Postoperative pain after clitoral reconstruction in women with female genital mutilation: An evaluation of practices.

INTRODUCTION: More than 200 million women and girls have undergone genital mutilation. Clitoral reconstruction (CR) can improve the quality of life of some of them, but is accompanied by significant postoperative pain. OBJECTIVE: Assess and describe the management of postoperative pain after CR, and the practices amongst specialists in different countries. METHODS: Between March and June 2020, 32 surgeons in 14 countries (Germany, Austria, Belgium, Burkina Faso, Canada, Ivory Coast, Egypt, Spain, United States of America, France, the Netherlands, Senegal, Switzerland, Sweden) responded to an online questionnaire on care and analgesic protocols for CR surgery. RESULTS: At day 7 post CR, 97% of the surgeons observed pain amongst their patients, which persisted up to 1 month for half of them. 22% of the participants reported feeling powerless in the management of such pain. The analgesic treatments offered are mainly step II and anti-inflammatory drugs (61%). Screening for neuropathic pain is rare (3%), as is the use of pudendal nerve block, used by 8% of the care providers and only for a small percentage of women. CONCLUSION: Pain after CR is frequent, long-lasting, and potentially an obstacle for the women who are willing to undergo clitoral surgery and also their surgeons. Most surgeons from different countries follow analgesic protocols that do not use the full available therapeutic possibilities. Early treatment of neuropathic pain, optimisation of dosing of standard analgesics, addition of opioids, use of acupuncture, and routine intraoperative use of pudendal nerve block might improve the management of pain after CR.

A randomized, placebo-controlled laboratory study of the effects of D-cycloserine on sexual memory consolidation in women.

RATIONALE AND OBJECTIVE: The aim of this study was to investigate the possible facilitating effect of the partial NMDA receptor agonist D-cycloserine (DCS) on memory consolidation of conditioned sexual responses and to examine the capability of DCS to reduce context-specificity of learning. METHODS: In a randomized placebo-controlled double-blind trial, 50 healthy females were exposed to a differential conditioning procedure. Two pictures of a male abdomen were used as conditional stimuli (CSs), of which one (the CS+) was followed by the unconditional stimulus (US), a genital vibrotactile stimulus. After the conditioning session on day 1, participants received either 125 mg of DCS or a placebo. The effects of DCS on affect, sexual arousal and US expectancy in response to the CS+ and CS- were examined 24 h after the conditioning procedure. RESULTS: A main effect of DCS was found on affect at the first test trials (p = 0.04, ηp2 = 0.09), and a similar non-significant but trend level effect was found for sexual arousal (p = 0.06, ηp2 = 0.07), which appeared to persist over a longer time (p = 0.07, ηp2 = 0.08). Unexpectedly, ratings of positive affect and sexual arousal in response to both the CS+ and the CS- were higher in the DCS condition compared to the control condition, possibly indicating that DCS administration reduced stimulus specificity. Since the results did not show clear evidence for context learning, we were not able to test effects on context-specificity of learning. CONCLUSION: Although largely inconclusive, the results provide tentative support for a facilitating effect of DCS on affect and sexual arousal in response to stimuli that were presented in a sexual conditioning procedure, however, no conclusions can be drawn about effects of DCS on sexual reward learning, since the design and results do not lend themselves to unambiguous interpretation.

Randomized crossover study investigating daily versus on-demand vulvar Visnadine spray in women affected by female sexual arousal disorder.

The aim of the study was to verify the efficacy of vulvar Visnadine spray in premenopausal women affected by female sexual arousal disorder (FSAD). Thirty-eight women aged 25-40 years affected by FSAD were enrolled in the randomized crossover study, by two possible sequences: on-demand, washout, daily (A sequence); and daily, washout, on-demand (B sequence). The Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale (FSDS) were used to assess sexual function and sexual distress, respectively. Color Doppler ultrasonography was used to measure clitoral blood flow. The study had two follow-ups at 30 (T1) and 60 days (T2). Thirty-one women completed the study. Mean (SD) sexual activity and vulvar Visnadine spray usage was 1 ± 0.9 weekly during on-demand administration for both the sequences (Vs T0, p = NS). The mean sexual activity during daily usage was 2 ± 0.9 (Vs T0, p < .004) and 2 ± 0.8 (Vs T0, p < .001) for A and B sequences, respectively. FSFI total score, particularly genital arousal, improved more during the daily than during on-demand phases of both sequences (p < .001). Finally, clitoral blood flow improved significantly during daily usage of both the sequences (p < .001). Our study suggests that vulvar Visnadine spray could improve sexual performance of women affected by FSAD, producing changes in subjective and objective sexual aspects.

Restless Genital Syndrome (ReGS) Should Be Distinguished From Spontaneous Orgasms: A Case Report of Cannabis-Induced Spontaneous Orgasm.

A case is described of a 40-year-old woman with persistent spontaneous orgasms after use of cannabis and five hours of intense pounding sexual activity. She presented with severe anxiety, in particular suffering from restless genital syndrome (ReGS). However, she did not fulfill any of the five criteria of ReGS. It was concluded that her spontaneous orgasms were the result of the use of cannabis combined with the long duration of previous sexual activity. This finding is not only important for physicians, but also for highly exposed subjects such as those active in the sex industry.

The sexuological impact of hormonal contraceptives based on their route of administration.

Evidence on the effects of hormonal contraceptives on female sexuality is conflicting. We enrolled 556 women, divided into six groups: two composed of subjects using a combined hormonal contraceptive (COC) containing 0.020 ("COC20") and 0.030 ("COC30") mg of ethynyl estradiol (EE), "natural", using COC containing 1.5 mg of estradiol (E2), "ring", using a vaginal ring releasing each day 0.015 mg of EE + 0.120 of etonogestrel, "subcutaneous", using a progestin only subcutaneous contraceptive implant releasing etonogestrel and "controls", using no hormonal contraceptive methods. The subjects were required to answer to the McCoy female sexuality questionnaire and were subjected to a blood test for hormonal evaluation. An ultrasound evaluation of the dorsal clitoral artery was also performed. The higher McCoy sexological value were recorded in the subdermal group; significant differences were recorded among the groups in terms of hormone distribution, with the higher levels of androstenedione in subdermal and control groups. The ultrasound evaluation of dorsal clitoral artery shows a significative correlation between pulsatility and resistance indices and orgasm parameters of McCoy questionnaire. The recorded difference in the sexual and hormonal parameters among the studied hormonal contraceptives may guide toward the personalization of contraceptive choice.

Differential Effects of Testosterone and Estradiol on Clitoral Function: An Experimental Study in Rats.

INTRODUCTION: Female sexual response is a complex phenomenon in which psychological, neurologic, and vascular mechanisms and hormonal factors interact. During the arousal phase, they cooperate to increase genital blood flow, thus inducing engorgement of the clitoris and lubrication of the vagina. Regulation of vascular and non-vascular smooth muscle tone is the crucial event in the erectile process. Preclinical studies have suggested that nitric oxide (NO) is the main vasodilator neurotransmitter modulating, through the second messenger cyclic guanosine monophosphate (cGMP), clitoral flow vessels. AIM: To investigate the effects of sexual steroid hormones on pro-erectile and relaxant (mediated by NO and cGMP) and anti-erectile and contractile (mediated by ras homolog gene family member A [RhoA] and Rho-associated protein kinase [ROCK]) mechanisms in the clitoris using a validated animal model of female ovariectomized Sprague-Dawley rats. METHODS: Subgroups of ovariectomized rats were treated with 17ß-estradiol, progesterone, testosterone, or testosterone and letrozole for 6 weeks. The experimental groups were compared with a control group of intact rats. MAIN OUTCOME MEASURES: Sex steroids plasma levels were assessed and in vitro contractility studies were carried out in order to investigate the effect of ovariectomy and in vivo treatments on clitoris smooth muscle activity. Smooth muscle cells (SMCs) from rat clitoral biopsies were isolated and characterized. RhoA activity was determined in SMCs cell cultures. RNA from tissues and cells was analyzed by quantitative real-time RT-PCR. RESULTS: Using real-time polymerase chain reaction, testosterone treatment upregulated the expression of NO-mediated pathway genes (endothelial and neuronal NO synthase, guanylate cyclase soluble subunit-α3, guanylate cyclase soluble subunit-ß3, cGMP-dependent protein kinase 1, and phosphodiesterase type 5). Conversely, estrogen replacement upregulated the expression of calcium-sensitizing RhoA-ROCK pathway genes. In vitro contractility studies were performed on phenylephrine pre-contracted clitoris strips. Ovariectomy resulted in a decreased responsiveness to Y-27632, a ROCK inhibitor, which was fully restored by 17ß-estradiol supplementation. To further examine the effect of 17ß-estradiol on the RhoA-ROCK pathway, smooth muscle cells were isolated from rat clitoris and their migration capacity was evaluated. CONCLUSION: Collectively, these data demonstrate that testosterone improves the relaxation of vascular smooth muscle cells through the NO-cGMP pathway, and that testosterone and 17ß-estradiol are necessary to maintain a functional contractile and relaxant machinery in the clitoris. This new concept might provide support for the concomitant use of estrogen and testosterone during the treatment of sexual arousal disorders related to hormonal imbalance or insufficiency.

Postnatal exposure to a progestin does not prevent uterine adenogenesis in domestic dogs.

To assess the effects of a single supraphysiological postnatal administration of a progestogen on uterine glands in dogs, 10 females were randomly assigned to a medroxyprogesterone acetate 35 mg (MPA; n = 6) or placebo (n = 4) group within the first 24 h of birth. The safety of the treatment was also evaluated. A transient mild clitoris enlargement appeared in MPA-treated females. Microscopic postpubertal uterine assessment revealed the presence of uterine glands in all cases without significant differences in the area occupied by the glands per µm(2) of endometrium nor in the height of the uterine epithelium.

Postnatal exposure to a progestin does not prevent uterine adenogenesis in domestic dogs

To assess the effects of a single supraphysiological postnatal administration of a progestogen on uterine glands in dogs, 10 females were randomly assigned to a medroxyprogesterone acetate 35 mg (MPA; n = 6) or placebo (n = 4) group within the first 24 h of birth. The safety of the treatment was also evaluated. A transient mild clitoris enlargement appeared in MPA-treated females. Microscopic postpubertal uterine assessment revealed the presence of uterine glands in all cases without significant differences in the area occupied by the glands per µm2 of endometrium nor in the height of the uterine epithelium.

Paced mating behavior is affected by clitoral-vaginocervical lidocaine application in combination with sexual experience.

The present study tested the effects of lidocaine anesthetic ointment applied to the vaginocervical (Experiment 1) or clitoral-vaginocervical (Experiment 2) areas on the display of paced mating behavior over the course of five weekly tests in ovariectomized, hormone-primed, Long-Evans rats. Experiment 3 tested whether rats that acquired sexual experience without ointment application would exhibit altered paced mating behavior on a fifth test under clitoral-vaginocervical lidocaine or vehicle application. Although rats in Experiment 1 and Experiment 2 exhibited shorter contact-return latencies after intromission and reduced likelihood of leaving the male compartment following mounts and intromissions after gaining sexual experience, only rats that received clitoral-vaginocervical lidocaine exhibited altered paced mating behavior relative to vehicle. Specifically, clitoral-vaginocervical lidocaine resulted in shorter contact-return latency to ejaculation and greater percentage of time with the male. Paced mating behavior of sexually experienced rats in Experiment 3 was not disrupted when tested after clitoral-vaginocervical lidocaine treatment. Together, these studies suggest that the sensory input during repeated mating encounters affects the pattern of paced mating behavior that develops with sexual experience.

Clitoral anesthesia disrupts paced copulation in the female rat.

Clitoral stimulation produced by sexual contact with a partner or during manual stimulation is associated with pleasure in humans, and produces conditioned place preference in rats. The present experiment investigated the effect of blocking genitosensory stimulation of the clitoris with lidocaine during copulation in female rats on a measure of female sexual motivation: pacing behavior. Sexually naïve, ovariectomized female rats were treated with 10µg estradiol benzoate 48h and 500µg progesterone 4h prior to a 30-min copulatory trial with a sexually vigorous stimulus male scheduled every 4days. A total of 10 copulatory sessions were divided into two phases of 5 trails each. In the first phase, females received an injection (0.05ml) of either 2% lidocaine, saline, or no injection to the clitoral sheath under isoflurane anesthesia immediately prior to the start of a copulatory session, and were then placed on one side of a paced mating chamber and allowed to copulate for 30min. In the second phase, females previously injected with lidocaine were switched to saline and vice versa, and the no injection group remained the same. Variables measured included overall time spent with the males, number of solicitations, contact-return latencies following male mounts, intromissions, and ejaculations; the frequency of entrances and exits from the male chamber, and frequency of mounts, intromissions, ejaculations. Sexual behavior was examined at session 1, session 5, and session 10. At test 5, females that received LID had a greater number of entrances/exits but spent significantly less time in the presence of the male during the copulatory bout than CNTL animals. These females also displayed a trend for longer contact return latencies s after ejaculations than VEH and CNTL groups. On session 10, females that received LID and subsequently switched to VEH treatment no longer differed from controls in entrance/exit numbers, time spent with males or ejaculation contact return latency. They did however, receive a greater number of intromissions and displayed shorter inter intromission intervals compared to CNTLs. We suggest that clitoral stimulation in the rat serves as both a reward signal and may contribute to the detection of differences in copulatory stimuli that are critical to pacing and potentially, the initiation of pregnancy.

Clitoral vascularization and sexual behavior in young patients treated with drospirenone-ethinyl estradiol or contraceptive vaginal ring: a prospective, randomized, pilot study.

INTRODUCTION: Oral contraceptives (OC) are effective for birth control and have good cycle control and tolerability. However, the hormonal components could modify mood and libido. AIM: The aim of this study is to evaluate the genital vascular effects and sexual behavior of an OC containing 30 µg ethinyl estradiol and 3 mg drospirenone in comparison with a flexible combined contraceptive vaginal ring. METHODS: Forty women underwent a sonographic assessment of the clitoral anatomy and vascularization and were administered the McCoy Female Sexuality Questionnaire (MFSQ) and the Beck's Depression Inventory questionnaire (BDI). Estradiol, androstenedione, testosterone, and SHBG were assayed. Free Androgen Index (FAI) and Free Estrogen Index (FEI) were calculated. The patients were randomly submitted to OC (group I; n = 21) or vaginal ring (group II; n = 19). MAIN OUTCOME MEASURES: Ultrasonographic clitoral volume, pulsatility index (PI) of dorsal clitoral arteries, MFSQ, BDI, and hormonal and biochemical assays were analyzed. RESULTS: After therapy, the testosterone levels were reduced in both groups, whereas estradiol decreased only in group I women. The SHBG increased in all the subjects, and both FAI and FEI decreased. The clitoral volume decreased in all the women. The PI of the dorsal clitoral artery increased only in patients on OC. The hormonal contraception was associated, in both studied groups, with a significant decrease of the two-factor Italian MFSQ score, which was more marked in OC users. In group I subjects, there was a reduction of the number of intercourse/week and a reduction of orgasm frequency during intercourse. The pain during intercourse worsened after OC use. The vaginal ring users reported a vaginal wetness. CONCLUSIONS: Six-month treatment with hormonal contraception is associated with a diminished MFSQ score. However, the frequency of sexual intercourse and orgasm was reduced only by the use of OC. The OC use was associated with increased pain during intercourse.

Vascular modifications of the clitoris induced by topic nitric oxide donor gel--preliminary study.

INTRODUCTION: The clitoral blood flow increase is dependent of nitric oxide (NO) and it occurs due to sexual arousal. Female sexual disorder mechanisms are poorly understood and NO therapeutic role in this scenario is to be determined. AIM: To assess topic NO donor S-nitrosoglutationa (GSNO) gel-100 µM effect on clitoral blood flow in healthy women. METHODS: Forty healthy women were double-blinded randomized for Group 1, GSNO gel, n=20 and Group 2, placebo gel, n=20. All patients underwent Doppler ultrasound test in the clitoral artery. Hemodynamic analysis consisted of: systolic peak speed, diastolic speed, and vase resistance rate. Ten random patients were analyzed regarding sexual function after two double-blinded placebo and NO donor gel periods of 30 days. MAIN OUTCOME MEASURES: To consider female sexual dysfunction treatment through local NO-dependent pathway. RESULTS: Mean age was 31 years (20-39) and mean female sexual function index score 31.5 (26-34). Group 1: The mean and standard deviation baseline and 15 minutes after the application of the GSNO gel systolic (11.7±2.1 cm/second to 15.9±2.4 cm/second) and diastolic speeds (2.7±0.3 cm/second to 4.2±0.4 cm/second) and resistance (0.71±0.04 to 1.38±0.06) were significantly increased (P=0.002) (P=0.043), and (P=0.005), respectively. No local or systemic adverse effect was observed in women or in their sexual partners and the sexual function presented a slightly insignificant improvement (P=0.065), although eight of 10 women could subjectively identify the GSNO gel as the preferred and most pleasant between both tried. Group 2 presented no significant differences at baseline and 15 minutes after the application of the placebo gel, P>0.05. CONCLUSION: The topic GSNO gel increased significantly the clitoral blood flow and could be considered therapeutically in selected cases of female sexual dysfunction warranting further investigation.

Clitoral and vulvar vestibular sensation in women taking 20 mcg ethinyl estradiol combined oral contraceptives: a preliminary study.

INTRODUCTION: Many women taking low-dose (20 mcg) oral contraceptive pills (OCPs) complain of decreased libido and arousal and some develop vulvar vestibular pain and dyspareunia. Free testosterone concentrations are decreased by the OCP. Genital sensation has not been objectively measured in women taking OCPs. AIM: We assessed whether the 20 mcg ethinyl estradiol combined OCP and associated decrease in free testosterone levels affected genital sensation in a pilot study of a group of asymptomatic OCP users and controls. METHODS: Clitoral thermal, vibratory, and vestibular pain thresholds, sexual functioning, and free testosterone levels were measured in 24 women taking 20 mcg ethinyl estradiol combined OCPs and 28 comparison women not using hormonal contraception. MAIN OUTCOME MEASURES: Female Sexual Functioning Index (FSFI), free testosterone, and clitoral heat, cold, and vibratory thresholds for sensation and vestibular pain thresholds. RESULTS: Free testosterone levels were lower in OCP users. There were no differences in FSFI scores, clitoral thermal or vibratory thresholds, or vestibular pain thresholds between groups. CONCLUSIONS: Low-dose (20 mcg) oral contraceptives decrease free testosterone but are not associated with alterations in clitoral or vestibular sensation. Further studies of genital sensation in women with OCP-related sexual dysfunction are warranted.

The effect of topical synthetic prostaglandin E1 (misoprostol) on clitoral hemodynamics.

INTRODUCTION: Genital blood flow plays an important role on female sexual function. Measures that increase genital blood flow may be a therapeutic approach for female sexual dysfunction. AIM: This study aims to show the effect of topical misoprostol, a synthetic prostaglandin, on clitoral blood flow. METHODS: Seventeen volunteers with female sexual dysfunction on the basis of female sexual function index scores were included in the study. All women were premenopausal and within their sexually active ages. Hormonal profiles were also normal. Those with suspected pregnancy, history of pelvic or vaginal surgery or radiotherapy, and diabetes or hypertension were excluded. Female sexual function index scores were determined. Clitoral peak systolic velocity (PSV) and clitoral artery diameter of all women were measured by using Doppler ultrasound. The measurements were done on two occasions as before and after placebo in one session and before and after 100 µg of misoprostol in another. This is a double-blind study where the patient and the ultrasonographist were unaware of either placebo or active drug has been applied before measurements. MAIN OUTCOME MEASURES: Clitoral artery diameter and peak systolic velocity. RESULTS: Misoprostol caused a significant increase in clitoral artery PSV compared to basal level (P = 0.0001), while changes in clitoral artery PSV with placebo remained insignificant. Remarkably, misoprostol caused 118.3% increase in clitoral artery PSV and 47.5% increase in clitoral artery diameter when compared to basal levels. No side effects were observed. CONCLUSION: Topical misoprostol can significantly increase clitoral blood flow without any unwanted effects and this finding may be promising for future investigations with relevance to female sexual dysfunction.

[Impact of topic administration of nitric oxide donor gel in the clitoridian blood flow, assessed by Doppler ultra-sound]. / Impacto en la administración de un donante de óxido nítrico en gel en el flujo sanguíneo clitoridiano, medido por eco-Doppler.

OBJECTIVE: This study aims to evaluate of the impact of NO molecules in Pluronic F-127 gel, applied topically in the clitoris, on the clitoridian blood flow of healthy volunteer women, using the Doppler ultra-sound. METHOD: A total of 20 healthy women over 18 years old and sexually active with no sexual hormones alteration were enrolled. The Doppler ultra-sound procedure was performed on the artery of the clitoris in patients without the NO donor gel, and then after fifteen minutes of its application the same procedure was done again, to compare the values. RESULTS: The hemodynamic results showed, that this formulation was responsible for the increase of the systolic and diastolic speeds in about 2,5 times after 15 min of the administration of the gel. The initial resistance index was increased in 1.2 due to the local venous congestion in only 15 min after the administration of gel. Indicating that this product can be used to promote the dilatation of the artery of the clitoris to treat women with sexual dysfunction. CONCLUSION: The use of topic hidrogel as a donor drug in the clitoris of women resulting in a local vasodilatation, without systemic effects. These findings suggest that this preparation may be useful in the management of selected cases of female sexual dysfunction.

Effects of intramuscular testosterone undecanoate on body composition and bone mineral density in female-to-male transsexuals.

INTRODUCTION: The most common treatment regimen in female-to-male transsexuals is administration of short-acting testosterone esters intramuscularly every 2 weeks. AIM: The aim of this study was to evaluate the effect of long-acting intramuscular testosterone undecanoate on body composition and bone mineral density during cross-sex hormone therapy in female-to-male transsexuals. METHODS: Forty-five female-to-male transsexuals (FtMs) were treated with injections of testosterone undecanoate 1,000 mg intramuscularly every 12 weeks over 24 months. MAIN OUTCOME MEASURES: Body composition, bone mineral density, hormone parameters, and lipids were compared after 12 months and after 24 months with baseline values. Sonographic findings in the ovaries and endometrium, clinical and adverse effects during the study period were recorded. RESULTS: There was a significant increase in lean mass in the FtMs during the study period in comparison with baseline values, whereas no change in BMI, fat mass, and bone mineral density was observed. There was a significant decline in gonadotropins, estradiol, dehydroepiandrosterone sulphate, sex hormone-binding globulin, and high-density lipoprotein, while testosterone and triglyceride levels increased significantly after 12 and 24 months. Ovaries remained unchanged and no noticeable endometrial pathology was observed. No mortality or morbidity was observed during the study period. We observed a cessation of menstrual bleeding, an increase in clitoral growth, libido, body and beard hair growth, deepened voices and decline in breast size. There was a significant increase in hemoglobin, hematocrit, glutamic-pyruvic transaminase, gamma-glutamyl transferase, and an increase in systolic blood pressure during the study period. CONCLUSIONS: There was an increase in lean mass during the study period in FtMs treated with testosterone undecanoate. Transsexual patients should be monitored for adverse effects on lipid profiles, blood pressure, and erythrocytosis during intramuscular testosterone undecanoate therapy.

UK-414,495, a selective inhibitor of neutral endopeptidase, potentiates pelvic nerve-stimulated increases in female genital blood flow in the anaesthetized rabbit.

BACKGROUND AND PURPOSE: Female sexual arousal consists of a number of physiological responses resulting from increased genital blood. Vasoactive intestinal peptide (VIP), neuropeptide Y and to a lesser extent nitric oxide are neurotransmitters found in the vasculature of the genitalia. Neutral endopeptidase (NEP) modulates the activity of neuropeptides including VIP. The aim of this study was to investigate the control of genital blood flow by VIP and endogenous neuropeptides using a selective NEP inhibitor [UK-414,495, ((R)-2-({1-[(5-ethyl-1,3,4-thiadiazol-2-yl) carbamoyl]cyclopentyl}methyl) valeric acid)]. EXPERIMENTAL APPROACH: Vaginal and clitoral blood flow (VBF and CBF) were monitored using laser Doppler in terminally anaesthetized New Zealand rabbits. Increases in VBF and CBF were induced by either electrical stimulation of the pelvic nerve or by i.v. infusion of VIP. KEY RESULTS: Stimulation of the pelvic nerve increased VBF and CBF, compared with basal flow. Increases were mimicked by infusion of exogenous VIP. UK-414,495 dose-dependently potentiated pelvic nerve-stimulated increases in VBF (EC(50)= 37 +/- 9 nM; 3.6 x IC(50) rabbit NEP). Nerve-stimulated increases in VBF and CBF were both enhanced after UK-414,495. UK-414,495 increased the amplitude and duration of VIP-induced increases in VBF. UK-414,495 had no effect on basal VBF or cardiovascular parameters. CONCLUSIONS AND IMPLICATIONS: Inhibition of NEP potentiates pelvic nerve-stimulated increases in genital blood flow. This suggests that the endogenous neurotransmitter mediating genital blood flow is a substrate for NEP (most likely VIP). NEP inhibitors may restore sexual arousal in women adversely affected by female sexual arousal disorder.

Phosphodiesterase type 5 inhibitors and female sexual response: faulty protocols or paradigms?

INTRODUCTION: Phosphodiesterase type 5 inhibitors (PDE5), such as sildenafil, tadalafil, and vardenafil, have revolutionized the treatment of erectile dysfunction. Few successes, in contrast, have been reported for the use of these agents in treatment of sexual arousal problems in women. AIM: To review research examining efficacy of PDE5 in women, critique the methods and models employed, and integrate the findings within a broader, gender-specific understanding of female sexual response. METHODS: A conceptual and methodological review of all published studies examining PDE5 efficacy in female samples. MAIN OUTCOME MEASURES: Study methods, populations, outcome measures, study results. RESULTS: A total of 16 studies were reviewed. Studies using self-reported measures of sexual functioning showed mixed results whereas studies examining physiological effects of PDE5 on genital vasocongestion consistently report significant effects on genital sexual response. CONCLUSIONS: The lack of efficacy of PDE5 treatment in women is likely attributable to gender differences in the concordance between physiological and psychological components of sexual response. Discordance between genital and subjective measures of sexual response in women may be augmented by PDE5 effects on genital vasocongestion in some populations, rendering successful treatment unlikely via pharmacological treatment alone.

Critical androgen-sensitive periods of rat penis and clitoris development.

Androgen control of penis development/growth is unclear. In rats, androgen action in a foetal 'masculinisation programming window' (MPW; e15.5-e18.5)' predetermines penile length and hypospadias occurrence. This has implications for humans (e.g. micropenis). Our studies aimed to establish in rats when androgen action/administration affects development/growth of the penis and if deficits in MPW androgen action were rescuable postnatally. Thus, pregnant rats were treated with flutamide during the MPW +/- postnatal testosterone propionate (TP) treatment. To assess penile growth responsiveness, rats were treated with TP in various time windows (late foetal, neonatal through early puberty, puberty onset, or combinations thereof). Phallus length, weight, and morphology, hypospadias and anogenital distance (AGD) were measured in mid-puberty (d25) or adulthood (d90) in males and females, plus serum testosterone in adult males. MPW flutamide exposure reduced adult penile length and induced hypospadias dose-dependently; this was not rescued by postnatal TP treatment. In normal rats, foetal (e14.5-e21.5) TP exposure did not affect male penis size but increased female clitoral size. In males, TP exposure from postnatal d1-24 or at puberty (d15-24), increased penile length at d25, but not ultimately in adulthood. Foetal + postnatal TP (e14-postnatal d24) increased penile size at d25 but reduced it at d90 (due to reduced endogenous testosterone). In females, this treatment caused the biggest increase in adult clitoral size but, unlike in males, phallus size was unaffected by TP during puberty (d15-24). Postnatal TP treatment advanced penile histology at d25 to more resemble adult histology. AGD strongly correlated with final penis length. It is concluded that adult penile size depends critically on androgen action during the MPW but subsequent growth depends on later androgen exposure. Foetal and/or postnatal TP exposure does not increase adult penile size above its 'predetermined' length though its growth towards this maximum is advanced by peripubertal TP treatment.