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Disorders of Sexual Desire or Interest in Women

An important example of how basic research translates into clinical treatments comes from the study of the neurochemistry of sexual desire. At least three potential treatments for disorders of sexual desire or interest in women are being considered, including the MC agonist bremelanotide, the serotonergic mixed 5-HT1A agonist/5-HT2A antagonist flibanserin, and a combined pill containing testosterone and a phosphodiesterase-5 (PDE-5) inhibitor called Lybrido^®. Acute bremelanotide increases solicitations selectively in preclinical models using OVX rats primed with low doses of EB, or low EB and progesterone.^30,516 Likewise chronic flibanserin increases solicitations and reduces rejection responses in OVX rats primed with EB or EB and progesterone.³¹⁶ Microdialysis samples from the mPFC, NAc, and mPOA showed that acute flibanserin increased basal levels of NE in all areas, along with DA in the mPFC and mPOA, but not the NAc. Acute flibanserin also decreased serotonin levels in all areas. However, chronic flibanserin increased DA and NE significantly in the mPFC, but did not alter serotonin, glutamate, or GABA relative to chronically injected controls. Finally, acute treatment of OVX rats primed with low EB with testosterone and a PDE-5 inhibitor increased solicitations and hops and darts.⁶⁴¹ All three drugs have shown significant efficacy in increasing self-reported sexual desire in pre- and post-menopausal women diagnosed with hypoactive desire disorder.^30,642–646 The ability of these three drugs to stimulate solicitations in a rat model of hypoactive sexual desire predicts their functional application in women with hypoactive sexual desire. This suggests strongly that the neurochemical systems underlying appetitive sexual behavior are conserved between at least rats and humans, and that translational work on the neural and hormonal systems that mediate sexual responses in women can be derived from basic and clinical research in other species.

3.1 Loss of libido

Loss of libido is characterized by lack or absence of sexual fantasies and desire for sexual activity. Sexual desire is controlled by brain systems involved in sexual excitation and inhibition. Loss of libido may result from hypofunctional excitation, hyperfunctional inhibition, or a mix of the two. Of note, dopaminergic pathways in the mesolimbic and incertohypothalamic systems have been associated with sexually excitatory processes, while inhibitory processes are controlled by opioid, endocannabinoid, and serotonergic systems (Pfaus, 2009).

Flibanserin, a centrally acting serotonin agonist/antagonist is FDA-approved for women with hypoactive sexual desire disorder (HSDD), a condition characterized by low sexual desire that causes marked distress or interpersonal difficulty. In three randomized, double-blind, placebo-controlled trials, flibanserin 100 mg once daily at bedtime increased sexual desire, sexual satisfaction, and decreased distress associated with HSDD in pre-menopausal women (DeRogatis et al., 2012; Katz et al., 2013; Thorp et al., 2012). Adverse events, such as dizziness, nausea, insomnia, somnolence, anxiety, and dry mouth are common among women taking flibanserin. Drinking alcohol while on flibanserin should be avoided since it may result in severe hypotension (Parish & Hahn, 2016). Although these pharmacologic measures have not been specifically studied in PD, they can be considered to treat loss of libido in women with PD.

Testosterone deficiency is a medical condition that negatively impacts male sexuality, reproduction, QoL and can manifest with decreased libido (Morgentaler, Zitzmann, Traish, et al., 2016). There is an unrecognized high prevalence of testosterone deficiency in elderly male patients with PD, similar to that found in the general population (20–25% of males over 60 years old). Okun and colleagues investigated whether testosterone replacement has beneficial effects on testosterone deficiency symptoms, cognitive, motor and nonmotor symptoms of PD. They showed that a daily dose of transdermal testosterone gel improved testosterone deficiency symptoms in men with PD (Okun et al., 2002). A recent study found that increasing the serum testosterone concentrations of men with 65 years of age or older had significant effects on all measures of sexual function and some measures of physical function and depressive symptoms (Snyder, Bhasin, Cunningham, et al., 2016).

7.1.2 Pharmaceuticalization of Daily Life

A major growth area for pharmaceuticals is the use of prescription drugs not as cures for underlying conditions but as “lifestyle enhancements” of normal function and of daily living. Increasingly, sales of prescription drugs exploit personal insecurities in the face of life’s challenges, aspirations for increased physical and social attractiveness, and desire for greater sexual fulfillment. The promise of chemically-assisted enhancement is underpinned by the blurring of distinctions between health and disease. The pharmaceuticalization of daily life is not merely disease mongering, but mongering of non-disease for the sale of useless and harmful clinical interventions. A notable example is sildenafil citrate (Viagra); initially used as an intervention for erectile dysfunction due to diabetes, spinal cord damage, or other medical condition, it has come to be used recreationally to enhance sexual performance in the absence of physical impairment. The immense success of Viagra for non-disease in men encouraged drug companies to search for a “pink Viagra” for women (Hartley, 2006).

The clinical diagnosis of erectile dysfunction long preceded the advent of Viagra, but to guarantee a market for a female equivalent it was necessary to create a relevant medical diagnosis for women where none existed previously. Arising from the work of international groups of researchers extensively entangled with industry, aspects of female sexual experience have come to be medicalized as “female sexual dysfunction” (Moynihan, 2003a). Allegedly afflicting almost half of all women aged under 60 years, this “disease” is diagnosed on the basis of ill-defined indications of unsatisfied sexual desire and arousal. Thus far, industry has failed to discover an effective pharmaceutical for the alleged “symptoms,” and such seems unlikely given that the symptoms in question are more plausibly explained on the basis of the emotional life, interpersonal relationships, and work and family stresses experienced by women than any underlying physical pathology.

Nevertheless, in August 2015 in the United States, the Food and Drug Administration (FDA) approved the use of flibanserin (Addyi) for hypoactive sexual desire disorder in premenopausal women. Flibanserin was originally developed for the treatment of depression, but failed due to absence of benefit. It was then “rescued” (see Chapter 8) for use with female sexual dysfunction. The FDA had twice refused approval for use of the drug as therapy for low sexual desire, finding that it lacked efficacy and posed serious safety concerns (Gellad et al., 2015). However, despite several indicators of sexual performance showing no benefit compared to placebo, advocates claimed efficacy on the basis of women reporting average improvement of one-half of a “satisfying sexual event” per month. Negative side-effects, on the other hand, include adverse cardiovascular effects, sleepiness, fainting, and dizziness. The FDA’s eventual decision to approve the drug appears to have been influenced by perceived consumer demand. In particular, an industry-initiated advocacy group called Even the Score mounted a campaign demanding “gender equality” in access to drugs for sexual dysfunction.

If the pharmaceutical industry is to be believed, it seems that “female Viagra” may finally have been discovered. However, in reality, there are no approved products specifically intended to address problems of low sexual desire in men, and therefore the equity argument and claims of success for Addyi are largely spurious. Moreover, the main mechanism of action for Viagra involves increased blood flow to the penis, and it is recommended that the drug be taken only prior to sexual activity. Addyi, on the other hand, alters brain chemistry in ways that are poorly understood, and despite being found to interact adversely with alcohol, oral contraceptives, and some prescribed medications, its use requires that it be taken daily. It is a cruel irony that success in obtaining approval for Addyi was obtained on a platform of gender equality for women. Current evidence indicates that the benefit to women is none to minimal on average, whereas the probability of harm from long-term use is not merely high but certain.

The home computer and Internet have been a boon to the pharmaceutical industry, offering unprecedented opportunity for direct marketing to prospective consumers and new distribution channels in the form of online pharmacies (Fox and Ward, 2008). Apart from the as-yet unfulfilled search for a female blockbuster equivalent of Viagra for men, the immense profits generated by Viagra, and subsequent imitators (tadalafil, Cialis, and vardenafil, Levitra), has provided impetus for “lifestyle marketing” of drugs for a wide range of common and often vaguely-defined conditions, including allergies, acid reflux, and insomnia. Prescription drugs were once limited to patients, a subset of the population under the care of a physician. Today, however, marketeering is a vital aspect of the drug distribution chain (Applbaum, 2006). The new industry objective is to transform entire populations into patients functioning as healthcare consumers exercising “independent” choice as they shop for pharmaceuticals within an unfettered marketplace.

One rapidly emerging source of harm associated with pharmaceutical consumerism comes from the black market rather than the conventional drug industry. A substantial trade has emerged in designer drugs, which are synthetic analogs of existing licensed drugs. By operating outside the usual regulatory and commercial framework, manufacturers of analogs avoid payments arising from intellectual property rights. The trade is particularly extensive in substances possessing psychoactive properties, doping agents to enhance sporting performance, and for controlling weight. In specific growth areas such as formulations for erectile dysfunction, illicit sales rival legitimate trade (Venhuis and de Kaste, 2012). Profitability is enhanced because of low production and operating costs, and commensurately poor quality control. Structurally or functionally similar to the parent drug, designer drugs are developed to mimic the effects of the original. However, the precise pharmacology of analogs is typically largely unknown. Consequently, the associated risk of toxic side effects, both short- and long-term, is high.

5-Hydroxytryptamine 1A (5-HT_1A) Receptor

The 5-HT_1A receptor is encoded by the 5-hydroxytryptamine receptor 1A (HTR1A) gene. Desensitization (or downregulation) of the somatodendritic 5-HT_1A receptor by chronic SSRI treatment results in enhanced serotonergic neurotransmission [106,107]. In addition, antagonism of the 5-HT_1A receptor has also been suggested to be associated with antidepressant effects [108,109]. Therefore, genetic variation of the HTR1A might change the functional properties of the 5-HT_1A receptor, resulting in differences in antidepressant response.

Of the 10 polymorphisms identified in the HTR1A gene, the most investigated ones are c.-1019C/G (rs6295) located in the promoter region, p.Gly22Ser (rs1799920), and p.Ile28Val (rs1799921). The G allele of the rs6295 polymorphism has been associated with up-regulation of 5-HT_1A receptor expression [110] and response prediction with antidepressant treatment [111]. In 118 patients treated with fluoxetine or nefazodone augmented with pindolol, or monotherapy with flibanserin (a 5-HT_1A agonist), the homozygous G/G genotype was more prevalent in nonresponders than the homozygous C/C genotype (P = .0497 for the augmentation group and P = .039 for the monotherapy group) [111]. However, other investigators reported positive association being evident only for females [112] or in patients with specific depressive manifestation [113]. In a retrospective study, Levin et al. found no association between seven HTR1A polymorphisms, including rs6295, and SSRI response in 100 responders and 33 nonresponders [114]. As additional evidence that response to antidepressants likely is influenced by more than one gene, Arias et al. reported in 130 subjects treated with citalopram that homozygosity for both the G allele of the HTR1A polymorphism and S allele of the SLC6A4 polymorphism predict nonresponse to SSRI treatment (P = .009) [115]. Differences in ethnic and allele distributions in study subjects could partially account for the conflicting results in replication studies. As an example, with very low frequencies of the Gly22Ser and Ile28Val polymorphisms in Japanese populations, the effect of the more common Gly272Asp polymorphism of the HTR1A on clinical response to fluvoxamine was studied in 65 depressed Japanese patients. Subjects with the Asp allele had a significantly higher % reduction in score of the 17-item Hamilton Rating Scale for Depression (HAMD-17) than homozygous carrier of the Gly allele at week 2 (P = .009), week 6 (P = .036) and at week 12 (P = .031) [116].

Antidepressant-associated side effects are well-known contributory factors to lower medication adherence, poor-health outcomes, and premature discontinuance of treatment. In a randomized placebo-controlled trial of 12-week treatment of escitalopram in patients 60 and older, Garfield et al. reported that side effects (increased sleep duration, dry mouth, diarrhea, and decreased sexual desire) are associated with genetic polymorphisms affecting SLC6A4, HTR1A, and HTR2A. Decreased sexual desire was experienced more in patients with high-expressing genotypes of the three serotonergic components, whereas higher incidence of dry mouth and diarrhea are associated more frequently with patients with the low-expression genotypes for SLC6A4 polymorphism and low-transcription genotype for the HTR1A polymorphism, respectively. In contrast, there was no relationship between the three genetic polymorphisms and drug concentration [117].

Treatment of sexual dysfunction

In line with the interdisciplinary approach recommended for assessment of sexual dysfunction, best practice for treatment involves collaboration among healthcare professionals. Family medicine physicians are commonly a first contact for those coping with sexual dysfunction. A physician may offer biomedical treatment options (e.g., medication management) and may refer to a medical specialist (e.g., gynecologist, urologist) to help rule out contributing biological factors and/or assist with treatment planning. Since the etiology and maintenance of sexual dysfunctions include a range of biological, psychological, social, and interpersonal factors, physicians frequently refer to other clinicians who can target different aspects of the sexual dysfunction. For example, those navigating genito-pelvic pain/penetration disorder may experience greater declines in pain and improvements in sexual function through a combination of pelvic floor physiotherapy to reduce muscle tension and psychological interventions that expand their inventory of pleasurable sexual activities (Brotto et al., 2015). Regardless of the factors that have contributed to an individual’s sexual dysfunction, coping with sexual difficulties is often associated with unpleasant emotions such as shame, guilt, sadness, anger, grief, and/or loss. Thus, mental health services are typically beneficial as part of any comprehensive, person-centered healthcare for sexual dysfunction.

5-HT_1A receptors

The 5-HT_1A receptor has been one of the most studied members of the serotonin receptor family. This receptor plays a profound role as a somatodendritic autoreceptor on serotonin-containing neurons throughout the midbrain and brainstem. These 5-HT_1A autoreceptors modulate the pacemaker activity of these neurons in a negative feedback fashion, and are discussed elsewhere (see Chapter 2.1 of this volume). In other regions of the brain, such as the prefrontal cortex, neocortex, hippocampal formation and amygdala, 5-HT_1A receptors exert direct inhibitory effects. In these different brain regions, the 5-HT_1A receptors usually are expressed in somatodendritic compartments of principal cells. In the neocortex, 5-HT_1A receptors are localized to the initial axon segment (or axon hillock) of layer III and layer V pyramidal cells (Azmitia et al., 1996). In the hippocampus, activation of 5-HT_1A receptors is known to suppress the activity of CA3 pyramidal cells, and this is an effect that is enhanced by many antidepressant drugs (Haddjeri et al., 1998). At a macro-level, activation of 5-HT_1A receptors reduces the frequency of hippocampal rhythmic slow activity, analogous to the actions of anxiolytic drugs such as benzodiazepines.

Concerns with Herbal Product Contamination

During growth, harvest, processing, and storage, natural products can be polluted by molds, pesticides, heavy metals, and other chemicals, resulting in contamination. Mycotoxins are secondary metabolites produced by certain fungi during growth in the field, processing, transport, or storage. These may cause cancer, abnormalities, neurological problems, stillbirths, neural tube defects, cardiovascular problems, and in some cases, death. Pesticides are among the most widely used chemicals in the world and the most dangerous contaminates for humans. Pesticide residues on HDS can result in many health problems, such as skin rashes, asthma attacks, emphysema and cancer. Heavy metals found in some water and soil sources used in growing botanicals or processing HDS can lead to contamination with lead, cadmium, mercury, and arsenic. Exposure to heavy metals may result in a variety of diseases, such as neurological damage, renal damage, and cancer. Other foreign matter, including sulfide residues and herbicides can also lead to the external contamination of herbal medicines. Some unscrupulous manufacturers of HDS can illegally add pharmaceutical grade ingredients to enhance a specific activity that would be less pronounced with the HDS alone [42R,6R,43R].

Analysis was conducted on 150 dietary supplements marketed to increase sexual performance, 61% included unlabeled phosphodiesterase-5 inhibitors (sildenafil, tadalafil, veradenafil, and 34% modified analogues) with a concern that 25% of them had higher than the maximum recommended dose. Another 5.5% found other drug treatments used for sexual dysfunction (yohimbine, flibanserin, phentolamine, dehydroepiandrosterone or testosterone). A further 2.5% contained products from plants known to improve sexual performance. Only 31% of the samples could be considered as true herbal/natural product. The authors state that contamination is possible due to inadequate cleaning of the manufacturing chain, presence of impurities or degradation products, various compositions of a given dietary supplement with the same batch number, and inadequate labelling [44E].

Di Lorenzo and colleagues [45M] reviewed the literature for causality of adverse effects from common ingredients of HDS. Adverse effects were reported for 39 of the 66 botanical substances selected to be included in their search. Most of the noted adverse effects (86.6%) were associated with 14 plants, including Glycine max/soybean (19.3%), Glycyrrhiza glabra/liquorice (12.2%), Camellia sinensis/green tea (8.7%) and Ginkgo biloba/gingko (8.5%). Reports of adulterated HDS included in the study:

(1) Camellia sinensis (L.) Kuntze (green tea) had reports of associated acute hepatotoxicity caused by catechins and their gallic esters. However, two reports indicated that the acute hepatotoxicity was due to Chinese herbal supplements containing green tea and an adulterant, N-nitroso-fenfluramine, the probable hepatotoxic agent. (2) Citrum aurantium (bitter orange) causes specific adverse effect and interactions when combined with conventional pharmaceuticals. Alone, the natural presence of sympathomimetic stimulant amines, such as synephrine, may be causative of the numerous adverse cardiovascular effects. When bitter orange was used in combination with caffeine, ephedrine, yohimbine, phenyl ethylamine, and thyroxine, enhancement of the cardiovascular adverse effects was reported, such as tachycardia, hypertension, ventricular fibrillation, angina, acute myocardial infraction, ischemic stroke, and exercise-induced syncope. (3) Glycine max (soybean) in the form of soy milk containing high levels of iodine is reported to cause thyroid dysfunction [45M].

Adulteration of HDS was recently reviewed [46R] highlighting concerns of augmentation with pharmaceutical drugs and active analogs to improve HDS product activity. The marketed products are often in weight loss, sexual enhancement, and performance enhancement categories. The products are often not labelled with all ingredients and do not undergo the rigorous testing required by the FDA or other regulatory agencies for these pharmaceutic drugs. The FDA and the European Union (E.U.) recalled hundreds of weight loss products during 2010–2015 due to safety concerns of illegal addition of sibutramine, a substance banned in the U.S. and the E.U. due to association of use with serious cardiovascular events, stroke or heart attack. Other recalled HDS weight loss products contained unlabeled phenolphthalein, a laxative, and fluoxetine, an antidepressant. Hundreds of notifications have been issued by the FDA for sexual enhancement dietary supplements due to positive detections of approved PDE-5 inhibitors or its analogs. The EU also sent out notifications for similar products and those containing stimulants such as alkaloids, ephedrine and synephrine. Patients hospitalized in Hong Kong were reported to have traces of sibutramine, fenfluramine analogs in blood samples after taking adulterated weight loss products. Evaluation of HDS products after recall continued to show the presence of banned or unlabeled drugs. Many remained available for purchase containing the same adulterant previously identified by the FDA and several products contained a different analog, or the same compound added with a new adulterant [46R].

A synthetic stimulant—1,3-dimethylbutylamine (DMBA)—is an intentional contaminant in herbal products labeled as AMP citrate, 4-amino-2-methylpentane citrate, Pentergy and others. Cohen et al. determined that at least 12 dietary supplements labeled to contain one or more of these ingredients also contained DMBA. The suggested serving size on the product could deliver between 13 and 120 mg of DMBA per serving which could cause potential health risks [47E].

A hospital in Connecticut notified the CDC and the Connecticut Department of Public Health of a fatal case of gastrointestinal mucormycosis in a preterm infant. Unopened bottles of ABC Dophilus Powder were tested and yielded Rhizopus species, a saprophytic fungus capable of causing this gastrointestinal toxicity. The product was voluntarily recalled by the manufacturer due to the safety hazard to the high risk pediatric populations that would receive this treatment [48A].

An investigation of store brand herbal supplements from four major retailers in New York found that only 21% of the products, when tested through DNA analysis, contained the herbs indicated on the label. For the retailer with the poorest outcome, only 4% of the products contained the herb(s) listed on the label. Contaminants included items like rice, bean, asparagus, primrose, wheat, etc. The herbal manufacturing industry contested this finding by observing that DNA can be damaged during processing of herbal supplements, leading to incorrect DNA analysis [49r].

Melamine, used to fraudulently enhance test results for protein content of foods and supplements, can potentially cause urate stones and nephropathy in persons ingesting this adulterant. These supplements were tested in 2008 in China. Almost 300 000 infants were screened and diagnosed with urinary tract stones and sand-like calculi associated with melamine in milk products. Of these, 50 000 infants were hospitalized, with six associated deaths. The study also reported that another source of contamination in these products could be pesticide residues such as cyromazine [50E].

A study reported liquid herbal supplement products contaminated with fecal coliforms, Klebsiella species and Enterobacter species, in Mwanza city. The contamination was associated with low socioeconomic conditions, lack of formal training in preparation of HDS, lack of registration with the ministry of health, lack of appropriate packaging of products, and use of solvents that were not sanitized before or during preparation. This was observed by doing a cross-sectional study involving 59 workers and 109 liquid HDS products[51E].

Hepatic Impairment

Flibanserin exposure is strongly affected by first-pass metabolism; when orally consumed, the exposure is only a mean of 33% of that after a corresponding intravenous dose. In a dedicated study of patients with hepatic impairment, systemic exposure to flibanserin was correspondingly increased. Although Cmax was unaffected, the area under the curve was profoundly increased 4.5-fold, even in patients with only mild hepatic impairment. Considering the known adverse effects of supra-therapeutic exposure to flibanserin (during CYP3A4 inhibitor use), flibanserin should not be used in patients with hepatic impairment.³⁵

Special Populations

Flibanserin is approved for use in premenopausal women. There are no human data on safety in pregnancy. In animal studies fetal toxicity occurred during episodes of maternal toxicity from higher-than-recommended dosages. Animal models may not accurately reflect human safety or harm. Flibanserin is not recommended for pediatric or geriatric use and is not indicated for use during and after the menopause transition. Flibanserin is excreted in animal milk, but data are lacking on human milk. Because of the possibility of drug excretion in human milk and potential sedative effects on the infant, flibanserin is not recommended during lactation (Sprout Pharmaceuticals, Inc., 2015).

Abstract

Introduction

Flibanserin, a multifunctional serotonin receptor agonist and antagonist, is currently approved in the United States and Canada for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. A post hoc analysis of HSDD clinical trial data found that flibanserin treatment was associated with statistically significant weight loss relative to placebo, even though study patients were not selected for being overweight/obese and were provided no expectation for weight reduction or interventions intended to promote weight loss.

Aim

To understand possible mechanisms by which flibanserin may produce weight loss.

Methods

A literature review was performed using Medline database for relevant publications on the mechanisms of action by which flibanserin may provide weight loss and the links between sexual function and weight management.

Main Outcome Measures

Examination of (i) biopsychosocial factors regulating sexual desire, food intake, and weight regulation; (ii) clinical pharmacology of flibanserin; (iii) neurobiology of brain reward circuitry; and (iv) identification of possible mechanisms common to flibanserin and weight loss.

Results

Based on flibanserin clinical trial data, there was no consistent correlation between weight loss and improvement in sexual function, as assessed by HSDD outcome measures. Nausea, a common adverse event associated with flibanserin use, also did not appear to be a contributing factor to weight loss. Hypothetical links between flibanserin treatment and weight loss include modulation of peripheral 5-HT_2A receptors and factors such as improved mood and improved sleep.

Conclusion

Mechanisms of flibanserin-induced weight loss have not been well characterized but may involve indirect beneficial effects on peripheral 5-HT_2A receptors and central regulation of mood and sleep. Future research may better elucidate the links between sexual function and weight management and the mechanism(s) by which flibanserin use may result in weight loss.

Simon JA, Kingsberg SA, Goldstein I, et al. Weight Loss in Women Taking Flibanserin for Hypoactive Sexual Desire Disorder (HSDD): Insights into Potential Mechanisms. Sex Med Rev 2019;7:575–586.