Dual delivery pharmaceutical composition and method for determining dosage thereof

Abstract

The present invention relates to a pharmaceutical composition comprising a steroid such as testosterone or a functional analogue or derivative thereof, in combination with a PDE5 inhibitor such as sildenafil. The testosterone or the functional analogue or derivative thereof is present in an amount equivalent to no less than 1 mg. The present invention also concerns the use of the pharmaceutical composition for enhancing female sexual desire in the treatment of FSIAD of a patient, as well as methods for identifying suitable patients and for identifying suitable dosage for the use thereof.

Description

[0001] Dual delivery pharmaceutical composition and method for determining dosage thereof TECHNICAL FIELD The invention relates to dual delivery pharmaceutical compositions and the use of such compositions in groups of women suffering from Female Sexual Interest / Arousal Disorder (FSIAD) according to a number of parameters influencing the dosage required or recommended. An algorithm useful for determining dosage per group is also provided. In particular, it specifically relates to dual delivery pharmaceutical compositions for enhancing female sexual desire for use in the treatment of FSIAD. The invention further relates to methods for determining a suitable (starting) dosage of the dual delivery pharmaceutical composition and subsequently optimising the dosage, if necessary. BACKGROUND OF THE INVENTION Sexual interest refers to the motivation to engage in sexual activity. It is also commonly referred to as “desire,” “sex drive,” and “sexual appetite,” and describes the sexual feelings motivating a person to seek some type of sexual activity, whether partnered or alone. Sexual arousal is conceptualized as the second phase of the sexual response cycle and defined by both mental and physical readiness for sexual activity. Physiological changes (for example erection in males, vaginal swelling and lubrication in females) occur in the body to prepare for a sexual interaction. Low sexual desire is the most common sexual complaint in women. As a result, many women suffer from sexual dissatisfaction and related distress which often negatively interferes with their quality of life. FSIAD refers to the lack of, or significantly reduced, sexual interest / arousal in women. According to the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), FSIAD represents the combination of two previously separate conditions Hypoactive Sexual Desire Disorder (HSDD) and Female Sexual Arousal Disorder (FSAD). This condition stands as the primary sexual health complaint among women, leading to widespread sexual dissatisfaction that negatively affects their overall well-being and life quality. Typical symptoms of FSIAD may include: absent or reduced interest in sexual activity; absent or reduced sexual thoughts or fantasies; no or reduced initiation of sexual activity, and typically unreceptive to a partner’s attempts to initiate; absent or reduced sexual excitement or pleasure in almost all or all sexual encounters; absent or reduced sexual interest / arousal in response to any internal or external sexual cues; and absent or reduced genital or non-genital sensations during sexual activity in all or almost all sexual encounters. Typically in patients with FSIAD, these symptoms have caused clinically significant distress and have persisted for a minimum of six months. The disorder is specified by severity level and subtyped into lifelong versus acquired, generalized versus situational. Previous studies have examined the prevalence of low sexual interest and low sexual arousal in women. One of the most frequently cited prevalence study found low sexual interest in 22% of women in the general U.S. population (Laumann, Paik, Rosen, & Page, 1999). In a survey of women from 29 countries, rates of self- reported low sexual interest ranged from 26 to 43% (Laumann et al., 2005). Taking levels of distress into account, rates may range from 7.3% (Bancroft, Loftus, & Long, 2003) to 23% (Witting et al., 2008), depending on a woman’s age, cultural background, and reproductive status.Treatment of FSIAD may include psychotherapy and / or medication. Currently, limited drug treatments are available globally to treat women with FSIAD. When assessing the efficacy of various treatments of FSIAD, women’s sexuality, particularly desire, often requires careful consideration of the multifactorial nature of it, and single-item scales, such as SSEs (satisfying sexual events) are often too simplistic and fail to account for the subtle multidimensional subjective issue that contribute to the construct of sexual desire. Currently, European medical systems lack any government-approved pharmaceutical treatments for FSIAD, creating a significant gap in care for the many women experiencing this condition. The biological mechanisms underlying FSIAD remain poorly understood by researchers. However, current theories suggest that healthy sexual function results from complex interactions between brain-based (central) and body-based (peripheral) processes. Scientists theorize that medications targeting both systems simultaneously could produce enhanced therapeutic effects that benefit women with FSIAD more than single-drug approaches. Oral dual delivery systems comprising an immediate release steroid such as testosterone and a delayed immediate release phosphodiesterase-5 (PDE5) inhibitor such as sildenafil have previously shown efficacy in the treatment of FSIAD. However, the performance of such oral dual delivery systems varies greatly between individual patients. Medical practitioners therefore need practical guidance on the determination of (starting) dosages for a patient, and additional pharmaceutical compositions that cater for patients who may have special needs. SUMMARY OF INVENTION According to the invention there are a number of factors in the general female population that may influence the efficacy of a combination treatment of FSIAD with testosterone (an immediate release formulation) and a PDE5 inhibitor (in a delayed immediate release formulation). These factors comprise the menopausal status of a woman, the use of combined oral contraceptives (COCs) or combined hormone replacement therapy (HRT), the sex hormone binding globulin (SHBG) levels, the albumin levels and the (body mass index) (BMI). Often these factors will be inter-related. For an all-comer population the 0.5mg, 50mg dual dosage of testosterone and sildenafil respectively will be efficacious, but for instance for post- menopausal women, in particular those with very low BMI a higher testosterone dosage (up to 4 mg) may be useful. Providing safe and efficacious dosages of both testosterone and sildenafil (or equivalents of either) for women that may not be served as well with the all-comer dosage are an important aspect of the present invention. The inventors of the present invention found that, surprisingly, patient stratification according to the method of the present invention helps to achieve better clinical results in terms of improvement of sexual function. According to a first aspect, the present invention provides a method for identifying a patient suitable for receiving a combination treatment with higher testosterone dosage (no less than 1.0mg) in the treatment of FSIAD. According to the method, the patient is identified as a suitable candidate when the patient has one of the following impact factors: 1) The patient is postmenopausal; 2) The patient’s BMI is no greater than a pre-determined threshold, for example 25, 24.5, 24, 23.5, 23, or preferably 22.5; 3) The patient is using COCs or receiving HRT; 4) The patient has a plasma SHBG level no lower than a pre-determined threshold, for example 80 nmol / L, 90 nmol / L, or preferably 100 nmol / L; or 5) the patient also has a plasma albumin level no greater than a pre-determined threshold, for example 45 g / L, 40 g / L, or preferably 37 g / L. As unexpectedly found by the inventors of the present invention, and as shown in the Examples described herein, the impact factors recited above can provide good indication on the dosage of testosterone required in order to achieve good efficacy in the treatment of FSIAD whilst avoiding any (serious) side effects. The present invention offers a simple yet effective way that helps to identify patients with different medication requirements at an early stage, thereby enhancing the chance of success with treatments and improving patient’s confidence levels. The impact factors can also interact with each other to further drive up requirements on testosterone. Patients with multiple impact factors may require further increase on the testosterone dosage in order to achieve satisfactory efficacy. For example, patients with one impact factor may require a combination therapy with at least 1-2mg testosterone. Testosterone dosage in the combination therapy can go even higher, for example to at least 4mg, for patients whose BMI is extremely low (for example lower than 20, lower than 18, or lower than 16; or patients whose plasma SHBG levels are very high (for example more than 20% higher, more than 30% higher, more than 40% higher, or more than 50% higher, than the pre-determined threshold. The present invention also provides a method for determining the testosterone dosage in a combination therapy (with a PDE5 inhibitor such as sildenafil) for a patient in the treatment of FSIAD. According to the method, the testosterone dosage in the combination therapy is determined based on the number of impact factors the patient has. Patients with at least one impact factor will start with a combination therapy comprising at least 1.0-2.0mg testosterone. Using this method, a medical practitioner can quickly choose a combination therapy that is likely to work for a particular patient, based on the patient’s demographic data or blood test results, broadening the window of opportunity for achieving desirable efficacy. Preferably, the testosterone is administered in a way that the testosterone is immediately bio- available upon administration. In other words, the testosterone is administered in a “immediate release” format. The term "immediate release" refers to a release of a substantial amount of an active ingredient within a predefined period of time. An immediate release, for example, provides the release of more than 60% of the ingredient, more preferred more than 70%, more preferred more than 80%, within 30 minutes after rupture of the coating, more preferred within 20 minutes, more preferred within 8 minutes upon administration or after rupture of the separating coating, when present. Preferably, the testosterone is administered orally, for example, released in the sublingual space in the mouth. For example, the testosterone may be administered as a sublingual tablet or oral solution / liquid. It may be applied some time (for example 120 seconds, 90 seconds, or 60 seconds) before swallowing. Alternatively, the testosterone may be administered as a sublingual or oral inhalation or intranasal inhalation spray. Previous test results indicate that after sublingual testosterone administration, serum free and total testosterone levels may peak at approximately 15 minutes and reach baseline levels within approximately 150 minutes. Due to the abundant vascularization in mouth, including the sublingual space in the mouth, rapid adsorption of testosterone is possible, helping to bring a rapid (high) peak of (bioavailable) testosterone in the bloodstream. The abundance of bioavailable testosterone sends a signal to the central system, and getting the body ready for the stimulation from the PDE5 inhibitor. The patient receiving a high testosterone combination therapy may be postmenopausal. Menopause significantly affects various hormone and protein levels in the body. For example postmenopausal women may see drops in estrogen, progesterone, and testosterone levels. The level of SHBG in menopausal women may also decrease. Nevertheless, high SHBG levels have also been reported in postmenopausal women, probably related to hormonal changes due to weight increase and / or use of HRT. It has been found in clinical trials that, surprisingly, patients in the treatment of FSIAD who are postmenopausal appeared to have benefited from high testosterone levels. As hormone and / or SHBG levels can also be affected by medications such as combined oral contraceptives (COCs) or combined hormone replacement therapy (HRT), patients who are using COCs or receiving HRT are also considered suitable for a high testosterone dosage in the combination therapy with a PDE5 inhibitor in the treatment of FSIAD. In addition, key general health indicators such as BMI also affect hormone levels. For example, insufficient body fat can lead to decreased hormone levels (such as estrogen, testosterone, thyroid hormones etc.) as adipose (body fat) tissues contribute to the production of hormones. Low BMI, particularly when associated with low body fat and muscle mass, can also lead to low insulin levels and potentially impact blood sugar regulation, which in turn effects hormone levels and balance. The inventors of the present invention found that, surprisingly, patients with low BMI, for example a BMI no greater than 25, 24.5, 24, 23.5, 23, preferably a BMI no greater than 22.5, or even lower than 20, require testosterone dosage of no less than 1.0mg, for example 1.0-4.0mg, in combination therapy for the treatment of FSIAD, for getting desired efficacy. SHBG and albumin are important proteins that bind to testosterone, thereby affecting the level of bio-available testosterone in the bloodstream, that are ready for biological activities. High SHBG level or low albumin level is indicative of in vivo allocation and activities of testosterone upon administration. Increasing the testosterone dosage to no less than 1.0mg, for example 1.0 to 4.0mg, in a combination therapy for the treatment of FSIAD for patients with high plasma SHBG level and / or low plasma albumin level has shown increased efficacy. A plasma SHBG level is considered “high” if it’s at least 80 nmol / L, 90 nmol / L, preferably at least 100 nmol / L, and, for example if it’s 80-250 nmol / L, or 100-200 nmol / L. A plasma albumin level is considered “low” if it’s no more than 45 g / L, 40 g / L, or preferably 37 g / L, even more preferably, and, for example if it’s 10-40 g / L, or 15-35 g / L. The combination therapy may comprise the PDE5 inhibitor in an amount sufficient for achieving the desired efficacy with low side effects. Preferably the PDE5 inhibitor is sildenafil (or a salt thereof), and the amount of sildenafil may be from 25 to 120mg, for example 25mg, 50mg, 75mg or 100mg. The combination therapy comprising (high dosage) testosterone and PDE5 inhibitor may be administered as one formulation or as separate formulations. The formulation or the separate formulations are such that testosterone is released as an immediate release and the PDE5 inhibitor is released as a delayed immediate release, and the delay is preferably 2-6 hours, most preferably 2.5-3.5 hours (after the release of testosterone). The method of the present invention may be further personalised. For example, the method may further comprise further personalisation or adjustment of the dosage of testosterone and / or the PDE5 inhibitor such as sildenafil, based on initial evaluation of efficacy and side effects after treating the patient with the chosen dosage / pharmaceutical composition for a pre- determined period of time. For example, if, according to the evaluation, the efficacy of the treatment is not sufficient, the dosage of testosterone may be further increased, for example increased by 0.5mg or 1.0mg. The additional testosterone can be administered in the form of an additional formulation, for example a separate formulation comprising 0.5mg or 1.0mg testosterone. Or the patient can take a combined formulation comprising the higher testosterone dosage (in combination with the desired dosage of PDE5 inhibitor). For example, the patient may administer a combination therapy comprising 1mg testosterone and a PDE5 inhibitor, and a further pharmaceutical composition comprising 1.0mg testosterone, for example an oral 1.0mg testosterone composition, preferably as a liquid or sublingual administration, or a 1.0mg testosterone composition in a solid dosage form such as a tablet, a capsule, or in a dosage form suitable for oral or intranasal inhalation. Alternatively, if the side effects of the treatment are too severe, the dosage of the PDE5 may be reduced. When the dosage of the PDE5 inhibitor is adjusted, the dosage of testosterone can be adjusted at the same time to 0.5mg or to 1.5mg. For example, the adjustment may comprise giving the patient a pharmaceutical composition comprising 0.5mg testosterone and 50mg sildenafil, optionally in combination with a further pharmaceutical composition comprising 1.0mg testosterone, preferably as a liquid or sublingual administration, for example an oral 1.0mg testosterone composition, or a 1.0mg testosterone composition in a solid dosage form such as a tablet, a capsule, or in a dosage form suitable for oral or intranasal inhalation. The method and composition of the present invention offers great flexibility in terms of tailoring it for individual needs. The pre-determined treatment period may be any period sufficient to establish both the efficacy and side effects of the treatment. For example, the pre-determined treatment period may be 4 weeks or 8 weeks, preferably 8 weeks. According to a further aspect, the present invention provides a combination therapy (a pharmaceutical composition) comprising a steroid such as testosterone or a functional analogue or derivative thereof, in combination with a PDE5 inhibitor, preferably for use for the patient identified by the method of the present invention. The testosterone or a functional analogue or derivative thereof is present in an amount equivalent to no less than 1mg, for example 1-5mg, preferably 1-4mg, testosterone. Based on earlier clinical studies it has been observed that 0.5 mg of testosterone may not be as efficacious in women with at least one of the following characteristics: post-menopausal, use of COC or receive HRT, high SHBG, low albumin and (very) low BMI. Women with one of these characteristics may typically benefit from a higher dose of testosterone, e.g. 1-2 mg. Women who have at least two of these characteristics may benefit from an even higher dose, such as 3-4 mg. The combination therapy of the present invention is useful for enhancing female sexual desire in the treatment of FSIAD, in particular acquired FSIAD. The inventors of the present invention have found that when used for enhancing female sexual desire in the treatment of FSIAD, testosterone and the PDE5 inhibitor can synergistically enhance both central and peripheral processes. In particular, the high dose (no less than 1mg) testosterone in the pharmaceutical composition of the present invention provides sufficient bioavailable testosterone in the bloodstream even in patients with relatively high SHBG level (thus high proportion of strongly bound testosterone) or relatively low albumin level (thus low proportion of weakly bound testosterone) due to, for example, their general health conditions, use of COC or HRT, or menopausal status). The combination therapy of the present invention may also be useful in alternative therapies such as psychotherapy and counselling, in particular with regards to relationship or couple therapy. Approximately 30-50% of couples in therapy report female sexual issues, and addressing female sexual issues in therapy often involves a multidisciplinary approach, including improving communication, exploring emotional and psychological factors, and incorporating medical interventions. The combination therapy of the present invention provides a tool for improving sexual relationship between couples and partners, and can increase chance of success and / or improve the outcome of psychotherapy and counselling. The pre-determined thresholds (referred to hereabove and hereafter) represents reference points for each of those parameters. The skilled person will be able to determine a suitable threshold, based on common general knowledge and the teaching of the current application, using means and methods already known in the art. In the context of the current application, the term “testosterone” is used to also encompass a functional analogue or derivative thereof, where it is not explicitly mentioned. The amount of testosterone specified in the current application is to be understood to refer to the “equivalent testosterone” amount, when a functional analogue or derivative of testosterone is used. Testosterone is also known under the chemical name 17-[beta]-hydroxyandrost-4-en-3-one which can be obtained in various ways: it may be isolated and purified from nature or synthetically produced by any manner. The term “testosterone or functional analogue or derivative thereof” refers to testosterone or a precursor or metabolite of testosterone that provides the same or a similar function as testosterone. Preferred precursors of testosterone are selected from pregnenolone, 17α- hydroxypregnenolone, progesterone,17α-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, and androstenediol. Preferred metabolites of testosterone are selected from hydroxyandrostenedione, hydroxytestosterone, including 2β-, 6β-, 7α-, 12α-, and 16α- hydroxytestosterone, and dihydrotestosterone, including 5 a- and 5β- dihydrotestosterone. A preferred analogue of testosterone is capable of binding to an androgen receptor. It is most preferred that said testosterone or a functional analogue or derivative thereof is testosterone. According to the invention, although it is not considered bound by theory, an effect on the central nervous system and the peripheral system are required, whereby the signal to the central system is provided by testosterone or a functional analogue or derivative thereof (having the same kind of activity) and the peripheral signal is provided by the PDE5-inhibitor. Testosterone in the circulation is typically bound by SHBG and by albumin. Albumin is the most abundant protein in human blood plasma. It plays a crucial role in maintaining oncotic pressure, which helps keep fluid within the blood vessels. Albumin also serves as a carrier protein, binding to various substances such as hormones, vitamins, and drugs, facilitating their transport through the bloodstream. In particular, albumin binds to testosterone with low affinity. Additionally, it has antioxidant properties and helps in maintaining pH balance. Low levels of albumin can indicate liver disease, kidney disease, or other medical conditions. Albumin is produced by the liver, and the production is influenced by including nutritional status, hormonal signals, and overall liver function. The binding of testosterone to albumin is a dynamic process characterized by a rapid equilibrium. This binding is relatively weak and reversible, which means that albumin-bound testosterone can quickly dissociate and become available for cellular uptake, contributing to the bioavailable fraction of testosterone. In particular, the binding is non-covalent (e.g. by hydrophobic interactions and electrostatic forces) and quickly reaches a state of equilibrium, where the rates of binding and unbinding are balanced. The association (binding) and dissociation (unbinding) of testosterone with albumin occur rapidly. The exact time frame for these interactions is in the order of milliseconds to seconds. Due to the rapid and reversible nature of its binding, albumin-bound testosterone is considered part of the bioavailable pool of testosterone. This means it can quickly dissociate and become free to enter cells and exert biological effects. The rapid binding and release of testosterone from albumin help buffer fluctuations in hormone levels, ensuring a relatively stable concentration of free testosterone available to tissues. Albumin is present in high concentrations in the blood. In healthy adults, the normal range for serum albumin is typically between 3.5 and 5.0 g / dL (grams per decilitre). Albumin levels can fluctuate slightly due to factors like hydration status, diet, and physical activity. Factors that may affect albumin levels include: ^ Age. In younger adults, albumin levels are generally stable and within the normal range, assuming good health and adequate nutrition. As people age, serum albumin levels tend to gradually decline. This decline is not always indicative of disease but may reflect age-related changes in liver function, protein synthesis, and overall health status. Lower albumin levels in older adults are often associated with malnutrition, frailty, and chronic diseases. In many cases, hypoalbuminemia (low albumin levels) can be a marker for poor nutritional status or the presence of an underlying chronic illness. Some studies suggest that low albumin levels may be associated with an increased risk of cognitive decline and dementia in older adults, although the exact relationship remains under investigation. Albumin is also important for immune function, and low levels in older adults can be linked to weakened immune responses and increased susceptibility to infections. ^ Hormonal changes, for example menopause, or hormone replacement therapy. Some studies suggest that albumin levels may decrease slightly during menopause, partly due to hormonal changes and the associated effects on liver function. However, this decline is often subtle and may not be significant in healthy women without underlying conditions. Hormone replacement therapy (HRT), often used to manage menopausal symptoms, can influence albumin levels. Estrogen therapy, particularly oral estrogen, can increase the production of proteins in the liver, including SHBG and possibly albumin, though the effects on albumin are less pronounced. The overall impact of HRT on albumin levels may depend on the type and route of administration (e.g., oral vs. transdermal). ^ Certain medications commonly used by older adults, such as nonsteroidal anti- inflammatory drugs (NSAIDs) and corticosteroids, can affect albumin levels by influencing liver function or causing fluid retention. ^ Health conditions, for example BMI, liver function, hyperthyroidism, obesity, insulin resistance, and polycystic ovary syndrome (PCOS). A low BMI, particularly in the context of malnutrition or underweight status, is often associated with lower albumin levels. Malnutrition leads to inadequate protein intake, which can reduce albumin synthesis in the liver. This is commonly seen in individuals with chronic illnesses, eating disorders, or severe weight loss. Obesity (high BMI) can have complex effects on albumin levels. In some cases, individuals with higher BMI may have normal or even slightly elevated albumin levels, particularly if their nutritional status is adequate. However, obesity is often associated with conditions like insulin resistance, chronic inflammation, and fatty liver disease, which can alter albumin production. Many diseases, such as liver disease, kidney disease, heart disease, inflammatory and autoimmune diseases, cancer, etc, can also influence albumin level. Low albumin levels often signal poor health outcomes and can be used as a marker for disease severity, prognosis, and the need for medical intervention. SHBG is a glycoprotein produced mainly by the liver. it binds to sex hormones, specifically testosterone and estradiol, which are the primary male and female sex hormones, respectively. By binding to testosterone and estradiol, SHBG controls the amount of these hormones that are free and active in the bloodstream. Only the unbound (free) hormones can enter cells and exert their effects. Several factors can influence SHBG levels, including age, sex, liver function, use of oral estradiol or testosterone, and the presence of certain medical conditions. Abnormal SHBG levels can indicate various health conditions. High SHBG levels, for example, can be seen in hyperthyroidism, liver disease, HIV infection, and anorexia. High SHBG level can reduce the availability of free testosterone, potentially leading to symptoms of testosterone deficiency. Conversely, low SHBG levels can be associated with hypothyroidism, obesity, polycystic ovary syndrome (PCOS), and use of anabolic steroids, and can result in excessive free testosterone, which might be seen in conditions like PCOS or insulin resistance. Approximately 60-70% of testosterone binds to SHBG, which binds more tightly and makes this fraction less readily available for tissue uptake. Only about 1-2% of testosterone remains free and biologically active. Free testosterone is rapidly metabolized (T1 / 2approximately 10 min.) which demonstrates the importance of SHBG binding and dissociation capacity, indicating that SHBG is the major determinant of the free fraction equilibrium. SHBG levels can be measured through a blood test. This measurement is often used in conjunction with tests for total testosterone to calculate the free testosterone level, which is important in diagnosing various hormonal disorders. SHBG is present in much lower concentrations compared to albumin. The normal range for SHBG can vary depending on age, sex, and the laboratory conducting the test. In general, normal SHBG level in adult men is approximately from 10 to 57 nmol / L, and for women it’s approximately 18 to 144 nmol / L in pre-menopausal women and approximately 14 to 103 nmol / L in post-menopausal women. Factors that may affect SHBG levels include: ^ Age. In childhood and early adolescence, SHBG levels are generally high. As puberty begins, SHBG levels start to decline. During adulthood, SHBG levels tend to stabilize. However, they can be influenced by various factors, including body weight, insulin levels, and overall hormonal balance. Men generally have lower SHBG levels than women. In women, SHBG levels may fluctuate with menstrual cycles, pregnancy, and (oral) contraceptive use. As people age, SHBG levels typically increase. This is particularly evident in men, where SHBG levels rise with age, leading to a reduction in the levels of bioavailable testosterone. This increase in SHBG is one of the factors contributing to the decline in testosterone levels often seen in older men. In women, SHBG levels also increase with age, especially after menopause, as estrogen levels decline. Higher SHBG levels can further reduce the availability of sex hormones, contributing to symptoms of aging such as reduced libido and bone density changes. ^ SHBG levels are closely linked to hormonal changes that occur during menopause. Menopause marks the end of a woman’s reproductive years, typically occurring around the age of 50, and it is characterized by a decline in estrogen and progesterone production. These hormonal shifts have significant effects on SHBG levels. Use of hormone replacement therapies, oral contraceptives, or medications that influence hormones can alter SHBG levels at different life stages. ^ Medication, such as oral contraceptives, estrogen therapy, and anti-androgens, hormonal therapies. ^ Health conditions, for example BMI, liver function, hyperthyroidism, obesity, insulin resistance, and polycystic ovary syndrome (PCOS). Higher BMI is often associated with lower SHBG levels. As people age and their body composition changes, SHBG levels can be affected. Since SHBG is produced in the liver, any changes in liver function (for example with age or disease) can impact SHBG levels. Testosterone in the bloodstream exists in three main fractions: 1. Free Testosterone: o Percentage: Approximately 1-2% of total testosterone. o Description: This fraction is not bound to any proteins and is biologically active. It is able to enter cells and exert its effects directly. 2. Albumin-bound Testosterone: o Percentage: About 30-40% of total testosterone. o Description: This fraction is weakly bound to albumin, a protein in the blood. It is considered bioavailable because the bond is not strong, allowing testosterone to be readily available for tissue uptake. 3. SHBG-bound Testosterone: o Percentage: Approximately 60-70% of total testosterone. o Description: This fraction is strongly bound to SHBG and is generally considered biologically inactive. SHBG-bound testosterone cannot easily enter cells, thus limiting its immediate biological effects. Free testosterone is the most important fraction for determining androgenic activity, as it represents the amount of hormone available to tissues. The sum of free testosterone and albumin-bound testosterone is bioavailable testosterone, and it is often used in clinical settings to access testosterone levels more accurately, as both fractions can exert biological effects. Total testosterone includes all three fractions, and is commonly measured. It does not always provide a complete picture of hormonal activity without considering SHBG levels. In addition to “bioavailable testosterone”, the term “bioactive testosterone” is also often used in the context of hormone physiology. Bioactive testosterone refers to the fraction of testosterone that is biologically active, meaning it can bind to androgen receptors in target tissues and elicit a physiological response. Whilst bioavailable testosterone include both free testosterone and albumin-bound testosterone, bioactive testosterone only includes free testosterone, because this is the fraction that can freely enter cells and bind to androgen receptors. Once free testosterone enters a cell, it binds to androgen receptors, leading to various biological effects, such as muscle growth, secondary sexual characteristics, and maintenance of libido. Bioactive testosterone directly reflects the hormone's capability to trigger a biological response within target tissues, and bioavailable testosterone is a more accurate indicator of the testosterone that is accessible to tissues for biological activity, as it includes both free and easily releasable testosterone. Bioavailable testosterone can be measured by considering both free and albumin-bound testosterone levels. This can be assessed through specific blood tests. Bioactive Testosterone: It is effectively measured by the levels of free testosterone alone, which can be directly tested. Both bioavailable and bioactive testosterone have important clinical relevance. For example, bioavailable testosterone is important for understanding the overall amount of testosterone that can potentially be used by the body, considering both free and weakly bound forms; and bioactive testosterone is critical for assessing the immediate hormonal activity and effects within the body, as it directly impacts physiological functions. Albumin levels impact the bioavailability of testosterone. In particular, albumin binds to about 30-40% of the testosterone in the blood. This bound testosterone is considered bioavailable because it is loosely attached to albumin and can easily dissociate to become active. When albumin levels are low, the total amount of albumin-bound testosterone decreases. the proportion of free testosterone (unbound) might increase. However, this does not necessarily mean that more testosterone is available to tissues. Free testosterone can be quickly degraded, and without sufficient albumin, the transport and regulation of testosterone are compromised. This could result in a reduction of bioavailable testosterone. Even if total testosterone levels remain stable, reduced albumin-bound testosterone can lead to symptoms of low testosterone. These include fatigue, decreased libido, erectile dysfunction, mood changes, and muscle weakness. In the context of the present invention, albumin levels can also influence the pharmacokinetics and efficacy of the PDE5 inhibitor such as sildenafil. Sildenafil is partially bound to plasma proteins, including albumin. Normally, about 96% of sildenafil in the bloodstream is bound to proteins, with albumin being one of the primary binding proteins. When albumin levels are low, there is less protein available to bind to sildenafil. This can lead to a higher proportion of free (unbound) sildenafil in the blood. Higher levels of free sildenafil may enhance the drug's effects, potentially improving its efficacy in treating erectile dysfunction (or vaginal bloodflow) or pulmonary hypertension. However, a higher concentration of free sildenafil can also increase the risk of side effects, such as headaches, flushing, dizziness, or more severe cardiovascular effects. With less albumin to bind to, free sildenafil may be more rapidly metabolized and cleared from the body, potentially shortening its duration of action. Patients with low albumin might experience more variability in how they respond to sildenafil, with either more pronounced effects or quicker subsidence of its action. The relationship between SHBG levels and bioavailability of testosterone is more straightforward. Higher SHBG levels lead to high proportion of SHBG-bound testosterone, thereby reducing the amount of testosterone readily available for biological activity. There are important differences between the usual chronic treatment with modest increased levels of testosterone (by means of patches, gels, pills, etc.) and the treatment according to the present invention (for example, in the form of sublingual administering of at least 0.5 mg, preferably at least 1.0 mg testosterone). Chronic treatment with modest levels of testosterone is accompanied by a slight increase in absolute levels of testosterone, and in the long run (days / weeks), an increase in the free fraction of testosterone. This gradual increase of the free fraction of testosterone is the result of an alteration in a homeo- static state regarding testosterone (metabolism), and is responsible for its positive as well as negative effects. In contrast, in our approach we produce a considerable increase in absolute levels of testosterone (about 15–20 times higher than in the chronic treatment) within and during a (very) short period, and we assume that this increase will produce a transient proportional increase in the free fraction of testosterone. We postulate an SHBG (and to a lesser extent albumin) saturation threshold mechanism. The increase in influx of testosterone into the body will be first bound to SHBG and (to a lesser extent) albumin, before it can produce an increase in the free fraction. Without wishing to be bound by theory, the dose of testosterone according to the pharmaceutical composition of the present invention is high enough to saturate the albumin and SHBG (i.e the concentration of testosterone is high enough to overcome complete binding of testosterone by SHBG or albumin) such that at least a fraction of testosterone not bound by albumin and SHBG is present in the blood (free testosterone). For this purpose, the pharmaceutical composition of the present invention comprises no less than 1mg, for example 1-5mg, preferably 1-4mg, testosterone. We have tentatively calculated that the increase of testosterone in the pharmaceutical composition of the present invention caters for women with an elevated plasma SHBG level, or for example post-menopausal women, with or without combined hormone replacement therapy (HRT), or pre-menopausal women who are taking COC (combined oral contraceptive) medications. It is large enough to “saturate” SHBG in the bloodstream, with sufficient bioavailable testosterone left for biological activity. Thus the pharmaceutical composition of the present invention will produce a short peak of free testosterone in the patient, and we believe that this short burst in the free fraction of testosterone is responsible for cognitive, affective, and behavioural effects a few hours later. Preferably, the pharmaceutical composition of the present invention comprises 1mg, 1.5mg, 2mg, 2.5mg, 3mg, 3.5mg, or 4mg testosterone. The inventors of the present invention found (through studies and tests) that high-dose testosterone helps to increase the chances of having sufficient bioavailable testosterone in the bloodstream, thereby improving sexual functions and responses, in particular when used in combination with a PDE-5 inhibitor. The effects of the pharmaceutical compositions of the present invention are further demonstrated in the Examples. Without wishing to be bound by theory, the inventors believe that the (enhanced) effects were (at least partially) contributed by dose-dependent effects of testosterone, which find support in various literature and publication. For example, Huang et al. 2015 showed that composite sexual function scores (including indications on thoughts, desire, arousal and activity frequency) significantly improved in hysterectomized women receiving weekly IM testosterone enanthate doses of 25mg. Lean body mass and functional power also improved dose-dependently. In a study of sexual desire in postmenopausal women with hypoactive sexual desire disorder, it was found that patients receiving transdermal testosterone patches delivering 300µg / day had significantly greater increase in frequency of satisfying sextual episodes. Similarly, a review and meta-analysis by Islam et al. 2019 found overall dose-related improvements in sexual function (desire, arousal, orgasm, pleasure, distress) with testosterone, although the most robust benefits were observed in non-oral routes. When looking closer at effects of testosterone metabolites in women, although the amount of direct research is limited, there are still studies that help to gain insights into dose influences. Most studies at least showed elevated metabolites levels (for example dihydrotestosterone (DHT), androstenedione, SHBG and / or DHEA) with high-dose testosterone (or testosterone enanthate). Studies on dose-dependent effects of testosterone and testosterone metabolites in men are more abundant. Typically, greater improvements on sexual desire and function were found associated with higher plasma testosterone levels. Testosterone exhibited clear dose- response relationships in men, both young and old. In men, DHT levels were found crucial for the sexual function response at higher doses of testosterone. In short, previous studies and test results observed dose-related increases in testosterone and testosterone metabolites levels, and increased efficacy was also previously reported (see for example Tuiten et al.2018) with increasing dose combinations. The inventors of the present invention validated in the Examples of the current application the efficacy of combination therapy with high-dose (at least 1 mg) testosterone and a PDE5 inhibitor (sildenafil). The use of high-dose testosterone for the treatment of women suffering from FSIAD is supported both by literature and by test results (of the present invention). Preferably, the PDE5 inhibitor in the pharmaceutical composition of the present invention is sildenafil, vardenafil, or tadalafil, or any of the other known PDE5 inhibitors, or a combination thereof. Further non-limiting examples of PDE5 inhibitors are: E-4021, E-8010, E-4010, AWD- 12-217 (zaprinast), AWD 12-210, UK- 343,664, UK-369003, UK-357903, BMS- 341400, BMS- 223131, FR226807, FR- 229934, EMR-6203, Sch-51866, IC485, TA-1790 (avanafil), DA-8159 (udenafil), NCX-911 or KS- 505a. Other examples can be found in WO 96 / 26940. In the context of the current application, the PDE5 inhibitors disclosed herein also encompass their pharmaceutically acceptable salts or combinations thereof. A preferred PDE5 inhibitor according to the invention is sildenafil which is preferably administered as sildenafil citrate (l- [[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl] -4-methylpiperazine citrate). Sildenafil (in a single API composition) was previously found (for example in Kling et al.2005) to have improved arousal and sexual satisfaction, with 50 mg being the dose leading to the most significant improvements in sexual arousal and overall satisfaction compared to placebo. Similarly, Goldstein et al.2003 also reported that sildenafil was effective in increasing sexual desire and arousal in women with hypoactive sexual desire disorder, but there was no clear advantage to higher doses over 50 mg (again in a single API composition). Most previous literature suggested an optimal dose of 50 mg for sildenafil when used for improving sexual function in women with various sexual arousal / desire disorders. When it comes to effects of sildenafil metabolites, the metabolite N-desmethylsildenafil was found to contribute to sildenafil’s overall effects, especially in the extended window of efficacy. To that extent, Rosen et al.2006 found that 100 mg of sildenafil produced the highest level of N-desmethylsildenafil. However, in Rosen, 100 mg dose was found to have no added benefits when compared to 50 mg dose, in improving sexual function. The same 50 mg dose was previously also found to be optimal in postmenopausal women (Ursini et al.2006). Other PDE-5 inhibitors, such as vardenafil and tadalafil. were also found to have dose- dependent improvements in sexual function. For vardenafil, the optimal dose (when used in a single API composition) in a typical case is 10 mg. Vardenafil metabolites (primarily M1) was found to increase dose-dependently with high doses (of parent drug), but the clinical effects after 10 mg dose were not considered significant. For tadalafil, 20 mg was found to show the most significant improvement in sexual function, although 10 mg was already considered effective. When it comes to metabolites, although they may play a role in tadalafil’s overall pharmacokinetics, they were found to have limited direct clinical effects in improving sexual function (see, for example, Brock et al.2008). The effect duration on sexual function between different PDE5 inhibitors may be different, due to, for example, their pharmacokinetics. Sildenafil and vardenafil have shorter half-lives (about 4-5 hours) and are processed out of body relatively quickly. Their effect duration are therefore around 4-6 hours. Tadalafil, which has a much longer half-life (about 17.5 hours), could remain in the system for 24-36 hours, and may has a more long-lasting clinical effect. In the methods of the present invention, the pharmacokinetics of PDE5 inhibitors are also taken into account, together with the pharmacokinetics of testosterone, in order to achieve desirable synergetic effects. Preferably, the PDE5 inhibitor is present in the pharmaceutical composition of the present invention in an amount of at least 10 mg, at least 25 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 90 mg, for example 100mg. In some (non-limiting) embodiments, the PDE5 inhibitor may be present in an amount even higher than 100mg, for example higher than 110mg or 120mg. Preferably, the PDE5 inhibitor is present in the pharmaceutical composition of the present invention in an amount of no more than 200 mg, no more than 190 mg, no more than 180 mg, no more than 170 mg, no more than 160 mg, no more than 150 mg. Preferably, the PDE5 inhibitor is present in the pharmaceutical composition of the present invention in an amount of 10 to 150 mg, 20 to 140 mg, 30 to 130 mg, 40 to 120 mg, 50 to 110 mg or 50 to 100 mg. In some preferred embodiment of the present invention, the PDE5 inhibitor is present in the pharmaceutical composition of the present invention in an amount of 50 mg, or 75 mg, or 100 mg, or 125 mg, or 150 mg. In some preferred embodiments of the present invention, the PDE5 inhibitor is sildenafil (or a salt thereof, for example sildenafil citrate). It may present in the pharmaceutical composition of the invention in an amount of from 25 to 120 mg, for example from 50 to 120mg. Preferably, sildenafil is present in the pharmaceutical composition of the invention in an amount of from 50 to 100 mg. For example, the PDE5 inhibitor is sildenafil (or a salt thereof, for example sildenafil citrate) present in an amount of 50mg or 100mg. In a preferred embodiment of the present invention, the pharmaceutical composition comprises testosterone in an amount of 1.0mg and sildenafil (or a salt thereof, for example sildenafil citrate) present in an amount of 100mg. In alternative but still preferred embodiments of the present invention, the pharmaceutical composition comprises testosterone in an amount of 1.0mg and sildenafil (or a salt thereof, for example sildenafil citrate) present in an amount of 25mg or 50mg or 75mg. As previously discussed, 50 mg was considered the optimal dose of sildenafil (when used on its own). The inventors of the present invention found that, surprisingly, when used in combination with high-dose testosterone, higher sildenafil doses, for example 75 mg or even 100 mg, can further enhance sexual function while being well tolerated. The high testosterone level allows the benefits of the PDE5 inhibitor (for example sildenafil) to go over the plateau previously shown when the PDE5 inhibitor was used on its own. Preferably, the pharmaceutical composition of the present invention comprises a core comprising the PDE5 inhibitor. Optionally, the PDE5 inhibitor is present in the core in a relative amount of preferably between 0.1 and 60% (w / w; based on the total weight of the core), more preferred between 0.1 and 30 % (w / w; based on the total weight of the core), more preferred between 5 and 25 % (w / w based on the total weight of the core). The core preferably further comprises cellulose and / or a filler selected from an organic and / or an inorganic salt. Optionally, the cellulose is present in the core in a relative amount of preferably between 10 and 60% (w / w based on the total weight of the core), more preferred between 10 and 50 % (w / w based on the total weight of the core (w / w based on the total weight of the core). The term cellulose comprises powdered cellulose, agglomerated cellulose, microcrystalline cellulose and / or combinations thereof. The term cellulose includes purified cellulose, methylcellulose, hydroxypropyl methylcellulose, and carboxy methyl cellulose. Powdered cellulose is composed mainly of cellulose obtained by decomposing pulp. Microcrystalline cellulose comprises a special grade of alpha cellulose. A preferred cellulose is microcrystalline cellulose. A preferred microcrystalline cellulose has a nominal particle size of between 30 and 250 μm, preferably of between 50 and 180 μm. A further preferred microcrystalline cellulose comprises a moisture of between 0.1 and 7.5 %, more preferred between 1 and 5.0 %. A preferred microcrystalline cellulose is selected from microcrystalline cellulose with a nominal particle size of 50 μηι and a moisture of 3.0 to 5.0 % such as, for example, Avicel PH 101; a microcrystalline cellulose with a nominal particle size of 100 μm and a moisture of 3.0 to 5.0 % such as, for example, Avicel PH 102; and a microcrystalline cellulose with a nominal particle size of 180 μm and a moisture less than 1.5 % such as, for example, Avicel PH 200. The amount of said microcrystalline cellulose is preferably more than 10 % (w / w; based on the total weight of the core), more preferred more than 20 % (w / w), more preferred more than 30 %, most preferred more than about 35%. It is further preferred that the amount of microcrystalline cellulose is less than 60%, more preferred less than 50%, more preferred less than 45% (w / w, based on the total weight of the core). Optionally, the filler is present in the core in a relative amount of preferably between 10 and 70% (w / w based on the total weight of the core), more preferred in an amount of between 10 and 60 % (w / w based on the total weight of the core). more preferred between 20 % and 60% (w / w), more preferred between 30 % and 50% (w / w), such as, for example, 35% (w / w). The filler is selected from the group of an organic salt and an inorganic salt. An organic salt is preferably selected from calcium citrate, magnesium citrate, calcium lactate, sodium lactate, magnesium lactate, calcium fumarate and magnesium fumarate. A most preferred filler is an inorganic salt. An inorganic salt according to the invention is preferably selected from calcium sulphate dehydrate, calcium silicate, silicium phosphate, calcium carbonate, anhydrous dibasic calcium phosphate, dibasic calcium phosphate monohydrate, tribasic calcium phosphate, sodium phosphate, sodium chloride, potassium phosphate, potassium sulphate, potassium chloride, sodium carbonate, magnesium carbonate, and magnesium oxide. The total amount of a soluble filler such as sodium lactate and sodium chloride is preferably below 50% (w / w; based on the total weight of the core). The selection of a filler is further determined by the intrinsic stability of the active ingredient in the core in combination with a filler or combination of fillers, as is known to the person skilled in the art. The core may further comprise a lubricant such as magnesium stearate, talc and the like. A preferred core comprises anhydrous dibasic calcium phosphate and magnesium stearate. The amount of said anhydrous dibasic calcium phosphate is preferably more than 10 % (w / w; based on the total weight of the core), more preferred more than 20 % (w / w), more preferred more than 30 %, most preferred more than about 35%. It is further preferred that the amount of anhydrous dibasic calcium phosphate is less than 70%, more preferred less than 60%, more preferred less than 50%, more preferred less than 45% (w / w, based on the total weight of the core). The amount of magnesium stearate is preferably between 0.1 % (w / w; based on the total weight of the core) and 10 % (w / w), more preferred between 0.5 and 5 % (w / w). The core additionally may comprise one or more disintegrants that, as a pure material, form a gel upon exposure to an aqueous liquid. A preferred disintegrant comprises one of more of a water- insoluble, gel-forming disintegrant, such as cross-linked sodium carboxy methylcellulose, sodium starch glycolate and / or cross-linked polyvinylpyrrolidone. When present, said disintegrant such as a water-insoluble, gel- forming disintegrant is preferably present in a relative amount of between 0.5 and 20 % (w / w). Disintegrants are substances or a mixture of substances that facilitate the breakup or disintegration of a tablet. Break up of a tablet results in smaller particles of which the ingredients, including the PDE5 inhibitor, are more rapidly available for uptake, compared to a whole tablet. Drug dissolution can be improved significantly with the addition of disintegrating ingredients into the formulation. Preferred disintegrants induce disintegration of a tablet by wicking, deformation, and / or the induction of electric repulsive forces between particles. A preferred disintegrant according to the invention is selected from sodium starch glycolate (Primojel®), cross-linked sodium carboxymethyl cellulose, for example ACDISOL®, cross-linked polyvinylpyrrolidone (Crospovidone) and low- substituted hydroxypropyl cellulose (L-HPC) having a hydroxypropoxyl content in the range of 5.0 to 16.0% by weight and an apparent average degree of polymerization in the range of 350 to 700. Said L- HPC preferably has a low particle size, preferably below 10 microns average particle size, more preferred below 5 micron, such as, for example, LH41. Said water-insoluble, gel-forming disintegrant is preferably present in a relative amount of between 0.0 and 6 % (w / w). The amount of said water-insoluble gel- forming disintegrant is preferably less than 6 % (w / w; based on the total weight of the core), more preferred less than 5 % (w / w), most preferred less than 4%. A preferred composition of a core according to the invention comprises a PDE5 inhibitor, a microcrystalline cellulose, for example PHARMACEL(R) pH102 or PHARMACEL(R) pH200, anhydrous dicalcium phosphate, a crosslinked sodium carboxy methylcellulose, for example croscarmellose, and magnesium stearate. Microcrystalline cellulose and crosslinked sodium carboxy methylcellulose are preferably present in a ratio of between about 6: 1 (w / w) to 14: 1 (w / w), preferably between 7.5 (w / w) and 12.5 (w / w). Preferred ratios are about 10 : 1 (w / w) and about 8: 1 (w / w). An effect of such ratio is that the core, while gel-forming, does not substantially swell prior to disintegration. A preferred ratio of anhydrous dibasic calcium phosphate and microcrystalline cellulose is between 3 : 1 (w / w) and 1 : 3 (w / w), more preferred between 2 : 1 (w / w) and 1 : 2 (w / w), most preferred in about 1 : 1 (w / w).The total weight of a core according to the invention is preferably between 50 and 500 milligram, more preferred between 200 and 400 milligram, more preferred between 300 and 400 milligram, such as about 340 milligram. The core is preferably pressed or compacted into a solid. A preferred core is a tablet. The term "tablet" encompasses a "capsule" and a "caplet". The preferred size of the core of a pharmaceutical composition according to the invention ranges from a few millimeters to about one centimeter. The core may comprise further excipients including, but not limited to, diluents, binders or granulating ingredients, a carbohydrate such as starch, a starch derivative such as starch acetate and / or maltodextrin, a polyol such as xylitol, sorbitol and / or mannitol, lactose such as a-lactosemonohydrate, anhydrous a-lactose, anhydrous 6-lactose, spray-dried lactose, and / or agglomerated lactose, a sugar such as dextrose, maltose, dextrate and / or inulin, or combinations thereof, glidants (flow aids) and lubricants to ensure efficient tabletting, and sweeteners or flavours to enhance taste. Preferably, the pharmaceutical composition further comprises a separating coating covering the outer surface of the coating described herein. The separating coating preferably comprises hydrophobic polymer and a (water-soluble and / or water-insoluble) hydrophilic substance. A hydrophobic coating polymer according to the invention is preferably selected from water- insoluble coating materials such as cellulose derivates and polymethacrylates that are generated, for example, by copolymerization of methacrylate monomers with hydrophobic groups. Preferred polymethacrylate hydrophobic polymers are EUDRAGIT® RL, EUDRAGIT ® RS, EUDRAGIT® NE, and EUDRAGIT® S. Preferred cellulose derivates are selected from ethylcellulose and derivatives thereof. In some preferred embodiments of the present invention, the hydrophobic polymer is a hydrophobic polymeric ethylcellulose. A most preferred hydrophobic polymer of the separating coating according to the invention comprises ethylcellulose. Ethylcellulose forms a mechanically weak hydrophobic film that ruptures easily. Preferably, the release of the PDE5 inhibitor from the core is caused by rupture of the coating after a pre-defined lag-time. The core may, for example, contain the PDE5 inhibitor in combination with a water-insoluble, gel-forming disintegrant that disintegrates upon contact with an aqueous medium. The formation of pores in the hydrophobic film, and the influx of water into the core, causes the rupture of the ethylcellulose coating. When the coating is ruptured, the core disintegrates within minutes followed by the release of the PDE5 inhibitor. A preferred ethylcellulose is ETHOCEL® . The hydrophilic substance according to the invention preferably is a water-insoluble hydrophilic substance, preferably a water-insoluble hydrophilic polymer. It is further preferred that said separating coating comprises pores prior to exposure to an aqueous liquid. The pores function as channels that interconnect the core with the outer surface of the inner coat for controlling the entry of aqueous liquid into the core. Said pores are present, for example, when the water- insoluble hydrophilic substance is or comprises a water-insoluble hydrophilic polymer, preferably cellulose. Preferred celluloses are cellulose derivatives such as, for example, hydroxypropylcellulose, crosslinked hydroxyethylcellulose, crosslinked hydroxypropylmethylcellulose and microcrystalline cellulose. Cellulose formed channels that connect the PDE5-inhibitor containing core with the outside of the pharmaceutical composition. The cellulose thereby controls the rate at which water is being transported through the channels into the core. When sufficient water reaches the core, the core loses its structural integrity. The core will disintegrate, followed by rupture of the coating and release of the drug. A preferred cellulose is a microcrystalline cellulose with a nominal particle size of between 20 and 200 micron and a moisture of less than 5 %. A preferred microcrystalline cellulose comprises a microcrystalline cellulose with a nominal particle size of about 150 micron and a moisture of 3.0 to 5.0 % such as, for example, Avicel® PH-102 SCG; a microcrystalline cellulose with a nominal particle size of about 100 micron and a moisture less than 5.0 % such as, for example Avicel® HFE-102; a microcrystalline cellulose with a nominal particle size of about 20 micron and a moisture less than 5.0 % such as, for example, Avicel® PH-105. Further preferred water insoluble hydrophilic substances include dicalcium phosphate. An advantage of using smaller particles of less than 50 micron, e.g. Avicel® PH-105, is that the coating suspension has better flow properties, which improves the overall film coating process. A preferred separating coating comprises Ethocel® and Avicel PH-105 as a water- insoluble hydrophilic substance. Preferred mass ratios of a hydrophobic coating polymer such as Ethocel® and a water-insoluble hydrophilic substance such as Avicel are between 1: 5 and 5: 1, more preferred between 1: 4 and 3: 1, more preferred between 1: 3 and 2: 1, most preferred about 1:2. In another embodiment, a hydrophilic substance according to the invention preferably is a water-soluble hydrophilic substance. This separating coating preferably does not comprise pores or only a few pores prior to exposure to an aqueous liquid. It is preferred that the water- soluble hydrophilic substance forms pores in the hydrophobic polymer upon exposure to an aqueous liquid. A preferred water-soluble hydrophilic substance comprises lactose, mannitol and / or sodium chloride. A preferred lactose is PHARMATOSE®. A preferred separating coating comprises Ethocel® and lactose as a water-soluble hydrophilic substance. Preferred mass ratios of a hydrophobic coating polymer such as Ethocel® and a water-soluble hydrophilic substance such as lactose are between 1: 5 and 5: 1, more preferred between 1: 3 and 3: 1, more preferred between 1: 2 and 2: 1, most preferred about 1: 1. The relative amount of a separating coating is preferably between 4 and 20 % (w / w; based on the total weight of the pharmaceutical composition), more preferred between 8 and 15 % (w / w), most preferred about 12% (w / w). Therefore, a preferred separating coating has a weight of between 10 and 75 milligram, more preferred between 25 and 50 milligram, most preferred about 40 milligram. Preferably, the separating coating does not comprise a drug. The separating coating may comprise a plasticizer such as, for example, dibutyl phthalate, triethyl citrate, acetyl triethyl citrate, dibutyl sebacate, diethyl phthalate, triacetin and / or tributyl citrate. When present, the plasticizer is preferably present in an amount of at most 0.5% (w / w; based on the total weight of the pharmaceutical composition). Preferably, the separating coating does not comprise a plasticizer. The separating coating is preferably sprayed, for example with a nozzle, onto the core. For this, the hydrophobic polymer and water-soluble and / or water- insoluble hydrophilic substance are suspended or dissolved, for example in water or an organic solvent or a mixture thereof, and sprayed onto the core until a predetermined average thickness of the separating coating is obtained. A preferred organic solvent is an alcohol, for example ethanol. The amount of the separating coating is preferably between about 0.5 and 30 % (w / w) of the total weight of pharmaceutical composition, more preferred between about 1 and 20 % (w / w). Preferably, the delayed release of the PDE5 inhibitor is an immediate release. Treatments with a dosage of testosterone combined with a PDE5 inhibitor produce alterations in brain and bodily functions which will make learning of positive associations between sexual stimuli, genital arousal and subjective experience possible, thereby enhancing female sexual desire. The PDE5 inhibitor is preferably released in an immediate release pattern at a time around 2- 6 hours after when the plasma testosterone level reaches or near its peak (indicative of maximum libido and sexual arousal) to achieve best efficacy. The time of the release is controlled in part by the thickness of the separating coating, which is preferably sprayed onto the core. The variation in the amount of the separating coating between individual compositions is preferably not more than 10 % (between 90 % and 110 %), based on the total weight of the separating coating. More preferred, the variation in the amount of a separating coating is not more than 5 % (between 95 % and 105 %), based on the total weight of the separating coating. Factors (process conditions) that may influence the intra- and inter-tablet uniformity of the separating coating include, for example, pan speed, spray rate, spray pattern, nozzle type, viscosity, drying temperature, air flow rate and coating time, as is known to the skilled person. When required, a temperature controlled curing step, for example heat treatment at 60-80 °C for 1-3 hours, is applied to the separating coating after application, preferably spraying, of the separating coating. In addition, the amounts of the water-soluble and / or water-insoluble hydrophilic substance in the separating coating, and the identity of the water-soluble and / or water-insoluble hydrophilic substance, further provide means to modulate the timing of release of the PDE5 inhibitor. For example, a tablet comprising a pressed core and a separating coating with an average thickness of about 35 micrometer, the coating comprising Ethocel 20 and lactose in a 3: 2 ratio, provides release of the PDE5 inhibitor at about 36 minutes after hydration of the tablet, while the same composition of a tablet with a separating coating with an average thickness of about 50 micrometer, provides release of the PDE5 inhibitor at about 84 minutes after hydration of the tablet. A tablet comprising a pressed core and a separating coating with an average thickness of about 90 micrometer, the coating comprising Ethocel 20 and Avicell PH102 in a 3: 2 ratio, provides release of the PDE5 inhibitor at about 105 minutes after hydration of the tablet. The skilled person is able to generate a pharmaceutical composition according to the invention with the desired release pattern(s), based on the teaching and the examples provided in this application. Preferably, the testosterone of the pharmaceutical composition is present in an outer coating covering the outer surface of the separating coating. The outer coating provides release of testosterone in an immediate release fashion, which ensures the maximum impact of testosterone. The outer coating may be pressed or sprayed onto the outer surface of the separating coating. Methods for pressing or spraying are known in the art. A outer coating that surrounds the separating coating advantageously protects the integrity of the separating coating, for example during packaging or storage of a dual drug delivery system. This will preferably decrease or minimize damage to the separating coating occurring during packaging or storage that might affect the lag time of the release of the PDE5 inhibitor from the core of the pharmaceutical composition. The outer coating is preferably sprayed onto the outer surface of the separating coating. When a spray coat is used it is generally formulated to contain a drug and film forming ingredient so that the drug is dispersed in the film that overlays the separating coating of the core. Such film forming ingredients are known in the art and may be for example hydroxypropylmethylcellulose, povidone, hydroxyethylcellulose, other modified celluloses known in the art, polyacrylates, polymethacrylates, and polymethyl / ethylmethacrylates. A film forming ingredient according to the invention preferably comprises hydroxypropylmethylcellulose, more preferred low molecular weight hydroxypropylmethylcellulose with a number average molecular weight below 20,000; more preferred below 10,000. The spray coat is formulated to give an immediate release by forming a coat that dissolves quickly. The amount of a film-forming ingredient is preferably between 0.05 and 40 % (w / w), based on the total weight of the outer coating, more preferred between 1 and 30 % (w / w) such as, for example, about 20% (w / w). The outer coating preferably comprises a weight of between 0.5 and 5% (w / w) based on the total weight of the pharmaceutical composition. Preferably said coating comprises a weight of between 1% and 3% and preferably between 1,5 and 2,5 % (w / w) based on the total weight of the pharmaceutical composition. In a preferred embodiment the outer coating of a pharmaceutical composition comprises a weight of between about 1-20 mg per unit. Preferably said outer coating comprises a weight of about 3-15 mg per unit. In a particularly preferred embodiment said outer coating of the pharmaceutical composition of the invention comprises a weight of about 4-10 mg per unit. Preferably, the variation in the amount of the outer coating between individual compositions is not more than 10 % (between 90 % and 110 %), based on the total weight of the outer coating. More preferred, the variation in the amount of the outer coating is not more than 5 % (between 95 % and 105 %), based on the total weight of the outer coating. Factors (process conditions) that may influence the intra- and inter-composition (for example intra- and inter-tablet) uniformity of the outer coating include, for example, pan speed, spray rate, spray pattern, nozzle type, viscosity, drying temperature, air flow rate and coating time, as is known to the skilled person. The amount of testosterone is preferably between 0.05 and 20 % (w / w), based on the total weight of the outer coating, more preferred between 0.5 and 10 % (w / w). Examples of known excipients that may be added to a sprayed or pressed outer coating for controlled release are one or more polymers or copolymers selected from acrylic and methacrylic acid polymers and copolymers such as acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), glycidylmethacrylate copolymers and ethylcellulose. The amount of known excipients is preferably below 10 % (w / w), based on the total weight of the outer coating, more preferred below 5 % (w / w), more preferred below 1 % (w / w). Optionally, the outer coating may comprise a mixture of testosterone in amorphous form in an amount of no less than 1.0mg, for example 1-4mg; a coating polymer in an amount of between about 0.25 - 25 mg; and water in an amount of between about 0.0 - 10% w / w of the outer coating. Alternatively, the outer coating may comprise a cyclodextrin or a polyvinylpyrolidone or a combination thereof, in an amount of between 0.25 - 25 mg. In some embodiments, the outer coating comprises a mixture of testosterone in amorphous form in an amount of no less than 1.0mg, for example 1-4mg; a cyclodextrin or a polyvinylpyrolidone or a combination thereof in an amount of between about 0.5 - 12,5 mg; and water in an amount of between about 0.0 - 5% w / w of the outer coating. The combination of cyclodextrin and polyvinylpyrolidone helps to improve the stability of testosterone in the pharmaceutical composition, in particular in tablets. Both cyclodextrin and polyvinylpyrolidone prevent amorphous testosterone or a functional analogue thereof from crystallizing in the coating when exposed to prolonged incubation and / or various temperatures such as can occur during storage of the composition. Preferably, the outer coating further comprises a carrier selected from hydroxypropyl-beta- cyclodextrin, poly-beta-cyclodextrin, gamma-cyclodextrin and polyvinylpyrolidone. A preferred polyvinylpyrolidone is low molecular weight polyvinylpyrolidone with a molecular weight of maximal 80000. A suitable polyvinylpyrolidone is preferably selected from K10, K15, K25, K30, and K50. A most preferred carrier is hydroxypropyl-beta-cyclodextrine. The presence of a poorly soluble steroid such as testosterone and a carrier such as a cyclodextrin provides rapid and efficient delivery of the testosterone to the mucous membrane, from which the testosterone is then rapidly absorbed into the circulation. The amount of said carrier is preferably between 0.5 and 70 % (w / w), based on the total weight of the outer coating, more preferred between 2 and 60 % (w / w), more preferred between 5 and 50 % (w / w). In one embodiment of the present invention, the outer coating comprises 1.0 mg testosterone and 5 mg hydroxypropyl-beta-cyclodextrines (carrier). Alternatively, the outer coating comprises 1.5mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg or 4.0mg testosterone and 5 mg hydroxypropyl-beta-cyclodextrins. The outer coating preferably comprises a flavouring compound in addition to testosterone and one or more excipients, such as, for example, a colouring agent. Said flavouring compound may be any natural, artificial or synthetic compound or mixture of compounds that is pharmaceutically acceptable. An illustrative list of flavours for pharmaceutical applications includes cyclic alcohols, volatile oils, synthetic flavour oils, flavouring aromatics, oils, liquids, oleoresins and extracts derived from plants, leaves, flowers, fruits, stems, roots, and combinations thereof. Non-limiting examples of cyclic alcohols include menthol, isomenthol, neomenthol and neoisomenthol. Non-limiting examples of flavour oils include spearmint oil, cinnamon oil, oil of wintergreen (methyl salicylate), peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, oil of nutmeg, allspice, oil of sage, mace, oil of bitter almonds, cassia oil, and combinations thereof. Suitable flavours also include, for example, artificial, natural and synthetic fruit flavours such as citrus oils (e.g., lemon, orange, lime, and grapefruit), fruit essences (e.g., lemon, orange, lime, grapefruit, apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot or other fruit flavours). Other useful artificial, natural and synthetic flavours include sugars, polyols such as sugar alcohols, artificial sweeteners such as aspartame, stevia, sucralose, neotame, acesulfame potassium, and saccharin, chocolate, coffee, vanilla, honey powders, and combinations thereof. Other useful flavours include aldehydes and esters, such as benzaldehyde (cherry, almond), citral (lemon, lime), neral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C- 9 (citrus fruits), aldehyde C-12 (citrus fruits), tolylaldehyde (cherry, almond), 2,6-dimethyloctanal (green fruit), 2-dodenal (citrus mandarin), and combinations thereof. A preferred flavouring compound is a cyclic alcohol such as, for example, menthol, isomenthol, neomenthol and neoisomenthol, preferably combined with an artificial sweetener such as aspartame. The amount of a flavouring compound is preferably between 0.1 and 60 % (w / w), based on the total weight of the outer coating, more preferred between 1 and 40 % (w / w). The presence of a flavouring compound in the outer coating of the composition according to the invention may mask a bitter or objectional-tasting ingredient or excipient. It is preferred that the flavouring compound in the outer coating rapidly disappears from the oral cavity. Sensing of the particular flavour in the oral cavity indicates to the user that the outer coating has not completely dissolved and that drug delivery system which is encompassed within the outer coating is to be held in the mouth. During use, when testosterone is co- delivered with a flavouring compound from the outer coating, the subject can easily recognize that the system is delivering the testosterone due to the presence of the flavour (taste). Eventually, the entire dose of testosterone is delivered. At this point, the composition may also stop delivering the flavour. The disappearance of the flavour (taste) indicates that the composition may be swallowed. The skilled person will understand that a flavouring compound may be present in the separating coating, instead of in the outer coating. In that case, the appearance of the flavour (taste) indicates that the composition may be swallowed. The skilled person will further understand that a first flavouring compound may be present in the outer coating, while a second flavouring compound is present in the separating coating. Upon disappearance of the first flavour (taste), and tasting of the second flavour (taste), the subject knows that the composition has delivered the entire dose of testosterone. It is further preferred that the roughness of the outer surface of the outer coating differs from the roughness of the outer surface of the separating coating in a composition according to the invention. A subject can be instructed to swallow the composition when a difference in roughness becomes evident. This provides sufficient retention time of the composition in the mouth so that testosterone is sufficiently released and absorbed. The outer coating of the pharmaceutical composition according to the invention provides immediate delivery of testosterone. Preferably, the composition is an oral composition. The outer coating of the pharmaceutical composition provides immediate delivery of testosterone in the mouth. The term "mouth" comprises the interspace between the lips and the teeth, the interspace between the cheek and the teeth, the oral cavity which is delimited by the palate and tongue and the sublingual area. Testosterone is preferably released in the sublingual space in the mouth. The term "immediate release of testosterone" refers to the rapid dissolution of the outer coating in the mouth such that testosterone is completely or substantially completely released within a short time frame within the mouth. The term "immediate release of testosterone" indicates that at least 50% of testosterone is released within 5 minutes, more preferred within 4 minutes, more preferred within 3 minutes, more preferred within 2 minutes, most preferred within 1 minute, for example within 90 seconds, after oral administration of the dual drug delivery system. It is more preferred that at least 70% of testosterone is released within 5 minutes, more preferred within 4 minutes, more preferred within 3 minutes, more preferred within 2 minutes, most preferred within 1 minute after oral administration of the dual drug delivery system. An advantage of a pharmaceutical composition according to the invention is that food-effects are minimized. The term "food-effects" refers to the difference in the rate and extent of absorption of a drug that is administered shortly after a meal (fed conditions), as compared to administration under fasting conditions. The release of the PDE5 inhibitor is not dependent on the pH and therefore not likely to be influenced by food effects. In addition, the formulation of testosterone as an immediate release formulation also minimizes food-effects for the release of testosterone. A further advantage of a pharmaceutical composition according to the invention is that it provides two independent dosing routes in one composition. A further advantage of a pharmaceutical composition according to the invention is that it provides first-pass free absorption into the systemic circulation of one active ingredient (testosterone) in combination with gastro-intestinal absorption of a further active ingredient (the PDE5 inhibitor) in one composition. Preferably, the testosterone of the pharmaceutical composition is released in an immediate release manner, and the PDE5 inhibitor of the pharmaceutical composition is released in a delayed immediate release manner. In a preferred embodiment of the present invention, the delayed release of the PDE5 inhibitor is an immediate release occurred between 1.5 to 6 hours, preferably between 2 to 6 hours, for example after about 2 hours, about 2.5 hours, preferably about 3 hours, and within about 6 hours, preferably within about 3.5 hours, after the release of testosterone. The term "time controlled" release or “delayed release” refers to a release of the active ingredient after a predetermined period of time, for example 2 hours, whereby the release is independent of pH. The predetermined period of time is set and not dependent on the pH history in the gastro-intestinal tract. Preferably, the pharmaceutical composition according to the invention is a tablet. The tablet form of the composition offers easy administration with minimum disruption of normal daily activities, and helps to encourage the use of the composition whenever and wherever needed. The term "tablet" encompasses a "capsule" and a "caplet". The total weight of the pharmaceutical composition according to the invention is preferably at least 50 milligram, more preferred at least 150 milligram, and preferably is between 50 and 500 milligram, more preferred between 150 and 400 milligram, more preferred between 300 and 400 milligram, such as about 301.5 milligram, 325 milligram, or about 340 milligram. For example, the tablet of the present invention comprises a core described herein comprising a cellulose, a filler selected from an organic and / or an inorganic salt and the PDE5 inhibitor, a separating coating described herein comprising a hydrophobic polymer and a hydrophilic substance, and an outer coating described herein comprising testosterone. Optionally, testosterone and the PDE5 inhibitor may present in the pharmaceutical composition in different dosage forms. For example, the PDE5 inhibitor and / or testosterone may be present in a solid dosage form, for example a solid dosage form selected from the group consisting of tablets, capsules, pills, granules, chewables and powders. Testosterone and the PDE5 inhibitor may be of the same or different dosage forms. For example, testosterone may be present in a form suitable for oral or intranasal inhalation and the PDE5 inhibitor may be present in a tablet. Naturally, the pharmaceutical composition of the present invention does not have to be a single formulation. Rather, it can be a mixture of a composition comprising testosterone and a composition comprising PDE5 inhibitor, as long as the compositions are prescribed or instructed to use together. Optionally, the combination therapy of the present invention is a kit comprising a formulation comprising testosterone and a formulation comprising a PDE5 inhibitor. Testosterone is present in the kit in an amount of no less than 1mg, for example 1-5mg, preferably 1-4mg. Each composition preferably further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of solvents, gelling agents, diluents, disintegrants, lubricants, glidants, fillers, binders, surfactants, colorants / pigments, flavourings, sweeteners, plasticizers, moisturizers, antioxidants, water absorbents, coating agents and preservatives. Separate formulations give great flexibilities to medical practitioners when personalising the required or recommended combination therapy for individual patients. Testosterone and the PDE5 inhibitor such as sildenafil may be formulated in any formulation suitable for use as a combination therapy. For the present invention the routes of administration of choice are those which are the least invasive (for example oral, buco-mucosal or intranasal), so as to cause the least negative impact on female sexual desire. Optionally, the level of free testosterone should be a peak serum level of free testosterone of from 0.01 to 1.0 ng / mL. Preferably, the peak serum free testosterone level is from 0.025 to 0.6 ng / mL, for example from 0.025 to 0.5 ng / mL. Alternatively, the level of peak free testosterone may be between 0.3-2%, preferably from 0.5-2%, of peak total serum testosterone. The peak of serum free testosterone level will typically occur between 5 and 30 minutes after administration of the testosterone. Preferably, the plasma / serum total concentration of the testosterone peaks within 1 hour, preferably within 30 minutes, after administration (of the testosterone). Testosterone is preferably given in a formulation wherein there is a (short-lasting) (high, i.e. 10-100 times increase of normal testosterone serum levels) peak of testosterone in the blood circulation of the subject to whom it is administered. The term "short-lasting" means that there is a sharp increase of the serum testosterone level and approximately 5-30 minutes after administration a peak serum level of testosterone is obtained. The peak serum level sharply decreases and after approximately 120 minutes the testosterone serum level is back to the level before testosterone administration. About 3 to 6 hours after this plasma testosterone peak, there is a testosterone effect peak, i.e. there is a time lag in the effect of testosterone on genital arousal in sexually functional women. The delayed release of the PDE5 inhibitor is an immediate release occurred between 1.5 to 6 hours, preferably between 2 to 6 hours, preferably between 2.5 to 3.5 hours, after the release of testosterone. The plasma concentration of the PDE5 inhibitor peaks between 3 to 6 hours, preferably between 3 to 5 hours, for example between 3 to 4 hours, after the administration of the composition of the present invention (or, if testosterone and the PDE5 inhibitor are in different compositions, the administration of the testosterone composition). Preferably, the effect of PDE5 inhibitor is present 3.5-5.5 hours after the induced plasma peak in testosterone. The skilled person can, based on the pharmacological kinetics of said compound and the teaching of the current application, determine a suitable formulation as well as a suitable concentration for said compounds. A preferred pharmaceutical composition suitable for the identified patient comprises 1.0mg testosterone and 100mg sildenafil. As discussed above, albumin binds (weakly) to both testosterone and sildenafil. Therefore the amounts of testosterone and sildenafil present in the pharmaceutical composition need to be balanced to achieve the desirable synergistical effects. It was found that the combination of 1.0mg testosterone and 100mg sildenafil is a promising dose combination for enhanced efficacy for the identified patients. According to a fifth aspect, the present invention also provides a method for determining a dosage for a patient in the treatment of FSIAD. The method comprises choosing a testosterone dosage of no less than 1.0mg in combination of a PDE5 inhibitor if: the patient is post-menopausal; or the patient is using COCs or receiving HRT; or the patient has a BMI (Body Mass Index) no greater than a pre-determined threshold, for example 25, 24.5, 24, 23.5, 23, or preferably 22.5; or the patient has a plasma SHBG (sex hormone-binding globulin) level of no less than pre-determined threshold, for example 80 nmol / L, 90 nmol / L, or preferably 100 nmol / L. Preferably, the method further comprises choosing sildenafil as the PDE5 inhibitor and / or choosing a PDE5 inhibitor dosage of no less than 25mg, no less than 50mg, for example 50mg, 75mg or 100mg. Optionally, the method comprises choosing a pharmaceutical composition comprising 1.0mg testosterone and 100mg sildenafil for the patient. According to a further aspect, the present invention also provides a method of determining a dosage regime of a pharmaceutical composition for a patient in the treatment of FSIAD. The pharmaceutical composition comprises sildenafil and testosterone, and the method comprises: a) collecting the following information of the patient: i) the patient’s menopausal status; ii) the patient’s BMI; iii) if the patient is using COCs or receiving HRT; iv) the plasma SHBG level of the patient; and v) the plasma albumin level of the patient, b) comparing the information collected to a pre-determined schedule; and c) choosing a dosage regime of sildenafil and / or testosterone for the patient based on the comparison. According to a further aspect, the present invention provides a method of enhancing female sexual desire in the treatment of FSIAD of a patient. The method comprises: a) collecting information on the following impactor factors of the patient: i) the patient’s menopausal status; ii) the patient’s BMI; iii) if the patient using COCs or receiving HRT; iv) the plasma SHBG level of the patient; and v) the plasma albumin level of the patient b) comparing the information collected to a pre-determined schedule; and c) administering a pharmaceutical composition to the patient, wherein the pharmaceutical composition comprises sildenafil and testosterone. The pre-determined schedule may include rules such that the patient receives a pharmaceutical composition of the present invention, preferably a pharmaceutical composition of the present invention comprising no less than 1mg, for example 1.0mg, 1.5mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, or 4.0mg, testosterone, preferably in an immediate release dosage form such as oral, sublingual, or intranasal, if: the patient is post-menopausal; or the patient is using COCs or receiving HRT; or the patient has a BMI (Body Mass Index) no greater than a pre-determined threshold, for example 25, 24.5, 24, 23.5, 23, or preferably 22.5; or the patient has a plasma SHBG (sex hormone-binding globulin) level of no less than pre-determined threshold, for example 80 nmol / L, 90 nmol / L, or preferably 100 nmol / L; or the patient also has a plasma albumin level no greater than a pre-determined threshold, for example 45 g / L, 40 g / L, or preferably 37 g / L. Preferably, the pre-determined schedule further includes rules such that the patient receives a pharmaceutical composition comprising 0.5mg testosterone in combination with less than 100mg, for example 75mg or 50mg or 25mg, PDE5 inhibitor, such as sildenafil, if the patient does not meet any of the criteria above. Preferably, the method further comprises treating the patient for a pre-determined period of time according to the schedule, evaluating the efficacy and side effects of the treatment, and adjusting the dosage of testosterone and the PDE5 inhibitor based on the evaluation. For example, if, according to the evaluation, the efficacy of the treatment is not sufficient, the dosage of testosterone can be adjusted. If testosterone dosage in the treatment was 0.5mg, it can be increased to, for example 1.0mg or 1.5mg, administered in the form of one or more compositions (for example two compositions comprising 0.5mg and 1.0mg testosterone, respectively, for the total dosage of 1.5mg). If testosterone dosage in the treatment was 1.0mg, it can be adjusted to 2.0mg. The 2.0mg testosterone can be administered by means of the pharmaceutical composition of the present invention in combination with a further pharmaceutical composition comprising 1.0mg testosterone, for example an oral 1.0mg testosterone composition, or a 1.0mg testosterone composition in a solid dosage form such as a tablet, a capsule, or in a dosage form suitable for oral or intranasal inhalation. Alternatively, if the side effects of the treatment are too severe, the dosage of the PDE5 inhibitor can be adjusted. If PDE5 inhibitor (such as sildenafil) dosage in the treatment was 50mg, it can be reduced to, for example 25mg. If PDE5 inhibitor (such as sildenafil) dosage in the treatment was 100mg, it can be reduced, for example to 75mg or 50mg. The dosage of testosterone can be adjusted at the same time. In a non-limiting embodiment of the present invention, a patient is initially treated with a pharmaceutical composition comprising 1.0mg testosterone and 100mg sildenafil, for example a pharmaceutical composition of the present invention, for a period of time such as 8 weeks, and is subsequently treated with a pharmaceutical composition comprising 1.0mg testosterone and 100mg sildenafil, for example a pharmaceutical composition of the present invention, in combination with a further pharmaceutical composition comprising 1.0mg testosterone, when the initial treatment does not provide sufficient efficacy. In a non-limiting embodiment of the present invention, a patient is initially treated with a pharmaceutical composition comprising 1.0mg testosterone and 100mg sildenafil, for example a pharmaceutical composition of the present invention, for a period of time such as 8 weeks, and is subsequently treated with a pharmaceutical composition comprising 0.5mg testosterone and 50mg sildenafil, optionally in combination with a further pharmaceutical composition comprising 1.0mg testosterone, when the initial treatment induces too severe side effects. In a non-limiting embodiment of the present invention, a patient is initially treated with a pharmaceutical composition comprising 0.5mg testosterone and 50mg sildenafil, for a period of time such as 8 weeks, and is subsequently treated with a pharmaceutical composition comprising 1.0mg testosterone and 100mg sildenafil, for example a pharmaceutical composition of the present invention, or a pharmaceutical composition comprising 0.5mg testosterone and 50mg sildenafil in combination with a further pharmaceutical composition comprising 1.0mg testosterone, when the initial treatment does not provide sufficient efficacy. In a non-limiting embodiment of the present invention, a patient is initially treated with a pharmaceutical composition comprising 0.5mg testosterone and 50mg sildenafil, for a period of time such as 8 weeks, and is subsequently treated with a pharmaceutical composition comprising 0.5mg testosterone and 25mg sildenafil, when the initial treatment induces too severe side effects. The further pharmaceutical composition comprising 1.0mg testosterone may be an oral 1.0mg testosterone composition, or a 1.0mg testosterone composition in a solid dosage form such as a tablet, a capsule, or in a dosage form suitable for oral or intranasal inhalation. The efficacy and side effects of the treatment may be evaluated by any methods suitable for use in the art. The skilled person is familiar with tools and protocols for such evaluations, based on the common general knowledge. A non-limiting example of evaluating the efficacy and side effects of a treatment for FSIAD is described in more detail in Example 1. According to a further aspect, the present invention provides testosterone or a functional analogue or derivative thereof in an amount equivalent to at least 1.0mg testosterone for use in combination with a PDE5 inhibitor, preferably sildenafil, in enhancing female sexual desire in the treatment of FSIAD of a patient, and the patient: is post-menopausal or the patient is using COCs or receiving HRT; or has a BMI (Body Mass Index) no greater than 22,5; or has a plasma SHBG (sex hormone-binding globulin) level of no less than 100 nmol / L. Preferably, the testosterone or the functional analogue or derivative thereof is used in combination with sildenafil in an amount of no less than 25mg, no less than 50mg for example 50mg, 75mg, for example 100mg. According to a further aspect, the present invention provides sildenafil in an amount of no less than 25mg, no less than 50mg, preferably no less than 25mg, no less than 50mg, for example 50mg, 75mg, or 100gm, for use in combination with testosterone or a functional analogue or derivative thereof in enhancing female sexual desire in the treatment of FSIAD of a patient, and the patient has a BMI no greater than 22.5; or a plasma albumin level of no greater than 37 g / L. Preferably, the testosterone or the functional analogue or derivative thereof is used in an amount equivalent to no less than 1.0mg, for example 1-5mg, preferably 1-4mg, testosterone. Any feature that has been described above in relation to any one aspect or embodiment of the invention is also disclosed hereby in relation to all other aspects and embodiments. Likewise, all combinations of two or more of the individual features or elements described above may be present in any aspect or embodiment. For brevity, all possible features and combinations have not been recited in relation to all aspects and embodiments, but they are expressly contemplated and hereby disclosed. Figures Figure 1a to 1g are diagrams showing numbers (and percentages) of participants showing improvements in each category in Example 1. Examples The invention will be explained in more detail in the following, non-limiting examples. Example 1 The experiment of Example 1 is as described in a previous publication (Tuiten et al, The Journal of Sexual Medicine, 2018:15, 201-216), the content of which is incorporated herein. Study Design and Oversight Double-blinded, randomized, placebo-controlled, dose-finding phase 2 studies (identical in study design) were con- ducted at 16 sites in the United States. Data were collected, managed, and analyzed under the supervision of the sponsor, which was monitored by Rasmussen Biotech and Pharma Consulting LLC (Princeton, NJ, USA). The participants, investigators, and site personnel were blinded to study treatment until database lock, as were the sponsor and those members of the vendors’ staff who were involved (eg, site monitors). The first study started on September 27, 2011 (first screening visit) and the final study ended on September 26, 2014 (database lock). The PSR-Group (Hoofddorp, The Netherlands) was responsible for data management. The trials are registered under identifiers NCT01432665, NCT01743235, and NCT02101203 (ClinicalTrials.gov). Study Population The requisite sample size was determined by a power analysis, which took account of the effect sizes found in previous studies. The female participants included in this study were 21 to 70 years old and had been diagnosed with HSDD (based on DSM-IV-TR criteria), with or without FSAD, but were otherwise healthy. Our inclusion criteria also were consistent with the current DSM-5 diagnosis of FSIAD. All diagnoses were performed by a trained professional. A demarcation formula was used to assign participants to 1 of the 2 FSIAD subgroups (see text and Tables 1-3 and Figures 1 and 2 of Tuiten et al). Participants who had been diagnosed with any psychiatric disorder other than FSIAD were excluded. Those scheduled for any other treatment for female sexual dysfunction during the study period also were excluded. Potential participants were excluded if they were using oral contraceptives containing anti- androgens, estrogen more than 50 mg, potent cytochrome P450 3A4 inhibitors or inducers, nitrates, monoamine oxidase inhibitors, antidepressants, and / or T compounds. The cardiovascular exclusion criteria included a history of myocardial infarction, stroke, or life-threatening arrhythmia in the previous 6 months. Other criteria were uncontrolled hypertension, hypotension, atrial fibrillation or flutter, or any other significant abnormality observed on an electrocardiogram. The gynecologic exclusion criteria included pelvic inflammatory disease, vaginal infection, previous prolapse and incontinence surgery affecting the vaginal wall, abnormal uterine bleeding patterns, pregnancy, and breastfeeding in the past 6 months. Perimenopausal women were excluded, which was defined as cycle shortening or irregular menstrual bleeding in the past 12 consecutive months and / or occurrence of vasomotor symptoms (eg, hot flashes, nocturnal sweats) in combination with increased follicle-stimulating hormone levels (>40 IU / L) for women at least 40 years old; for women with a history of hysterectomy, perimenopausal status was determined by assessing follicle-stimulating hormone levels (>40 IU / L) and / or vasomotor symptoms. Women with clinically relevant endocrine disease, neurologic disease, severe or acute liver disease, or a history of severe hepatic impairment were excluded. Participants were excluded if they had free and / or total T levels that were beyond the upper limit of the central laboratory’s reference range. All participants provided written informed consent. 497 women were randomized to 1 of the 12 treatment regimens: placebo, the monotherapies (T 0.5 mg, S 50 mg, and B 10 mg), and 4 types of combination tablets (containing different dose combinations). In participants with low levels of sensitivity, the doses of T+S (milligrams) were T0.25+S25, T0.25+S50,T0.5+S25, andT0.5+S50. After a baseline period of 4 weeks, participants underwent an 8-week, single-blinded, placebo run-in (PRI) period, which was intended to stabilize placebo responses before active treatment. The PRI period was followed by an 8-week, double-blinded ATP. Those participants who according to the demarcation formula had low sensitivity (and therefore allocated to T + S treatments) were randomly assigned to 1 of the following treatment arms: (i) placebo, (ii) S 50 mg, (iii) T 0.50 mg, (iv) T0.25mg+S25mg, (v) T0.25mg+S50mg, (vi) T0.50mg+S25mg,or (vii) T0.50mg+S50mg. All dose combinations, including the placebo, were contained in combination tablets that were identical in size, taste, texture, and odor. The participants were instructed to take the study medication approximately 3 to 6 hours before they anticipated engaging in sexual activity (ie, on-demand use). Each participant was issued with 28 U of medication during each 8-week treatment period. They were instructed to allow a minimum period of at least 48 hours between individual doses. The participants were interviewed every 4 weeks, at which time they also completed questionnaires designed to assess sexual function and mood. In addition, their vital signs were measured, any signs of hyperandrogenism were evaluated, a pregnancy test was administered, and any adverse events were monitored. A psychological interview was conducted at weeks 8 and 16 to evaluate each 8-week treatment period, at which time blood samples were collected to assess each participant’s chemistry, hematology, lipids, and hormones. Medication, Dosing, and Instructions Sublingual Testosterone+Sildenafil (T+S). This drug is a dual-route, dual-release, fixed-dose combination of T and S citrate. The drug product is a 9-mm, round, biconvex, white, menthol- flavored tablet for sublingual administration. The outer coating (a polymeric film) contains T (0.5 mg) that is released immediately at sublingual administration. The inner core of the tablet, which contains S (50 mg), has a polymeric coating designed to delay the release of that drug for approximately 2.5 hours. When that period elapses, S is released immediately (ie, there is no sustained release). The placebo tablets were identical in appearance and flavor to the fixed-dose combination T + S tablets containing the active pharmaceutical ingredients. All study medication was manufactured and packaged at Piramal Healthcare UK (Morpeth, UK). Participants were instructed to keep the tablet under their tongues for 90 seconds and then to swallow it whole, without chewing it or otherwise disrupting the dosage form. They were permitted to take the tablet with a little water. The participants were instructed to engage in sexual activity 3 to 6 hours after ingestion. The dosing instructions were the same for all regimes. 28 doses were provided in the 8-week treatment period. The participants were asked to endeavor to take a minimum of 1 dose per week. They were informed that they could take the remaining doses as required (ie, on demand) throughout the 8-week treatment period. The minimum period between individual doses was 2 days (ie, on alternate days). Randomization and Masking Participants who met the inclusion and exclusion criteria were randomized and allocated to a treatment sequence. The randomization list was designed by an independent statistician at Pharma Consulting Group (Uppsala, Sweden). Randomization was performed using an interactive web response system (Viedoc; Pharma Consulting Group), with a unique numeric medication code from the randomization list being assigned to each randomized subject. The corresponding medication kit (bearing the same unique number) was sent to the site by the warehouse where the study medication was stored (Sentry BioPharma Services Inc, Indianapolis, IN, USA). The factors body mass index and menopausal status (pre- or postmenopausal) were balanced across treatment arms. A unique subject identification code was used to ensure that the data were anonymous. Access to the key to this identification code was restricted. An 8-week, single-blinded PRI period was used to dampen the usual placebo effect during active treatments. Investigators were aware that all participants received placebo during the PRI period, but the participants were not. The investigators and site personnel involved were given appropriate instruction and training to minimize potential effects of this knowledge. The blinding could be broken only under exceptional circumstances, for example, if the investigator believed that it was vital for the medical management of the participant in question. In such cases, investigators were required to contact the sponsor’s medical monitor who had access to the sealed code envelopes. Outcomes and Assessments Primary and secondary outcome variables were measured using the validated Sexual Event Diary (SED). The SED is a secure web-based diary that participants were required to com- plete within a period of 24 hours after each sexual event. This information was used to assess each participant’s satisfaction and sexual functioning during that event. Participants were asked to indicate whether the event was satisfactory and whether they experienced an orgasm (dichotomous items). They also were asked to indicate the associated levels of sexual desire, pleasure, bodily arousal, and subjective arousal (using 5-point Likert scale items). In addition, they were asked for details of the type and duration of the sexual event in question and whether they used the study medication before that event. The primary end point was the change In the number of SSEs (as recorded by the SED) in the interval from the 4-week baseline to the 4-week mean of the 8-week ATP. This end point is one of the FDA’s accepted primary end points for clinical trials in HSDD and FSIAD. The following formula (Formula 1) was used to calculate change in the number of SSEs from baseline (DSSE) for each participant: where ATP1-4 represents ATP weeks 1 through 4, ATP5-8 represents ATP weeks 5 through 8, and BLE1-4 represents baseline establishment at weeks 1 through 4. The key secondary end point was the change (during the same interval) in the cumulative level of subjective sexual satisfaction (4-item mean of desire, pleasure, bodily arousal, and subjective arousal) during the SSEs produced by the treatments. Another secondary end point was the change in the number of orgasms (as recorded by the SED) from the 4-week baseline to the 4-week mean of the 8-week ATP. The PRI period was not used in the analyses because it was intended only to stabilize placebo responses. Additional secondary outcome variables were assessed using the Weekly Diary (WD). Each week, participants filled out the WD at home using the same secure web-based platform as the SED. The WD assessed how often participants experienced sexual desire and arousal during the preceding week, ranging from “not at all” to “more than a couple of times a day” on a 6-point scale. Also, subjects were asked whether the perceived change was caused by the study medication. Efficacy of the treatment was evaluated by assessing responses to questionnaires measuring sexual function, satisfaction and distress associated with sexual function. In particular, the questionnaire contains questions on ‘Pleasurable (Q5)’, ‘Mood for sex / Sexual desire (Q7)’, ‘Bodily arousal (Q8)’, ‘Sexually aroused (Q9)’, ‘Feel good about body (Q10)’, ‘Feelings of disgust (Q13)’, ‘Let go (Q6)’, ‘Afraid (Q11)’, ‘Distracting thoughts (Q13), ‘Partner (Q14, Q15)’, and ‘Orgasm (Q16)’. Statistical Analyses To assess the primary end point, interaction effects were calculated among the highest-dose combinations, the placebo condition, and the monotherapies (S and T alone). This allowed the comparison of the change in the number of SSEs from the 4-week baseline establishment period to the 4-week mean of the 8-week ATP. The primary end point and the method of analysis were agreed upon with the regulatory agencies (FDA and European Medicines Agency [EMA]). A similar approach was used to assess the key secondary end point and the other secondary end points. The interaction effects were derived by using regression analyses on each imputed dataset (see supporting information for a description of the imputation methods). The difference between baseline and active treatment was used as the dependent variable and the treatment group indicator was used as the independent variable. The regression coefficient of the treatment group indicator represents the difference in change from baseline between the 2 treatment groups. Regression coefficient estimates and standard errors were combined according to Rubin’s Rules. The p value was set at 0.05 (2-sided). Statistical analyses were performed in line with the statistical analysis plan as described in the clinical study protocols (see supporting information; note that the SED was formerly named SSEQ) using IBM SPSS Statistics 21.0 for Windows (IBM Corp, Armonk, NY, USA) and R 3.2 (The R Project for Statistical Computing, The R Foundation, Vienna, Austria). The safety analysis population consisted of all those participants who received at least 1 dose of study medication. Descriptive statistics were calculated for all safety data. All adverse events were listed, as were the number of participants in each treatment group involved and details of the incidence of these events. For the incidence assessment, cases in which a single participant experienced adverse events on more than 1 occasion were counted as single incidents. Results and Observations: Participants are categorised into four different groups based on the criteria below: 1) Group 1: No impact on SHBG nor Albumin 1a: Premenopausal + no COC + BMI > 22.5 1b: Premenopausal + no COC + 22.5 < BMI < 30 2) Group 2: 1 impact on SHBG and / or Albumin: 2a: Premenopausal + COC + BMI > 22.5 2b: Premenopausal + no COC + BMI < 22,5 2c: Postmenopausal + no COC / HRT + BMI > 22,5 3) Group 3: 2 impacts on SHBG and / or Albumin: 3a: Premenopausal + COC + BMI < 22.5 3b: Postmenopausal + COC / HRT + BMI > 22.5 3c: Postmenopausal + no COC / HRT + BMI < 22.5 4) Group 4: 3 impacts on SHBG and / or Albumin: 4a: Postmenopausal + COC / HRT + BMI < 22.5 The numbers of participants in each (sub)group and the percentages of (those) participants showing improvement in any arm (including the placebo arm), in the combination therapy arm, and in the monotherapy (T only) arm, are shown in Table 1. Table 1 – stratification of participants Group Total Participants Any T+S Combi T only 1a 78 53% 27% 24% 1b 46 43% 24% 26% 2a 11 73% 45% 45% 2b 26 58% 42% 31% 2c 54 46% 24% 22% 3a 14 29% 21% 7% 3b 0 N / A N / A N / A 3c 10 30% 20% 10% 4a 0 N / A N / A N / A Figures 1a to 1g are diagrams are bar charts based on the data included in Table 1. Observations: 1) The number of participants falling in a group decreases with increasing number of impacts of the group; 2) In premenopausal women the type of impact (COC use versus BMI < 22,5) makes no significant difference on the efficacy and effects of the treatment. 3) Impact of (only) menopause seems to have the same magnitude as (as influential as) 2 impacts (COC use plus BMI < 22,5) in premenopausal women. 4) High BMI (> 30) has no impact on percentage of responders, and 5) Increasing the testosterone dose seems to broaden the window of opportunity to increase the percentage of responders, in premenopausal women and even more in postmenopausal women. Exemplary participants and results thereof from each (sub)group are further analysed. In results shown below, level of SHBG is expressed in nmol / L, level of albumin is expressed in g / dL, total and free testosterone levels are expressed in ng / dL, follicle-stimulating hormone (FSH) level is expressed in IU / L. Scores for Q7 (Sexual Desire), Q8 (Bodily Arousal), Q9 (Sexually Aroused), the Desire Domain (composite of Q7 and Q9), the Satisfaction Domain (the mean of Q5-Q9 plus Q11-Q13) and SSE (calculated according to Formula I) are analysed. Response in the placebo arm is used as a reference point:

[0002] Exemplary results of participants in Group 1 treated with 0.5mg testosterone in combination with 50mg sildenafil Exemplary results of participants in Group 2a treated with 0.5mg testosterone, optionally with 25mg or 50mg sildenafil

[0003] Exemplary results of participants in Group 2b treated with 0.5mg testosterone, optionally with 25mg or 50mg sildenafil Exemplary results of participants in Group 2c treated with 0.5mg testosterone, optionally with 25mg or 50mg sildenafil

[0004] Exemplary results of participants in Group 3a treated with 0.5mg testosterone, optionally with 25mg or 50mg sildenafil Exemplary results of participants in Group 3c treated with 0.5mg testosterone, optionally with 25mg or 50mg sildenafil

[0005] Exemplary results of pre-menopausal participants having a plasma SHBG level of high than 100 nmol / L, treated with 0.5mg testosterone alone. Discussion of the results: With increasing the number of “impact actors”, the improvement by T0,5 + / - S on sexual function outcomes appear to have decreased. Menopausal status seems to be the strongest (negative) impact factor on the efficacy of the treatment. In pre-menopausal women, it was noted that COC medication has given rise to strong increase in SHBG levels, and low BMI also has, in some cases, impacted the SHBG level. COC medication in combination with low BMI gave strong increase in SHBG level in pre-menopausal women. Low BMI had shown some impact on SHBG level in post-menopausal women. The results show that high SHBG levels, as well as being post-menopausal, has a strong (negative) impact on sexual function outcomes of the treatments, indicating that a higher testosterone dosage may be required. Example 2 Study Design and Oversight Earlier Phase II clinical trial data using a combination product called Lybrido (containing both testosterone and sildenafil) showed promising trends in patient-reported improvements across multiple aspects of sexual dysfunction, with particularly notable benefits in sexual desire. This study was performed to gain objective physiological measurements to validate and strengthen previous test results and reports, in preparation for advancing this combination therapy toward wider clinical use. Clitoral blood vessel function has been explored as a potentially important biological indicator of sexual response in women. The clitoris receives its nerve supply and blood circulation through pathways that are largely separate and distinct from those serving the vagina. During normal sexual arousal, the body undergoes specific physiological changes including increased blood flow to pelvic organs and swelling of external genital structures, particularly the clitoris and vaginal tissues. Clitoral swelling appears to occur primarily through blood vessel mechanisms involving the relaxation of smooth muscle tissue within blood vessel walls. FSIAD partially manifests as persistent or recurring difficulty achieving or maintaining adequate sexual excitement, which causes personal distress. This can present as reduced subjective feelings of excitement or diminished physical responses such as decreased vaginal lubrication and reduced genital swelling. Currently, researchers assess female sexual arousal blood flow responses using a non- invasive technique called Vaginal Photoplethysmography (VPA), though this remains primarily limited to research environments rather than clinical practice. Recent scientific work suggests that vaginal lubrication problems and clitoral swelling difficulties in some women may stem from underlying blood vessel abnormalities. However, direct diagnostic procedures for evaluating blood flow events in vaginal and clitoral systems are not available in standard clinical settings. Colour Doppler ultrasonography (CDU) offers a potential solution to this diagnostic gap. This technique, already established as a diagnostic tool for measuring penile blood flow in men with erectile dysfunction, provides a useful non-invasive method for measuring clitoral blood flow to assess female sexual response. Previous research using clitoral Doppler ultrasound has shown that during sexual arousal, Peak Systolic Velocity (PVS) increases while the Resistance index (RI) decreases. Similar patterns have been observed with sildenafil use, a PDE5 inhibitor medication that dilates blood vessels, increases blood flow, and treats erectile dysfunction. No previous studies have examined the effects of testosterone combined with sildenafil on clitoral blood flow patterns. This study uses CDU for the measurements of clitoral blood flow as an indication of female sexual response. Methods and A small case series measurements have been conducted, involving three premenopausal women suffering from secondary / acquired generalized FSIAD. The aim is to investigate how a fixed-dose combination of testosterone gel (1.0 mg) and sildenafil tablets (100 mg) influences clitoral blood flow as measured by Doppler Duplex Ultrasound. The three participants averaged 37.7 years of age (±3.5 years). All maintained stable heterosexual relationships lasting longer than 10 years and had children. All used low-dose estrogenic-containing contraceptive medications. Physical examinations revealed no abnormalities. Individual Participant Details: Participant 1: 34 years old, healthy medical history, weighed 62 kg, height 168 cm, BMI 22, blood pressure 116 / 67 Participant 2: 41 years old, controlled hypertension, weighed 59 kg, height 170 cm, BMI 20.4, blood pressure 110 / 90 Participant 3: 38 years old, well controlled type 2 diabetes, weighed 67 kg, height 164 cm, BMI 25, blood pressure 122 / 91 Outcomes and Assessments The primary measurements included changes from baseline in several parameters: Clitoral Peak Systolic Velocity (PSV), End-diastolic Velocity (EDV), Resistance Index (RI), and Pulsatility Index (PI). Participants watched erotic film content through 3D glasses before measurements to stimulate sexual arousal. The three participants were healthy premenopausal women meeting FSIAD diagnostic criteria with FSFI total scores below 26 and desire domain scores below 5. All participants were free from systemic, hormonal, cardiovascular, or neurological conditions that could cause FSIAD. None had previous pelvic surgery, radiation therapy, or current antipsychotic medication use. None were pregnant or breastfeeding at the time of participation. After privately viewing erotic video content, participants underwent initial CDU measurements. A testosterone 1.0 mg has been applied through topical gel. Three hours later, participants took 100 mg sildenafil orally. The CDU measurement procedure, including erotic video viewing, was repeated one hour after sildenafil intake. Adverse events were monitored up to 3 hours later. All CDU measurements were performed by one expert to reduce results variability. Results and Observations Individual Participant Measurements are as follows: Participant 1: Dorsal artery diameter increased from 0.9 to 1.0 mm (change of 0.1), PSV increased from 9.3 to 14.7 (change of 5.4), EDV decreased from 0.92 to 0.86 (change of -0.06), RI decreased from 0.82 to 0.79 (change of -0.03), PI increased from 1.23 to 1.29 (change of 0.06). Participant 2: Dorsal artery diameter increased from 0.8 to 1.0 mm (change of 0.2), PSV increased from 12.4 to 16.4 (change of 4.0), EDV decreased from 2.2 to 0.62 (change of -1.58), RI decreased from 0.9 to 0.82 (change of 0.08), PI increased from 1.02 to 1.12 (change of 0.10). Participant 3: Dorsal artery diameter increased from 0.6 to 0.9 mm (change of 0.3), PSV increased from 13.4 to 15.3 (change of 1.9), EDV decreased from 1.6 to 0.98 (change of 0.62), RI decreased from 1.03 to 0.92 (change of 0.11), PI decreased from 1.4 to 1.2 (change of - 0.2). Results of CDU examination at baseline and after the administration of the medication are shown in Table 2. Table 2: Results of CDU examination Parameter Patient 1 Patient 2 Patient 3 Baseline After Δ Baseline After Δ Baseline After Δ A. dorsalis ɸ mm 0.9 1.0 0.1 0.8 1.0 0.2 0.6 0.9 0.3 PSV 9.3 14.7 5.4 12.4 16.4 4.0 13.4 15.3 1.9 EDV 0.92 0.86 -0.06 2.2 0.62 -1.58 1.6 0.98 0.62 RI 0.82 0.79 -0.03 0.9 0.82 -0.08 1.03 0.92 0.11 PI 1.23 1.29 0.06 1.02 1.12 0.10 1.4 1.2 -0.2 When analysing all three participants together, the average results showed: PSV: Increased from baseline average of 11.70±1.75 to post-treatment average of 15.47±0.70 (average change of 3.77±1.76) EDV: Decreased from baseline average of 1.57±0.52 to post-treatment average of 0.82±0.15 (average change of -0.34±1.12) RI: Decreased from baseline average of 0.92±0.09 to post-treatment average of 0.84±0.06 (average change of 0.20±0.56) PI: Decreased slightly from baseline average of 1.22±0.16 to post-treatment average of 1.20±0.07 (average change of -0.12±0.07) Mean ± Standard deviation results are shown in Table 3. Table 3: Mean ± Standard deviation of the hemodynamic measurements at baseline and after medication administration Parameter Baseline Post Δ PSV 11,70±1,75 15,47±0,70 3,77±1,76 EDV 1,57±0,52 0,82±0,15 -0,34±1,10 RI 0,92±0,09 0,84±0,06 0,20±0,56 PI 1,22±0,16 1,20±0,07 -0,12±0,07 This case series involving healthy premenopausal women with FSIAD diagnosis - confirmed by sexual medicine specialists and meeting DSM-5 diagnostic criteria - demonstrated improved primary measurements following administering testosterone 1 mg combined with sildenafil 100 mg . Even with a relatively small study group (with 3 participants), the PSV improvements reached statistical significance (p<0.05), demonstrating clear medication effects. These improvements correlated with increases in dorsal artery diameter size EDV and RI parameters also improved in all three participants. Important to note that PI serves as a calculated measurement of blood vessel health and correlates with cardiovascular health conditions rather than functioning as a direct measurement of increased blood flow related to sexual arousal. To assess subjective effects on sexual desire, researchers also measured changes from baseline using standardized questionnaires: the Female Sexual Function Index Desire Domain (FSFI-D), Arousal domain (FSFI-A), and total FSFI weighted score for overall sexual function assessment. The results showed a positive trend of improvements in sexual function following the administration (of the combination therapy). One participant showed significant improvement in total FSFI scores. As these assessments occurred on the same day in a clinical research setting, further investigations on longer term effects may be performed to establish clinical relevance. In summary, it is successfully demonstrated that the testosterone-sildenafil combination (1 mg / 100 mg) produces measurable physiological effects on clitoral blood flow, providing objective evidence to support subjective reports from earlier clinical trials. This physiological validation represents an important step in advancing combination therapy development for FSIAD treatment. Further, it is noted that all three participants are using COCs, meeting criteria for choosing the high-dose testosterone treatment according to the present invention. Improvements on PSV are more significant in Participants 1 and 2, whose BMI are under 22.5, which is also in line with the criteria according to the method of the present invention.

Claims

Claims 1. A pharmaceutical composition comprising a steroid such as testosterone or a functional analogue or derivative thereof, in combination with a PDE5 inhibitor such as sildenafil, wherein the testosterone or the functional analogue or derivative thereof is present in an amount equivalent to no less than 1mg, for example 1-5mg, preferably 1-4mg, testosterone.

2. The pharmaceutical composition according to claim 1, comprising testosterone or a functional analogue or derivative thereof in an amount equivalent to 1mg, 2mg, 3mg or 4mg testosterone; and no less than 25mg, no less than 50mg, for example 50mg, 75mg or 100mg, sildenafil.

3. The pharmaceutical composition according to claim 1 or 2, wherein the composition comprises: a core comprising cellulose, a filler selected from an organic and / or an inorganic salt, and the PDE5 inhibitor, preferably sildenafil, for delayed immediate release; a separating coating surrounding the core, comprising a hydrophobic polymer and a hydrophilic substance; and an outer coating surrounding the separating coating, comprising testosterone or the functional analogue or derivative thereof, for immediate release.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the delayed release of the PDE5 inhibitor is an immediate release occurring between 1.5 to 6 hours, preferably between 2.5 to 3.5 hours, after the release of testosterone or the functional analogue or derivative thereof.

5. The pharmaceutical composition according to any one of claims 1 to 4, where testosterone or the functional analogue or derivative thereof is to be administered sublingually.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the composition is a tablet.

7. The pharmaceutical composition according to any one of claims 1 to 6 for use in enhancing female sexual desire in the treatment of FSIAD in a patient, wherein: the patient is post-menopausal; the patient is using COCs or receiving HRT; or the patient has a BMI no greater than 22.5; orthe patient has a plasma SHBG level of no less than 100 nmol / L.

8. The pharmaceutical composition for use according to claim 7, wherein the patient has a plasma albumin level of no greater than 37 g / L.

9. Testosterone or a functional analogue or derivative thereof in an amount equivalent to at least 1.0mg testosterone for use in combination with a PDE5 inhibitor, preferably sildenafil in enhancing female sexual desire in the treatment of FSIAD of a patient, wherein the patient is post-menopausal or the patient is using COCs or receiving HRT; or wherein the patient has a BMI (Body Mass Index) no greater than 22,5; or wherein the patient has a plasma SHBG (sex hormone-binding globulin) level of no less than 100 nmol / L.

10. Sildenafil in an amount of no less than 25mg, no less than 50mg, for example 75mg, preferably 100mg, for use in combination with testosterone or a functional analogue or derivative thereof in enhancing female sexual desire in the treatment of FSIAD of a patient, wherein the patient has a BMI (Body Mass Index) no greater than 22,5; or wherein the patient has a plasma albumin level of no greater than 37 g / L.

11. Sildenafil for use according to claim 10, wherein the patient is post-menopausal or the patient is using COCs or receiving HRT; and wherein testosterone or the functional analogue or derivative thereof is used in an amount equivalent to at least 1.0mg testosterone.

12. A method for identifying a suitable patient for the use of the pharmaceutical composition according to any one of claims 1 to 6 for enhancing female sexual desire in the treatment of FSIAD, wherein the patient is identified when at least one of the following criteria is met: the patient is postmenopausal; the patient’s BMI is no greater than a pre-determined threshold, for example 25, 24.5, 24, 23.5, 23, or preferably 22.5; or the patient is using COCs or receiving HRT.

13. A method for determining a dosage for a patient in the treatment of FSIAD, comprising choosing a testosterone dosage of no less than 1.0mg in combination of a PDE5 inhibitor, preferably sildenafil, if: the patient is post-menopausal orthe patient is using COCs or receiving HRT; or the patient has a BMI no greater than a pre-determined threshold, for example 25, 24.5, 24, 23.5, 23, or preferably 22.5; or the patient has a plasma SHBG level of no less than pre-determined threshold, for example 80 nmol / L, 90 nmol / L, or preferably 100 nmol / L.

14. The method according to claim 13, wherein the method further comprises choosing a dosage of no less than 75mg, for example 100mg, for the PDE5 inhibitor, preferably sildenafil.

15. A method of determining a dosage regime of a pharmaceutical composition for a patient in the treatment of FSIAD, wherein the pharmaceutical composition comprises a PDE5 inhibitor, preferably sildenafil, and testosterone or a functional analogue or derivative; and: wherein the method comprises: a) collecting information on the following impactor factors of the patient: i) the patient’s menopausal status; ii) the patient’s BMI; iii) if the patient is using COCs or receiving HRT; iv) the plasma SHBG level of the patient; and v) the plasma albumin level of the patient b) comparing the information collected to a pre-determined schedule; and c) choosing a dosage regime of sildenafil and / or testosterone for the patient based on the comparison.

16. A method of enhancing female sexual desire in the treatment of FSIAD of a patient, the method comprising: a) collecting information on the following impactor factors of the patient: vi) the patient’s menopausal status; vii) the patient’s BMI; viii) whether the patient is using COCs or receiving HRT; ix) the plasma SHBG level of the patient; and x) the plasma albumin level of the patient b) comparing the information collected to a pre-determined schedule; and c) administering a pharmaceutical composition to the patient, wherein the pharmaceutical composition comprises a PDE5 inhibitor, preferably sildenafil, and testosterone or a functional analogue or derivative, and wherein the dosage regime of sildenafil and / or testosterone for the patient is determined based on the comparison of step b).

17. A dual release drug delivery system for use in enhancing female sexual desire in the treatment of FSIAD, the composition comprising: a core comprising cellulose, a filler selected from an organic and / or an inorganic salt, and delayed immediate release sildenafil in an amount of 100mg; a first coating surrounding the core, the first coating comprising a hydrophobic polymer and a hydrophilic substance; and a second coating surrounding the first coating, the second coating comprising testosterone, or a functional analogue or derivative thereof in an amount equivalent to at least 1.0mg testosterone; wherein the delayed release of sildenafil occurs between 1.5 to 6 hours, preferably between 2 to 6 hours, more preferably between 2.5 to 3.5 hours, after the release of the testosterone, or the functional analogue or derivative thereof.

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