Treatment options: hormonal, non- hormonal, and others
While a number of treatment options are available for male sexual problems, FSD still remains an incompletely managed clinical condition, awaiting the advent of safe and efficacious therapies (38).
That being so, the multifactorial dimension of women's sexual disorders also warrants an integrated approach encompassing biopsychosocial within possible pharmacological therapies, subsequent to a detailed diagnostic workup (Table 60.2). In a generic sense, psychosexual education through empowerment and knowledge to improve an understanding of the basic reproductive anatomy, physiology, and aetiopathology forms the essential first step. At this time point, it would be beneficial to make attempts to eliminate any misguided information or myths, which may be negatively impacting the sexual behaviour. To have a significant sexual outcome, any underlying interpersonal or relationship issues need to be addressed and managed carefully. These measures can be combined with important lifestyle-modifying behaviours of diet, exercise, and control over day-to-day stress and substance use, if any (4, 32).Systemic hormone therapy is considered in two forms, viz. oestrogen and progesterone for women with an intact uterus or oestrogen alone for those without; the hormone therapy is preferential, used with caution, only in the absence of contraindications and customized to suit individual's needs. Local or vaginal oestrogen as a cream, gel, tablet, or ring is thought of as an equally effective and safer alternative to systemic hormone. However, it must be remembered that, albeit small, variable increases in serum E2 levels have been reported in studies following local applications. Nevertheless, local hormones have specific usefulness in addressing the clinical signs and symptoms of menopausal genitourinary syndrome (39). Ospemifene, as an oestrogen agonist/antagonist (selective oestrogen receptor modulator/SERM) and approved (by the United States Food and Drug Administration (FDA)) agent for moderate to severe dyspareunia is useful in postmenopausal women.
In doubleblind, placebo-controlled studies, the vulvovaginal atrophy reversal was founded by an increase in superficial cell content and decreases in parabasal cells and vaginal pH. These functionally relevant improvements in vaginal atrophy not only addressed the genital signs and symptoms but also translated into significant recovery for the other domains in sexual function. Available clinical evidence from short-term follow-up studies thus far is supportive of its safety profile on breast and endometrium, in the absence of changes leading to hyperplasia or uterine bleeding (40). Another agent that may be considered in the treatment of postmenopausal women with vaginal atrophy, dyspareunia, and secondary HSDD is tibolone (41). It is a synthetic hormonal prodrug with oestrogenic and androgenic effects in the body; it is approved and available in many countries and is credited with beneficial effects for loss of libido and overall sexual function.Apart from those mentioned, several others have been tried as non-specific and off-label drugs in the treatment of women's sexual disorders. Most theories on the purported efficacy of dehydroepiandrosterone (DHEA) are based on its role as a precursor for sex steroids and their actions after conversion in the body. Thus, the potential sequelae of DHEA administration in postmenopausal women would include improvements in sexual desire/arousal on one hand and general well-being on the other. Although data from randomized controlled studies are not forthcoming with the necessary information for its safety and efficacy, a local, intravaginal application of 0.50% DHEA for 12 weeks provided statistically significant improvement in the co-primary parameters of vulvovaginal atrophy in a clinical study (42).
Normally, testosterone is essential in women not only as a major precursor in the oestrogenic steroid pathway but also by virtue of its own androgen receptor-mediated effects in the body. Literature evidence points to an improvement in a number of satisfying sexual events (and concomitant reduction in personal distress) through studies investigating testosterone implants, oral methyl testosterone, or transdermal testosterone.
While the transdermal patch is used by surgically menopausal women in some countries for their HSDD, a pharmaceutical attempt to test the efficacy of testosterone gel forTable 60.2 Female sexual dysfunction: information at a glance
| Type of sexual disorder | DSM-5 criteria | Options: approved/off-label/ trial/others | Mode of action |
| Female sexual | Manifested by three of the following: | Flibanserin | 5-HT1a agonist and 5-HT2a antagonist |
| interest/arousal disorder | 1. Absent or reduced sexual interest 2. Absent or reduced sexual or erotic thoughts or | Tibolone | Selective tissue oestrogenic activity regulator |
| fantasies 3. No or reduced initiation of sexual activity and unreceptive to partner's attempts to initiate | Testosterone | Hormone | |
| Testosterone + oestrogen | Hormone | ||
| 4. Absent or reduced sexual excitement or pleasure during sexual activity in almost all or all (75-100%) sexual encounters | Testosterone + sildenafil | Hormone + PDE5 inhibitor | |
| Testosterone + buspirone | Hormone + 5-HT1a receptor partial agonist | ||
| 5. Absent or reduced sexual interest or arousal in response to any internal or external sexual or erotic cues (written, verbal, or visual) 6. Absent or reduced genital or non-genital sensations during sexual activity in almost all or all (75-100%) sexual encounters | DHEA | Hormone precursor | |
| Bremelanotide | Melanocortin receptor 3,4 agonist | ||
| Bupropion | Dopamine agonist | ||
| PGE1 topical | Direct action through cAMP | ||
| Female orgasmic | Presence of either of the following on all or almost all | Oxytocin | Hormone |
| disorder | (75-100%) occasions of sexual activity: | Clitoral vacuum device | External device |
| 1. Marked delay in, marked infrequency of, or absence of orgasm 2. Markedly reduced intensity of orgasmic sensations | Vibrators and self-stimulators | External device | |
| Genitopelvic pain or | Persistent or recurrent difficulties with one or more of the | Oestrogen | Local/systemic hormone |
| penetration disorder | following: | Oestrogen + progesterone | Hormone |
| 1. Vaginal penetration during intercourse 2. Marked vulvovaginal or pelvic pain during intercourse or penetration attempts | Oestrogen + testosterone | Hormone | |
| Ospemifene | Selective oestrogen receptor modulator | ||
| 3. Marked fear or anxiety about vulvovaginal or pelvic pain in anticipation of, during, or because of vaginal penetration | Lignocaine | Local anaesthetic agent | |
| SSRIs/SNRIs/tricyclic drugs | Serotonergic, antidepressant drugs | ||
| 4. Marked tensing or tightening of pelvic floor muscles during attempted vaginal penetration | Dilators | Mechanical device | |
| Vaginal moisturizers and lubricants | Topical restoration | ||
| Vestibulectomy | Surgical option | ||
| Pelvic floor muscle exercises | Physical therapy |
SNRIs, serotonin and norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors.
Source data from Kingsberg SA, Woodard T Female sexual dysfunction: focus on low desire. Obstet Gynecol 2015 Feb;125(2):477-86, Nappi RE, Cucinella L. Advances in pharmacotherapy for treating female sexual dysfunction. Expert Opin Pharmacother 2015 Apr;16(6):875-87, and Basson R. Pharmacotherapy for women's sexual dysfunction. Expert Opin Pharmacother 2009 Jul;10(10):1631-48.
women was withdrawn at the level of phase III clinical studies. If testosterone is thought of as an off-label option for postmenopausal sexual complaints, due caution for its systemic liabilities especially changes to liver function and breast cancer potential and warnings for virilizing effects viz. acne, hirsutism, voice deepening, and androgenic alopecia need to be in place (8, 13). Lately, studies are ongoing with synergistic combinations of sublingual testosterone with either a phosphodiesterase type 5 (PDE5) inhibitor or a 5-HTia receptor partial agonist.
The former combination is envisaged to improve sensitivity and responsiveness to sexual stimuli while the latter is aimed to overcome any excessive sexual inhibition. Researchers have demonstrated significant improvements in the subjective and objective measures of sexual response in women undergoing these trials and the combinations show unique promise as targeted approaches for the selective types of sexual disorders (43).Flibanserin is a novel non-hormonal therapy for HSDD; it is a 5-HTia agonist and 5-HT2A antagonist, with moderate affinity also towards 5-HT2B, 5-HT2C, and dopamine D4 receptors, which was initially developed as an antidepressant (44). The recognition that flibanserin inhibited the serotoninergic antisexual influence and concurrently enhanced the dopaminergic prosexual response was the exploited mechanism for its clinical efficacy in HSDD. In large, randomized cohort studies flibanserin significantly increased the number of satisfying sexual events, also particularly in the context of desire, compared to placebo. In approximately less than 10%, nausea, dizziness, fatigue, and somnolence were noted as adverse events related to treatment; any serious hypotension or syncope was precipitated by concurrent alcohol intake. Currently, flibanserin is the only FDA-approved treatment for premenopausal HSDD and clinical trials evaluating its safety and efficacy in postmenopausal HSDD are ongoing (45, 46).
Another centrally acting antidepressant agent, bupropion, which is a combined dopamine, norepinephrine reuptake inhibitor, is also thought to contribute to significant improvements in the key outcome measures of HSDD when tried off-label. Its efficacy is somewhat similar to that of trazodone, which shares its 5-HT receptor antagonism with reuptake inhibition. In the initial years of drug development, clinical studies using the direct-acting dopamine agonist, apomorphine, in the management of desire/arousal disorder yielded variable data on efficacy and tolerability. More
recently, bremelanotide, a synthetic agonist of melanocortin 3 and 4 receptors, improved central desire/arousal parameters in controlled studies, with some promise for a therapeutic effect in the combined FSIAD in women (43, 47). In the available literature, the role of PDE5 inhibitors including sildenafil is appreciated only in selective cohorts of organic FSD viz. type 1 diabetes mellitus, spinal cord injury, or multiple sclerosis while in a vast majority of the remaining FSD aetiology, their efficacy was discounted (48). As for the other vasoactive drugs tested, both phentolamine mesylate, an alpha adrenergic agonist, and prostaglandin Ei failed to provide consistent data for their efficacy in the treatment of FSAD. Several ongoing studies are evaluating the potential efficacy of oxytocin neuropeptide in improving the specific outcome measures for arousal and orgasm, with sufficient preliminary evidence to stimulate further investigation (43).
A significant gap in scientific knowledge exists for the usefulness of nutritional or herbal supplements such as red clover to treat sexual disorders in women (49). Similarly, the only surgical option which is vestibulectomy, removal of painful tissues from the vestibule to treat vulval vestibulitis, has mixed clinical outcomes for patient satisfaction scores (50). Lastly, the drug-induced FSD is an established clinical entity which can benefit from a reduced dosage of the offending agent, change to medications without sexual side effects, or even a brief drug holiday.