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SOCIETY STATEMENT

Hormonal Contraception and Female Sexuality: Position Statements from the European Society of Sexual (ESSM)

Stephanie Both, MD,1 Michal Lew-Starowicz, MD, PhD,2 Mijal Luria, MD,3 Gideon Sartorius, MD,4,5 Elisa Maseroli, MD,6 Francesca Tripodi, PsyD,7 Lior Lowenstein, MD,8,9 Rossella E. Nappi, MD, PhD,10 Giovanni Corona, MD, PhD,11 Yacov Reisman, MD, PhD,12 and Linda Vignozzi, MD, PhD6

ABSTRACT

Introduction: is available worldwide in many different forms. Fear of side effects and health concerns are among the main reasons for not using contraceptives or discontinuing their use. Although the safety and efficacy of contraceptives have been extensively examined, little is known about their impact on female sexual function, and the evidence on the topic is controversial. Aim: To review the available evidence about the effects of hormonal contraceptives on female sexuality in order to provide a position statement and clinical practice recommendations on behalf of the European Society of . Methods: A comprehensive review of the literature was performed. Main Outcome Measure: Several aspects of female sexuality have been investigated, including desire, orgasmic function, lubrication and vulvovaginal symptoms, pelvic floor and urological symptoms, partner preference, and relationship and sexual satisfaction. For each topic, data were analyzed according to the different types of hormonal contraceptives (combined -progestin methods, progestin-only methods, and oral or non-oral options). Results: Recommendations according to the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence criteria and specific statements on this topic, summarizing the European Society of Sexual Medicine position, were developed. Clinical Implications: There is not enough evidence to draw a clear algorithm for the management of hormonal contraception-induced , and further studies are warranted before conclusions can be drawn. A careful baseline psychological, sexual, and relational assessment is necessary for the health care provider to evaluate eventual effects of hormonal contraceptives at follow-up. Strengths & Limitations: All studies have been evaluated by a panel of experts who have provided recom- mendations for clinical practice. Conclusion: The effects of hormonal contraceptives on sexual function have not been well studied and remain controversial. Available evidence indicates that a minority of women experience a change in sexual functioning with regard to general sexual response, desire, lubrication, , and relationship satisfaction. The patho- physiological mechanisms leading to reported sexual difficulties such as reduced desire and vulvovaginal atrophy remain unclear. Insufficient evidence is available on the correlation between hormonal contraceptives and pelvic

Received June 10, 2019. Accepted August 2, 2019. 8Department of Obstetrics and Gynecology, Rambam Health Care Campus, 1Outpatient Clinic of Psychosomatic Gynecology and , Leiden Haifa, Israel; University Medical Centre, Leiden, the Netherlands; 9Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel; 2Department of Psychiatry, Centre of Postgraduate Medical Education, 10Research Center for , Gynecological Endocrinology Warsaw, Poland; and , Obstetrics and Gynecology Unit, IRCCS S. Matteo 3Center for Sexual Health, Department of Obstetrics and Gynecology, Foundation, Department of Clinical, Surgical, Diagnostic and Paediatric Hadassah University Hospital, Jerusalem, Israel; Sciences, University of Pavia, Pavia, ; 11 4Department of Obstetrics and Gynecology, University Hospital, Basel, Endocrinology Unit, Medical Department, Azienda Usl di Bologna, Switzerland; Maggiore-Bellaria Hospital, Bologna, Italy; 12 5Fertisuisse, Olten and Basel, Switzerland; Ziekenhuis Amstelland, Department of , Amsterdam, the Netherlands 6Andrology, Women’s Endocrinology and Gender Incongruence Unit, ª Department of Experimental and Clinical Biomedical Sciences “Mario Copyright 2019, International Society for Sexual Medicine. Published by Serio,” University of Florence, Florence, Italy; Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jsxm.2019.08.005 7Institute of Clinical Sexology, Rome, Italy;

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floor function and urological symptoms. Both S, Lew-Starowicz M, Luria M, et al. Hormonal Contraception and Female Sexuality: Position Statements from the European Society of Sexual Medicine (ESSM). J Sex Med 2019;16:1681e1695.

Copyright 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. Key Words: Hormonal Contraception; Female Sexual Dysfunction; ; Vulvovaginal Atrophy; Oral Contraceptives;

INTRODUCTION in order to provide a position statement and recommendations The development of modern forms of contraception had a for clinical practice on behalf of the European Society of Sexual major social, economic, and political impact by empowering Medicine. women to take greater control over . In partic- ular, development of the contraceptive pill and the “sexual rev- METHODS olution” that followed broadened the availability of A comprehensive search conducted on the main medical contraception in industrialized countries and led to the separa- database included studies up to July 30, 2018. The statements tion of sexuality from procreation. This development changed were internally discussed, and levels of evidence were provided our perspectives on sex and the values linked to sexuality beyond according to the Oxford 2011 Levels of Evidence criteria reproduction, such as emotional and physical pleasure, intimacy, (https://www.cebm.net/2009/06/oxford-centre-evidence-based- and bonding. Within the last decades, an increasing variety of medicine-levels-evidence-march-2009); moreover, the quality of contraceptive options have been developed, and women can now evidence was graded applying the Oxford Centre for Evidence- select the most appropriate method for their individual situa- Based Medicine recommendations. tions, as needs and preferences change from woman to woman across the reproductive life span. A skilled approach that includes shared decision making in the selection of optimal contraceptive RESULTS methods not only improves patient satisfaction but also might Hormonal Contraceptives and Sexual Function: fi optimize contraceptive ef cacy by fostering correct use of a Potential Mechanisms of Action 1 contraceptive agent. Statement #1. Hormonal contraceptives can positively affect There is a huge discrepancy among countries in the use of sexuality by different means, including (i) overcoming fear of modern methods of contraception, including barrier methods, unwanted during sexual activity, (ii) resolution of , injections, implants, intrauterine devices (IUDs), painful or troublesome gynecologic disorders such as endome- and oral contraceptives. Rates vary from 1.7% in South Sudan to triosis and , and (iii) reduction of body image 81.6% in Finland, with the majority of industrialized countries concerns with an increase in self-esteem for women with clinical having rates of use of about 60e75% in women of reproductive hyperandrogenism (eg, acne, hirsutism) (Level 4; Grade C). e 2 age (15 49 years) who are married or in a stable relationship. Statement #2. All available combined HCs reduce Among hormonal contraceptives (HCs), the most commonly levels regardless of estrogen dosage and progestin type (Level 2; used in European countries are short-acting reversible contra- Grade B). ceptives, including combined oral contraceptives (COCs), the Statement #3. Combined oral contraceptives, transdermal patch, and the , followed by long-acting reversible patches, and vaginal rings showed a similar effect in increasing contraceptives, such as (LNG) or copper IUDs binding globulin (SHBG) levels and in reducing and implants.2 levels (Level 2; Grade B). Despite good health education and the availability of contra- ceptives, it is estimated that around 34% and 54% of pregnan- Evidence cies in Western and Eastern , respectively, are currently 3 HCs can positively affect sexuality by different means, unintended. Women who neither desire pregnancy nor use including (i) overcoming fear of unwanted pregnancy during contraception report that a fear of side effects and health con- sexual activity; (ii) resolution of painful or troublesome gyne- cerns are among the main reasons for not using them or dis- 4 cologic disorders, such as , dysmenorrhea, menor- continuing their use. In the last decades, extensive literature has rhagia, and menometrorrhagia; and (iii) reduction of body image fi examined the safety and ef cacy of contraceptives, but surpris- concerns with an increase in self-esteem for women with clinical ingly little is known about the impact of HCs on female sexual hyperandrogenism (eg, acne, hirsutism).5 On the other hand, function, and available evidence on the topic is controversial. concerns about the negative sexual impact of HCs have been The aim of the present study is to review the available evidence expressed ever since they have become commercially available, about the effects of hormonal contraceptives on female sexuality with reports of detrimental effects on desire, arousal, lubrication,

J Sex Med 2019;16:1681e1695 Hormonal Contraception and Female Sexuality: ESSM Position Statements 1683 and orgasm.6,7 These potential negative effects are hypothesized Types of Hormonal Contraception to be due to central effects in different brain regions, including Combined Estrogen-Progestin Methods the mediobasal hypothalamus and the arcuate nucleus, where sex CHCs have a progestogenic and an estrogenic component. might alter the complex interplay between neurotrans- Both components act on hypothalamic and pituitary levels and mitters and neuropeptides.8 Other effects are attributed to lead to an inhibition of folliculogenesis, , and endo- peripheral changes of sex steroids—for example, the reduced metrial maturation. An additional contraceptive effect results serum concentration in or reduction in non-bound from modification of the cervical , which becomes thick androgens due to the estrogen-induced increase in binding and impervious to sperm transportation.15 Over the years, con- globulins as SHBG.9 Reduced concentrations of estrogens and traceptives have evolved to include gradual lowering of estrogen androgens can lead to reduced activation of sex receptors doses and the introduction of new formulations. Most CHCs in peripheral tissues, which might lead, for example, to vulvo- available today are manufactured with 15e35 mg of ethinyl vaginal atrophy (VVA) in the case of a relative estrogen defi- (EE) or 1.5e2mgof17b-estradiol (E2), combined ciency, whereas the peripheral effects of reduced androgen with one of several synthetic progestational agents that vary in concentrations remain controversial.7 their potency, affinity for steroid receptors, interaction with es- It is widely accepted that the female sexual response is a result trogens, and physiological effects.16 Older progestins derived of the complex interaction among psychological, relational, and from (eg, norethindrone, levonorgestrel) are associ- organic factors, including anatomical, neurological, and hor- ated with androgenic side effects. Newer progestins with higher monal factors. Sexual hormones elicit important actions on both specificity derived from and (eg, the central nervous system and genital tissues, targeting the acetate or ) have a partial anti- molecular mechanisms implicated in sexual desire, orgasm, and androgenic effect (Table 1).17 Three types of CHCs are currently 10 satisfaction and in , respectively. The sex steroid available: combined oral contraceptives, the transdermal patch, ’ milieu changes during a woman s life, as it is modulated by and the vaginal ring. puberty, phases, postpartum periods, meno- pause, and, no less importantly, contraception. Indeed, due to Oral Contraceptives their primary mechanism of action, most HCs dramatically Combined oral contraceptives are categorized as monophasic fl depress ovulatory uctuations of all sex steroids (estradiol, or multiphasic, depending on the different levels of hormones testosterone, and progesterone), so that their endogenous levels contained in each pill per cycle phase. COCs suppress ovarian remain constantly similar to those physiologically detected in the 11 biosynthesis of the testosterone precursor and early follicular phase of normally cycling women. Moreover, testosterone, such that women taking COCs will experience a the evolution of HCs led to a progressive reduction of ethinyl reduction in their total endogenous testosterone production. estradiol content in order to reduce the risk of side effects, but a COCs also reduce free androgen levels by increasing levels of price was paid for the clinical consequences of hypoestrogen- 13 12 SHBG, a carrier protein synthesized by the . Around ism. In addition, the estrogen component of combined HCs 65e70% of circulating testosterone is bound and therefore (CHCs) leads to increased hepatic production of SHBG, which 13 13 temporarily inactivated by SHBG and other binding proteins, in turn leads to decreased levels of free testosterone. Testos- such as albumin, until unbinding. However, the free hormone terone is well known to be a pivotal positive modulator of male hypothesis, according to which only the unbound or free frac- sexuality; it seems to play also a role in female sexuality, albeit less tion of the sex steroid is biologically active in target tissues, has fi well de ned, as shown in women with surgically induced been debated extensively.18 Indeed, the dynamics of testos- menopause and reduced sex drive who show an increase in sexual terone binding to SHBG and albumin are poorly understood, interest and activity after supplementation of transdermal fi 14 resulting in oversimpli ed and inaccurate linear binding testosterone. Therefore, it has been acknowledged that models.18 For this and other reasons, the clinical significance of fi androgen de ciency might be related to negative mood and the free testosterone fraction has been questioned (see Goldman sexual side effects of CHCs. et al18 for a review). Estrogen increases SHBG, and this can be enhanced or reduced Remarks by adding progestins, depending on their androgenic or anti- The impact of contraception on female sexual function is androgenic properties.19 Progestins with androgenic activity complex and still inadequately studied. Women and their health induce a less pronounced increase in SHBG, whereas those with care providers are attributing greater importance to sexual health, antiandrogenic activity lead to higher SHBG levels (Table 1).13 which includes sexual well-being and self-fulfillment and goes SHBG levels may not decrease to values consistent with women beyond having intercourse without the fear of conception. This who have never used COCs, even 6 months after COC discon- shapes awareness for an optimized, personalized selection of tinuation.20 COCs containing second-generation progestins contraceptive means that balance the advantages and side effects ( and levonorgestrel) and/or the lower estrogen doses of specific methods. (20e25 mg EE) have the least impact on SHBG concentrations.13

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Table 1. Synthetic progestins according to their structure and activities17 Progestin Progestogenic activity Androgenic activity Antiandrogenic activity

Cyproterone acetate þ e þþ Drospirenone þ e þ þ e þ þ e þ þ e ± acetate þ e ± Nestorone þ ee acetate þ ± e þþe Levonorgestrel þþe þþe þþe þþe

Nevertheless, the COC estrogen dose and progestin type do not CHC transdermal patch and the vaginal ring showed a similar significantly influence the decrease of circulating total testosterone effect in increasing SHBG levels.31 and free testosterone levels as much as they increase SHBG con- centrations. Furthermore, it is uncertain whether the reduction in Progestin-Only Contraceptives the free testosterone fraction that occurs in women who have an Progestin-only contraceptives (POCs) are appropriate for increase in SHBG is clinically important.21 many women who cannot or should not take estrogen.32 Four In summary, the clinical implications of suppressed total types of POCs are currently available: progestin-only injectable and/or free androgen levels during COC use are still a matter of contraceptives, progestin-only pills (POPs), progestin-only debate. Aside from some cohort studies,22,23 only a single ran- implants, and an IUD containing levonorgestrel. Progestin- domized (RCT) in patients with COC-associated only injectables (containing medroxyprogesterone acetate or female sexual dysfunction (FSD) has evaluated the effect of ) are administered approximately every switching to a COC containing either antiandrogenic or 3 months. They prevent pregnancy through ovulation suppres- androgenic progestins.24 Although both groups showed sion, inhibition of endometrial activity, and thickening of cer- 33,34 fi improvement of sexual function, no difference was observed vical mucus. POPs and implants are highly ef cacious between antiandrogenic or androgenic progestins.24 through similar mechanisms, although they block ovulation in only 60e80% of cycles.35 POPs contain norethindrone (also Non-Oral Options known as norethisterone), levonorgestrel, or desogestrel and Non-oral administration of EE offers less variability in should be taken daily without interruption and at the same time ± fi plasma concentrations of estrogen. The transdermal patch re- each day ( 3 hours). The desogestrel pill is more ef cacious in leases 35 mg EE and 150 mg (active metabolite suppressing ovulation than other POPs and has to be taken daily of norgestimate) per day. Although the transdermal patch was with a maximum delay of 12 hours. A new POP containing 4 mg designed to deliver a low daily dose of EE, a study comparing drospirenone has been developed with a 24/4 intake regimen, serum EE levels in women using the patch, the ring, or a 30-mg and it will become available soon. EE COC found that the EE mean concentration in the patch Implants contain either levonorgestrel or etonogestrel, a group was 3.4 times higher than in the ring group and 1.6 desogestrel derivative, and last 3 to 5 years. The levonorgestrel- timeshigherthanintheCOCgroup.25 Two new patches with containing IUD (LNG-IUD) prevents fertilization, thickens lower estrogen exposure and different progestins are being cervical mucus, and thins the .36 LNG-IUDs are developed, but their availability is not yet widespread.26,27 The available in 3 different doses: 52 mg, 19.5 mg, and 13.5 mg. vaginal ring releases 15 mgEEand120mgetonogestrelperday. The 52-mg LNG-IUD is also used to treat menstrual-related Several new developments, such as estrogen-free rings and dual- disorders such as menorrhagia and dysmenorrhea and to treat protection rings that will protect against sexually transmitted atypical .34 After IUD insertion, plasma infections as well as pregnancy, are possible in the near concentrations of LNG range between a mean concentration of future.28 It has been postulated that estrogens provided by a 166 and 131 pg/mL for the first 18 months of use and between parenteral route avoid first-pass metabolism, resulting in a 101and74pg/mLat24to60months.37 Thus, low- different proteinemic and lipemic response,29 but this concentration LNG-IUDs do not suppress ovulation and hypothesis has not yet been confirmed.30 In fact, both the ovarian function but can exert systemic effects. A recent report

J Sex Med 2019;16:1681e1695 Hormonal Contraception and Female Sexuality: ESSM Position Statements 1685 suggested that LNG-IUDs might cause emotional lability by pleasure scores in COC users compared to placebo were sensitization of the hypothalamic-pituitary-adrenal axis observed, with a small effect size.51 COC users showed a sig- responsivity.38 nificant reduction in total and free testosterone, but no sig- fi Most women will experience irregular bleeding patterns dur- ni cant correlation with changes in sexual function was 51 ing the first year of progestin-only contraceptive use, although found. this irregularity declines over time.39 Similar to other side effects In a systematic review of 36 studies (prospective and retro- such as acne or breast tenderness, this might have an impact on spective, controlled and uncontrolled), published between 1975 sexual behavior. Weight gain as a side effect of POCs has been and 2011 and involving more than 13,000 women, Pastor et al54 debated.40,41 An increased likelihood of mood disorders for POC found that 21.7% of the COC users reported an increase, users has been disputed, as well.42,43 SHBG levels decreased 63.6% no change, and 14.7% a decrease in sexual desire. Of the slightly during oral LNG contraception, which might be in part 18 studies that reported the impact of COCs on hormone levels, responsible for an increased risk for the occurrence of acne. The 15 confirmed elevated SHBG and a decrease in free testos- SHBG decrease was not observed during use of the LNG-IUD.44 terone.54 However, examination of the sample of women However, a cross-sectional study that enrolled 402 women who showing reduced levels of free testosterone showed that in 20% a used IUDs (353 women were LNG-IUD users and 49 were decrease in sexual desire was observed and in 80% sexual desire copper IUD users) demonstrated that sexual symptoms in was unchanged or increased.54 The authors conclude that, women using a LNG-IUD did not differ from those of women although COCs were found to reduce free testosterone, a clear wearing a copper IUD.45 The impact of IUD use on sexuality effect on sexual desire was not confirmed.54 As supported by should not be overestimated. Graham et al,55 these findings might indicate that some women are more sensitive to changes in testosterone than others. Hormonal Contraception and Sexual Desire A few studies examined whether a COC with lower hypoan- Sexual desire, also termed “sexual interest,” is considered to be drogenic activity or the addition of androgen to COCs can the result of a complex interplay of physical, cognitive, counteract the negative effects of COCs on testosterone levels emotional, and interpersonal factors.46,47 Hormonal contracep- and sexual desire. Some low-quality, uncontrolled prospective tion, as a highly effective form of contraception, likely has a studies indicated that, in women with complaints of COC- positive effect on sexual desire through the removal of the fear of associated low sexual desire, a switch to a COC with lower pregnancy.48 However, because hormonal contraceptives directly hypoandrogenic activity (17b-estradiol/nomegestrol) resulted in impact levels of hormones that are implicated in sexual function decreased SHBG, increased free testosterone, increased sexual and possibly mood, they may also have positive or negative desire, and increased intercourse and self-stimulation fre- e 56 24 effects via central mechanisms.49 52 quency. However, in a recent RCT, Davis et al observed improved sexual desire in women with COC-associated sexual dysfunction when switching to either an antiandrogenic (estra- Combined Oral Contraceptives diol valerate/dienogest) or androgenic progestin (EE/levonor- Statement #4. In the vast majority of the cases, the use of gestrel)-containing COC, challenging the idea that switching to COCs resulted in an increase or no change in sexual desire (Level an androgenic progestin is needed to improve sexual function. 2; Grade B). The authors suggested that the overall effect of a COC on sexual function is likely to reflect a balance between the androgenicity Evidence of the progestin and the impact on SHBG; moreover, a placebo Very few placebo-controlled randomized trials have been effect of changing COC cannot be ruled out.24 conducted. Graham and Sherwin50 investigated the effects of a COC (EE/norethindrone) on mood and sexual interest in 45 A recent study tested the effects of adding dehydroepian- drosterone during COC use.57 Compared to baseline, use of the women with premenstrual complaints and found a decrease in 57 sexual interest in the COC group after 3 months of use but an COC resulted in lower sexual desire and activity diary ratings. There was a small positive effect of the improvement in mood. In a second study, the effects of com- — bined and progestin-only oral contraceptives on well-being and addition in only 1 item of the diary namely, less rejection of partner-initiated sex—and no effects were observed on Female sexuality were assessed in a cohort of women who had been 57 sterilized or whose partners had been vasectomized.53 One Sexual Function Index (FSFI) scores. hundred-fifty women were randomly assigned to a COC Remarks (EE/norethindrone), a progestin-only pill (levonorgestrel), or Whether decreased sexual desire is related to COC-associated placebo. Assessment after 4 months showed a negative effect of reductions in testosterone is not clear, because in general no COCs, but not of the progestin-only pill, on sexuality and significant correlations between changes in testosterone or free especially on sexual interest.53 InamorerecentRCTin340 testosterone and changes in sexual desire were observed. How- women receiving a COC (EE/levonorgestrel) or placebo for ever, it may be possible that some women are more sensitive to 3months,significantly lower sexual desire, arousal, and reductions in testosterone.

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Non-Oral Hormonal Contraceptives HCs can have a potential negative impact on other crucial Statement #5. Studies on the effects of non-oral forms of aspects of sexual functioning, such as orgasm and pleasure. Some hormonal contraception are scarce, precluding definite authors have hypothesized that the use of contraceptives, which conclusions. can make the couple feel protected from the risk of pregnancy, increases the chances of engaging in penile-vaginal intercourse, Evidence with less time spent on or other sexual activities; this Global improvement in sexual function among vaginal ring may be perceived as less sexually arousing by some women and users compared to controls or to pre-use assessment has been lead to orgasmic disorders.7 In turn, fewer and decreased e reported.58 60 Some studies report stronger sexual desire in pleasure could be responsible for perpetuating a cycle of pro- women using a ring compared to women using COCs,61,62 but gressively less interest in sex. Furthermore, women who use HCs others report the reverse.63 In a randomized trial, increased with the aim of pleasing their partner—for example, because he SHBG, decreased testosterone, and diminished sexual function feels uncomfortable with barrier methods—can experience an were observed in the vaginal ring and COC group, with the emotional burden on their sexual life that can affect orgasmic COC group showing a stronger decrease in intercourse fre- function. quency.64 An open-label randomized trial comparing sexual function in those using a vaginal ring vs patch did not note any Evidence significant difference in the FSFI desire domain with either ring A large study performed on 1,101 women taking part in an or patch use.65 Studies on the effect of depot medrox- online health and sexuality survey found that women using yprogesterone acetate (DMPA) in adolescents showed no changes hormonal contraception were more likely to report lower sexual in sexual interest compared to COC users or nonusers of hor- pleasure and less frequent orgasms than women using non- monal contraception.66,67 One study observed lower free hormonal methods.7 In a prospective study of 22 eumenor- testosterone in COC users compared to DMPA users but no rheic, healthy women taking a COC (30 mg EE and 3 mg difference in sexual desire.68 drospirenone), a significant decrease in the McCoy Female Some studies report that hormonal IUDs are associated with Sexuality Questionnaire score and a reduction in the frequency greater sexual desire compared to copper IUDs,69 but others of orgasm during intercourse were found after 3 months of 74 report no difference in the sexual effects of either IUD.45 In a treatment. Similar results were obtained in 2 studies on women 58,65 study comparing copper IUD, hormonal IUD, and use, using the patch or the ring. Secondary anorgasmia tempo- none of the groups showed significant changes in sexual function rally associated with etonogestrel implant insertion has also been 75 from baseline.70 Di Carlo et al71 observed no significant differ- reported. On the other hand, in a double-blind, randomized, ences in sexual desire after 6 months of implant use. In a large placebo-controlled trial on 340 healthy women randomized to study on contraceptive choice, almost 24% of the women re- treatment with a COC containing an androgenic progestin ported a lack of sexual interest following 6 months of using a new (30 mcg EE and levonorgestrel) or placebo for 3 months, only fi contraceptive method.72 Compared to copper IUD users, the Pro le of Female Sexual Function pleasure domain was fi DMPA, vaginal ring, or implant users more often reported a lack signi cantly reduced in the treated group, whereas orgasm did fi 51 of sexual interest, but there was no difference between copper not signi cantly change. IUD users and hormonal IUD, COC, or patch users.72 In a These data are not without contradiction. In separate studies, e study comparing women using an implant, COC, vaginal ring, Caruso et al76 78 prospectively assessed the impact of different or no hormonal contraception, no significant differences between COCs containing antiandrogenic progestins (monophasic 30 mg groups in testosterone or free testosterone levels were observed.73 EE and 3 mg drospirenone, monophasic 30 mg EE and 2 mg Women using the implant showed stronger sexual interest chlormadinone acetate, or 4-phasic and compared to the COC users.73 dienogest) on sexual behavior and observed an increase in sexual enjoyment and orgasm frequency. Finally, a multi-center cross- Remarks sectional study enrolling users of LNG-IUDs (n ¼ 353) and Studies on the effects of non-oral forms of hormonal contra- copper IUDs (n ¼ 49) reported that the prevalence of problems ception are scarce, precluding definite conclusions, but the out- with orgasm was comparable in both groups (7.1% vs 10.2%) comes do not point to differential effects of non-oral hormonal and comparable with the prevalence reported in the general contraception vs oral contraception on sexual desire. population.45

Hormonal Contraception and Orgasm Remarks Statement #6. HCs induce a reduction in orgasm frequency Large, well-powered, and well-designed RCTs are advisable to (Level 3; Grade C). The LNG-IUD does not seem to have an better characterize the role of hormonal contraception on impact on orgasmic function (Level 2; Grade C). orgasmic function.

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Hormonal Contraception and Lubrication antiandrogenic vs an androgenic progestin are compared (Level Statement #7. Good-quality data assessing the role of COCs 2; Grade C). on vaginal lubrication and symptoms of vulvovaginal atrophy are Statement #9. Other types of HCs (etonorgestrel implant, lacking, and no conclusion can be drawn. vaginal ring, and LNG-IUD) do not seem to have any negative effect on vulvovaginal morphology and lubrication (Level 3; Evidence Grade C). Reduced levels of estrogens commonly result in VVA, leading to sensitivity to touch, burning, itching, and dryness Evidence during sexual activity, as observed in menopause (also referred As stated before, it could be argued that not only the relative to as the genitourinary syndrome of menopause) and, to a lesser but also the associated decrease of circulating 79 extent, among HC users. Hypoandrogenism is also consid- free androgen levels typical of HCs may contribute to decreased 79 ered a pathogenic factor inducing or worsening VVA. Pre- vaginal lubrication and favor vestibulodynia. Preclinical and clinical and clinical studies have consistently shown that both clinical research supporting this aspect has already been reviewed hypoestrogenism and hypoandrogenism cause vulvovaginal elsewhere.79,80 Goldstein and colleagues89 reported that women epithelial alterations and that treatments with topical estrogens with COC-induced vestibulodynia were more likely to have 79e81 and/or androgens might counteract them. In this context, longer cytosine-adenine-guanine trinucleotide repeats in the some authors have suggested that COCs, particularly those androgen receptors, which may predispose them to vestibular m containing low-dose (20 g or less) EE, were associated with pain in the presence of low free testosterone. Moreover, recent morphological alterations of the vulvar vestibular mucosa, data have demonstrated that the erectile tissue of the leading to atrophy, secondary vulvar vestibulitis, and shares the same molecular relaxant and contractile pathways as 12,82e87 . the cavernous and spongy body in males and that androgens Accordingly, negative side effects of COCs on lubrication and positively modulate nitric-oxide-dependent relaxant machinery perceived peripheral arousability during sexual activity have been in clitoral vessels.90 In order to compare the sexual effects of reported. In 1996, a study on university women reported that COCs containing an antiandrogenic vs an androgenic progestin COC users were significantly more likely to complain of in women with COC-induced sexual dysfunction, Davis et al24 decreased lubrication than non-users.88 In a larger study per- performed a randomized, double-blind, non-inferiority trial. formed in the that involved more than 1,000 Interestingly, the authors reported that switching to both prep- sexually active women, researchers found that those who were arations resulted in equivalent improvements in sexual function, using HCs experienced significantly less arousal and unsatisfac- including FSFI lubrication scores and subjective symptoms of tory vaginal lubrication when compared to non-users.7 atrophy, whereas Vaginal Health Index scores for signs of atro- Furthermore, in a more recent prospective study on women phy did not show any change.24 Data on the effect of other types randomized to 2 different COCs (low and very-low EE dose) or of HCs on lubrication are scant. The etonorgestrel implant, the to the vaginal ring, COC use was associated with a significantly vaginal ring, and the LNG-IUD do not seem to have any higher prevalence of vaginal dryness than the vaginal ring (up to negative effect.60,71,91,92 In fact, a significant improvement in approximately 30% and 2% of women, respectively); however, FSFI arousal and lubrication scores has been reported in vaginal the prevalence significantly decreased by cycle 12.61 The authors ring users at second cycle vs baseline.59 hypothesized that the lower risk of vaginal dryness in vaginal ring users could be due to constant hormonal levels and local estrogen release.61 Battaglia and colleagues74 performed color Doppler Hormonal Contraception and Pelvic Floor and ultrasonography in 22 healthy women under baseline conditions Urological Symptoms and after 3-month treatment with a COC (30 mg EE and 3 mg Due to the same embryological origin, hormonal status in- fl drospirenone). They were able to determine that minora uences all the tissues in the pelvic region, including bladder, thickness and vaginal introitus area were decreased, but vascular urethra, and muscles. Epidemiological studies have implicated resistance indexes of clitoral and labial arteries increased. In the hypoestrogenism in the etiology of lower urinary tract symptoms, same study, COC use exacerbated dyspareunia and worsened such as frequency, urgency, incontinence, dysuria, and recurrent 93 spontaneous arousability.74 urinary tract infection. Ultrasonographic evaluation of women with and without polycystic ovary syndrome suggested a direct Remarks correlation between testosterone levels and the volume of ure- Large, well-powered, well-designed RCTs are advisable to throvaginal tissue.94 Androgens have also been reported to exert better characterize the role of COCs on lubrication and vulvo- an anabolic effect on pelvic floor musculature.95,96 vaginal symptoms. Statement #10. Prior or current use of COCs has been asso- Statement #8. No difference in lubrication and VVA symp- ciated with an increased risk of painful bladder syndrome (Level toms has been observed when COCs containing an 3; Grade C).

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Statement #11. No sufficient evidence is available on the Hormonal Contraception, Partner Preference, and correlation between HCs and incontinence, pelvic floor function, Relationship and Sexual Satisfaction and urinary tract infection (UTIs) (Level 4; Grade D). Fluctuations in the perception of male attractiveness were found in women across the menstrual cycle, with a preference Evidence toward more masculine traits (face, voice) and symmetry, as well e Only a few studies have investigated the association between as odor cues of genetic dissimilarity, in the fertile period.103 106 HCs and pelvic floor function and dysfunction. With regard to It was documented that women prefer cues of mate, non-genetic urinary symptoms, a meta-analysisof2trialsshowedastatis- material benefits and assistance during less fertile periods, and tically significant association between painful bladder syndrome cues reflecting mate genetic quality or compatibility during more andthepriororcurrentuseofCOCs(oddsratio fertile periods.107 Female preferences for partner dominance were [OR] ¼ 2.31).97 The association between HCs and urinary elevated on cycle days when estrogen tends to be highest; incontinence is unclear. In a large mail survey of more than stronger short-term mate attractiveness was found on days when 21,000 premenopausal women in the United States, the in- luteinizing hormone and follicle stimulating hormone are typi- vestigators highlighted a statistically significant 27% increased cally elevated.108 At the same time, hormonal fluctuations across odds of developing urinary incontinence among prior or current the ovulatory cycle induce changes in the female physical char- users of COCs compared with those never using a COC; COC acteristics such as appearance of the face, voice, and scent, as well use was specifically associated with urge, not stress, urinary as behavior (eg, motivation to look attractive, dressing more incontinence.98 In contrast with these findings, a Swedish provocatively during the fertile phase), to which men are e cohort study of 10,791 women observed that COC use was sensitive.109 114 As sexual encounters are commonly sought significantly related to a reduced risk for symptoms of stress independently of the relatively short (less than 1 week) monthly (OR ¼ 0.57), mixed (OR ¼ 0.52), and urge (OR ¼ 0.36) periods of , the fertile status is therefore not a prerequisite urinary incontinence, independent of age, , or of sexual activity, but hormonal status may influence sexual pregnancy history.99 Inthesamestudy,theLNG-IUDdidnot behavior. show any correlation with lower urinary tract symptoms compared to controls; therefore, the authors speculated that the HCs and Partner’s Attractiveness observed protective effects of COCs on the lower urinary tract Statement #12. HCs may be associated with changes in female were mediated by the estrogen rather than the progestin 99 perception of male attractiveness with a generally weaker overall component. preference for cues of genetic fitness (Level 3; Grade C). In an internet survey conducted on a university population, < m low-dose ( 20 g EE) COCs appeared to increase the incidence Evidence of chronic symptoms and pain during sexual climax, > m A few controlled, non-randomized studies have suggested that but 20 g EE COC users had similar incidences of pelvic pain women using HCs demonstrate weaker overall preferences for compared to non-users; in fact, normal-dose COCs showed a cues of genetic fitness (choosing less masculine faces) than do non- 100 e protective effect in individual pelvic pain symptoms. users.103,115 118 Also found were conflicting results regarding a With regard to recurrent UTIs, frequent greater preference for masculinity in males’ faces among HC users and a prior history of UTIs have been suggested as the factors as compared to non-users and postpartum women.119 Little 101 most associated with recurrence in premenopausal women. et al118 found that initiation of HC use significantly decreased Diaphragm and spermicidal agents have also been shown to women’s preferences for male masculinity but did not in- independently increase the risk. On the other hand, an associa- fluence preferences for same-sex faces. HC users also exhibited 101 tion with HCs has not been demonstrated. A case-control reduced neural response to the expectation of erotic stimuli120 and study in young women found that subjects with recurrent a preference shift toward olfactory cues of genetic similarity.105 UTIs were more likely to report exposure to and to Gangestad et al107 reported that HC users maintained a prefer- 102 COCs compared to controls during the preceding year. ence for such male traits as financial success and intelligence to a Finally, data on the effect of HCs and pelvic floor/urinary tract greater extent than did naturally cycling women. function are scarce, and no final conclusion can be drawn. This is . More recently, attention has been given to alterations in brain an important area of research that should be further investigated reward responses to a partner’s face as a result of suppression of oxytocin (OXT, considered to be a pair-bonding neuropeptide) Remarks in women who used HCs.121 In a double-blind RCT imple- Available evidence on the impact of HCs on the pelvic floor is menting functional magnetic resonance imaging, the authors insufficient. Although some data indicate a possible negative investigated 40 pair-bonded women, 21 of whom were using impact on painful bladder syndrome, incontinence, and urinary HCs, to evaluate whether a 24-IU nasal dose of OXT would tract infections, more well-designed RCTs are necessary to better modulate brain reward responses evoked by the romantic part- understand the clinical impact of HCs on these aspects. ner’s face relative to the faces of familiar and unfamiliar

J Sex Med 2019;16:1681e1695 Hormonal Contraception and Female Sexuality: ESSM Position Statements 1689 people.121 They found that OXT increased the perceived male-to-female attractiveness that might influence the change in attractiveness of the partner relative to other men, which was sexual satisfaction due to HC discontinuation (eg, fear of preg- paralleled by elevated responses in reward-associated regions, nancy, irregular menses). including the nucleus accumbens, but the effect was found only Finally, Roberts et al125 suggested that congruency in current 121 in women who did not use HCs. The authors concluded that and previous HC use (when the relationship formed), and not the mechanism of OXT-related reinforcement of partner value current use alone, predicted a woman’s sexual (but not representations via the brain reward system may be disturbed in nonsexual) satisfaction with her partner (“congruency hypothe- 121 women using HCs. It was not elaborated which gonadal sis”). Sexual dissatisfaction associated with non-congruency was steroids, in particular, may induce this central neuropeptide- particularly evident in women who met their partners while dependent mechanism. Other limitations of the study include using COCs and subsequently discontinued the treatment. small sample sizes and comparison with women not using HCs only in the follicular and luteal phases. Regarding endogenous Hormonal Contraception, Fidelity, and Partnership OXT, its plasma levels were found to be lower during the luteal Retention Strategies phase in comparison with both the follicular and ovulatory Statement #15. Women using HCs and their male partners phases in ovulating women and were significantly correlated with manifest more frequent mate retention behaviors as compared to the lubrication domain of the FSFI during the ; HC non-users and their male partners (Level 3; Grade C). conversely, in women taking COCs, OXT did not show any significant fluctuation throughout the menstrual cycle.122 Evidence Some authors reported that female hormonal contraceptive use Influence of the Change of Hormonal Contraception is associated with a greater interest in short-term sexual en- Status on Sexual and Non-Sexual Satisfaction and counters.119,126 This seems not to be the case for committed Relationship Stability relationships. Both women using HCs and their male partners Statement #13. Discontinuation of HC use can result in a reported more frequent mate retention behaviors as compared to woman’s sexual dissatisfaction due to less positive perception of HC non-users and their male partners in a cross-sectional study her partner’s attractiveness (Level 3; Grade D). by Welling et al.127 This is in agreement with the preference for “ Statement #14. HC use relative to the initial phase of mate less masculine but more reliable and responsible partners ( non- ” fi choice and the long-term relationship may have implications for genetic bene ts), more intense affective responses to partner fi 128 relationship satisfaction related to the female preferences for in delity, and greater overall sexual jealousy in HC users. partner genetic fitness (Level 4; Grade D). More recently, in a study involving 275 females who had been using COCs for at least 3 months, the authors found that using Evidence HCs with higher levels of synthetic estradiol, but not progestin, It has been proposed that changes in women’s HC use may is associated with significantly higher levels of self-reported alter adaptive mate choice, with downstream consequences on jealousy.129 In a study by Cobey et al,130 women reported relationship quality and outcome. In research on women who higher levels of jealousy when their current HC use was incon- met their partners while using COCs vs women who were not gruent with that at the start of the relationship as compared with using COCs when they met their partners, the authors found women reporting HC use congruency. This outcome was inde- that study participants who used COCs scored lower on mea- pendent from the relationship satisfaction assessment. sures of sexual satisfaction and partner attraction, experienced According to Welling et al,127 the dose of synthetic estradiol, increasing sexual dissatisfaction during the relationship, and were but not of synthetic progesterone, positively predicts mate 123 more likely to be the one to initiate an eventual separation. retention behavior frequency. In women, HC use significantly This is consistent with previous evidence indicating that COCs predicted more frequent self-reported intersexual manipulations might interfere with the preference for major histocompatibility (ie, mate retention behaviors directed at one’s partner). HC use 105 complex-dissimilar men. In the same study, however, women did not significantly predict a woman’s self-reported intrasexual fi who met their partner while using COCs were more satis ed manipulations (ie, mate retention behaviors directed at rivals) or with non-sexual aspects of the relationship, including their a woman’s reports of her partner’s intrasexual or intersexual ’ partner s paternal provision, and thus had longer relationships manipulations.127 In men, partner HC use significantly pre- 123 and were less likely to separate. dicted self-reported intersexual manipulations, reports of a man’s Two longitudinal studies of revealed that dis- partner utilizing intrasexual and/or intersexual manipulations, continuing CHC use was associated with changes in wives’ and men’s self-reported intrasexual manipulations.127 However, marital satisfaction depending on their husbands’ facial attrac- the authors point out that mate retention behaviors may be tiveness; in fact, the discontinuation was associated with lower driven by other underlying factors, such as relationship satisfac- satisfaction only among wives with relatively less attractive hus- tion or commitment, so the self-reported mate retention be- bands.124 However, one must acknowledge factors other than haviors should be interpreted with caution.127

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WOMEN COUNSELLING FOR CONTRACEPTION

1. Perform baseline psycho-sexual-relational assessment 2. Check WHO medical elegibility criteria for contraceptive use 3. Explain potential sexual (and non-sexual) side effects for each method 4. Support a patient centered decision

combinedEstrogen + Progestin no-Estrogen containing contraception contraception

- Women react differently to the various HCs - LNG-IUD (low dose LNG-IUD does not - All CHCs, independently from type and route of inhibit ovulaon): no effect on sexual administraon, reduce free androgen levels, but the symptoms is expected (LoE 2-3) clinical impact of this on desire is unclear (LoE 1) - Implants: have not been associated to VVA - In COC with higher EE doses, a lower incidence of (LoE 3) VVA and reduced lubricaon is expected (LoE4) - Copper IUD: potenally no sexual side- - In vaginal ring users, a lower incidence of VVA and effects (LoE 3) reduced lubricaon is expected (LoE 2-3)

FOLLOW UP AFTER 3 MONTHS

No FSD FSD Counseling FOLLOW UP for psycho- Is FSD no relational or contraception-related? other factors

Reduced lubrication Reduced desire and/or VVA yes

- switch to non-hormonal forms of - switch to non-hormonal forms of contracepon (LoE 3) contracepon (LoE 3) - switch from oral to non-oral form of - switch from oral to non-oral forms of HC, such HC, such as LNG-IUD, the vaginal ring as LNG-IUD, the vaginal ring or implants (LoE 3) or implants (LoE 2-3) - switch to other oral forms of contracepon - switch to other oral forms of (e.g. to a POP - LoE 3; E2/NOMAC - LoE3; contracepon with higher EE doses E2V/DNG or EE/LNG - LoE1). (LoE 3)

FOLLOW UP Figure 1. Evidence-based flow chart to manage and cope with possible sexual dysfunctions related to the use of hormonal contraception. CHCs ¼ combined hormonal contraceptives; COCs ¼ combined oral contraceptives; DNG ¼ dienogest; E2 ¼ 17b-estradiol; EE ¼ ethinyl estradiol; FSD ¼ female sexual dysfunction; HCs ¼ hormonal contraceptives; IUD ¼ intrauterine device; LNG-IUD ¼ levonorgestrel in- trauterine device; LoE ¼ level of evidence; NOMAC ¼ nomegestrole acetate; POP ¼ progestin-only pill; VVA ¼ vulvovaginal atrophy; WHO ¼ World Health Organization. Figure 1 is available in color online at www.jsm.jsexmed.org. In contrast to the increased mate retention behaviors among experience, COC users were found to have fewer extra-pair HC users and their male partners, the results of a cross-sectional sexual partners but only on a trend level. study on a representative sample of Czech women showed that the use of COCs (n ¼ 493) was associated with having more Remarks frequent dyadic intercourse than non-users (n ¼ 662), and the Important limitations of research related to this section must be overall incidence of having had an extra-pair partner or one-night highlighted. There is a paucity of double-blind RCTs investigating stand in the previous year was not related to current COC the differences in partner choice (a continuous process that is not use.131 Among women who have had an extra-pair sexual solely related to hormonal balance and fertile or non-fertile phases

J Sex Med 2019;16:1681e1695 Hormonal Contraception and Female Sexuality: ESSM Position Statements 1691 of the cycle), couple sexual and nonsexual satisfaction, partner STATEMENT OF AUTHORSHIP fi delity, and partner retention strategies in HC users vs non-users. Category 1 Such studies are complicated due to ethical issues (randomization, (a) Conception and Design double-blinding) and might be at least replaced by long-term Stephanie Both; Michal Lew Starowicz; Mijal Luria; Gideon observational studies and experiments controlled by the use of Sartorius; Elisa Maseroli; Francesca Tripodi; Lior Lowenstein; barrier methods or non-hormonal intrauterine devices as alterna- Rossella E. Nappi; Giovanni Corona; Yacov Reisman; Linda tive contraceptive strategies. Furthermore, to our knowledge, no Vignozzi data are available on the impact of HCs and partner preference in (b) Acquisition of Data populations with different sexual orientations. Stephanie Both; Michal Lew Starowicz; Mijal Luria; Gideon Sartorius; Elisa Maseroli; Francesca Tripodi; Lior Lowenstein; Rossella E. Nappi; Linda Vignozzi CONCLUSION (c) Analysis and Interpretation of Data Stephanie Both; Michal Lew Starowicz; Mijal Luria; Gideon The effects of HCs on sexual function have been inadequately Sartorius; Elisa Maseroli; Francesca Tripodi; Lior Lowenstein; studied and remain controversial. Available evidence indicates Rossella E. Nappi; Linda Vignozzi that the vast majority of COC users do not experience a change in sexual function, with a minority of women experiencing either Category 2 a better or worse sexual functioning with regard to general sexual (a) Drafting the Article response, desire, arousal, and orgasm. Figure 1 shows an Stephanie Both; Michal Lew Starowicz; Mijal Luria; Gideon European Society of Sexual Medicine evidence-based approach Sartorius; Elisa Maseroli; Francesca Tripodi; Lior Lowenstein; Rossella E. Nappi; Linda Vignozzi to managing and coping with possible sexual dysfunctions related (b) Revising It for Intellectual Content to the use of HCs. It should be noted that a careful baseline Stephanie Both; Michal Lew Starowicz; Mijal Luria; Gideon psychological, sexual, and relational assessment is necessary for Sartorius; Elisa Maseroli; Francesca Tripodi; Lior Lowenstein; the health care provider to evaluate eventual effects of HCs at Rossella E. Nappi; Giovanni Corona; Yacov Reisman; Linda follow-up. Vignozzi Studies evaluating lubrication generally show that HCs have a Category 3 reducing effect. Switching to a COC containing an androgenic (a) Final Approval of the Completed Article progestin has not been demonstrated to improve COC-induced Stephanie Both; Michal Lew Starowicz; Mijal Luria; Gideon sexual dysfunction, reduced desire, or lubrication. HC by vaginal Sartorius; Elisa Maseroli; Francesca Tripodi; Lior Lowenstein; ring diminished sexual function, as well, but it is associated with Rossella E. Nappi; Giovanni Corona; Yacov Reisman; Linda a lower prevalence of VVA. Similarly, sexual symptoms in Vignozzi women using a LNG-IUD were similar to those of women fi wearing a copper IUD, suggesting their safe sexual pro le. REFERENCES The pathophysiological mechanisms leading to reduced desire 1. Dehlendorf C, Krajewski C, Borrero S. Contraceptive coun- remain unclear, with the most commonly discussed hypotheses seling: best practices to ensure quality communication and referring to central effects in hypothalamic mediators and HC- enable effective contraceptive use. Clin Obstet Gynecol 2014; induced hypoandrogenism; in contrast, hypoestrogenism and 57:659-673. increased vascular resistance of clitoral and vaginal arteries seem 2. 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