Journal of Clinical Lipidology (2016) -, --

1 52
2 53
3 54
4 Original Contribution 55
5 56
6 57
7 The effects of statin treatment on adrenal and 58
8 59
9 sexual function and nitric oxide levels in 60
10 61
11 hypercholesterolemic male patients treated with 62
12 63
13 a statin
Q3 Q1
64
14 65
15 66
16
Q10
Osman Baspnar, MD, Fahri Bayram, MD, Selda Korkmaz, MD, Murat Aksu, MD, 67
17 Derya Kocer, MD, O
guzhan Stk Dizdar, MD, Yasin Simsek, MD, 68
18
Peter P. Toth, MD, PhD* 69
19 70
20 71
21 Department of Internal Medicine, Erciyes University Medical School, Kayseri, Turkey (Dr Baspnar); Department of 72
22 Endocrinology and Metabolism, Erciyes University Medical School, Kayseri, Turkey (Drs Bayram and Simsek); 73
23 Department of Neurology, Acbadem University Medical Faculty, Acibadem Kayseri Hospital, Kayseri, Turkey (Dr 74
24 Korkmaz); Department of Neurology, Erciyes University Medical School, Kayseri, Turkey (Dr Aksu); Department of 75
25 Biochemistry, Kayseri Training and Research Hospital, Kayseri, Turkey (Dr Kocer); Department of Internal Medicine, 76
26Q4 Kayseri Training and Research Hospital, Kayseri, Turkey (Dr Dizdar); CGH Medical Center, Sterling, IL, USA (Dr Toth); 77
27 and Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, 78
28 Baltimore, MD, USA (Dr Toth) 79
29 80
30 81
31 KEYWORDS: BACKGROUND: Erectile dysfunction complaints among men treated with a statin are not uncom- 82
32 Hypercholesterolemia; mon. 83
33 Statin; OBJECTIVES: To evaluate the effect of lowering low-density lipoprotein cholesterol (LDL-C) to 84
34 ACTH; target levels using varying doses of atorvastatin therapy in hypercholesterolemic male patients on adre- 85
Cortisol; nocortical hormones, sexual functions, and serum nitric oxide (NO) levels.
35 86
Testosterone; METHODS: Eleven hypercholesterolemic male patients who had LDL-C levels greater than
36 87
Erectile dysfunction; 160 mg/dL were included in the study and 11 healthy male individuals served as controls. Following
37 basal hormone measurements, 1-and 250-mcg adrenocorticotropic hormone stimulation tests were per- 88
Somatosensory evoked
38 formed in both groups, and blood sampling was performed at 0, 30, and 60 minutes for the determi- 89
potential
39 nation of blood levels of cortisol, total testosterone (TT), free testosterone (FT), 11-deoxycortisol, 90
40 and dehydroepiandrostenedione. Depending on baseline LDL-C concentrations, atorvastatin therapy 91
41 was given to patients with daily doses of 5 or 10 mg and the study procedures were repeated once pa- 92
42 tients reached risk stratified goal LDL-C levels. LDL-C values after treatment were classified into 3 93
43 groups as LDL-C . 160 mg/dL, LDL-C 100 to 130 mg/dL and LDL-C , 100 mg/dL. NO levels 94
44 were measured at baseline and after statin therapy. Erectile function was assessed both objectively 95
45 and subjectively by using penile somatosensory evoked potential (SEP) and the International Index 96
of Erectile Function-5 Questionnaire, respectively, at 3 different LDL-C levels.
46 97
47 98
48 99
49 Q5 * Corresponding author. CGH Medical Center, School of Medicine, Submitted February 11, 2016. Accepted for publication September 4, 100
50 Johns Hopkins University, Sterling, IL 61081, USA. 2016. 101
51 E-mail address: peter.toth@cghmc.com 102

1933-2874/ 2016 Published by Elsevier Inc. on behalf of National Lipid Association.

http://dx.doi.org/10.1016/j.jacl.2016.09.004

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 2 Journal of Clinical Lipidology, Vol -, No -, - 2016

103 160
104 RESULTS: With regard to adrenocorticotropic hormone stimulation test (1 or 250 mcg) results, peak 161
105 cortisol levels before and after statin treatment among 3 LDL-C groups and among controls did not 162
106 differ significantly. However, peak TT and FT hormone levels decreased in conjunction with decreasing 163
levels of LDL-C among the statin-treated patients, whereas dehydroepiandrostenedione and 11-11-
107 164
deoxycortisol peak values did not change. N1 latency obtained during SEP, which is the first negative
108 165
deflection, was prolonged with decreasing levels of LDL-C and a significant decrease in International
109 Index of Erectile Function-5 scores were observed. When LDL-C levels of $ 160 mg/dl was reduced to 166
110 100 to 130 mg/dl, maximal NO elevations were noted. 167
111 CONCLUSIONS: Our results suggest that decreased LDL-C levels caused by different doses of ator- 168
112 vastatin treatment did not associate with significant changes in adrenal hormone levels. In contrast, 169
113 there was a significant relationship between attained LDL-C on statin therapy and TT and FT levels. 170
114 Electrophysiologically, abnormal SEP responses obtained in the patient group with LDL-C levels 171
115 below 100 indicate a negative impact on the integrity of the somatosensory pathway, which plays a 172
116 role in erectile function. Reducing LDL-C with a statin was associated with both decreased testosterone 173
117 levels and erectile dysfunction. 174
2016 Published by Elsevier Inc. on behalf of National Lipid Association.
118 175
119 176
120 177
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122 179
Introduction Materials and methods
123 180
124 Q6 Hypercholesterolemia is a major cardiovascular risk fac- 181
125 Study population 182
tor. Statins are the most efficacious and widely used drug
126 for treating hypercholesterolemia. Statins decrease the mor- 183
Eleven male patients diagnosed with hypercholesterole-
127 tality and morbidity of cardiovascular disease.14 Atorvas- 184
128 mia were enrolled in the study. Eleven age-matched healthy 185
tatin is the most commonly used statin and has been
men without hypercholesterolemia were included as a
129 evaluated in a broad range of clinical trials.5 186
130 control group. The following inclusion criteria were used: 187
Cholesterol is an important regulator of cell membrane
131 (1) age of 18 to 65 years and body mass index , 30 kg/m2; 188
fluidity and is a precursor to bile acids and steroid
132 (2) presence of hypercholesterolemia (morning fasting 189
hormones. Currently available lipid-lowering medications,
133 serum LDL-C . 160 mg/dL); (3) absence of malignant 190
especially when used in combination, can induce consider-
134 hypertension (especially diastolic blood pressure 191
able reductions in circulating levels of low-density lipo-
135 . 95 mm/Hg); (4) absence of diabetes mellitus; (5) absence 192
protein cholesterol (LDL-C). LDL particles are believed to
136 of chronic drug use (except some drugs not affecting the 193
be an important delivery vehicle of cholesterol to steroido-
137 basal hormone levels and without interaction with statins); 194
genic tissues. There is some lingering concern that LDL-C
138 and (6) absence of smoking. Inclusion criteria for the con- 195
lowering may adversely impact the capacity of steroido-
139 trol group were the same as the study group except for fast- 196
genic tissues to produce adrenocortical hormones and sex
140 ing lipid levels. 197
steroids such as testosterone. Some studies have shown a
141 Physical examinations were normal in both study and 198
correlation of statin use with increased risk for erectile
control groups. Liver function tests, thyroid function tests,
142 dysfunction (ED).6,7 The role of endothelial dysfunction is 199
143 and other biochemical tests were normal. Sexual, psycho- 200
well known in atherosclerosis development and nitric oxide
social, and medical histories were assessed in both groups.
144 (NO) plays a crucial role in endothelial dysfunction.8,9 Sta- 201
145 The quality of sexual function was evaluated by using the 202
tins potentiate increased NO production and improved
146 International Index of Erectile Function-5 (IIEF-5) 203
endothelial function by a pleiotropic mechanism indepen-
Questionnaire.11
147 dent from lipid-lowering effects.10 204
148 LDL-C values in the control and patient groups before 205
We investigated the effects of lipid-lowering treatment
149 and after treatment were classified into 3 groups as LDL- 206
with atorvastatin on (1) adrenocortical and androgen
150 C . 160 mg/dL, LDL-C 100 to 130 mg/dL, and LDL-C , 207
hormones and (2) sexual function at different levels of
151 100 mg/dL. 208
LDL-C in hypercholesterolemic male patients. To evaluate
152 erectile function, we performed penile somatosensory 209
153 Atorvastatin therapy 210
evoked potential (SEP) measurements, to assess the impact
154 of statin therapy on the sensorimotor component of penile 211
155 Daily 5- or 10-mg atorvastatin was initiated in all 212
erection. To our knowledge, penile SEP has not been
156 patients according to risk stratified goal LDL-C level to 213
previously studied in hypercholesterolemic patients having
157 be reached. At the end of the first 10-day treatment period, 214
different levels of LDL-C. We also explored the effect of
158 patients were evaluated for myalgia symptoms. aspartate 215
statin treatment on serum NO levels as a pleiotropic effect.
159 aminotransferase, alanine aminotransferase, and creatinine 216

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 Baspnar et al The effects of statin treatment on adrenal and sexual function 3

217 phosphokinase levels were measured. Patients were evalu- Before the SEP recordings, sensory thresholds were 274
218 ated on a monthly basis to assess treatment compliance and determined in each subject. This procedure was defined as 275
219 treatment-related adverse events until an LDL-C level of the lowest stimulus intensity necessary to evoke a sensory 276
220 100 to 130 mg/dL was reached. Pretreatment investigations perception. An initial electrical stimulus, which is 1 mA in 277
221 (steroid hormone levels, 1- and 250-mcg adrenocorticotro- intensity and 0.1 ms in duration is applied to patient/control 278
222 pic hormone (ACTH) stimulation test, SEP, and question- via stimulus electrodes. The stimulus intensity is increased 279
223 naires) were repeated in patients after reaching target gradually by 1 mA until the participant feels the stimulus 280
224 LDL-C level of 100 to 130 mg/dL and ,100 mg/dL. sensation. This stimulus level is described as a sensory 281
225 threshold. For the SEP study, stimulus intensity was 282
226 ACTH stimulating testing determined as 2 times sensory threshold. An average of 283
227 300 stimuli were recorded, and the test repeated 3 times to 284
228 Study and control groups were subjected to hormone testing ensure reproducibility. Latency of N1 was defined as the 285
229 in an endocrinology clinic. ACTH stimulation tests were first negative (upward) deflection of the W-shaped averaged 286
230 performed in both groups by administering 1- and 250-mcg cortical waveform. If the response could not be reproduced 287
231 ACTH. The 2 tests were performed 48 hours apart. Tetraco- at least twice or if the cortical response could not be clearly 288
232 sactrin (1-24, Synacthen; Novartis, Switzerland) was used for identified, the N1 was classified as not evocable. 289
233 the ACTH 250-mcg test. For the 1-mcg ACTH test, tetraco- 290
234 sactrin (1-24, Synacthen; Novartis) was diluted in 250 mL of Erectile dysfunction 291
235 saline and stored at 14
C in the refrigerator up to 6 months. 292
236 Tests were carried out at 8:00 to 9:00 after fasting about 8 to The IIEF-5 questionnaire was used to assess ED in 293
237 10 hours. After taking blood samples for cortisol, total patients (Figure 1).11 The IIEF-5 questionnaire consists of 5 294
238 testosterone (TT), free testosterone (FT), 11-deoxycortisol questions and responses scored from 0 to 5 points and has 295
239 (11-DOC), and dehydroepiandrostenedione (DHEAS) base- been shown to be a good diagnostic tool in making the 296
240 line measurements, 1-mcg ACTH was given by intravenous diagnosis of ED. Patients having scores #21 should be 297
241 bolus for stimulation test. Blood samples were obtained at 30 evaluated for ED.17 298
242 and 60 minutes and assayed for changes in corticosteroid 299
243 levels. The same procedure was performed for the 250-mcg Biochemical procedures 300
244 ACTH test. Sera were stored at 280
C until assayed. 301
245 Measurements of lipid and steroid hormone levels were 302
246 Penile SEP study performed in the Nuclear Medicine and Clinical Biochem- 303
247 istry Laboratories of Erciyes University Medical Faculty. 304
248 A number of clinical neurophysiological tests have been Serum levels of cortisol (IM1841; Prague, Czech Republic), 305
249 used in the evaluation of ED.12,13 SEP is a method to TT (Diasource, Nivelles, Belgium), FT (DSL4900, Prague, 306
250 demonstrate integrity of the somatosensory pathway from Czech Republic), DHEAS (KIP0481; Louvain-la-Neuve, 307
251 peripheral nerve to a relevant region in the brain. Latencies Belgium), and 11-DOC (KIPI20000; Louvain-la-Neuve, 308
252 of the deflections obtained during SEP study is the most Belgium) were measured by radioimmunoassay methods. 309
253 important output. The dorsal penile nerve is one of the 3 Reference values for cortisol, TT, FT, DHEAS, and 11-DOC 310
254 major branches of the pudendal nerve and plays a crucial were 5 to 26 mcg/dL, 134 to 625 ng/dL, 8.69 to 54.6 pg/mL, 311
255 role in male sexual function. The dorsal penile nerve SEP 300 to 3330 ng/dL and 0 to 8 ng/dL, respectively. Serum lipid 312
256 study has been frequently used to evaluate ED in previous levels were measured by an autoanalyzer (Architect c16000; 313
257 investigations.14,15 In the present study, we used penile SEP Abbott Laboratories, Abbott Park, IL) with original kits. 314
258 to assess ED in hypercholesterolemic patients treated with Serum NO levels were measured using Cayman (Catalog No. 315
259 atorvastatin. 780001) commercial enzyme-linked immunosorbent assay, 316
260 Penile SEP studies were performed in a neurophysiology according to the manufacturers instructions. 317
261 laboratory during afternoon hours between 3 PM and 5 PM, 318
262 at room temperature of 23
C. SEP testing was applied only Statistical analysis 319
263 once in members of the healthy control group, whereas it 320
264 was repeated 3 times in the treatment group: LDL-C . In statistical analysis, for normal distribution suitability of 321
265 160 mg/dL (basal measurement), 100 to 130 mg/dL, and the data histogram q-q graphs and the Shapiro-Wilk test were 322
266 ,100 mg/dL. All subjects abstained from sexual activity used. In group comparisons, the Student t test and Mann- 323
267 for 24 hours before testing. Before SEP, nerve conduction Whitney U test were used for independent samples and 324
268 studies were done on all study subjects to exclude periph- one-sided variation analysis (repeated measures analysis of 325
269 eral neuropathy. For SEP studies, stimuli were applied with variance) was used for dependent samples with multiple 326
270 penile ring electrodes according to guidelines of the measurements. A P , .05 was considered significant. Data 327
271 International Federation of Clinical Neurophysiology.16 were expressed as mean 6 standard deviation or median 328
272 Cutaneous stimulus parameters were set at 0.1-ms duration, (25th and 75th percentiles). IBM SPSS analysis Statistics 329
273 square wave pulse, and a frequency of 4 Hz. 20.0 (IBM Inc, Armonk, NY) software package was used. 330

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 4 Journal of Clinical Lipidology, Vol -, No -, - 2016

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375 Figure 1 International Index of Erectile Function-5 (IIEF-5) Questionnaire. Q11 432
376 433
377 The Fishers least significant difference test was used for and control groups were 200.5 6 26.3 and 434
378 multiple comparisons. Also, Bonferroni correction was 100.2 6 16.3 mg/dL, respectively, and there was a statistically 435
379 applied for multiple testing adjustments. A value of P , .01 significant difference between groups (P , .001). Although 436
380 was considered significant for Bonferroni correction analysis. high-density lipoprotein cholesterol and triglyceride levels 437
381 were not different from the controls, total cholesterol levels 438
382
Results were significantly higher in the treatment group (P , .001). 439
383 Table 2 summarizes 1-mcg ACTH stimulation test re- 440
384 As shown in Table 1, there was no statistically significant sults for the control and treatment groups at 0, 30, and 441
385 difference in age between treatment and control groups 60 minutes with peak values and area under the curve 442
386 (P 5 .532). The mean baseline LDL-C levels in treatment values of TT, FT, DHEAS, 11-DOC, and cortisol, before 443
387 444

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 Baspnar et al The effects of statin treatment on adrenal and sexual function 5

445 Q7
502
Table 1 Pretreatment lipid levels of treatment and control groups
446 503
447 Parameters Control group (n 5 11) Treatment group (n 5 11) P 504
448 Age (y) 35.1 6 6.8 37.6 6 11.4 .532 505
449 LDL-C (mg/dL) 100.2 6 16.3 200.5 6 26.3 ,.001 506
450 HDL-C (mg/dL) 37.7 6 6.4 42.3 6 5.5 .089 507
451 Triglyceride (mg/dL) 111.0 (89.0171.0) 154.0 (106.0234.0) .300 508
452 Total cholesterol (mg/dL) 171.0 (157.0176.0) 289.0 (247.0304.0) ,.001 509
453 LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol. 510
454 The data are expressed as mean 6 standard deviation or median (25th or 75th percentiles). 511
455 512
456 513
457 514
458 and after statin treatment. When we compared the treatment Discussion 515
459 group to the control group, we observed that TT and FT 516
460 levels were significantly lower in patients with LDL- LDL particles are a potential reservoir of cholesterol for 517
461 C,100 mg/dL at 0, 30, and 60 minutes. adrenal and gonadal steroidogenesis.7 For this reason, it is 518
462 Table 3 shows 250-mcg ACTH stimulation test results of possible that low LDL-C levels may correlate with reduced 519
463 control and treatment groups at 0, 30, and 60 minutes with production of adrenal and gonadal hormones, but the 520
464 peak values and area under the curve values of TT, FT, threshold level of LDL-C that might induce this effect is 521
465 DHEAS, 11-DOC, and cortisol, before and after statin unknown. Studies on this issue in the literature are scarce 522
466 treatment. Similar to the 1-mcg ACTH stimulation test and available data are conflicting.18,19 523
467 results, the 250-mcg ACTH stimulation test TT and FT Our study investigating the relationship between statin 524
468 levels were significantly lower in patients with LDL-C therapy and ED by using SEP has not been previously 525
469 , 100 mg/dL than control and other study groups with performed, although some studies suggested that statin 526
470 LDL-C . 160 mg/dL and LDL-C 100130 mg/dL. Com- therapy does not have any effect on erectile function.20,21 In 527
471 parison of steroid hormone levels of groups according to a study conducted by Santini et al,22 diabetic patients were 528
472 1- and 250-mcg ACTH stimulation tests are summarized treated with daily 20-mg atorvastatin for 3 months. No sta- 529
473 in Tables 2 and 3. tistically significant difference was found between pretreat- 530
474 There was a significant difference between patients hav- ment and posttreatment levels of cortisol, DHEAS, TT, and 531
475 ing LDL-C . 160 mg/dL and the control group in terms of androstenedione. Stanworth et al23 conducted a study in 532
476 basal N1 latency (P 5 .029). In the patient group, a second which 355 patients with diabetes were treated with atorvas- 533
477 measurement of N1 latency was performed when LDL-C tatin or simvastatin. Statistically significant decreases in TT 534
478 130 to 160 mg/dL and a third was done when LDL-C , levels were found in the atorvastatin group but not the sim- 535
479 100 mg/dL. There was no significant difference between first vastatin group. Medras et al24 assessed the effect of treat- 536
480 and second measurements or between second and third mea- ment with statins on testosterone levels in men. They 537
481 surements. However, when comparing the first to the last studied 189 men, 38 of whom were treated with simvastatin 538
482 measurement, when LDL-C , 100 mg/dL, N1 latency was or atorvastatin and the study demonstrated that men treated 539
483 prolonged (P 5 .029). In addition, severity of sensory with statins had significantly lower TT and FT levels. A 540
484 threshold in patients having LDL-C , 100 mg/dL was higher meta-analysis of placebo-controlled randomized trials that 541
485 than in healthy controls (P 5 .039). SEP data of study sub- assessed the effect of statins on testosterone among men 542
486 jects are summarized in Table 4. Table 5 summarizes IIEF- suggested statins reduce testosterone.25 543
487 5 scores in the control and patient groups. Baseline IIEF-5 To evaluate adrenal function, Sezer et al26 performed a 544
488 scores in control and treatment groups with LDL-C . 1-mcg ACTH stimulation test in their study conducted 545
489 160 mg/dL were 23.7 6 1.4 and 24.1 6 1.5, respectively, with 41 patients (mean LDL-C level 58 mg/dL on statin 546
490 and there was no statistically significant difference. IIEF-5 treatment) and 38 healthy controls (mean LDL-C level 547
491 scores in the treatment groups before and after statin treat- 131 mg/dL). They found no difference in cortisol levels be- 548
492 ment (LDL-C with 160 mg/dL, LDL-C 100130 mg/dL, tween patient and control groups, consistent with our study. 549
493 and LDL-C , 100 mg/dL) were 24.1 6 1.5, 16.1 6 3.0, But in contrast to our study they did not analyze sex ste- 550
494 9.73 6 3.0, respectively. The difference between groups roids, especially testosterone. In a 2-year study conducted 551
495 was statistically significant (P , .05). by Kanat et al,27 98 diabetic patients from 4 centers in 552
496 As shown in Table 6, NO levels in patients with LDL-C Turkey were divided into 2 groups. Patients in group 1 553
497 100 to 130 mg/dL increased significantly compared with were treated with 10-mg ezetimibe and 10-mg atorvastatin 554
498 baseline. NO levels in the treatment group with LDL-C daily for the first 3 months and 80 mg atorvastatin daily for 555
499 , 100 mg/dL was significantly higher compared with base- the next 3 months. Patients in group 2 were treated with 80- 556
500 line, but it was lower than in patients with LDL-C between mg atorvastatin daily for the first 3 months and 10-mg eze- 557
501 100130 mg/dL. timibe plus 10-mg atorvastatin daily for the next 3 months. 558

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6
Table 2 Steroid hormone levels in controls and statin-treated groups in response to 1-mcg ACTH
Control LDL-C . 160 mg/dL LDL-C, 100130 mg/dL LDL-C , 100 mg/dL
Variable (n 5 11) (n 5 11) P1 (n 5 11) P2 (n 5 11) P3 P4
TT
00 780.4 6 295.9 659.4 6 229.1 .296 589.0 6 204.3 .093 435.1 6 169.6 .003 ,.001
300 767.2 6 277.5 602.4 6 212.8 .134 491.1 6 133.9 .008 379.6 6 115.2 ,.001 ,.001
600 697.3 6 281.9 652.6 6 235.9 .691 547.7 6 136.1 .129 399.5 6 133.4 .005 .005
6 6 6 6 ,.001
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Peak 864.4 290.8 761.4 226.6 .365 666.0 165.6 .063 497.4 155.6 .001
AUC 45,180.0 6 15,108.6 37,750.9 6 11,061.9 .203 31,783.6 6 6946.0 .015 23,907.2 6 6804.0 ,.001 ,.001
FT
00 13.8 6 4.2 12.8 6 3.5 .558 10.0 6 2.5 .019 7.9 6 1.9 ,.001 ,.001
300 14.6 6 3.0 12.5 6 4.4 .189 8.8 6 1.7 ,.001 7.4 6 2.3 ,.001 ,.001
600 13.9 6 4.6 11.61 6 3.9 .224 9.76 6 2.5 .016 7.05 6 2.5 ,.001 ,.001
Peak 15.97 6 3.9 13.9 6 4.2 .249 10.7 6 2.4 .001 8.4 6 2.2 ,.001 ,.001
AUC 853.9 6 187.2 739.5 6 218.0 .202 561.4 6 109.0 ,.001 446.1 6 125.9 ,.001 ,.001
DHEAS
00 2565.6 6 946.9 2630.4 6 1078.4 .882 1992.9 6 878.9 .157 2101.6 6 1078.4 .296 .033
300 2494.1 6 708.6 2491.9 6 1153.6 .996 2129.0 6 822.1 .278 1904.0 6 827.6 .088 .109
600 2494.5 6 712.3 2552.0 6 1195.4 .892 2102.3 6 909.2 .273 2065.0 6 974.5 .252 .124
Peak 2730.9 6 829.9 2818.4 6 1145.1 .840 2284.6 6 867.0 .232 2259.6 6 1048.3 .256 .055
AUC 150,722.7 6 44,625.3 152,492.7 6 67,497 .943 125,297.7 6 49,831.4 .222 119,619.5 6 53,254.3 .153 .068

Journal of Clinical Lipidology, Vol -, No -, - 2016

11-DOC
0 1.6 6 0.3 1.9 6 0.7 .099 1.8 6 0.7 .332 1.7 6 0.7 .634 .410
30 2.1 6 0.7 3.24 6 0.56 ,.001 2.67 6 0.82 .077 2.87 6 0.9 .030 .148
60 1.7 6 0.4 2.6 6 0.7 ,.001 2.2 6 1.0 .087 1.9 6 0.7 .193 .149
Peak 2.2 6 0.6 3.3 6 0.6 ,.001 3.1 6 0.9 .012 2.9 6 0.8 .020 .525
AUC 109.9 6 24.4 165.5 6 26.7 ,.001 140.4 6 29.6 .016 140.6 6 33.7 .024 .044
Cortisol
00 10.7 6 2.3 12.8 6 3.7 .123 11.4 6 3.6 .592 10.6 6 1.8 .859 .219
300 23.8 6 5.8 20.7 6 3.9 .153 20.9 6 6.8 .294 19.5 6 5.6 .094 .705
600 17.8 6 3.8 13.7 6 2.4 .007 14.4 6 3.8 .046 15.8 6 3.2 .203 .048
Peak 24.5 6 5.2 20.7 6 3.8 .066 21.6 6 5.8 .226 19.9 6 5.2 .055 .564
AUC 1141.9 6 187.3 1017.5 6 126.2 .083 1014.0 6 266.7 .208 982.0 6 212.3 .076 .786
ACTH, adrenocorticotropic hormone; AUC, area under the curve; DHEAS, dehydroepiandrostenedione; 11-DOC, 11-deoxycortisol; FT, free testosterone; TT, total testosterone.
P1 shows the somatosensory evoked potential data comparison with the Student t test between control group and patients with low-density lipoprotein cholesterol . 160 mg/dL. P2 shows the somato-
sensory evoked potential data comparison with the Student t test between control group and patients with low-density lipoprotein cholesterol 100130 mg/dL. P3 shows the somatosensory evoked potential
data comparison with the Student t test between control group and patients with low-density lipoprotein cholesterol , 100 mg/dL. P4 shows the participant somatosensory evoked potential values at different
low-density lipoprotein cholesterol values comparison with the 1-way analysis of variance in repeated measurements.
Adjusted P values less than .01 was considered statistically significant.
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Baspnar et al
Table 3 Steroid hormone levels in controls and statin treatment groups in response to 250-mcg ACTH Q9

LDL-C . 160 mg/dL LDL-C, 100130 mg/dL LDL-C , 100 mg/dL

Variable Control (n 5 11) (n 5 11) P1 (n 5 11) P2 (n 5 11) P3 P4

The effects of statin treatment on adrenal and sexual function

TT
00 730.3 6 207.0 592.6 6 237.6 .163 554.7 6 203.3 .059 416.7 6 169.5 .001 .022
300 755.5 6 261.2 542.9 6 167.0 .034 413.3 6 176.3 .002 384.7 6 147.3 .001 .001
600 727.3 6 246.6 589.8 6 278.1 .234 435.8 6 158.0 .004 344.3 6 141.4 ,.001 ,.001
Peak 829.4 6 245.2 702.2 6 236.6 .230 579.4 6 191.4 .015 441.6 6 158.4 ,.001 .002
AUC 44,526.8 6 13,591.6 34,022.7 6 11,360.6 .063 27,256.3 6 9070.9 .002 22,956.8 6 8566.5 ,.001 ,.001
FLA 5.4.0 DTD  JACL988_proof  29 September 2016  8:18 pm

FT
00 13.7 6 3.9 11.2 6 3.0 .116 9.7 6 2.8 .012 7.6 6 2.3 ,.001 ,.001
300 14.7 6 3.2 12.1 6 3.3 .078 9.6 6 2.7 .001 7.4 6 2.1 ,.001 ,.001
600 14.7 6 3.9 10.4 6 3.5 .013 8.3 6 1.4 ,.001 7.4 6 2.4 ,.001 .003
Peak 16.1 6 3.2 12.7 6 3.1 .018 10.4 6 2.8 ,.001 862.2 ,.001 ,.001
AUC 865.5 6 183.2 688.4 6 185.1 .036 557.8 6 133.3 ,.001 448.3 6 126.7 ,.001 ,.001
DHEAS
0 2422.7 6 673.1 2568.4 6 1208.3 .731 2168.6 6 986.9 .489 1832.7 6 833.8 .083 .043
30 2357.2 6 606.0 2583.8 6 1073.8 .549 2104.3 6 894.5 .448 1835.8 6 780.9 .096 .012
60 2492.7 6 657.7 2759.1 6 1335.3 .559 2175.9 6 891.9 .354 1955.0 6 610.2 .061 .060
Peak 2578.6 6 674.7 2922.4 6 1388.5 .469 2358.6 6 1006.9 .555 2150.9 6 717.6 .165 .074
AUC 144,447.2 6 37,181.4 157,426.3 6 68,301.8 .586 128,296.3 6 53,735.5 .423 111,890.4 6 42,353.4 .070 .021
11-DOC
00 1.7 6 0.4 2.0 6 0.5a .066 1.6 6 0.5a .918 1.3 6 0.3b .020 .002
300 2.6 6 0.9 3.4 6 1.0 .090 2.9 6 0.8 .496 2.5 6 0.9 .731 .054
600 2.5 6 0.9 3.8 6 1.2 .008 4.0 6 1.4 .006 3.7 6 1.4 .020 .738
Peak 3.1 6 0.9 4.1 6 1.1 .024 4.1 6 1.3 .036 3.8 6 1.3 .166 .558
AUC 140.8 6 32.6 188.8 6 45.3 .010 171.5 6 37.6 .054 150.0 6 44.1 .585 .007
Cortisol
00 12.5 6 3.4 11.7 6 4.2 .630 11.9 6 3.4 .699 12.3 6 3.0 .917 .872
300 20.8 6 5.3 18.7 6 5.3 .365 22.2 6 5.1 .528 21.2 6 3.2 .824 .137
600 27.2 6 7.3 27.3 6 7.2 .980 25.3 6 5.2 .483 26.8 6 7.2 .897 .646
Peak 27.6 6 6.6 27.4 6 6.9 .957 25.9 6 5.4 .516 27.5 6 6.4 .974 .668
AUC 1219.1 6 241.3 1145.1 6 246.9 .486 1224.4 6 218.1 .957 1223.5 6 203.1 .963 .482
ACTH, adrenocorticotropic hormone; AUC, area under the curve; DHEAS, dehydroepiandrostenedione; 11-DOC, 11-deoxycortisol; FT, free testosterone; LDL-C, low-density lipoprotein cholesterol; TT, total
testosterone.
P1 shows the somatosensory evoked potential data comparison with the Student t test between control group and patients with LDL-C . 160 mg/dL. P2 shows the somatosensory evoked potential data
comparison with the Student t test between control group and patients with LDL-C 100130 mg/dL. P3 shows the somatosensory evoked potential data comparison with the Student t test between control
group and patients with LDL-C , 100 mg/dL. P4 shows the participant somatosensory evoked potential values at different LDL-C values comparison with the 1-way analysis of variance in repeated
measurements.
Adjusted P values less than .01 were considered statistically significant.

7
786
785
784
783
782
781
780
779
778
777
776
775
774
773
772
771
770
769
768
767
766
765
764
763
762
761
760
759
758
757
756
755
754
753
752
751
750
749
748
747
746
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739
738
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736
735
734
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731
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 8 Journal of Clinical Lipidology, Vol -, No -, - 2016

787 844
Table 4 Variables obtained from SEP comparison among patients with different LDL-C value and control group
788 845
789 LDL-C . LDL-C, LDL-C 846
790 Control 160 mg/dL 100130 mg/dL , 100 mg/dL 847
791 Variable (n 5 11) (n 5 11) P1 (n 5 11) P2 (n 5 11) P3 P4 848
792 Warning 12.3 6 2.8 14.6 6 4.9 .217 15.7 6 5.7 .115 18.0 6 7.3 .039 .275 849
793 threshold 850
794 N1 latency 26.2 6 2.1 27.20 6 2.41 .443 31.8 6 6.7 .070 33.3 6 6.7 .029 .029 851
795 SEP, somatosensory evoked potential; LDL-C, low-density lipoprotein cholesterol. 852
796 P1 shows the SEP data comparison with the Student t test between control group and patients with LDL-C . 160 mg/dL. P2 shows the SEP data 853
797 comparison with the Student t test between control group and patients with LDL-C 100130 mg/dL. P3 shows the SEP data comparison with the Student 854
798 t test between control group and patients with LDL-C , 100 mg/dL. P4 shows participant SEP values at different LDL-C values comparison with the 1-way 855
analysis of variance in repeated measurements.
799 856
800 857
801 858
802 859
DHEAS, FT, and cortisol levels were measured. DHEAS mean IIEF-5 score decreased from 21 (normal value) to
803 860
and FT decreased significantly in both groups. Cortisol 6.5 after statin treatment.
804 861
levels decreased to below normal range during the daily Theoretically, statins seem to be a double-edged therapy
805 862
80-mg atorvastatin but increased to previous levels during for patients with ED. Kostis et al29 examined the effect of
806 863
daily combination atorvastatin and ezetimibe therapy. How- statin therapy on ED using the IIEF; the average age of par-
807 864
ever, patients were not evaluated with sexual scoring or ticipants and the degree of LDL cholesterol lowering did
808 865
ACTH stimulation tests. not alter the effect on IIEF. In contrast to our work, they
809 866
In our study, although TT, FT, DHEAS, and 11-DOC found that statins caused a clinically relevant improvement
810 867
levels decreased by lowering LDL-C levels, no significant of erectile function. Other studies have shown that statin
811 868
reduction in cortisol levels was detected. Patients reported therapy may reduce levels of testosterone and aggravate
812 869
libido reduction after lowering LDL-C levels. Contrary to ED.30 However, Nurkalem et al31 suggest that different sta-
813 870
the aforementioned studies, we evaluated not only baseline tins may have different effects on ED.
814 871
hormone levels but also hormone levels after standard and In the present study, IIEF-5 scores decreased signifi-
815 872
low-dose ACTH stimulation tests. Therefore, this is the first cantly from 24.1 at baseline decreased to 16.1 and 9.7 in
816 873
study evaluating hormonal changes in high, moderate, and patients treated to LDL-C levels of 100 to 130 mg/dL and
817 874
low LDL-C levels with 1- and 250-mcg ACTH stimulation ,100 mg/dL, respectively. Our study is the only study
818 875
tests. The aforementioned studies are generally short-term investigating ED caused by low LDL-C level on statin
819 876
studies in which the duration of treatment might affect treatment by using not only IIEF-5 but also the SEP test.
820 877
hormonal levels. In our study, patients used statins for There is clinical evidence that peripheral somatosensory
821 878
approximately 9 months. input to the central nervous system contributes to the male
822 879
The number of studies investigating ED caused by low sexual response. The primary source of somatosensory
823 880
LDL-C levels on statin treatment by using the ACTH information for sexual reflexes is mediated through the
824 881
stimulation test and IIEF-5 questionnaire are negligible. dorsal penile nerve. Our study demonstrates that N1 latency
825 882
Solomon et al28 treated 93 patients with cardiovascular risk is prolonged when LDL-C , 100 mg/dL compared with
826 883
factors with a statin for 6 months and reported that the other measurements and healthy controls. Consequently,
827 884
828 885
829 886
830 887
Table 5 Comparison of IIEF-5 scores among patients in different LDL-C groups and patient and control groups
831 888
832 LDL-C between 889
833 LDL-C . 160 mg/dL 100 and 130 mg/dL LDL-C , 100 mg/dL 890
834 Group (n 5 11) (n 5 11) (n 5 11) P* 891
835 Patient 24.1 6 1.5 16.1 6 3.0 9.7 6 3.0 ,.001 892
836 Control 23.7 6 1.4 893
837 P .549 894
838 IIEF-5, International Index of Erectile Function-5; LDL-c, low-density lipoprotein cholesterol. 895
839 Data are expressed as mean 6 standard deviation. Different letters in the same row refers to differences between groups, the same letters in the same Q8 896
840 row refers to the similarity between the groups. 897
841 *The comparison between LDL groups. 898
The comparison between patient and control.
842 899
843 900

FLA 5.4.0 DTD  JACL988_proof  29 September 2016  8:18 pm

 Baspnar et al The effects of statin treatment on adrenal and sexual function 9

901 958
Table 6 Comparison of nitric oxide levels among patients in different LDL-C groups and patient and control groups
902 959
903 LDL-C . 160 mg/dL LDL-C 5 100130 mg/dL LDL-C , 100 mg/dL 960
904 Group (n 5 11) (n 5 11) (n 5 11) P* 961
905 Patient 42.3 6 10.7a 54.3 6 16.6b 47.9 6 11.5ab .016 962
906 Control 35.1 6 7.2 35.1 6 7.2 35.1 6 7.2 963
907 P .078 .004 .005 964
908 LDL-c, low-density lipoprotein cholesterol. 965
909 Data are expressed as mean 6 standard deviation. Different letters in the same row refers to differences between groups, the same letters in the same 966
910 row refers to the similarity between the groups. 967
911 *The comparison between LDL groups. 968
The comparison between patient and control.
912 969
913 970
914 971
915 972
916
abnormal penile SEP responses are an indicator of the 59.7 years; mean LDL-C 126.34 mg/dL) were treated with 973
917
presence of ED. atorvastatin (10-80 mg/day) for 3 months and plasma NO 974
918
Penile SEP measurements were repeated 3 times during was significantly increased. In the present study, increased 975
919
this study and the latency of N1 was found to be prolonged NO levels with statin treatment were found but NO levels 976
920
when the levels of LDL-C were reduced progressively more decreased when LDL-C decreased to ,100 mg/dL. SEP indi- 977
921
by statin therapy. The most prominent prolongation of N1 cated prolonged latency at LDL-C , 100 mg/dL. In addition, 978
922
latency was observed in patients with the lowest LDL-C the IIEF-5 questionnaire score decreased at levels of LDL-C 979
923
levels (below 100 mg/dL). The prolongation in the N1 , 100 mg/dL. In this context, reductions in NO levels at 980
924
latency was consistent with the alteration of serum low LDL-C concentrations could potentiate ED. 981
925
testosterone and the complaints related to ED, which was The small number of cases we evaluated is a limitation 982
926
assessed by using a questionnaire. The clinical importance of this study. But the present study is an exploratory study. 983
927
of the elevation in the sensory threshold is unknown and SEP was performed 3 times for each patient and patients 984
928
further studies are necessary. were followed for 3 years. Long study duration and the 985
929
There is some evidence that penile SEP may be used to testing required proved difficult for many patients and 986
930
assess integrity of the sensorimotor pathway, which is precluded us from including more patients in the study. 987
931
essential for the maintenance of penile erection during In conclusion, decreased LDL-C levels caused by 988
932
sexual intercourse,32 although the literature is controver- different doses of atorvastatin treatment did not associate 989
933
sial.33 Based on our study results, it is clear that the SEP with significant changes in adrenal hormone levels. In 990
934
response is a useful diagnostic tool for the definition of contrast, there was a significant relationship between attained 991
935
ED development during statin use in hypercholesterolemic LDL-C on statin therapy and TTand FT levels. We also found 992
936
patients. Another very important finding from our study is decreased IIEF-5 scores in response to LDL-C lowering. SEP 993
937
the observation that high LDL-C levels did not interrupt data support the conclusion that the development of ED 994
938
the central response to dorsal penile nerve stimulation, sug- correlates with low LDL-C and testosterone levels. This will 995
939
gesting that hypercholesterolemia (in the absence of signif- need to be studied further in a larger number of patients. 996
940
icant pudendal artery atherosclerosis) in and of itself is not 997
941
etiologic for ED. 998
The role of endothelial dysfunction is established in Acknowledgments
942 999
atherogenesis and NO plays a crucial role in normal
943 The authors are thankful to Turcosa Analytics Ltd Co 1000
vascular function.8,34 In the setting of endothelial dysfunc-
944 (www.turcosa.com.tr) for their statistical assistance. 1001
tion, increased NO modification by oxidative mechanisms
945 Authors Contributions: Drs Bayram, Baspnar, Aksu, and 1002
is activated in patients with hypercholesterolemia. Unlike
946 Korkmaz participated in the design of the study, data 1003
947
other cholesterol-lowering agents, statins in vitro increase acquisition, and managed the patients. Drs Baspnar, Dizdar, 1004
948
NO production by inducing and regulating endothelial ni- and Simsek analyzed the data. Drs Baspnar, Kocer, and Toth 1005
tric oxide synthase.35 NO is an important vasodilator pro-
949 wrote the manuscript. All authors participated in data 1006
duced by arterial endothelial cells. Smooth muscle cells
950 interpretation and read and approved the final manuscript. 1007
951
of penile cavernous tissue relax and blood vessels dilate 1008
952
in response to NO during penile erection. 1009
953
There are studies showing the effect of statin therapy on NO Financial disclosures 1010
954
in the literature, but studies showing NO levels according to 1011
955
different serum LDL-C levels and the relationship with libido The authors report no conflicts of interest. The authors 1012
956
are scarce. In a study conducted by Basarl et al,36 50 patients alone are responsible for the content and writing of the 1013
957
with an acute myocardial infarction (42 males; mean age: article. 1014

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 10 Journal of Clinical Lipidology, Vol -, No -, - 2016

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