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Basic Science

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  2. Basic Science
  3. Psychology
  4. Clinical Research—Female
  5. Clinical Research—Male Editor's Note:
  6. Editor's Note:

Androgen and estrogen receptor-mediated mechanisms of testosterone action in male rat pelvic autonomic ganglia. TD Purves-Tyson, MS Arshi, DJ Handelsman, Y Cheng, JR Keast. Neuroscience 2007;148:92–104.

Editorial Comment: There is an increasing appreciation for the impact of steroid hormones on nerve growth and function. Recent studies have specifically examined the dependence of pelvic autonomic nerves on testosterone during development and maturation. In addition, as new data continue to confirm the critical role of androgens in multiple aspects of erectile function, detailed examination of androgenic mechanisms is warranted. In this study, the investigators examined the pelvic ganglia from intact and orchiectomized rats. Subgroups of orchiectomized animals were subjected to estradiol, testosterone, or dihydrotestosterone (DHT) replacement regimens for 4 weeks. The soma size of the pelvic ganglia decreased in vehicle-treated and estradiol-treated orchiectomized animals, whereas testosterone or DHT treatment prevented this atrophic response. Neurite growth was stimulated by estradiol, testosterone, or DHT in cultured pelvic ganglion cells that were positive for either tyrosine hydroxylase (adrenergic nerve marker) or nitric oxide synthase. Importantly, the effects of testosterone were prevented or attenuated by androgen or estrogen receptor antagonists or by the aromatase inhibitor letrozole. Further, the expression of aromatase and both isoforms of the estrogen receptor (ERα and ERβ) were confirmed in the pelvic ganglia by reverse transcriptase polymerase chain reaction, Western blot analyses, and immunohistochemical localization. These data suggest that estrogen can be synthesized from testosterone within the pelvic ganglion and that estradiol is partially responsible for some of the trophic effects of testosterone, particularly on neurite growth and branching. Future studies along these lines should prove beneficial in understanding the consequences of changes in the hormonal milieu with regard to nerve growth, regeneration, and function of urogenital tissues.

Noel N. Kim, PhD

Transforming growth factor-β1 null mutation causes infertility in male mice associated with testosterone deficiency and sexual dysfunction. WV Ingman, SA Robertson. Endocrinology 2007;148:4032–43.

Editorial Comment: Elevated levels of transforming growth factor beta-1 (TGF-β1) have been widely associated with tissue fibrosis and pathophysiologic conditions, including genital organ dysfunction. Yet, the elimination of TGF-β1 expression can have equally drastic consequences. Mice that do not express the Tgfb1 gene are deficient in TGF-β1 protein and acquire multifocal inflammatory lesions with a severely compromised lifespan (3 weeks). In this study, immunodeficient Tgfb1 null mice were used, as they can survive well into adulthood. Tgfb1 null mice had significantly lower concentrations of serum luteinizing hormone, follicle stimulating hormone, testosterone, and androstenedione, while serum estradiol was unaffected. Serum testosterone was similarly reduced in heterozygous mice. While Tgfb1 null mice had lower body weights (20% less than age-matched controls), wet weights for testis, seminal vesicle, and penis were not significantly different from the controls when adjusted for total body weight. Notably, the lungs of Tgfb1 null mice had 50% greater mass than the controls, while peritoneal fat and spleen mass were 40% and 60% lower, respectively. Histologic examination revealed no overt differences in tissue structure of seminal vesicle and penis between null mutants, heterozygotes, and controls. However, mating behavior was attenuated in Tgfb1 null mice when exposed to healthy, receptive females. Although initial interest was normal, mounting activity and intromission were decreased with no ejaculation during the 2-hour test period, as evidenced by lack of vaginal plugs or sperm-positive vaginal smears. Spermatogenesis was normal in some Tgfb1 null mice, while others exhibited impaired sperm development. Mature sperm extracted from Tgfb1 null mice were shown to be competent by successful in vitro fertilization of oocytes that developed into the blastocyst stage at a rate comparable to the sperm from the control animals. Erectile response was deemed normal, as rectal electroejaculation probes produced normal cups and flips of the penis with ejaculation in half of the test subjects irrespective of genotype. However, further investigation into potential deficits in the erectile function (either neurogenic or vasculogenic) should be pursued. The administration of human chorionic gonadotropin increased testosterone levels in both Tgfb1 null and heterozygous mice. Surprisingly, testosterone replacement regimens did not restore mating behavior or reproductive success in Tgfb1 null mice, irrespective of whether they were exposed to testosterone during neonatal development. These findings suggest that TGF-β1 deficiency may cause alterations in the hypothalamic–pituitary–gonadal axis and thereby disrupt steroid hormone production. The unexpected responses of Tgfb1 null mice may be because of the compensation by other cytokines in the TGF-β family. The role of TGF-β1 in modulating reproductive behavior and sexual function is undoubtedly complex and likely involves numerous, independent mechanisms.

Noel N. Kim, PhD

An animal model to study lower urinary tract symptoms and erectile dysfunction: The hyperlipidaemic rat. NU Rahman, S Phonsombat, D Bochinski, RE Carrion, L Nunes, TF Lue. BJU Int 2007;100:658–63.

Editorial Comment: There is a strong association between lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) in aging men. This correlation has led many to postulate that common mechanisms may underlie the development of LUTS and ED. Yet, explicit links between LUTS and individual risk factors for ED remain unclear. Given that hyperlipidemia is a known risk factor for ED and men with increased waist circumference are more likely to develop LUTS, the investigators evaluated the hyperlipidemic rat as a model for studying both LUTS and ED. Male Sprague-Dawley rats were placed on a high-fat, high-cholesterol diet for 6 months. Predictably, these rats had higher body weight and total cholesterol and, as shown previously, they had significantly compromised erectile function. In addition, hyperlipidemic rats had higher prostate weights and overactive bladders. In hyperlipidemic rats, smooth muscle hypertrophy was observed in the anterior lobe of the prostate. Immunohistochemical analyses in prostate tissue sections indicated decreased nitric oxide synthase-containing nerve fibers, while staining for adrenergic nerve fibers was intense. Hyperlipidemic rats also had increased expression of α1A-adrenergic receptors in the endothelium and on the nerve fibers and higher levels of purinergic (P2X1 and P2X3) and vanilloid (VR1) receptors in the bladder. In addition to mediating bladder contractility (α1A and P2X1), some of these receptors are thought to mediate bladder sensation (P2X3), and pain and micturition reflex (VR1). Interestingly, although the bladder wall was thickened, no fibrosis was noted in hyperlipidemic rats. Thus, changes in innervation, prostate and bladder cellular hypertrophy, and overexpression of specific receptors may be responsible for the development of LUTS symptoms. The investigators further speculate that the hyperlipidemic rat may even be a better model to study benign prostatic hypertrophy as these rats exhibit smooth muscle hypertrophy, similar to humans, whereas hormonally manipulated rats exhibit only glandular hyperplasia. While the progression of pathophysiologic complications in a hyperlipidemic individual remains poorly defined, the characterization of an animal model that could be used for further investigation into these combined conditions, is noteworthy.

Noel N. Kim, PhD

Psychology

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  2. Basic Science
  3. Psychology
  4. Clinical Research—Female
  5. Clinical Research—Male Editor's Note:
  6. Editor's Note:

A study of sexuality and health among older adults in the United States. ST Lindau, LP Schumm, EO Laumann, W Levinson, CA O’Muircheartaigh, LJ Waite. N Engl J Med 2007;357:762–74.

Editorial Comment: In a representative, probability sample of community-dwelling US adults (75% response rate), between 57 and 85 years of age (N = 3,005; 1,550 women and 1,455 men), women were significantly less likely than men at all ages to report sexual activity. Those who had had sex with at least one partner in the previous 12 months declined with age, ranging among men from 39% to 84%, and among women from 54% to 68%. One-half of the men and one-quarter of the women reported masturbating in the last year. Among the sexually active subjects, about half of both genders reported at least one bothersome sexual problem with more than one-third of the women reporting low desire, problems with vaginal lubrication, and inability to climax, and 37% of the men reporting erectile dysfunction. Sexual inactivity was associated with poor perceived health, presence of diabetes, partner's sexual dysfunction, and lack of a partner (greatest in the oldest group of women). Few subjects had discussed their sexual problems with their doctor, and only 14% of men and 1% of women had taken medication or supplements to improve their sexual function in the last year. Limitations of this study include underestimation of the extent of sexual problems in this population because of assessing prevalence only among those who were sexually active. These data suggest that a significant percentage of elder adults are sexually active; thus, health care providers should initiate discussions about sexual function with their older patients. Level of evidence = 3

Anita H. Clayton, MD

Sexual practices and sexual satisfaction: A population-based study of Chinese urban adults. WL Parish, Y Luo, R Stolzenberg, EO Laumann, G Farrer, S Pan. Arch Sex Behav 2007;36:5–20.

Editorial Comment: A nationally representative urban Chinese sample of 1,194 women and 1,217 men, ages 20–64 years, who had had sex in the previous year with a spouse or long-term partner were interviewed as part of the China Health and Family Life Survey. With oversampling of geographic areas with high rates of sexually transmitted diseases, the response rate was 76%. On five indicators of sexual satisfaction, significantly more men (8–24% greater likelihood) reported extreme categories of response than women, and men reported more frequent orgasm. Types of sexual behaviors were similar among both genders for woman on top, sex from behind, oral sex, and anal sex, with one-third reporting that their living situation hindered sexual activity. Women were less likely to believe in sexual equality or to be able to identify the clitoris, with sexual satisfaction primarily affected by ability to achieve orgasm and diverse sexual activities, and to a lesser degree, perceived partner affection. Greater education was associated with lower sexual satisfaction. Relationship variables significantly affected sexual satisfaction, with partner's physical attractiveness important to men, while women valued their own attractiveness. Reduced physical vitality and fear of pregnancy negatively affected satisfaction. Limitations include assessing only a sexually active urban population in a long-term relationship or marriage. The authors suggest that the Chinese society is in the middle of a sexual transition, although attitudes remain primarily driven by evolutionary influences for both genders. Level of evidence = 3

Anita H. Clayton, MD

Clinical Research—Female

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  2. Basic Science
  3. Psychology
  4. Clinical Research—Female
  5. Clinical Research—Male Editor's Note:
  6. Editor's Note:

Mediterranean diet improves sexual function in women with metabolic syndrome. K Esposito, M Ciotola, F Giugliano, B Schisano, R Autorino, S Iuliano, MT Vietri, M Cioffi, M De Sio, D Giugliano. Int J Impot Res 2007;19:486–91.

Editorial Comment: Investigators in this study examined the effect of the Mediterranean diet on sexual function in women with metabolic syndrome (increased abdominal adiposity, low levels of high density lipoprotein, hypertriglyceridemia, increased blood pressure, and abnormal glucose metabolism). Only patients diagnosed with sexual dysfunction were included in the study. The diet was regulated with measured portions and consisted of whole grains, fruits, vegetables, legumes, walnuts, and olive oil. Study subjects were screened with the Female Sexual Function Index (FSFI) questionnaire and were instructed to keep nutritional diaries. Women on the Mediterranean diet were noted to have lower levels of C-reactive protein, potentially indicative of less vascular inflammation. Patients on the diet were advised to increase consumption of fish and decrease intake of red or processed meat. Both the diet and control groups were advised to increase exercise levels mainly by walking, aerobic ball games, or swimming for a minimum of 30 minutes per day. The control group was given information concerning healthy food choices but no specific program was offered to them. After 2 years, women on the Mediterranean diet had improved sexual function, as assessed by the FSFI scores. Although thought provoking and clearly based in excellent nutritional principles, female sexuality is a complex entity and no definitive conclusions can be stated linking sexual vitality to diet. Man's quest for sexual nutrition dates back in history and at one point, nearly every food was associated with sexual enhancement or a possible treatment for sexual complaints. There are many diets on the market, including the orgasmic diet, the testosterone diet, the gladiator diet, the testosterone advantage plan, the ultimate sex diet, and the great American sex diet to name a few. The US Food and Drug Administration noted in the 1980s that sexual effects of so-called aphrodisiacs are based in folklore, not fact, and reaffirmed that there was no methodic scientific verification that any over-the-counter aphrodisiacs exerted any effect to treat sexual dysfunction. Level of evidence = 2b

Michael L. Krychman, MD

Reproductive and sexual function after platinum-based chemotherapy in long-term ovarian germ cell tumor survivors: A Gynecologic Oncology Group Study. DM Gershenson, AM Miller, VL Champion, PO Monahan, Q Zhoa, D Cella, SD Williams. J Clin Oncol 2007;25:2792–7.

Editorial Comment: The purpose of this study was to examine ovarian germ cell tumor survivors with a matched control group of females and evaluate several parameters, including sexual function. Patients had a history of malignant germ cell ovarian tumors, had surgery and chemotherapy with a platinum-based product, were 18 years or older, disease-free for at least 2 years, completed an informed consent, and underwent a telephone interview. The control group was a group of acquaintances recommended from the survivors and matched for demographics. One hundred thirty-two patients and 137 controls completed the study. Compared to the controls, survivors had more concerns with respect to fertility, and lowered scores on the total Sexual Activity Scale score. Interestingly, although those survivors had decreased sexual pleasure, this study did find that they had stronger and more positive relationships. This article reinforces the importance of survivorship concerns at the time of diagnosis, whereas sexual function is a critical facet for cancer patients. Physicians and patients should address sexual concerns at the time of primary diagnosis. Reproductive health care concerns are important concepts for the survivor. Level of evidence = 2b

Michael L. Krychman, MD

Clinical Research—Male Editor's Note:

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  2. Basic Science
  3. Psychology
  4. Clinical Research—Female
  5. Clinical Research—Male Editor's Note:
  6. Editor's Note:

This article is also reviewed in the psychology section of this issue's literature survey. The subject matter of this epidemiologic survey was believed to be of sufficient importance to keep both commentaries that highlight different aspects of the study.

A study of sexuality and health among older adults in the United States. ST Lindau, LP Schumm, EO Laumann, W Levinson, CA O’Muircheartaigh, LJ Waite. N Engl J Med 2007;357:762–74.

Editorial Comment: In a cross-sectional study, a nationally representative probability sample of community-dwelling persons aged 57–85 years (N = 3,005; 1,550 women and 1,455 men) from households across the United States was screened about their sexual activities, behaviors, and problems. The prevalence of sexual activity in men was as follows: 73% for 57–64 years; 53% for 65–74 years; and 26% for 75–85 years. Women showed significantly lower sexual activity figures. Respectively in the same age groups, the figures for the most often reported sexual problems in men were as follows: 30.7%/44.6%/43.5% for erectile difficulties; 29.5%/28.1%/21.3% for climaxing too quickly; 16.2%/22.7%/33.2% for inability to climax; 28.2%/28.5%/24.2% for lack of interest in sex; and 25.1%/28.9%/29.3% for anxiety about performance. Whereas a total of 37% of all men reported erectile difficulties, only 14% of all men were using medication or supplements to improve sexual function. A total of 38% of men compared to only 22% of women reported having discussed sexual issues with a physician. This representative survey provides a lot of new interesting data on the sexual life in the middle-aged and elderly US population. This survey shows once more that only a minority of men with erectile dysfunction is using erectile function-enhancing treatments although many remain sexually active up to 75 years. This survey also directs our attention to the fact that other sexual problems in men such as libido and orgasm disorders (here also inability to climax) are of major importance reaching age-dependent prevalence rates between 16% and 33%. All of us are aware that for these sexual problems, no really effective drugs are available and quite often we have to leave these patients with their problems alone. Hopefully, this survey may be an incentive both for researchers and pharmaceutical companies to focus their research work on these topics to which they have paid little or even no attention in the past. Level of evidence = 3

Hartmut Porst, MD

The early use of transurethral alprostadil after radical prostatectomy potentially facilitates an earlier return of erectile function and successful sexual activity. R Raina, G Pahlajani, A Agarwal, CD Zippe. BJU Int 2007;100:1317–21.

Editorial Comment: In a prospective study, 91 sexually active men (mean age 59 years) who had undergone nerve-sparing radical prostatectomy for prostate cancer were enrolled. Three weeks after the procedure, patients were assigned either to 125 or 250 mg of alprostadil medicated urethral system for erections (MUSE) (N = 56) three times per week for 6 months, regardless of the frequency of sexual activities. The control group was assigned on-demand erectogenic aids, if needed (N = 35). After 6 months follow-up, the Sexual Health Inventory for Men score in the MUSE group was 18.9, compared to only 15.8 in the control group. In the MUSE group, 74% were able to have successful vaginal intercourse at 6 months follow-up compared to 37% in the control group. In the MUSE group, 32% discontinued treatment because of penile/urethral aching/burning. This well-done study is in line with other recently published articles on this topic indicating that active sexual rehabilitation after radical prostatectomy results in much better erectile function than is the case with “wait and see” policy or on-demand therapy. In this regard, we should not forget that transurethral alprostadil application with MUSE is a viable option for many of these patients. Personally, I start with my patients’ sexual rehabilitation 1–2 weeks after radical retropubic prostatectomy and continuing for 6 months with daily use of low dose tadalafil (5–10 mg/day) and combine this regimen with MUSE as needed in whom daily use of phosphodiesterase type 5 inhibitors alone does not result in satisfying erections. Level of evidence = 2a

Hartmut Porst, MD

New insights into the pathogenesis of penile shortening after radical prostatectomy and the role of postoperative sexual function. P Gontero, M Galzerano, R Bartoletti, C Magnani, A Tizzani, B Frea, N Mondaini. J Urol 2007;178:602–7.

Editorial Comment: In 126 patients undergoing radical prostatectomy (RP), penile measurements and assessments by the International Index of Erectile Function were conducted immediately before surgery, at catheter removal, and at 3, 6, and 12 months postoperatively. The maximum degree of shortening was noted at the time of catheter removal (mean 0.84 cm, confidence interval 0.62–1.06, P < 0.0001 for stretched penis). Penile shortening continued to a lesser but still a significant degree for at least 1 year after RP. Multivariate analysis showed that nerve-sparing technique (P < 0.0001) and recovery of erectile function (P = 0.053) were independent predictors of the final changes in penile length. This study addresses two different issues of interest. First, patients are loosing penile length after RP and this continues at least up to 1 year. To my knowledge, while all patients are informed about erectile dysfunction, hardly any hospital patients are informed about the complication of penile shortening before surgery for prostate cancer. Therefore, the informed consent, signed by the patients prior to the procedure, should contain this complication. Second, all efforts to preserve or rehabilitate erectile function in context with RP also contribute to diminish loss of penile size, which speaks once more for early sexual rehabilitation. Level of evidence = 3.

Hartmut Porst, MD

Editor's Note:

  1. Top of page
  2. Basic Science
  3. Psychology
  4. Clinical Research—Female
  5. Clinical Research—Male Editor's Note:
  6. Editor's Note:

Commentaries on clinical studies include a “level of evidence” rating to assist readers in evaluating the significance of the findings and conclusions. The simplified rating scale below is adapted from the more complete recommendations of the Center for Evidence-Based Medicine (http://www.cebm.net/levels_of_evidence.asp).

Level of evidenceType of evidence
1aEvidence from systematic reviews or meta-analysis of randomized controlled trials
1bEvidence from at least one randomized control trial
2aEvidence from at least one controlled study without randomization
2bEvidence from at least one other type of quasi-experimental study
3Evidence from nonexperimental descriptive studies, such as comparative studies, correlation studies, and case-control studies
4Evidence from expert committee reports or opinions and/or clinical experience of respected authorities