Use of testosterone and a 5-ht1a agonist in the treatment of sexual dysfunction

[0001] The invention relates to the field of male and / or female sexual dysfunction. The present disclosure relates in particular to the use of testosterone and a 5-HT1A agonist, optionally in combination with a PDE5 inhibitor.

[0002] Male sexual dysfunction (MSD) refers to various disorders or impairments of male sexual function, including inhibition of sex drive (ISD), erectile dysfunction (ED) or impotence and premature ejaculation (PE, also known as rapid ejaculation, early ejaculation or ejaculatio praecox) and lack of orgasm. ED is successfully treated with PDE5 inhibitors such as sildenafil, tadalafil and vardenafil. Current effective PE treatment includes anesthetic creams (like lidocaine, prilocaine and combinations thereof) that reduce penis sensitivity and SSRI antidepressants such as paroxetine, fluoxetine and sertraline. Effective ISD drugs are not yet known.

[0003] Female sexual dysfunction (FSD) refers to various disorders or impairments of sexual function, including a lack of interest in sexual activity, repeated inability to achieve or maintain sexual excitement, inability to reach orgasm following sufficient stimulation. Recent studies estimate that 43% of women suffer from sexual dysfunction in the US [1]. Low sex drive (incidence of 22%) and problems with sexual arousal (14% prevalence) are among the most common female sexual dysfunction. These categories conveniently provide working definitions and vocabulary accepted by scientists and therapists. However, it may be incorrect to recognize that these diseases are completely independent of each other. Both case studies and epidemiological studies indicate that these disorders may overlap and may be interdependent. In some cases, it may be possible to identify the underlying disease that led to others, but in many cases this may not be possible.

[0004] For the treatment of male and / or female sexual dysfunction (or dysfunction), a variety of different treatment methods have been suggested and used to a greater or lesser degree of success,. For example, WO 2005/107810 describes the use of testosterone and a phosphodiesterase type 5 inhibitor (PDE5) that should be released in a specific order and time in terms of sexual activity. Although this therapy has promising results, there is a need to develop alternative treatments.

[0005] In one embodiment, the present invention relates to the use of testosterone and a 5-HT1A agonist in the preparation of a medicament intended for the treatment of sexual dysfunctions, wherein said 5-HT1A is substantially released one hour before and testosterone 3.55.5 hours before sexual activity . In a preferred embodiment of the invention, the testosterone is in the form of sublingual testosterone. In one embodiment, the invention provides testosterone or a metabolite or precursor thereof and a 5-HT1A agonist for use in the treatment of sexual disorders, wherein the 5-HT1A agonist is generally released from one hour to 1.5 hours before and the testosterone or metabolite thereof , or its precursor 3.5-5.5 hours before sexual activity, such that the peaks of the 5-HT1A and testosterone agonist or its metabolite or precursor partially overlap.

[0006] Testosterone is also known under the chemical name 17-βhydroxyandrost-4-en-3-one, which can be obtained in various ways: it can be isolated and purified from a natural source or synthetically produced in any way. In addition to testosterone, "testosterone analogues" can also be used. The term "or analog thereof" includes any useful metabolite or testosterone precursor, for example dihydrotestosterone. It will be clear to a person skilled in the art that if the testosterone metabolite or its precursor is used, the time of administration, for example a 5-HT1A agonist (and optionally also a PDE5 inhibitor) must be re-determined. If, for example, dihydrotestosterone is used, the time of administration of the 5-HT1A agonist is approximately half an hour earlier (because this is the approximate time needed to convert excess testosterone to dihydrotestosterone).

[0007] According to the present disclosure, the level of free testosterone should be equal to the peak level of free testosterone in plasma, equal to at least about 0.010 nmol / L, which usually occurs between 1 and 20 minutes after testosterone administration. Approximately three and a half to five and a half hours after this peak of testosterone plasma levels, there is a peak testosterone effect, i.e. there is a delay in the effect of testosterone on genital stimulation in sexually functional women.

[0008] Testosterone is preferably administered in a formulation for which there is a short-lived high testosterone peak in the bloodstream of the patient to whom it is administered. The disclosure therefore provides for a use in which testosterone or an analogue thereof is in the form of a sublingual formulation, such as a sublingual formulation containing cyclodextrins as a carrier. Another example of a suitable mode of administration is mucosal or nasal administration, which may also be carried out using a formulation with cyclodextrin or other conventional excipients, diluents and the like. A typical example of a preparation contains hydroxypropyl-beta-cyclodextrin, however the preparation may contain other beta cyclodextrins and other common auxiliaries, diluents and the like, which are within the skill of those skilled in the art, for making a composition containing testosterone or an analogue thereof that releases essentially all testosterone in a short pulse. Release will usually occur in a short period of time (e.g., 60-120 seconds, more preferably within 60 seconds) after administration, leading to peak testosterone levels in the blood about 1-20 minutes later. In a preferred embodiment of the invention, the pharmaceutical composition is for sublingual administration, and even more preferably, the composition comprises cyclodextrins, such as hydroxypropyl beta-cyclodextrin. A typical example of a prepared testosterone sample (0.5 mg testosterone) contains 0.5 mg testosterone, 5 mg hydroxypropyl betacyclodextrin (carrier), 5 mg ethanol and 5 ml water, but each of these substances may be contained in a greater or smaller amount .

[0009] Circulating testosterone is usually associated with SHBG (steroid hormone binding globulin) and albumin. It is important that the plasma testosterone level, as defined herein, is present and calculated as free testosterone, i.e. the portion not associated with SHBG and albumin. Thus, the testosterone dose administered should be high enough to saturate albumin and SHBG (i.e., the testosterone concentration must be high enough to exceed the total testosterone binding by SHBG or albumin), or other means should be provided to avoid binding to albumin or SHBG, for example using a competitor for testosterone binding site in SHBG.

[0011] Unlike other testosterone-based sexual dysfunction treatments, the use (and method) described herein is intended to temporarily increase testosterone levels in a treated patient. Most other methods are aimed at restoring / replacing / replenishing testosterone levels to normal (i.e. physiological) serum levels (found in a normal individual). In a preferred embodiment of the invention, testosterone is administered such that a temporarily high peak of testosterone is obtained in the blood circulation of the patient to whom it is administered. The term "short-term" refers to such testosterone use that the serum testosterone level returns to baseline within 2 hours after administration.

[0012] Preferably, the 5-HT1A agonist used is selective for the 5-HT1A receptor over other 5-HT receptors and the alpha adrenergic receptor and dopamine receptor. Non-limiting examples of 5-HT1A agonists are 8-OH-DPAT, Alnespiron, AP-521, Buspar, Buspiron, Dippropyl-5-CT, DU-125530, E6265, Ebalzotan, Eptapirone, Flesinoxan, Flibanserine, Gepiron, Ipsapiron, LYPITONON , LY301317, MKC242, R (+) - UH-301, Repinotan, SR57746A, Sunepitron, SUNN4057, Tandosporin, U, 92016A, Urapidyl, VML-670, Zalospiron or Zaprasidone.

[0013] The use of the 5-HT1A agonist is such as testosterone, there is a peak in the blood. In a preferred embodiment of the invention, the 5-HT1A agonists used are used such that a peak in the blood occurs within 4 hours after (rapid release) administration of testosterone.

[0014] The administration of testosterone as well as the 5-HT1A agonist is acute, i.e. on demand rather than chronic. In other words, the administration of testosterone and / or 5-HT1A agonists takes place only just before sexual activity, compared to a chronic dosage / placement / administration regimen that aims to bring the level back to physiological levels.

[0015] Reference to sexual disorders includes male and / or female dysfunction. References to male sexual dysfunction include suppressed sexual desire (ISD), erectile dysfunction (ED) and premature ejaculation (PE).

[0016] References to female sexual dysfunction include reduced sex drive syndrome (HSDD), female sexual arousal disorder (FSAD) and female orgasm disorder (FOD).

[0017] Without being bound by it, the inventors provide the following explanation for the treatment of sexual dysfunction by providing a patient in need of such treatment with testosterone and a 5-HT1A agonist. Testosterone makes the brain more open to sexual stimuli and increases subjective sexual arousal. To prevent such excitation in humans when it is considered inappropriate, the prefrontal cortex may inhibit feedback / automatic reactions, thereby also inhibiting physical sexual arousal. We think that women with FSD, especially women with FSAD, suffer from excessive inhibitory action of the prefrontal cortex, which is suppressed (inhibition - inhibition) with 5-HT1A agonists.

[0018] The illustrated embodiments relating to the 5HT1A agonist are preferably used for the treatment of female sexual dysfunction, i.e. to improve subjective and physical sexual arousal (female sexual arousal disorder) and is particularly effective in women suffering from sexual arousal disorder, by abolition of cerebral inhibition of sexual behavior.

[0019] In a preferred embodiment, the present invention relates to the use of testosterone and a 5-HT1A agonist in the preparation of a medicament intended for the treatment of sexual dysfunction, said 5-HT1A being essentially released one hour before and testosterone 3.55.5 hours before sexual activity. In another preferred embodiment, the present invention relates to the use of testosterone, a PDE5 inhibitor and an HT1A agonist in the manufacture of a medicament for the treatment of female sexual dysfunction, wherein 5-HT1A is generally released one hour before, the PDE5 inhibitor 1-2 hours and testosterone 3, 5-5.5 hours before sexual activity. Preferably female sexual dysfunction means female sexual arousal disorder (FSAD).

[0020] In yet another preferred embodiment, said sexual disorder is male sexual dysfunction.

[0021] Of course, the beneficial (peak) activity of the 5-HT1A agonist as well as the (peak) activity of testosterone occur simultaneously (completely). It should be noted, however, that if the maximum effect of testosterone and 5-HT1A agonist, only partially overlap, they still produce the desired effect. When testosterone is delivered such that substantially all of the testosterone is released in one short impulse in a patient (e.g. female), the 5-HT1A agonist is preferably administered such that it leads to maximum plasma concentration within at least 3 hours after testosterone administration. Even more preferably, the action of the 5-HT1a agonist occurs 3.5-5.5 hours after ingestion of testosterone. It is clear that the exact time of administration of the 5-HT1A agonist depends on the type of preparation used. If the 5-HT1a agonist preparation is released shortly after administration, its use to deliver it at the same time as testosterone is useless, as there is virtually no overlap. If the availability of the 5-HT1A agonist from the formulation used occurs after a certain period of time, for example

3.5 to 4.5 hours, it can be / is given at the same time as testosterone.

[0022] Without being bound by theory, the experimental section of this document describes the inventor's hypothesis regarding the action of a 5-HT1A agonist in the treatment of sexual disorders.

[0023] In yet another preferred embodiment, the present invention provides uses of testosterone, a PDE5 inhibitor and a 5-HT1A agonist in the manufacture of a medicament intended for the treatment of sexual dysfunction, wherein 5-HT1A is substantially released one hour, the PDE5 inhibitor 1-2 hours, and testosterone 3.5-5.5 hours before sexual activity. In a preferred embodiment, the testosterone is in the form of sublingual testosterone.

[0024] Many PDE5 inhibitors are available. An example of a PDE5 inhibitor is vardenafil HCl which is chemically referred to as 1 - [[3 (1,4-dihydro-5-methyl-4-oxo-7-propylimidazo [5,1-f] [1,2,4] triazine hydrochloride -2-yl) -4etoksyfenylo] sulfonyl] -4-ethyl-piperazine. In addition to the active substance, vardenafil HCl, each tablet contains microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, yellow iron oxide and red iron oxide. Another example is sildenafil citrate, which is chemically designated as 1 - [[3- (6,7-dihydro-1-methyl-7-oxo-3-propyl1H-pyrazolo [4,3-d] pyrimidin-5-yl) - 4-ethoxyphenyl] sulfonyl] -methylpiperazine. In addition to the active ingredient, sildenafil citrate, each tablet contains the following ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, lactose, triacetin and FD&C Blue # 2 aluminum lacquer. Another example is tadalafil, chemically designated as 6- (1,3-benzodioxol-5-yl) -2,3,6,7,12,12a-hexahydro-2-methyl (6R, 12aR) -pyrazine [1 ', 2' : 1,6] pyrido [3,4-b] indole-1,4-dione. In addition to the active ingredient, tadalafil, each tablet contains the following ingredients: croscarmellose sodium, hydroxypropyl methylcellulose, hydroxypropyl cellulose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide and triacetin.

[0025] The number of PDE inhibitors continues to increase, and other non-limiting examples are: E-4021, E-8010, E-4010, AWD-12-217 (zaprynast), AWD 12-210, PL-343664, PL- + 369003, PL-357903, BMS-341400, BMS223131, FR226807, FR- 229934 , EMR-6203, SCH-51866, IC485, TA-1790 DA-8159, NCX-911 or KS-505A and the compounds disclosed in WO 96/26940, [0026] It will be obvious to a person skilled in the art that the active ingredients are preferably administered / released so that their peak activities (their activities) at least partly overlap / overlap, and preferably overlap completely. With regard to testosterone, peak activity means a maximum increase in impact on erotic stimuli and sexual motivation. For a PDE5 inhibitor, maximal activity means maximal increase in NANC (non-adrenergic non-cholinergic) activity of the autonomic nervous system, and for 5-HT1A receptor agonist means maximal behavioral inhibition. This goal can be achieved through various strategies.

[0027] As mentioned above, in order to achieve an optimal testosterone effect of the 5HTla agonist and PDE5 inhibitor, it is desirable that the peaks of the maximal effect of these compounds coincide. However, even if the peak effects only partially overlap, this leads to the desired effect (e.g. in the treatment of FSD). The delay of action of the 5-HT1A agonist is about 1 hour, and the action of the 5-HT1A agonist several hours (for example, Flesinoxan reaches maximum plasma concentration after 1-2 hours and single doses have a half-life of 5.5 hours). PDE5 inhibitors such as vardenafil and sildenafil usually reach their maximum plasma concentration (which should be at least 35 ng / ml for sildenafil, 2 mg / l for vardenafil and 40 μgl for tadalafil) after about 1 hour after administration, then they also occur action. When the 5-HT1A agonist and PDE5 inhibitor are released at approximately the same time, their actions overlap, at least partially. It will be apparent to those skilled in the art that the 5-HT1A receptor agonist and the PDE5 inhibitor may be formulated so that their release will be delayed. For example, the active ingredients will be placed in or surrounded by a coating that dissolves after 2 hours. In this case, the active substances must be taken 1.5-3.5 hours before sexual activity. One skilled in the art can easily make other variants and they are within the scope of the present invention. [0028] For the purposes of the present disclosure, those routes of administration that are least invasive (for example, orally, mucosal or intranasal) are selected. The influence of invasive methods of administration on the motivation of sexual behavior should be avoided.

[0029] An application as described herein may alternatively be represented as:

(i) testosterone and a 5-HT1A agonist, for use in a method of treatment of sexual dysfunction; or (i) testosterone, a PDE5 inhibitor and a 5-HT1A agonist, for use in a method of treatment of sexual dysfunction.

[0030] The disclosure further provides a pharmaceutical composition comprising testosterone and a 5-HT1A agonist, wherein the formulation is intended to essentially release 5-HT1A one hour and testosterone 3.5-5.5 hours prior to sexual activity.

[0031] The testosterone content of the pharmaceutical composition containing testosterone is at least 0.3 mg testosterone and at most 2.5 mg testosterone. Depending on the albumin and SHBG levels and weight of the patient being treated, higher or lower doses may be required. The appropriate amount of 5-HT1A agonist depends on the 5HT1A agonist used, as well as, for example, the weight of the patient. For example, Flesinoxane is usually used in an amount of about 1 mg.

[0032] The disclosure further provides a pharmaceutical composition comprising testosterone and a PDE5 inhibitor and a 5-HT1A agonist, wherein the preparation is intended essentially to release 5-HT1A one hour, an ODE5 inhibitor 1-2 hours, and testosterone 3.5-5.5 hours before sexual activity. A suitable amount of 5-HT1A agonist is about 1 mg. The advantage of using at least three different active ingredients is that the individual amounts used can be reduced compared to a therapy based on two active ingredients.

[0033] The active ingredients (e.g. testosterone, PDE5 inhibitor or 5-HT1A agonist) may be present in any suitable form, for example in the form of tablets, capsules, multi-particles, gels, films, solutions or suspensions and may contain diluents and / or auxiliaries and / or binders and / or disintegrants and / or lubricants and / or coloring agents. Also, the types of release patterns used may be different, e.g., direct or delayed release.

[0034] Since the actions of the different active ingredients must at least partially overlap, and preferably overlap completely, the disclosure preferably also provides directions for administration. Therefore, the disclosure also provides a kit comprising at least one pharmaceutical composition containing testosterone and at least one composition containing a 5-HT1A receptor agonist, the kit further comprising instructions for administering these compositions. In yet another embodiment, the disclosure also provides a kit comprising at least one pharmaceutical composition comprising testosterone, at least one composition comprising a PDE5 inhibitor and at least one composition comprising a 5-HT1A receptor agonist, the kit further comprising instructions for administering these compositions.

[0035] It should be obvious that depending on the content of the individual active ingredients in the formulation, different administration regimens can be used.

[0036] To further increase the effect of the kit of parts of the invention, the kit may further include cognitive intervention and stimulation agents. Such information can be present on any data carrier (paper, CD, DVD), passive and interactive, or it can be a link to a website at least partly designed for cognitive stimulation. Sometimes it is beneficial to provide subconscious stimulating information, e.g. subliminal.

[0037] The combinations of active ingredients described herein can also be used in combination with other suitable active ingredients.

[0038] The disclosure further includes methods of treating men or women suffering from sexual dysfunction by administering a male or female combination of testosterone and a 5-HT1A agonist (and optionally a PDE5 inhibitor).

[0039] The invention will be explained in more detail in the following non-limiting examples.

Experimental part

Case reports of FSD treatment with drugs containing a combination of testosterone and buspirone

Justification [0040] Many women who have participated in our FSD drug research have reported strong inhibition sensations when considering or having sexual intercourse. Three of these women, by a qualified doctor, in the laboratory, a single dose of testosterone (T) was prescribed in combination with one dose of buspirone (B). It is known that T makes the brain more sensitive to sexual stimuli, B was given with due to its 5-HT1A agonism, to reduce said inhibition.

Settings [0041] All women received a placebo or T / B medicine randomly on different days. T (0.5 mg, suspension, sublingual) was given for 4 hours and B (5 mg tablet, orally) was given 1.5 hours before measurements. Physical arousal was measured using Clitoral Blood Volume (CBV) measurements; Subjective sexual arousal was measured using the Sexual Arousal Response Self-Assessment Questionnaire (SARSAQ). In addition, Vaginal Pulse Amplitude (VPA) pulses were measured as a means of physically predicting sexual activity. CBV and VPA were measured during neutral video clips and then subsequent erotic video clips. SARSAQ was conducted after each session of neutral and erotic video clips. Erotic music videos were bolder in the next (four) sessions. The following results are described as an overall increase in relative physical arousal (CBV and VPA, in percentage points) and subjective sexual arousal (SARSAQ, on the Likert point scale) during erotic video clips after placebo and T / B administration.

Case A [0042] This woman has been diagnosed with both decreased sexual desire disorder (HSDD, DSM-IV TR inclusion criteria) and female sexual arousal disorder (FSAD, DSM-IV TR inclusion criteria). A woman feels sexually inhibited, free only when she drinks a lot. She interprets compliments about her appearance as a direct invitation to sex, which immediately causes feelings of inhibition. [0043] The average SARSAQ increase was 0.44 points, reaching a peak of 0.9 points during the third session of neutral / erotic video clips. The average VPA increase was 1.3 points, reaching a peak of 3.9 during the second session. The average increase in CBV was

10.2 points, reaching a peak of 12.6 during the third session.

Case B [0044] This woman was also diagnosed with both HSDD and FSAD. The patient says that she has lost her previous desire for sex and states that it is very difficult to relax and distract herself, which means that she does not become physically stimulated. The average SARSAQ increase was 2.03 points, reaching a peak of 6.23 points during the second session of neutral / erotic video clips. The average VPA increase was -0.4 points, reaching a peak of -0.0 during the first session. The average increase in CBV was 4.0 points, reaching a peak of 5.8 during the first session.

Case C [0045] Case C suffers from HSDD but not FSAD. She puts a lot of effort in trying to regain her desire for sex, but is often held back by her partner, whom she claims is too sticky.

[0046] The average SARSAQ increase was -0.44 points, reaching a peak of 0.01 points during the first session of neutral / erotic video clips. She told the doctor that she felt more sexually aroused during verum. The average VPA increase was 0.3 points, reaching a peak of 0.3 during the first session. The average increase in CBV was

17.5 points, reaching a peak of 19.3 during the first session.

Overall conclusion [0047] Combination therapy with T / B increased physical sexual arousal (CBV) compared to placebo in all three cases. Physical prediction of sexual activity (VPA) increased in two out of three cases. All these measurements indicate a significant improvement in physical sexual arousal. CBV increased in both patients with FSAD, VPA in one of two.

[0048] Subjective sexual arousal, measured by SARSAQ, increased in two of three cases, both in patients with HSDD and FSAD. Although the SARSAQ results for C did not increase, the patient stated that she was more sexually aroused during verum.

[0049] We expect that further improvement of these results will result from the use of the full rather than partial 5-HT1A agonist (flesinoxane instead of buspirone), the use of a variable dose of 5-HT1A agonist and the combination of T / B therapy with PDE5 inhibitors.

Experiment 1 testosterone and flesinoxane in FSD [0050] Efficacy of the combined administration of testosterone and 5-HT1A receptor agonist - flesinoxane - on VPA in response to fragments of erotic films in women with FSD [0051] In a double-blind, controlled randomly assigned placebo in a cross-over study , a group of 16 women with female sexual dysfunction (FSD) will receive

1. testosterone (0.5 mg) and flesinoxane (1 mg)

2. only testosterone (0.5 mg)

3. Flesinoxane only (1 mg)

4. placebo for 4 separated study days.

[0052] Four experimental days were separated for (at least) three days. During each administration, patients receive one capsule containing either flesinoxane or placebo, and a liquid formulation with testosterone or placebo. The vaginal pulse amplitude will be measured in response to inert and erotic film fragments, immediately after administration of the liquid preparation and 4 hours after administration of the liquid preparation. Thus, the liquid formulation will be taken four hours before testing, capsule one hour before testing. The effects of sublingual testosterone and flesinoxane overlap due to their different delays (3.5-4.5 hours and 0-1 hours, respectively).

Experiment 2 testosterone, flesinoxane and sildenafil in FSD [0053] Efficacy of combined administration of testosterone and 5-HT1A agonist - flesinoxane and PDE5 inhibitor - sildenafil on VPA in response to fragments of erotic films in women with FSD [0054] In a double-blind trial, randomized placebo-controlled cross-over study, a group of 16 women with female sexual dysfunction (FSD) will receive

1. testosterone (0.5 mg), flesinoxane (1 mg) and sildenafil (10 mg)

2. testosterone (0.5 mg) and flesinoxane (1 mg)

3. Flesinoxane (1 mg) and Sildenafil (10 mg)

4. only testosterone (0.5 mg)

5. Flesinoxane only (1 mg)

6. placebo for 6 days separated by study.

[0055] Six experimental days were separated for (at least) three days. At each administration, patients receive one capsule containing either flesinoxane and / or sildenafil or placebo, and a liquid formulation with testosterone or placebo. The vaginal pulse amplitude will be measured in response to inert and erotic film fragments, immediately after administration of the liquid formulation and 4 hours after administration of the liquid formulation. Thus, the liquid formulation will be taken four hours before testing, capsule one hour before testing. The effects of sublingual testosterone, flesinoxane and sildenafil overlap due to their different delays (3.5-4.5 hours, 0.1 hours and 0-1 hours, respectively).

During experimental sessions in experiments 1-2, the patient must place a tampon-shaped vaginal probe (photopletysmograph) to measure VPA. Then, patients will see a 10-minute fragment of a neutral film, followed by a 5-minute fragment of an erotic film. After these preliminary measurements, patients receive one of four drug combinations as described above. After administration of the drug, a different set of fragments of neutral (5 minutes) and erotic (5 minutes) films is shown. Then the probe will be removed from the vagina. After 4 hours, another VPA measurement of the response to fragments of neutral (5 minutes) and erotic (5 minutes) films will be made. Blood pressure (lying down and standing), heart rate, respiratory rate and body temperature will be monitored on the days of the experiment.

[0056] The experimental session will be preceded by a screening visit. During screening, an interview and examination is carried out by a resident of the gynecology department at the Flevo Hospital, Almere in order to diagnose FSD and qualify for participation in the study. Patients will be asked to complete a survey; The Female Sexual Function Index (FSFI). Patients will be examined to exclude pregnancy or breastfeeding, vaginal infection, major vaginal and / or vulva surgery, undetected gynecological diseases or unexplained gynecological problems. Weight, height, blood pressure (lying and standing) will be measured. The cardiovascular system will be examined and the ECG checked for significant abnormalities.

Patients with disease incidents and / or treatment of endocrine, neurological and psychiatric disease. Standard blood tests and hematology will be performed. Participants are required not to use alcohol or psychoactive substances in the evening before and on the day of the experiment. Patients will not be examined during menstruation.

Testosterone and Flesinoxane Experiment 3 in MSD [0057] Efficacy of the combined administration of testosterone and 5-HT1A receptor agonist - Flesinoxane - on male sexual function in response to fragments of erotic films in men with MSD [0058] In a double-blind, randomly controlled placebo controlled Cross-examination, a group of 16 men with male sexual dysfunction (MSD) will receive

1. testosterone (0.5 mg) and flesinoxane (1 mg)

2. only testosterone (0.5 mg)

3. Flesinoxane only (1 mg)

4. placebo for 4 separated study days.

[0059] Penile swelling and stiffness will be measured in response to audiovisual stimulation with neutral and erotic films (VSTR), immediately after drug administration and 1 hour after drug administration, followed directly by measuring the latency of ejaculation time latency with vibroactive stimulation (VTS-ELT) and post-erectile resistance time for erection. Four experimental days were distributed over (at least) three days. During each administration, patients receive one capsule containing either flesinoxane or placebo, and a liquid formulation with testosterone or placebo. VSTR will be measured in response to fragments of inert and erotic films, immediately after administration of the liquid preparation and 4 hours after administration of the liquid preparation, when VTS-ELT is also measured. Thus, the liquid formulation will be taken four hours before testing, capsule one hour before testing. The effects of sublingual testosterone and flesinoxane overlap due to their different delays (3.5-4.5 hours and 0-1 hours, respectively).

Experiment 4 testosterone, flesinoxane and sildenafil in MSD [0060] Efficacy of the combined administration of testosterone and 5-HT1A receptor agonist - flesinoxane - and PDE5 inhibitor - sildenafil - male sexual function in response to fragments of erotic films in men with MSD [0061] In Double blinded, randomized placebo-controlled cross-over study, a group of 16 men with male sexual dysfunction (MSD) will receive

1. testosterone (0.5 mg), flesinoxane (1 mg) and sildenafil (10 mg)

2. testosterone (0.5 mg) and flesinoxane (1 mg)

3. Flesinoxane (1 mg) and Sildenafil (10 mg)

4. only testosterone (0.5 mg)

5. Flesinoxane only (1 mg)

6. placebo for 6 days separated by study.

[0062] Penile swelling and stiffness will be measured in response to audiovisual stimulation with neutral and erotic films (VSTR), immediately after drug administration and 1 hour after drug administration, followed directly by measuring the latency of ejaculation time latency with vibroactive stimulation (VTS-ELT) and post-erectile resistance time for erection. Six experimental days were separated for (at least) three days. During each administration, patients receive one capsule containing either flesinoxane or placebo, and a liquid formulation with testosterone or placebo. VSTR will be measured in response to fragments of inert and erotic films, immediately after administration of the liquid preparation and 4 hours after administration of the liquid preparation, when VTS-ELT is also measured. Thus, the liquid formulation will be taken four hours before testing, capsule one hour before testing. The effects of sublingual testosterone, flesinoxane and sildenafil overlap due to their different delays (3.5-4.5 hours, 0.1 hours and 0-1 hours, respectively).

[0063] Experiments 3-4 will be preceded by a screening visit. During screening, an interview and examination is carried out by a resident of the gynecology department of the Flevo Hospital, Almere in order to diagnose MSD and qualify for participation in the study. Patients will be asked to complete a survey; international erection index questionnaire (IIEF). Weight, height, blood pressure (lying and standing) will be measured. The cardiovascular system will be examined and the ECG checked for significant abnormalities. Participants are required not to use alcohol or psychoactive substances in the evening before and on the day of the experiment.

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