone, HbA1c, and fasting serum glucose. The biochemical diagnosis of hypogonadism should be made carefully, as there are significant intra-individual fluctuations in testosterone levels  and no accepted cut-off that defines "low testosterone". At least separate two measurements of serum testosterone should be taken to confirm any biochemical diagnosis of hypogonadism.
Finally, testosterone replacement should only be considered for symptomatic hypogonadal men after full clinical assessment and correlation. Despite this obvious caveat, numerous men are still treated for symptoms of hypogonadism with either normal serum levels or without level having been checked at all. 
| Research Pending/Opportunities|| |
Unfortunately, the lack of large prospective RCTs makes the application of evidence-based medicine in this area difficult for urologists and their patients.
The challenge for the basic science and clinical researcher is to determine the real effect of TRT on BPH for hypogonadal men, while identifying those patients who may be harmed from such a therapy. Unfortunately, as Francomano et al.  point out, the economics of performing such a large RCT in this area are prohibitive.
There is also a need for further basic science research into the exact mechanisms of prostate growth, the effect of testosterone (or lack thereof) and its relationship to LUTS. 
| Conclusions|| |
While packet warnings still remain, and there is no high-level evidence to support either position, patients should be warned regarding potential worsening of LUTS if treated with testosterone. Despite this, there is emerging evidence that testosterone plays an important part in the role of treating BPH/LUTS in the aging male.
| Competing Interests|| |
The authors declare that they have no competing interests.
| References|| |
Corona G, Vignozzi L, Sforza A, Maggi M. Risks and benefits of late onset hypogonadism treatment: an expert opinion. World J Mens Health
2013; 31: 103-25.
Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol
1984; 132: 474-9.
Vignozzi L, Rastrelli G, Corona G, Gacci M, Forti G, et al
. Benign prostatic hyperplasia: a new metabolic disease? J Endocrinol Invest
Berry SJ, Coffey DS, Strandberg JD, Ewing LL. Effect of age, castration, and testosterone replacement on the development and restoration of canine benign prostatic hyperplasia. Prostate
1986; 9: 295-302.
Sasagawa I, Nakada T, Kazama T, Satomi S, Terada T, et al
. Volume change of the prostate and seminal vesicles in male hypogonadism after androgen replacement therapy. Int Urol Nephrol
1990; 22: 279-84.
Nicholson TM, Ricke WA. Androgens and estrogens in benign prostatic hyperplasia: past, present and future. Differentiation
2011; 82: 184-99.
Wilson JD. Recent studies on the mechanism of action of testosterone. N Engl J Med
1972; 287: 1284-91.
Kaplan SA, Roehrborn CG, McConnell JD, Meehan AG, Surynawanshi S, et al.
Long-term treatment with finasteride results in a clinically significant reduction in total prostate volume compared to placebo over the full range of baseline prostate sizes in men enrolled in the MTOPS trial. J Urol
2008; 180: 1030-2.
Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR, et al
. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab
2001; 86: 724-31.
Araujo AB, O′Donnell AB, Brambilla DJ, Simpson WB, Longcope C, et al.
Prevalence and incidence of androgen deficiency in middle-aged and older men: festimates from the massachusetts male aging study. J Clin Endocrinol Metab
2004; 89: 5920-6.
Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract
2006; 60: 762-9.
Liu CC, Huang SP, Li WM, Wang CJ, Chou YH, et al.
Relationship between serum testosterone and measures of benign prostatic hyperplasia in aging men. Urology
2007; 70: 677-80.
Isaacs JT, Coffey DS. Changes in dihydrotestosterone metabolism associated with the development of canine benign prostatic hyperplasia. Endocrinology
1981; 108: 445-53.
Marks LS, Mazer NA, Mostaghel E, Hess DL, Dorey FJ, et al.
Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: arandomized controlled trial. JAMA
2006; 296: 2351-61.
Favilla V, Cimino S, Castelli T, Madonia M, Barbagallo I, et al
. Relationship between lower urinary tract symptoms and serum levels of sex hormones in men with symptomatic benign prostatic hyperplasia. BJU Int
2010; 106: 1700-3.
Holmäng S, Mårin P, Lindstedt G, Hedelin H. Effect of long-term oral testosterone undecanoate treatment on prostate volume and serum prostate-specific antigen concentration in eugonadal middle-aged men. Prostate
1993; 23: 99-106.
Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, et al.
Testosterone therapy in men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab
2010; 95: 2536-59.
Buvat J, Maggi M, Guay A, Torres LO. Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment. J Sex Med
2013; 10: 245-84.
Liverman CT, Blazer DG, eds. Testosterone and Aging: Clinical Research Directions. The National Academies Press, Washington DC; 2004.
Kaplan AL, Hu JC. Use of testosterone replacement therapy in the United States and its effect on subsequent prostate cancer outcomes. Urology
2013; 82: 321-6.
Behre HM, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxf
) 1994; 40: 341-9.
Raynaud JP, Gardette J, Rollet J, Legros JJ. Prostate-specific antigen (PSA) concentrations in hypogonadal men during 6 years of transdermal testosterone treatment. BJU Int
2013; 111: 880-90.
Morales A. Androgen replacement therapy and prostate safety. Eur Urol
2002; 41: 113-20.
Jin B, Conway AJ, Handelsman DJ. Effects of androgen deficiency and replacement on prostate zonal volumes. Clin Endocrinol (Oxf)
2001; 54: 437-45.
Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol
2009; 55: 310-20.
Rastrelli G, Corona G, Vignozzi L, Maseroli E, Silverii A, et al.
Serum PSA as a predictor of testosterone deficiency. J Sex Med
2013; 10: 2518-28.
Schatzl G, Brössner C, Schmid S, Kugler W, Roehrich M, et al.
Endocrine status in elderly men with lower urinary tract symptoms: correlation of age, hormonal status, and lower urinary tract function. The Prostate Study Group of the Austrian Society of Urology. Urology
2000; 55: 397-402.
Kohnen PW, Drach GW. Patterns of inflammation in prostatic hyperplasia: a histologic and bacteriologic study. J Urol
1979; 121: 755-60.
Roehrborn CG, Kaplan SA, Noble WD, Lucia MS, Slawin KM, et al
. The impact of acute or chronic inflammation in baseline biopsy on the risk of clinical progression of BPE: results from the MTOPS study. In: proceedings From the Annual Meeting of the American Urological Association. San Antonio, TX, USA; 2005.
Nickel JC, Roehrborn CG, O′Leary MP, Bostwick DG, Somerville MC, et al
. The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the reduce trial. Eur Urol
2008; 54: 1379-84.
Maserejian NN, Chen S, Chiu GR, Araujo AB, Kupelian V, et al.
Treatment status and progression or regression of lower urinary tract symptoms in a general adult population sample. J Urol
2014; 191: 107-13.
Walther HW, Willoughby RM. Hormonal treatment of benign prostatic hyperplasia. J Urol
1938; 40: 135-44.
Pearl JA, Berhanu D, François N, Masson P, Zargaroff S, et al.
Testosterone supplementation does not worsen lower urinary tract symptoms. J Urol
2013; 190: 1828-33.
Yassin DJ, El Douaihy Y, Yassin AA, Kashanian J, Shabsigh R, et al
. Lower urinary tract symptoms improve with testosterone replacement therapy in men with late-onset hypogonadism: 5-year prospective, observational and longitudinal registry study. World J Urol
2014; 32: 1049-54.
Ko YH, Moon du G, Moon KH. Testosterone replacement alone for testosterone deficiency syndrome improves moderate lower urinary tract symptoms: one year follow-up. World J Mens Health
2013; 31: 47-52.
Shigehara K, Sugimoto K, Konaka H, Iijima M, Fukushima M, et al.
Androgen replacement therapy contributes to improving lower urinary tract symptoms in patients with hypogonadism and benign prostate hypertrophy: a randomised controlled study. Aging Male
2011; 14: 53-8.
Park YW, Kim SB, Kwon H, Kang HC, Cho K, et al.
The relationship between lower urinary tract symptoms/benign prostatic hyperplasia and the number of components of metabolic syndrome. Urology
2013; 82: 674-9.
Kwon H, Kang HC, Lee JH. Relationship between predictors of the risk of clinical progression of benign prostatic hyperplasia and metabolic syndrome in men with moderate to severe lower urinary tract symptoms. Urology
2013; 81: 1325-9.
Antunes AA, Araújo LH, Nakano E, Muracca E, Srougi M. Obesity may influence the relationship between sex hormones and lower urinary tract symptoms. Int Braz J Urol
2014; 40: 240-6.
Selice R, Caretta N, Di Mambro A, Torino M, Palego P, et al.
Prostate volume and growth during testosterone replacement therapy is related to visceral obesity in Klinefelter syndrome. Eur J Endocrinol
2013; 169: 743-9.
Vignozzi L, Morelli A, Sarchielli E, Comeglio P, Filippi S, et al.
Testosterone protects from metabolic syndrome-associated prostate inflammation: an experimental study in rabbit. J Endocrinol
2012; 212: 71-84.
Vignozzi L, Gacci M, Cellai I, Morelli A, Maneschi E, et al.
PDE5 inhibitors blunt inflammation in human BPH: a potential mechanism of action for PDE5 inhibitors in LUTS. Prostate
2013; 73: 1391-402.
Francomano D, Ilacqua A, Bruzziches R, Lenzi A, Aversa A. Effects of 5-year treatment with testosterone undecanoate on lower urinary tract symptoms in obese men with hypogonadism and metabolic syndrome. Urology
2014; 83: 167-73.
Speakman M, Kirby R, Doyle S, Ioannou C. Burden of male lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) - Focus on the UK. BJU Int
Yassin DJ, Doros G, Hammerer PG, Yassin AA. Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life. J Sex Med
2014; 11: 1567-76.
Takao T, Tsujimura A, Nakayama J, Matsuoka Y, Miyagawa Y, et al.
Lower urinary tract symptoms after hormone replacement therapy in Japanese patients with late-onset hypogonadism: a preliminary report. Int J Urol
2009; 16: 212-4.
Kaplan SA, Lee JY, O′Neill EA, Meehan AG, Kusek JW. Prevalence of low testosterone and its relationship to body mass index in older men with lower urinary tract symptoms associated with benign prostatic hyperplasia. Aging Male
2013; 16: 169-72.
Paduch DA, Brannigan RE, Fuchs EF, Kim ED, Marmar JL, et al
. The laboratory diagnosis of testosterone deficiency. Urology
2014; 83: 980-8.
Layton JB, Li D, Meier CR, Sharpless JL, Stürmer T, et al.
Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011. J Clin Endocrinol Metab
2014; 99: 835-42.
Kaplan SA. Re: relationship between lower urinary tract symptoms and serum levels of sex hormones in men with symptomatic benign prostatic hyperplasia. J Urol
2011; 186: 1983-4.
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| ||Genetics and Molecular Biology. 2020; 43(3) |
|[Pubmed] | [DOI]|
||Obesity’s role in secondary male hypogonadism: a review of pathophysiology and management issues
| ||Omar Seyam,Jason Gandhi,Gunjan Joshi,Noel L. Smith,Sardar Ali Khan |
| ||SN Comprehensive Clinical Medicine. 2019; |
|[Pubmed] | [DOI]|
||Sex hormones and oxidative stress mediated phthalate-induced effects in prostatic enlargement
| ||Wei-Hsiang Chang,Yuh-Shyan Tsai,Jia-Yu Wang,Hsiu-Ling Chen,Wen-Horng Yang,Ching-Chang Lee |
| ||Environment International. 2019; 126: 184 |
|[Pubmed] | [DOI]|
||“Prostate telocytes change their phenotype in response to castration or testosterone replacement”
| ||Sérgio Luis Felisbino,Bruno Domingos Azevedo Sanches,Flávia Karina Delella,Wellerson Rodrigo Scarano,Fernanda Cristina Alcântara Dos Santos,Patrícia Simone Leite Vilamaior,Sebastião Roberto Taboga,Luis Antônio Justulin |
| ||Scientific Reports. 2019; 9(1) |
|[Pubmed] | [DOI]|
||The association between body mass index and testosterone deficiency in aging Chinese men with benign prostatic hyperplasia: results from a cross-sectional study
| ||Yu Wu,Ding Xu,Hai-Bo Shen,Su-Bo Qian,Jun Qi,Xu-Jun Sheng |
| ||The Aging Male. 2019; : 1 |
|[Pubmed] | [DOI]|
||Prostate volume index and prostatic chronic inflammation predicted low tumor load in 945 patients at baseline prostate biopsy
| ||Antonio B. Porcaro,Alessandro Tafuri,Marco Sebben,Giovanni Novella,Tania Processali,Marco Pirozzi,Nelia Amigoni,Riccardo Rizzetto,Aliasger Shakir,Arianna Mariotto,Matteo Brunelli,Maria Angela Cerruto,Giovanni Enrico Cacciamani,Filippo Migliorini,Salvatore Siracusano,Walter Artibani |
| ||World Journal of Urology. 2019; |
|[Pubmed] | [DOI]|
||Association between the symptoms of benign prostatic hyperplasia and social disparities: Does social capital promote prostate health?
| ||Myung-Bae Park,Dae Sung Hyun,Jae Mann Song,Hyun Chul Chung,Sung Won Kwon,Sae Chul Kim,Chhabi Lal Ranabhat,Tae Sic Lee,Sang-Baek Koh |
| ||Andrologia. 2018; : e13125 |
|[Pubmed] | [DOI]|
||Serum Steroid Ratio Profiles in Prostate Cancer: A New Diagnostic Tool Toward a Personalized Medicine Approach
| ||Adriana Albini,Antonino Bruno,Barbara Bassani,Gioacchino D’Ambrosio,Giuseppe Pelosi,Paolo Consonni,Laura Castellani,Matteo Conti,Simone Cristoni,Douglas M. Noonan |
| ||Frontiers in Endocrinology. 2018; 9 |
|[Pubmed] | [DOI]|
||Methyl jasmonate reduces testosterone-induced benign prostatic hyperplasia through regulation of inflammatory and apoptotic processes in rats
| ||Oluwatosin Adekunle Adaramoye,Olubukola Oyebimpe Akanni,Olusoji John Abiola,Solomon Eduviere Owumi,Oluyemi Akinloye,Emiola Olubunmi Olapade-olaopa |
| ||Biomedicine & Pharmacotherapy. 2017; 95: 1493 |
|[Pubmed] | [DOI]|
||Withania coagulans Extract Induces Cell Apoptosis and Inhibits COX-2 Expression in a Rat Model of Benign Prostatic Hyperplasia
| ||Maryam Sarbishegi,Ozra Khajavi,Mohammad Reza Arab |
| ||Nephro-Urology Monthly. 2016; Inpress(Inpress) |
|[Pubmed] | [DOI]|
||Testosterone Replacement Therapy on the Natural History of Prostate Disease
| ||Aaron Moore,Michael J. Butcher,Tobias S. Köhler |
| ||Current Urology Reports. 2015; 16(8) |
|[Pubmed] | [DOI]|
||Controversies in testosterone supplementation therapy
| ||Mohit Khera |
| ||Asian Journal of Andrology. 2015; 17(2): 175 |
|[Pubmed] | [DOI]|