Female Sexual Function and Dysfunction

Chapter 12. Female Sexual Dysfunction in Alcohol and Drug Abuse

Marina Ziche

12.1 Introduction

Sexual dysfunction is a very common problem that affects many men and women in their lifetime, but, unfortunately, this condition remains a largely unexplored field in medicine and pharmacology. The incidence of this condition is more prevalent in women (40-45 %) than in men (20-30 %) [28]. Research suggests that the majority of women experience sexual dysfunction at some point in their lives, and for many it is an ongoing or recurring issue.

Female sexual dysfunction has many causes, related to physiological, psychological, and pharmacological events. At present, in women sexual dysfunction consists of four recognized disorders with the following symptoms [5]:

(a) Hypoactive sexual desire disorder (HSDD, decreased arousal and sexual aversion)

(b) Female sexual arousal disorder (FSAD, decreased arousal and/or arousal problems)

(c) Orgasmic disorder (difficulty or inability to achieve orgasm)

(d) Sexual pain disorder

A woman can have more than one of these problems and can actually move between the four recognized disorders, making diagnosis and treatment a challenge. The two subtypes of female sexual dysfunctions that have been the focus of pharmacological research are FSAD and HSDD. However, the incomplete knowledge and understanding of physiology and pathophysiology of human sexual function reduced the development of new drugs.

At physiological level, reduction of sexual desire has been related to dopamine imbalance, decreased sexual arousal to deficiencies in nitric oxide and acetylcholine pathways, and orgasmic disorders to changes in serotonin and norepinephrine levels. Hormonal changes occurring during menarche, menstrual cycling, pregnancy, lactation, the post-partum period, and the menopause also have a negative impact on sexual function. It is not therefore surprising that a decline in sexual arousal and desire are linked to the menopause; in fact physiological changes during menopause decrease tactile stimulation, decrease mucous secretions, and induce atrophy of reproductive organs. For these reasons, age has been proven to be a substantial risk factor for increased rates of female sexual dysfunction. However, very few studies outline the prevalence of sexual dysfunction with age. For example, the relationship between sexual pain prevalence and age appeared controversial, with some studies showing a direct relationship between age and pain prevalence and others suggesting that the relationship is inverse. Certainly, the prevalence of low “interest” and low desire in women appears to be age dependent. Lewis and coworkers outlined that low desire had a prevalence of 10 % in women up to 49 years of age and then increases to 22 % among the 50- to 65-year-old group [27].

At the pharmacological level, medical conditions, particularly those that affect the neurological, vascular, and endocrine systems, can result in female sexual dysfunction. Prescription drugs (e.g., antidepressants, as selective serotonin reuptake inhibitors), alcohol, tobacco, and illicit drugs (i.e., cocaine and heroin) contribute to sexual dysfunction. At present, the level of illicit drug use is about twice the rate for men compared to women; however, women tend to abuse drugs at an earlier age than males. In addition, the drug abuse in women is increasing, and the younger generation of women is more likely to try drugs than in the past years [15, 46]. Further, drug abuse and alcohol lead women to having unprotected sex and to being caught in a cycle of violence that are responsible of many sexual dysfunctions.

In conclusion, the incidence of sexual disorders in women is closely related to physiological and psychological/emotional characteristics, but also to socioeconomic status and drug and alcohol abuse.

12.2 Sex Differences in Drug Pharmacokinetics

Recently, a large number of evidences outline the differences between man and woman as regards to drug pharmacokinetics and pharmacodynamics [17, 29, 35]. Firstly, there are many physiological parameters that characterize men and women and that influence the drug fate in the body. As reported in Table 12.1, the body mass and the body surface area are higher in men than women, and other differences are clearly visible also in tissue mass (i.e., liver) and blood flow rate [29].

Second, there are substantial differences between men and women in all the pharmacokinetic steps driving drug activity (absorption, distribution, metabolism, and elimination) [17]. Changes in drug bioavailability will depend on the route of administration and absorption. As reported, gastrointestinal motility is affected by sexual hormones and the gastrointestinal emptying time is higher in women than in men [30, 40]. Similarly, the gastrointestinal proteins/enzymes responsible for drug transport and metabolism are different between men and women. Also drug distribution is influenced by sex, since the differences in body mass index, plasma volume, and plasma-binding protein influence drug bioavailability (Table 12.2) [45].

In addition, a great deal of new publications outlined gender differences in adverse drug reaction (ADR), since women have been reported to have a 1.5-1.7- fold greater risk than men in experiencing an ADR (Table 12.3) [31]. These events are linked to multiple factors including differences in several drug metabolizing enzymes as CYP3A [35], CYP1A2 [14], and CYP2D6 [47]. In fact, it is known that women have higher rates of CYP3A substrate metabolism compared with men [24, 43]. However, the fundamental biological differences in drug metabolism between sexes are poorly understood in molecular and cellular terms.

At last, there are sex differences in drug elimination with respect to renal drug clearance as a result of differences in blood flow [17].

Table 12.1 Physiological parameters that characterize men and women

	Male	Female
Mass (kg)	73	60
Height (cm)	176	163
Body surface area (m2)	1.90	1.66
Fat (kg)	14.6	18.0
Tissue mass (g, varies with age)
Liver	1.800	1.400
Lung	500	420
Kidneys	310	275
Fat (storage fat)	14.600	18.000
Blood flow rate (% cardiac output)
Liver	25.5	27
Kidneys	19	17
Fat	5.0	8.5
Skeletal muscle	17	12
Modified from Mattison [29]

Table 12.2 Sex differences in drug pharmacokinetics

Parameter	Physiologic difference	Pharmacokinetic impact
Gastric pH	Acidity M > F	Absorption
Gastric emptying	M > F	Absorption
Intestinal motility	M > F	Absorption
Body surface area	M > F	Absorption
Plasma volume	M > F	Distribution
Body mass index	M > F	Distribution
Total body water	M > F	Distribution
Body fat	F > M	Distribution
Plasma protein	M > F	Distribution

Modified from Mattison [29]

Table 12.3 Why women experience more ADR than men?

Factors	Explanation
Physiological and lifestyle factors	Women take more medications than men Women report ADR more often than men (reporting bias) Women are exposed to drugs in different ways to men (i.e., occupation or diet)
Pharmacokinetic differences	Dose recommendations are not sex specific Drug bioavailability is sex dependent Different tissue distribution between men and women Differences in metabolism (i.e., different CYP expression) Elimination rate might be different
Differences in pharmacodynamics	Differences in drug target Membrane phenomena (differences in membrane transport) Receptor pehomena (differences in receptor number and binding) Different interaction with macromolecules
Differences in hormones	Influence of sex hormones, especially estrogen effects

Modified from Mennecozzi et al. [31]

12.3 Antidepressants and Sexual Dysfunction

Antidepressants are prescription drugs that have been used effectively and appropriately to treat both medical and psychiatric illness in the vast majority of patients, but in the past years, rates of prescription abuse have escalated and have reached epidemic proportions. The use/abuse of antidepressant is very high, and, for example, in the USA, the National Center for Health Statistics (NCHS) reported that the rate of antidepressant use in this country among teens and adults (people ages 12 and older) increased by almost 400 % between 1988-1994 and 2005-2008 [38]. Concerning female use/abuse of antidepressant, data indicate that 23 % of women in their 40s and 50s take antidepressants, a higher percentage than any other group (by age or sex), and that women are 2/ times more likely to be taking an antidepressant than men. The different use of antidepressant depends also on women’s age (Fig. 12.1).

The reported incidence of sexual dysfunction associated with all the different classes of antidepressants varies between studies, but is very high (from 25 to 90 % depending on the studied compound). As shown in Table 12.4 perhaps all the antidepressants can induce sexual dysfunction.

All the drugs inhibit the breakdown of norepinephrine causing an increased neurotransmitter availability at the synapse. In addition, most antidepressants modulate the serotonin concentration, a well-known modulator of sexual function, since elevated serotonin levels diminish sexual functions. In the brain, serotoninergic nerve terminals interfere with dopamine and norepinephrine pathways blocking their activity. Similarly in the periphery, serotonin directly reduces sensation in the anatomical structure of the reproductive tract by diminishing vaginal lubrication and orgasm [22].

Fig. 12.1 Distribution of antidepressant drug users in the USA by age and sex [38]

Table 12.4 Antidepressants and female sexual dysfunction

Drug class	Medication	Mechanism of action	Prevalence and symptoms of female sexual dysfunction
TCAs	Amitriptyline, desipramine, doxepin, imipramine	Inhibition of serotonin and norepinephrine reuptake	Prevalence: 30 % Breast enlargement and decreased orgasm
SSRIs	Citalopram, escitalopram, fluoxetine, sertraline	Inhibition of serotonin reuptake	Prevalence: from 25 to 75 % Decreased libido and delayed or inability to reach orgasm
SNRIs	Duloxetine, venlafaxine	Inhibition of serotonin and norepinephrine reuptake	Prevalence: 58-70 % Delayed or absent orgasm
MAOIs	Phenelzine	Monoamine oxidase inhibitors	Prevalence 40 % Decreased libido, delayed orgasm
	Bupropion	Inhibition of serotonin, dopamine, and norepinephrine reuptake	Prevalence 10-25 %

Modified from [22]

12.4 Alcohol and Sexual Dysfunction

An association between chronic and high amount of alcohol consumption and sexual dysfunction has been widely reported [37]. Several clinical and experimental studies concluded that in male alcoholics, the greater quantity, frequency, and duration of drinking are associated with inhibited libido and retarded ejaculation. In alcohol-dependent women, the incidence of sexual dysfunction is very high when compared with nonalcoholic women [37], and the most common forms of sexual dysfunctions observed include dyspareunia, high rates of genitourinary problems, and low vaginal lubrication, revealing problems with sexual arousal [12, 41]. At present epidemiological data correlate gender prevalence of sexual dysfunction to alcohol abuse but, in general, women tend to be more vulnerable to alcohol-induced physical illness [8, 23] and display more severe cognitive and motor impairment with lower alcohol assumption when compared with men [33].

Barquin and colleagues in a recent paper showed the different effects of acute alcohol consumption in men and women. Fifteen minutes after drinking 95 ml of wine, almost half of the female participants had breath alcohol levels above the legal limit for driving in Europe. None of the males had levels above that limit. Over the time the women’s alcohol levels continued to remain higher than in men [4]. This is a simple example that clearly demonstrates the differences after alcohol assumption in women and men. Indeed, several studies have demonstrated gender differences in alcohol pharmacokinetics both in animal and human models [10, 42]. Women have higher and persistent blood alcohol levels when compared with men for a given dose indicating gender differences in drug bioavailability, linked to speed of gastric emptying, gastric enzyme activity, and first-pass metabolism [19]. In fact, the activity of gastric alcohol dehydrogenase (ADH) is lower in women than in men [18]. Moreover, also the alcohol distribution is different, being the alcohol volume of distribution lower in women than in men [3].

12.5 Tobacco and Sexual Dysfunction

Cigarette smoking is the most preventable cause of morbidity and premature mortality worldwide. Impairment in sexual functioning has also been reported as a consequence of long-term tobacco intake both in men and in women. Several reports indicate that tobacco is an independent risk factor for promoting erectile dysfunction in men, but limited research has investigated the link between sexual dysfunction and tobacco in women [7, 9, 36]. The pathological processes by which tobacco may affect physiological mechanisms underlying sexual function are not understood. Sexual arousal in men and women is a complex neurovascular event in which smooth muscle relaxation promotes arterial inflow to the genitals thereby facilitating vasocongestion [39]. Nitric oxide (NO), produced within endothelial cells, has been identified as the principal mediator of vascular events in men and the primary regulator of vaginal hemodynamics in women [6, 25], and several studies have clearly shown that smoking is associated with decreased NO in arteries and veins. For these reasons, investigators have proposed that free radicals and other compounds found within cigarettes may decrease the synthesis of NO directly, or indirectly, resulting in decreased genital vasoengorgement in men [13]. Harte and Meston, in two different works, studied the acute effects of isolated nicotine in nonsmoking men and women [20, 21]. They observed that nicotine significantly reduced physiological sexual arousal responses [20, 21]. In addition Diehl and colleagues, in a study on female sexual dysfunction associated with an history of drug abuse and smoking, showed that the sexual symptoms are primarily associated with high levels of nicotine dependence in respect to other drugs (i.e., cocaine, crack)

[11]. Considering that in women and men the hemodynamic processes of sexual arousal are similar and considering that NO isoforms have been shown to be present in genital epithelia of both men and women, smoking may affect physiological mechanisms underlying sexual arousal similarly in men and women. This may be the result of nicotine and/or particular tobacco compounds exerting their effects in the different ways: (a) centrally, by eliciting dose-dependent neurotransmitter and neuroendocrine effects; (b) peripherally, by acting as a sympathetic nervous system agonist; or (c) by disrupting NO synthesis directly or indirectly by targeting biochemical precursors.

12.6 Illicit Drug Abuse/Dependence and Sexual Dysfunction

Illicit drugs as cocaine, heroin, and cannabis have long been associated with sexual dysfunction although with not unequivocal data since cocaine, for example, facilitates sexual behavior directly through its acute pharmacological activity [2, 26, 32]. In fact, cocaine has a reputation as an aphrodisiac, and ends up having the reverse effect. It increases sexual desire while impairing or delaying orgasm. However, a symptom of heavy cocaine abuse is a massive decline in sex drive and activity. Chronic cocaine use can impair sexual function in men and women.

As for alcohol dependence, men are more likely to be cocaine dependent than women, but women have a more rapid progression of the illness and higher incidence of comorbid psychiatric disorders [34]. At this time very few studies have investigated sex differences in cocaine pharmacokinetics. Evans and Foltin, in a recent review, concluded that there are minimal sex differences in the pharmacokinetics of both smoked and intranasal cocaine administration, while these differences appear to be related to progesterone levels [16]. Chronic cocaine abuse is also associated with hyperprolactinemia and sexual dysfunction symptoms, such as diminished libido and difficulty reaching orgasm.

Among chronic heroin and morphine users, a review study noted decreases in sexual intercourse frequency, in the quality and frequency of orgasm and masturbation [41]. These effects are linked to opioid-induced inhibition of the hypothalamic- pituitary-gonadal axis and increase of prolactin levels, which affect both the male and female sexual response [2, 26].

Experimental studies, examining the effects of cannabis abuse on sexual function, have identified potential links between chronic cannabis smoking and inhibited orgasms [1, 44].

Conclusions

Sexuality is a complex phenomenon that is being influenced by psychological as well as physiological factors. Sexual dysfunctions, including desire, arousal, orgasmic, and sex pain disorders, are coordinated by neurologic, vascular, and endocrine systems. The incidence of sexual disorders in women is higher than in men and previous studies indicated that about 76 % of women experience sexual disorders. In particular it is clear that drug abuse, including alcohol consumption and smoking, affects women sexuality; however, the knowledge about association between sexual dysfunction and substance abuse remains largely unexplored.

Physiological/anatomical and genetic differences between men and women may partially account for the higher incidence of sexual dysfunction in women abusing of illicit drugs or alcohol or smoking; however, psychological/emotional and sociocultural differences among women make it difficult to clearly correlate substance abuse with sexual dysfunction.

Although the focus on gender is relatively new in medicine and pharmacology, it is now well known that gender’s impact is complex and far to be reached. A broad and detailed picture of gender-related sexual dysfunctions, linked to drug abuse/ misuse, tobacco, or alcohol, can lead to improvements in prevention efforts that bring us closer to the goal of gender-specific interventions.

References

1. Aversa A, Rossi F, Francomano D, et al. Early endothelial dysfunction as a marker of vasculo- genic erectile dysfunction in young habitual cannabis users. Int J Impot Res. 2008;20(6): 566-73.

2. Bang-Ping J. Sexual dysfunction in men who abuse illicit drugs: a preliminary report. J Sex Med. 2009;6(4):1072-80.

3. Baraona E, Abittan CS, Dohmen K, et al. Gender differences in pharmacokinetics of alcohol. Alcohol Clin Exp Res. 2001;25(4):502-7.

4. Barquin J, Luna Jde D, Hernandez AF. A controlled study of the time-course of breath alcohol concentration after moderate ingestion of ethanol following a social drinking session. Forensic Sci Int. 2008;177(2-3):140-5.

5. Basson R, Berman J, Burnett A, et al. Report of the international consensus development conference on female sexual dysfunction: definitions and classifications. J Urol. 2000;163(3): 888-93.

6. Burnett AL, Lowenstein CJ, Bredt DS, et al. Nitric oxide: a physiologic mediator of penile erection. Science. 1992;257(5068):401-3.

7. Cayan S, Akbay E, Bozlu M, et al. The prevalence of female sexual dysfunction and potential risk factors that may impair sexual function in Turkish women. Urol Int. 2004;72(1):52-7.

8. Ceylan-Isik AF, McBride SM, Ren J. Sex difference in alcoholism: who is at a greater risk for development of alcoholic complication? Life Sci. 2010;87(5-6):133-8.

9. Christensen BS, Gr0nbaek M, Pedersen BV, et al. Associations of unhealthy lifestyle factors with sexual inactivity and sexual dysfunctions in Denmark. J Sex Med. 2011;8(7):1903-16.

10. Crippens D, White ML, George MA, et al. Gender differences in blood levels, but not brain levels, of ethanol in rats. Alcohol Clin Exp Res. 1999;23(3):414-20.

11. Diehl A, Lopes da Silva R, Laranjeira R. Female sexual dysfunction in patient with substance- related disorders. Clinics (San Paulo). 2013;68(2):205-11.

12. Diçsiz M, Oskay UY, Beji NK. Use of alcoholic beverages and other psychoactive substances among women in Turkey: medical, biological, and social consequences. A pilot study. Subst Use Misuse. 2010;45(7-8):1060-76.

13. Elhanbly S, Abdel-Gaber S, Fathy H, et al. Erectile dysfunction in smokers: a penile dynamic and vascular study. J Androl. 2004;25(6):991-5.

14. Ereshefsky L, Saklad SR, Watanabe MD, et al. Thiothixene pharmacokinetic interactions: a study of hepatic enzyme inducers, clearance inhibitors, and demographic variables. J Clin Psychopharmacol. 1991;11(5):296-301.

15. European monitoring center for drug and drug addiction, annual report 2006.

16. Evans SM, Foltin RW. Does the response to cocaine differ as a function of sex or hormonal status in human and non-human primates? Horm Behav. 2010;58(1):13-21.

17. Franconi F, Brunelleschi S, Steardo L, et al. Gender differences in drug responses. Pharmacol Res. 2007;55(2):81-95.

18. Frezza M, di Padova C, Pozzato G, et al. High blood alcohol levels in women. The role of decreased gastric alcohol dehydrogenase activity and first-pass metabolism. N Engl J Med. 1990;322(2):95-9. Erratum in: N Engl J Med 1990 323(8):553. N Engl J Med 1990 322(21):1540.

19. Graziani M, Nencini P, Nistico R. Genders and the concurrent use of cocaine and alcohol: pharmacological aspects. Pharmacol Res. 2014;87:60-70.

20. Harte CB, Meston CM. Acute effects of nicotine on physiological and subjective sexual arousal in nonsmoking men: a randomized, double-blind, placebo-controlled trial. J Sex Med. 2008;5(1):110-21. Erratum in: J Sex Med. 2010 7(11):3803.

21. Harte CB, Meston CM. The inhibitory effects of nicotine on physiological sexual arousal in nonsmoking women: results from a randomized, double-blind, placebo-controlled, cross-over trial. J Sex Med. 2008;5:1184-97. Erratum in: J Sex Med. 2010 7(11):3803.

22. Higgins A, Nash M, Lynch A. Antidepressant-associated sexual dysfunction: impact, effects, and treatment. Drug Healthc Patient Saf. 2010;2:141-50.

23. Hommer D, Momenan R, Kaiser E, et al. Evidence for a gender-related effect of alcoholism on brain volumes. Am J Psychiatry. 2001;158(2):198-204.

24. Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol. 1992;44(2):275-83.

25. Kim SW, Jeong SJ, Munarriz R, et al. Role of the nitric oxide-cyclic GMP pathway in regulation of vaginal blood flow. Int J Impot Res. 2003;5(5):355-61.

26. Kopetz CE, Reynolds EK, Hart CL, et al. Social context and perceived effects of drugs on sexual behavior among individuals who use both heroin and cocaine. Exp Clin Psychopharmacol. 2010;18(3):214-20.

27. Lewis RW, Fugl-Meyer KS, Bosch R, et al. Epidemiology/risk factors of sexual dysfunction. J Sex Med. 2004;1(1):35-9.

28. Lewis RW, Fugl-Meyer KS, Corona G, et al. Definitions/epidemiology/risk factors for sexual dysfunction. J Sex Med. 2010;7(4 Pt 2):1598-607.

29. Mattison DR. Pharmacokinetics in real life: sex and gender differences. J Popul Ther Clin Pharmacol. 2013;20(3):e340-9.

30. Mearadji B, Penning C, Vu MK, et al. Influence of gender on proximal gastric motor and sensory function. Am J Gastroenterol. 2001;96(7):2066-73.

31. Mennecozzi M, Landesmann B, Palosaari T, et al. Sex differences in liver toxicity-do female and male human primary hepatocytes react differently to toxicants in vitro? PLoS One. 2015;10(4):e0122786.

32. Mialon A, Berchtold A, Michaud PA, et al. Sexual dysfunctions among young men: prevalence and associated factors. J Adolesc Health. 2012;51(1):25-31.

33. Miller MA, Weafer J, Fillmore MT. Gender differences in alcohol impairment of simulated driving performance and driving-related skills. Alcohol Alcohol. 2009;44(6):586-93.

34. Najavits LM, Lester KM. Gender differences in cocaine dependence. Drug Alcohol Depend. 2008;97(1-2):190-4.

35. Nicolson TJ, Mellor HR, Roberts RR. Gender differences in drug toxicity. Trends Pharmacol Sci. 2010;31(3):108-14.

36. Oksuz E, Malhan S. Prevalence and risk factors for female sexual dysfunction in Turkish women. J Urol. 2006;75(2):654-8.

37. Peugh J, Belenko S. Alcohol, drugs and sexual function: a review. J Psychoactive Drugs. 2001;33(3):223-32.

38. Pratt LA, Brody DJ, Qiuping GU. Antidepressant use in person aged 12 and over: United states, 2005-2008. NCHS data brief 76. Hyattsville: U.S. Dept. of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics; 2011.

39. Rosen RC, McKenna KE. PDE-5 inhibition and sexual response: pharmacological mechanisms and clinical outcomes. Annu Rev Sex Res. 2002;13:36-88.

40. Sadik R, Abrahamsson H, Stotzer PO. Gender differences in gut transit shown with a newly developed radiological procedure. Scand J Gastroenterol. 2003;38(1):36-42.

41. Saso L. Effects of drug abuse on sexual response. Ann Ist Super Sanita. 2002;38(3):289-96.

42. Sato N, Lindros KO, Baraona E, et al. Sex difference in alcohol-related organ injury. Alcohol Clin Exp Res. 2001;25(5 Suppl ISBRA):40S-5.

43. Schmidt R, Baumann F, Hanschmann H, et al. Gender difference in ifosfamide metabolism by human liver microsomes. Eur J Drug Metab Pharmacokinet. 2001;26(3):193-200.

44. Shamloul R, Bella AJ. Impact of cannabis use on male sexual health. J Sex Med. 2011;8(4):971-5.

45. Soldin OP, Mattison DR. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2009;48(3):143-57.

46. Stengel C, Fleetwood J. GDPO, global drug policy observatory. 2004.

47. Walle T, Walle UK, Cowart TD, et al. Pathway-selective sex differences in the metabolic clearance of propranolol in human subjects. Clin Pharmacol Ther. 1989;46(3):257-63.