Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2021 Jun 1.
Published in final edited form as: BJU Int. 2020 Mar 20;125(6):911–919. doi: 10.1111/bju.15022

Effects of a Selective Androgen Receptor Modulator (SARM), GSK2849446A, on Stress Urinary Incontinence and Bladder Activity in Rats with Ovariectomy-induced Estrogen Deficiency

Katsumi Kadekawa 1, Naoki Kawamorita 1, Takahiro Shimizu 1, Masahiro Kurobe 1, Philip S Turnbull 2, Sundeep Chandra 2, Takahito Kambara 2, Joanna C Barton 2, Alan J Russell 2, Naoki Yoshimura 1,*
PMCID: PMC7261644  NIHMSID: NIHMS1555719  PMID: 32011085

Abstract

Objectives

To report the effect of a Selective androgen receptor modulators (SARMs) on the urethral continence mechanisms in a rat model of stress urinary incontinence (SUI) induced by bilateral ovariectomy (OVX).

Materials and Methods

Female Sprague-Dawley rats with bilateral OVX were used. Rats were divided into 5 groups; sham operated, vehicle-treated OVX, low-dose SARM treated OVX (GSK2849466A: 0.005 mg/kg/day, p.o.), high-dose SARM treated OVX (GSK2849466A: 0.03 mg/kg/day, p.o.) and dihydrotestosterone (DHT) treated OVX (1 mg/kg/day, s.c.) groups. After 4 weeks of SARM treatments or 3 weeks of DHT treatment (6 weeks after OVX), rats were subjected to evaluation of the sneeze-induced continence reflex using microtransducer-tipped catheter methods, sneeze-induced leak point pressure (S-LPP) and continuous cystometry measurements, following by histological analyses of urethral tissues.

Results

(1) OVX significantly impaired urethral continence function after 6 weeks to induce SUI during sneezing. (2) Low-dose SARM treatment restored urethral baseline pressure (UBP) without affecting the amplitude of urethral response during sneezing (A-URS), partially reversing OVX-induced SUI during sneezing. (3) High-dose SARM treatment reversed decreases in both UBP and A-URS, more effectively preventing SUI during sneezing. (4) DHT treatment, only restored A-URS without affecting UBP, partially preventing OVX-induced SUI during sneezing. (5) The high-dose SARM treatment induced hypertrophy of the striated and smooth muscle around the urethra. (6) SARM treatment did not affect bladder function in sham or OVX rats.

Conclusion

Treatment with SARMs could be a more effective modality for the treatment of SUI than DHT without affecting bladder function by enhancing smooth and striated muscle mediated urethral function under stress conditions such as sneezing.

Introduction

Stress urinary incontinence (SUI) is a common condition that is defined as involuntary loss of urine secondary to increase in abdominal pressure during events such as sneezing, coughing or laughing in the absence of bladder contraction.[1] Although the etiology of SUI in women is multifactorial, a history of vaginal childbirth and menopause, which can induce alterations in the urethral and extraurethral mechanisms controlling urinary continence contributes significantly to the emergence of SUI.[2] Also, SUI is common in post-menopausal women, suggesting that aging and estrogen deficiency contribute to its etiology.[3] It is also reported that estrogen deficiency due to menopause is one of the major causes of SUI that induces atrophic and degenerative changes in urethral and pelvic floor muscles.[2] Therefore, it is important to maintain the contractile function for the treatment and/or prevention of SUI. In this regards, pelvic floor muscle training to strengthen striated muscles is frequently recommended as the first-line option for treatment of SUI although this behavioral treatment is not always effective.[4] It has previously been reported in rats that an active urethral closure mechanism prevents SUI during the sneeze reflex, and that the sneeze-induced continence reflex is mediated by somatic nerve-induced reflex contractions of the external urethral sphincter and pelvic floor striated muscles.[1] Using this model system, we previously reported that ovariectomy (OVX) impairs urethral function by reducing urethral baseline pressure (UBP) and urethral responses to sneezing to induce sneeze-induced SUI at 6 weeks after OVX in rats and that the estrogen replacement treatment effectively enhances smooth muscle activity, leading to partial improvement in sneeze-induced SUI.[5]

The pelvic floor and lower urinary tract are regulated by estrogen as well as androgen signaling pathways because muscles in these structures, particularly levator ani and urethral sphincter muscles, are sensitive to androgens,[6] and contain large numbers of androgen receptors.[7] Therefore, androgenic effects on the lower urinary tract may play an important role in urethral continence mechanisms. Androgens, which work as sex steroids and anabolic hormones, play vital roles in maintaining the male phenotype.[8] Androgen supplementation can have positive effects in osteoporosis, and sexual dysfunction,[9] and anabolic effects on striated muscle mass in wasting diseases such as HIV are well known.[10] However, clinical use of androgens has been limited because of concerns about side effects,[11] including prostate hypertrophy and prostate cancer in men [12] and virilizing effects such as hirsutism, voice change and acne in women.[13] Although anabolic steroids were developed to reduce these side effects, their actions were not sufficient to reduce virilizing and hepatotoxic effects.[14] Recently, the actions of non-steroidal selective androgen receptor modulators (SARMs) have been investigated,[15, 16] which selectively stimulate anabolic pathways of the androgen receptor in muscle and bone while sparing the androgenic effects typically seen with steroidal androgens [17]. Since levator ani and urethral sphincter muscles are sensitive to androgen, we hypothesized that SARM treatment would increase the striated muscle around the urethra, resulting in the prevention of SUI in the post-menopausal condition.

In this study, we therefore examined the effect of a SARM (GSK2849466A) and dihydrotestosterone (DHT) on the urethral continence mechanisms in a rat model of SUI induced by bilateral OVX.

Materials and Methods

Animals

We studied 104 adult nulliparous Sprague-Dawley female rats weighing 177 to 248 g according to experimental protocols approved by the University of Pittsburgh institutional animal care and use committee. Rats were divided into 5 groups; sham operated (sham, n=21), vehicle-treated OVX (OVX-Vehicle, n=24), low dose GSK2849466A-treated OVX (0.005 mg/kg/day, p.o., OVX-low SARM, n=19), high dose GSK2849466A-treated OVX (0.03mg/kg/day, p.o., OVX-high SARM, n=22) and DHT-treated OVX (1 mg/kg/day, s.c., OVX-DHT, n=18) groups. At 2 weeks after OVX, oral vehicle or SARM treatments were started. The DHT treatment was started at 3 weeks after OVX using subcutaneously-implanted tablets in a separate group of rats.

Ovariectomy

In OVX groups, bilateral dorsolateral incisions through skin, muscle and peritoneum were made 2 cm below the last rib bone, and the left and right ovaries were removed under isoflurane anesthesia. The remaining animals were subjected to sham surgery, during which the ovaries were exteriorized, but kept intact and the wound were closed with absorbable sutures. All rats were treated for 3 days postoperatively with subcutaneous injection of ampicillin (Fort Dodge Animal Health, Fort Dodge, Iowa) (100 mg/kg, s.c.).

Drug treatment

Two weeks after OVX, rats were treated with oral gavage of vehicle (0.5% hydroxypropyl methylcellulose + 0.1% Tween 80 in water) or GSK2849446A (0.005 or 0.03 mg/kg in vehicle) for 4 weeks. In another group of rats, a controlled-release tablet of DHT (1 mg/kg/day), which can release DHT for 21 days (Innovative Research of America, Sarasota, FL), was subcutaneously implanted on the lateral side of the neck at 3 weeks after OVX.

Measurement of urethral pressure response

After 4 weeks of SARM treatment or 3 weeks of DHT treatment (both at 6 weeks after OVX), rats were subjected to the evaluation of sneeze-induced continence reflex in sham (n=9), OVX-Vehicle (n=12), OVX-low SARM (n=6), OVX-high SARM (n=9) and OVX-DHT (n=10) groups.

Under isoflurane anesthesia, a PE-10 polyethylene catheter (Clay-Adams, Parsippany, New Jersey) was inserted into a jugular vein to maintain anesthesia. The bladder was exposed and emptied through an abdominal incision. The ureters were cut bilaterally and the distal ends were ligated. The visceral branches of the pelvic nerves were transected bilaterally near the internal iliac vessels to prevent reflex bladder contractions.[18] Feces were removed from the distal colon through a small incision in the colon wall. A handmade balloon catheter with a 1 cm diameter balloon connected to a pressure transducer was inserted through the rectal incision into the abdominal cavity to record abdominal pressure (Pabd) during sneezing. After closing of the wound with suture, isoflurane anesthesia was turned off and replaced with urethane anesthesia (0.72 gm/kg) intraperitoneally. Rats were placed on a board in a supine position and a 3.5 Fr nylon SPR-524 catheter (Millar Instruments, Houston, Texas) with a side mounted microtransducer 1 mm from the catheter tip was inserted into the middle urethra 10 to 15 mm from the urethral orifice.[19] The microtransducer tipped catheter was connected to a Transbridge 4M pressure transducer (World Precision Instruments, Sarasota, Florida). Urethral responses were recorded with Chart data acquisition software with a sampling rate of 400 Hz on a computer system equipped with a Power Lab analog-to-digital converter (ADI Instruments®). Catheter position was monitored throughout the experiments to confirm that the transducer site did not change. Additional doses of urethane anesthesia (0.1 g/kg per injection) were administered intravenously as required before sneeze reflex testing to determine a sufficient level of anesthesia, which was confirmed by negative reflex responses to toe pinch. The final urethane dose ranged from 1.0 to 1.2 g/kg among the animals used.

The sneeze reflex was induced by inserting a whisker of a rat gently into the nostril under urethane anesthesia, as we previously reported.[18, 19] During the sneeze reflex, we measured amplitudes of urethral pressure response during sneezing (A-URS) and urethral baseline pressure (UBP). A-URS was determined as the maximal pressure change from baseline in cmH2O. Average UBP was determined from a plateau section of pressure recordings just before the sneeze response, as previously described.[18] To evaluate the intensity of the induced sneeze, which varied with each sneeze event, Pabd increases during sneezing were also measured by an intra-abdominal balloon catheter.

Measurement of leak point pressure during sneezing

In a separate group of rats, the animals were subjected to the evaluation of leak point pressure during sneezing in sham (n=8), OVX-Vehicle (n=8), OVX-low SARM (n=9), OVX-high SARM (n=9) and OVX-DHT (n=8) groups. A jugular vein catheter for maintenance of anesthesia during experiments and an intra-abdominal balloon catheter were placed, and bilateral ureters and visceral branches of the pelvic nerves were transected under isoflurane anesthesia as mentioned above. A PE-90 catheter connected to a pressure transducer was inserted into the bladder through the bladder dome to record intravesical pressure and a purse suture was placed tightly around the catheter. After replacement of anesthesia and wound closure, animals were placed on a board in a supine position. The bladder was emptied and 0.4 ml saline solution containing Evans blue (100 μg/ml) were injected into the bladder through the intravesical catheter. The sneeze reflex was induced to examine whether fluid leakage from the urethral orifice was induced by sneezing. Intravesical pressure changes were recorded to monitor the increase in Pabd during sneezing. Maximal intravesical pressure was measured at each sneeze event and the lowest pressure that induced fluid leakage from the urethral orifice was defined as leak point pressure during sneezing (S-LPP). [18, 19]

Continuous cystometry analysis

In separate groups of sham, vehicle and SARM treatments, the animals (n=4 each group) were anesthetized with isoflurane, the bladder was exposed via a lower abdominal incision, and a polyethylene catheter (PE-50) was inserted through the bladder dome and a purse suture was placed tightly around the catheter. Thereafter, the rats were placed in restraining cages (W 80 mm × L 300 mm × H 150 mm, Yamanaka Chemical Ind., Ltd). After the recovery from anesthesia, bladder activity was monitored under an awake condition via bladder catheter, which was connected via a three-way stopcock to a pressure transducer and a pump for infusion of physiological saline at a rate of 0.1 ml/min. After rhythmic bladder contractions had become stable for at least 60 min, interval between voiding bladder contractions (ICI) and maximum voiding bladder contraction pressure (MCP) were measured during the final 30 min of cystometry. After measurement of these parameters, fluid voided from the urethral meatus was collected and measured to determine the voided volume, and residual saline in the bladder was withdrawn through the bladder catheter by gravity to determine residual volumes. Bladder capacity was calculated as the sum of the voided and residual volumes. Voiding efficiency was also calculated as voided volume divided by bladder capacity.

Histological Analyses

At the end of the pressure analyses, all animals were sacrificed humanely with CO2, and then the uterus, bladder and urethra were harvested and weighed. Urethras in sham, OVX-vehicle, OVX-high SARM and OVX-DHT groups (n=4–5 per group) were fixed in 4% paraformaldehyde for 48 h, and then were cryprotected in 20% sucrose for 72 h. Thereafter, urethral tissues were embedded in OCT compound and immediately frozen at −80°C. For histological evaluation, 4–5 urethras per group were randomly selected, the OCT blocks were thawed, and the tissues were fixed in formalin. After fixation, urethral tissues were embedded in paraffin, microtomed and stained with HE and Masson Trichrome stain. The same region of the middle urethra was examined in all rats.

Statistical Analysis

All data are shown as the mean ± standard error (SE). Excessively large sneezes that induced Pabd increases greater than +2 SD above the average and small responses that induced Pabd increases less than 3 cm H2O were excluded from data analysis. A-URS, UBP and increases in Pabd during sneezing were averaged in each rat. The mean ± SE in a group was then calculated from the averaged value in each rat of that group. One-way analysis of variance (ANOVA) followed by Tukey’s multiple comparison test was used to compare changes in body, bladder and uterus weights, A-URS, UBP and Pabd during sneezing. Mann-Whitney test was used to compare in S-LPP between the OVX-vehicle, OVX-low SARM and OVX-DHT groups. P<0.05 was considered to indicate statistical significance.

Results

Animal and Tissue Weight

At 6 weeks after OVX, rats had significantly greater body weight than the age-matched sham control group. In contrast, OVX-vehicle, OVX-low SARM and OVX-DHT groups had significantly lower uterine weight than the sham group (228 ± 11, 267 ± 19, 181 ± 13 and 636 ± 46 mg, respectively), but uterine weight in the OVX-high SARM group was significantly higher (800 ± 32 mg) than in all other OVX groups. Bladder weight in the OVX-high SARM group was significantly higher than in the sham, OVX-vehicle, OVX-low SARM groups (139 ± 13, 77 ± 3, 96 ± 5 and 99 ± 4 mg, respectively).

Urethral pressure responses

UBP was significantly lower in the OVX-vehicle group (by 46%), compared to the sham group (19.8 ± 2.1 vs. 36.8 ± 4.9 cm H2O). (Fig. 1 A-1, A-2, B) The amplitude of urethral responses during sneezing (A-URS) was also significantly lower in the OVX-vehicle group (by 38%) compared to the sham group (40.3 ± 5.4 vs. 65.3 ± 7.5 cm H2O). (Fig. 1 A-1, A-2, C). In the OVX-low SARM group, UBP was significantly higher (by 123%; 44.1 ± 2.2 cm H2O) compared to the OVX-vehicle group. (Fig. 1 A-2, A-3, B). In the OVX-high SARM group, UBP and AURS were significantly greater than the OVX-vehicle group (by 86%; 36.9 ± 5.4 cm H2O and 106%; 83.2 ± 10.9 cm H2O), respectively). (Fig. 1 A-2, A-4, B, C). In the OVX-DHT group, A-URS was significantly greater (by 60%; 64.5 ± 3.9 cm H2O) compared to the OVX-vehicle group (Fig. 1 A-2, A-5, B, C). Average values of sneeze induced increases in Pabd measured by intra-abdominal catheters were not significantly different among the experimental groups (data not shown).

Fig. 1.

Fig. 1

Open in a new tab

Representative recordings of urethral baseline pressure (UBP) and amplitudes of urethral responses (A-URS) (A1–5) and comparison of the UBP (B) and A-URS (C) in rats with or without SARM treatment and rats with DHT treatment. UBP and A-URS were significantly lower in the Vehicle treated OVX group compared to the sham group. Low dose SARM treatment exhibited significantly greater UBP, but not in A-URS, compared to the Vehicle treated group. High dose SARM treatment normalized the decrease of both parameters of UBP and A-URS observed in the Vehicle treated group. DHT treatment significantly improved A-URS, but not in UBP, compared to the Vehicle treated group. * p<0.05, ** p<0.01 vs. Sham. # p<0.05, ## p<0.01, ### p<0.001.

Sneeze LPP

In S-LPP measurements, the sham group did not leak during sneezing. In this group, mean intravesical pressure during sneezing was 110.7 ± 7.4 cmH2O. However, fluid leakage was observed with S-LPP values of 59.9 ± 9.5 cmH2O during sneezing in all rats of the OVX-vehicle group (n=8). In the OVX-low SARM group, fluid leakage during sneezing was observed in 7 of 9 rats (78%) and mean S-LPP in these 7 incontinent rats was 67.4 ± 3.0 cm H2O. In the OVX-high SARM group, only 1 of 8 rats (12%) showed fluid leakage during sneezing with the S-LPP value at 82.9 cmH2O. In the OVX-DHT group, 3 of 8 rats (38%) showed fluid leakage during sneezing with the S-LPP value at 73.2 ± 12.8 cmH2O (Fig. 2). There was no significant difference of S-LPP between OVX-vehicle and OVX-low SARM groups.

Fig. 2.

Fig. 2

Open in a new tab

Comparison of the maximal intravesical pressure and sneeze-leak point pressure (S-LPP). In S-LPP measurements, the sham rats did not show fluid leakage during sneezing. However, all rats of the Vehicle treated group showed fluid leakage with the SLPP of 60 cm of water. In the low dose SARM treated group, fluid leakage during sneezing was observed in 7 of 9 rats. In the high dose SARM treated group, only 1 rat showed fluid leakage, and the other 7 rats did not leak. In the DHT treated group, 3 rats showed fluid leakage, and the other 5 rats did not leak.

Continuous cystometry analysis

In cystometry measurements, there were no significant differences in any of parameters including ICI, MCP, voiding efficiency and bladder compliance among sham control, OVX-Vehicle, OVX-low SARM, OVX-high SARM groups. (Fig. 3)

Fig. 3.

Fig. 3

Open in a new tab

Comparison of cystometric parameters. In cystometric measurements, there were no significant differences in any of parameters including intercontraction interval, maximum contraction pressure, bladder compliance or voiding efficiency among sham control, OVX-Vehicle, OVX-low SARM, OVX-high SARM groups.

Histological Analyses

Two OVX-vehicle rats had minimal striated and smooth muscle atrophy. Striated muscle content in the other 3 rats in the OVX-vehicle groups was similar to the sham group. In the OVX-high SARM group, the striated muscles showed mild or minimal hypertrophy, and the smooth muscle around the urethra was hypertrophied compared to the sham group and OVX-vehicle groups. In the OVX-DHT group, minimal atrophic striated muscle was observed (Fig. 4)

Fig. 4.

Fig. 4

Open in a new tab

Histopathological comparison of cross section of the urethra. In the Vehicle treated OVX group, 2 of 5 urethra showed atrophy of striated and smooth muscles compared to the Sham group. The high dose SARM treatment induced hypertrophy of smooth and striated muscles fascicles compared to the other groups. In the DHT treated OVX group, minimal atrophic striated muscle was observed.

Discussion

We investigated the effect of SARM, GSK2849446A, on urethral continence function during the sneeze reflex in a rat model of SUI induced by bilateral ovariectomy (OVX). The results indicate that high-dose SARM treatment restores the reductions in UBP and A-URS accompanied with urethral muscle hypertrophy, more effectively prevented OVX-induced SUI during sneezing without affecting bladder activity whereas low-dose SARM or DHT treatment only partially prevented SUI during sneezing.

We observed increased body weight and decreased uterine weight after OVX compared to sham operated rats, indicating the success of surgical estrogen deprivation by OVX because previous studies have shown that changes in body and uterine weight are correlated with serum estrogen levels.[20] In addition, our previous study examining the effect of estrogen deficiency on urethral function in rats [5] showed that A-URS is decreased at an early stage (3 weeks after OVX) without inducing SUI during sneezing, and that further reductions of A-URS and UBP are associated with fluid leakage during sneezing at a later stage (6 weeks after OVX).

In the present study, low-dose SARM treatment only restored UBP function without affecting A-URS and partially prevented SUI during sneezing, and t high-dose SARM treatment restored both UBP and A-URS to control levels, and more effectively prevented SUI during sneezing. We previously reported that increased A-URS is mediated by striated muscle contraction of the external urethral sphincter and the pelvic floor muscle due to activation of the pudendal nerves and the somatic nerves, respectively.[7] Thus, the decrease in A-URS after OVX in the current series indicates impaired striated muscle mediated continence mechanisms. Since this neurally evoked striated muscle contraction of the urethral sphincter is important to prevent SUI during sneezing,[19] the decrease in A-URS after OVX likely contributed directly to sneeze induced incontinence in OVX rats at 6 weeks. In contrast to the striated muscle contribution to A-URS, UBP seems to predominantly reflect urethral smooth muscle activity since in our pervious study the increase in UBP was blocked by α-adrenoceptor antagonists such as prazosin or by hypogastric nerve transection.[21] Thus, the decreased UBP 6 weeks after OVX is likely attributable to a decrease in urethral smooth muscle activity rather than striated muscle activity.

Androgen receptors were widely distributed in the pelvic floor and lower urinary tract, particularly striated muscle of levator ani and urethral sphincter.[6, 7] Furthermore, androgen receptors were also found in the smooth muscles of the lower urinary tract.[22] In rabbits, androgen receptors were found in the urethral and trigonal epithelium, detrusor muscle, and smooth muscle of the urethra.[23] Studies on male rats demonstrated that androgen receptors and beta-estrogen receptors were co-expressed in the urothelium, neurons, bladder smooth muscle cells, and urethral striated muscle cells.[24] In the histopathological analysis of this study, high-dose SARM treatment induced hypertrophy not only in the striated muscle but also in the smooth muscle around the urethra. These results suggest that the effects of SARM treatment are dose-dependent and have two phases to restore smooth muscle-related urethral function (=UBP) first at a low dose and then striated muscle-related urethral function (=A-URS) at a high dose. In addition, the urethral sphincter muscle hypertrophy after the SARM treatment in this study is in line with the results of a recent study by Ponnusamy et al. [25] showing the increased weight of pelvic floor muscles in OVX mice after the treatment using other SARM compounds (GTx-024 and GTx-027) although their study did not examine a correlation with functional changes in urethral continence mechanisms.

In the present study, high-dose SARM induced the increase of uterus and bladder weights, but SARM treatment does not affect bladder function in sham or OVX rats. The uterus, which is composed of an endometrium and a myometrium (smooth muscle), is both an estrogen- and androgen-responsible tissue. Administration of dehydrotestosterone (DHT), an active metabolite of testosterone, in OVX rats increased uterus weight, mainly in the myometrium, but DHT also affects the endometrium.[26] The increase in endometrial weight is a serious side effect that could induce uterine cancer or endometriosis. This effect of androgens should be separated from the anabolic effects on micturition so that androgen can be used for the treatment of SUI. However, it has been reported that SARM administration induces the increase the weight of the uterus, especially in the myometrium, the smooth muscle of the uterus, but not the endometrium.[27] Therefore, it seems that SARM treatment is less likely to affect uterine endometrium morphology compared to testosterone or DHT. In addition, the current study showed that SARM treatment at a high dose was more effective at improving SUI in multiple VD rats than DHT. Similar to the anabolic effect of SARM on uterine smooth muscle, the increase of the bladder weight after high-dose SARM treatment might be due to an effect on detrusor smooth muscles. However, the high-dose SARM treatment had no effect on bladder activity, including intravesical pressure and voiding efficiency although we need to pay attention to the anabolic effect of SARM on the uterus, which could induce or worsen myoma or fibroids of the uterus.

In this study, there are some limitations as follows; (1) bladder function was evaluated by cystometry in SARM-treated rats, but not DHT rats because the main purpose of this study was to evaluate the effects of SARM treatment. The role of androgen and its signaling pathways in the control of bladder function will be investigated in future studies, (2) we measured the urethral activity at 6 weeks after OVX in all groups. However, the time schedule of treatments was different between SARM and DHT groups due to the difference in methods of oral or subcutaneous delivery of drugs. Thus, the possibility that the different treatment protocols may be a confounding factor for the data comparison of SRAM and DHT experiments cannot be excluded, (3) we performed cystometry to evaluate bladder activity under an awake condition. However, for the measurements of urethral and leak point pressures during sneeze, we needed to use urethane anesthesia to reduce the body movement of animals. Thus, there is the possibility that these results of our study may not reflect true functionality in the conscious condition, and (4) our results suggest that the mechanism of therapeutic effects of SARM treatment on SUI conditions would involve the urethral sphincter muscle hypertrophy. However, it is possible that SARM may have some effects other than urethral smooth and striated muscle hypertrophy; for example, neuronal or urothelial effects that can improve the urethral continence function. Further studies are needed to clarify these points.”

In conclusion, treatment with SARMs could be an effective modality for the treatment of SUI without affecting bladder function by enhancing smooth and striated muscle mediated urethral function under stress conditions such as sneezing.

Acknowledgement

This work was supported by a research grant from GlaxoSmithKline and a grant from National Institutes of Health (R01 DK107450).

Footnotes

Conflict of interest

The authors of P.T., S.C., T.K., J.B. & A.R. were employees at GlaxoSmithKline; J.B. & A.R. participated in study design, data evaluation and manuscript editing, and P.T., S.C. & T.K. performed the histological analyses with data interpretation.

References

  • 1.Chancellor MB, Perkin H, Yoshimura N. Recent advances in the neurophysiology of stress urinary incontinence. Scand J Urol Nephrol 2005; 39: 21. [DOI] [PubMed] [Google Scholar]
  • 2.Melville JL, Katon W, Delaney K et al. Urinary incontinence in US women: a population-based study. Arch Intern Med 2005; 165: 537–42. [DOI] [PubMed] [Google Scholar]
  • 3.Brown JS, Grady D, Ouslander JG et al. Prevalence of urinary incontinence and associated risk factors in postmenopausal women. Heart & Estrogen/Progestin Replacement Study (HERS) Research Group. Obstet Gynecol 1999; 94: 66–70. [DOI] [PubMed] [Google Scholar]
  • 4.Lucacs ES, Lawrence JM, Contreras R et al. Parity, mode of delivery and pelvic floor disorders. Obstet Gynecol 2006; 107:1253–60. [DOI] [PubMed] [Google Scholar]
  • 5.Kitta T, Haworth-Ward DJ, Miyazato M et al. Effects of ovariectomy and estrogen replacement on the urethral continence reflex during sneezing in rats. J Urol 2011; 186: 1517–23. [DOI] [PubMed] [Google Scholar]
  • 6.Nnodim JO. Testosterone mediates satellite cell activation in denervated rat levator ani muscle. Anat Rec 2001; 263: 19–24. [DOI] [PubMed] [Google Scholar]
  • 7.Celayir S, Ilce Z, Dervisoglu S. The sex hormone receptors in the bladder in childhood-I: preliminary report in male subjects. Eur J Pediatr Surg 2002; 12: 312–7. [DOI] [PubMed] [Google Scholar]
  • 8.George FW, Wilson JD. Hormonal control of sexual development. Vitam Horm 1986; 43: 145–96. [DOI] [PubMed] [Google Scholar]
  • 9.Gooren L Testosterone supplementation: why and for whom? Aging Male 2003; 6: 184–99. [PubMed] [Google Scholar]
  • 10.Bhasin S, Calof OM, Storer TW et al. Drug insight: Testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Pract Endocrinol Metab 2006; 2: 146–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Bhasin S, Bremner WJ. Clinical review 85: Emerging issues in androgen replacement therapy. J Clin Endocrinol Metab 1997; 82: 3–8. [DOI] [PubMed] [Google Scholar]
  • 12.Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004; 350: 482–92. [DOI] [PubMed] [Google Scholar]
  • 13.Davis SR, Tran J. Testosterone influences libido and well being in women. Trends Endocrinol Metab 2001; 12: 33–7. [DOI] [PubMed] [Google Scholar]
  • 14.Ishak KG, Zimmerman HJ. Hepatotoxic effects of the anabolic/androgenic steroids. Semin. Liver Dis 1987; 7: 230–6. [DOI] [PubMed] [Google Scholar]
  • 15.Hanada K, Furuya K, Yamamoto N et al. Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis. Biol Pharm Bull 2003; 26: 1563–9. [DOI] [PubMed] [Google Scholar]
  • 16.Schmidt A, Harada S, Kimmel DB et al. Identification of anabolic selective androgen receptor modulators with reduced activities in reproductive tissues and sebaceous glands. J Biol Chem 2009; 284: 36367–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Narayanan R, Mohler ML, Bohl CE et al. Selective androgen receptor modulators in preclinical and clinical development. Nucl Recept Signal 2008; 6: e010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Miyazato M, Kaiho Y, Kamo I et al. Effect of duloxetine, a norepinephrine and serotonin reuptake inhibitor, on sneeze-induced urethral continence reflex in rats. Am J Physiol Renal Physiol 2008; 295: 264–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Kamo I, Torimoto K, Chancellor MB et al. Urethral closure mechanisms under sneeze-induced stress condition in rats: a new animal model for evaluation of stress urinary incontinence. Am J Physiol Regul Integr Comp Physiol 2003; 285: 356–65. [DOI] [PubMed] [Google Scholar]
  • 20.Yoshida J, Aikawa K, Yoshimura Y et al. The effects of ovariectomy and estrogen replacement on acetylcholine release from nerve fibres and passive stretch-induced acetylcholine release in female rat bladder. Neurourol Urodyn 2007; 26: 1050–5. [DOI] [PubMed] [Google Scholar]
  • 21.Kaiho Y, Kamo I, Chancellor MB et al. Role of noradrenergic pathways in sneeze-induced urethral continence reflex in rats. Am J Physiol Renal Physiol 2007; 292: 639–46. [DOI] [PubMed] [Google Scholar]
  • 22.Berman JR, Almeida FG, Jolin J et al. Correlation of androgen receptors, aromatase, and 5-alpha reductase in the human vagina with menopausal status. Fertil Steril 2003; 79: 925–31. [DOI] [PubMed] [Google Scholar]
  • 23.Rosenweig BA, Bolina PS, Birch L et al. Location and concentration of estrogen, progesterone and androgen receptors in the bladder and urethra of the rabbit. Neurourol Urodyn 1995; 14:87–96. [DOI] [PubMed] [Google Scholar]
  • 24.Salmi S, Santti R, Gustafsson JA et al. Co-localization of androgen receptor with estrogen receptor beta in the lower urinary tract of the male rat. J Urol 2001; 166: 674–7. [PubMed] [Google Scholar]
  • 25.Suriyan P, Ryan DS, Thirumagal T et al. Tissue Selective Androgen Receptor Modulators (SARMs) Increase Pelvic Floor Muscle Mass in Ovariectomized Mice. J Cell Biochem 2017; 118: 640–6. [DOI] [PubMed] [Google Scholar]
  • 26.Furuya K, Yamamoto N, Ohyabu Y et al. The novel non-steroidal selective androgen receptor modulator S-101479 has additive effects with bisphosphonate, selective estrogen receptor modulator, and parathyroid hormone on the bones of osteoporotic female rats. Bio Pharm Bull 2012; 35: 1096–104. [DOI] [PubMed] [Google Scholar]
  • 27.Jones A, Hwang DJ, Duke CB 3rd et al. Nonsteroidal selective androgen receptor modulators enhance female sexual motivation. J Pharmacol Exp Ther 2010: 334: 439–49. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES