Obstetrics and Gynecology Clinics of North America35 (2008) ppt

Female Sexual Function and Dysfunctiona ABQ Health Partners, Women’s Pelvic Specialty Care, University of New Mexico Hospital, 5150 Journal Center Blvd NE, Albuquerque, NM 87109, USA b U

Tristi Muir, MD Guest Editor

The scope of practice of the gynecologist is broad and challenging Thegynecologist is blessed with the longitudinal care of women from adoles-cence through the end stages of life In fact, many women consider theirgynecologist their primary care physician

This edition of Obstetrics and Gynecology Clinics of North Americaexplores many of the daily challenges of office practice Updates in newcontraceptive options and in management of dysfunctional uterine bleedingare presented For the first time in practice of gynecology, we can offer a vac-cine to reduce the risk or prevent the development of cervical dysplasia andcancer The prevention and treatment of human papilloma virus is dis-cussed, including indications for the vaccine Urinary tract infections affectmost of the women in our practice Diagnosis and current treatmentstrategies of primary and recurrent urinary tract infections are delineated.Ovarian and breast disorders are common and are a concern for manywomen These topics are expanded upon As women age, osteoporosisand fecal incontinence limit the quality of life of many of our patients.Understanding management strategies is a goal of this edition One of themost challenging problems that a gynecologist faces, female sexual dysfunc-tion, is explored in detail Procedures that commonly were performed in theoperating room now are moving to the office Endometrial ablation isexamined, and tips on its performance are presented

I thank the contributing expert authors for their informative reviews onthese topics I also thank Carla Holloway for her editing and support

0889-8545/08/$ - see front matter Ó 2008 Elsevier Inc All rights reserved.

35 (2008) xv–xvi

The breadth of knowledge required to practice gynecology continues toexpand and evolve Education is truly a lifelong pursuit in medicine.Although the science of gynecology is multifaceted, the art of medicine ispracticed on a complex, unique individual The trust and faith that womenplace in their gynecologists immeasurably reward all our efforts to expandour knowledge in the practice of medicine.

Tristi Muir, MDSection of Female Pelvic Medicine and Reconstructive Pelvic Surgery

Scott & White Temple Clinic

2401 S 31st StreetTemple, TX 76508, USAE-mail address:tmuir@swmail.sw.org

This issue of the Obstetrics and Gynecology Clinics of North Americapertains to office gynecology, reflecting the expanding outpatient servicesavailable to optimize women’s health and prevent disease Its content, as de-veloped by guest editor Tristi Muir, MD, encompasses the detection andevaluation of common disorders and addresses special concerns among vul-nerable populations Common benign breast and gynecologic disorders areaddressed within the context of screening and initial management Certainsections cover topics that have a major prevention component, such as os-teoporosis, new forms of contraception, and human papilloma virus preven-tion More procedures previously performed in the operating room are nowmoving into the office.

This issue is not intended to be a comprehensive guide to women’s health;instead, it consolidates useful information on a variety of topics in a singleplace Particular emphasis is given to information not necessarily found incurrent textbooks Treatment guidelines often change, so gynecologists

0889-8545/08/$ - see front matter Ó 2008 Elsevier Inc All rights reserved.

35 (2008) xiii–xiv

should check sources to ensure that they have the most recent tions The practical information provided by this distinguished panel of con-tributors will stimulate us further in providing comprehensive health care towomen in our offices.

recommenda-William F Rayburn, MD, MBADepartment of Obstetrics and GynecologyUniversity of New Mexico School of Medicine

MSC10 5580

1 University of New MexicoAlbuquerque, NM 87131-0001, USAE-mail address:wrayburn@salud.unm.edu

Female Sexual Function and Dysfunction

a

ABQ Health Partners, Women’s Pelvic Specialty Care, University of New Mexico Hospital,

5150 Journal Center Blvd NE, Albuquerque, NM 87109, USA

b University of New Mexico Hospital, 2211 Lomas Blvd NE, Albuquerque, NM 87131, USA

Sexual health is defined by the World Health Organization as the tion of somatic, emotional, intellectual, and social aspects in ways that arepositively enriching and that will enhance personality, communication, andlove This article identifies models of sexual function, defines and categorizessexual dysfunction, identifies therapeutic modalities for patients who havesexual dysfunction, and discusses some of the questionnaires used to evalu-ate sexual function

a ‘‘Sexual Response Circle’’ that incorporates psychological and social pects into female sexual function, such as emotional intimacy and emotional

as-* Corresponding author.

E-mail address: dorothy.kammerer-doak@lovelace.com (D Kammerer-Doak).

0889-8545/08/$ - see front matter Ó 2008 Elsevier Inc All rights reserved.

35 (2008) 169–183

satisfaction as well as sexual desire and physical satisfaction (Fig 2)[2] Thismodel recognizes that sexual function and response are different in men andwomen Importantly, for women, desire does not always precede sexualarousal, with many women participating in sexual activity out of love andaffection for their partners Once engaged in sexual activity, women may

Fig 1 Sexual response cycle defined by Masters and Johnson (From Masters WH, Johnson

VE Human sexual response Boston: Little Brown & Company; 1966; with permission.)

Fig 2 The interrelatedness of intimacy, sexual arousal, desire and satisfaction (From Basson

R Are the complexities of women’s sexual function reflected in the new consensus definitions of dysfunction? J Sex Marital Ther 2001;27:105–12; with permission.)

then become aroused, and then experience desire For many women, the ual response cycle is intimately intertwined with the overall relationship thatthey are in, and incorporates the societal and psychological milieu.Although prevalence and incidence data are scarce for rates of sexual ac-tivity, what data there are support the conclusion that women are sexuallyactive throughout the lifespan Data from the National Survey of FamilyGrowth indicate that approximately 40% of females 15 to 19 years of agehave had sexual intercourse within the last 3 months[3] Although frequency

sex-of sexual activity declines with age, population-based studies indicate tinued sexual activity in 47% of married women aged 66 to 71 years, and

con-in one third of women over the age of 78 Recent population-based surveys

of younger as well as middle aged and older women reported that 50% to75% are sexually active [4,5] Lack of interest and lack of partner werethe most common reasons for sexual inactivity Norms of sexual activityare not well characterized for women Most women engage in heterosexualpractices, with only 1.2% reporting sex with other women[3,6] The averagefrequency of sexual activity is six times per month for women comparedwith seven for men, with vaginal intercourse the most common sexual prac-tice, and oral sex a distant second, although not an uncommon practice[6].Most women report the inability to achieve orgasm with vaginal intercourseand require direct clitoral stimulation[7,8] About 20% have coital climaxes,and 80% of women climax before or after vaginal intercourse when stimu-lated manually, orally, or with a vibrator or other device Only 30% womenalmost always or always achieve orgasm with sexual activity in contrast to75% of men[7,8]

Although there are variations among individuals, differences in the sexualfunction of men and women start with the sexual response For men, sexualfunction and response centers on the ability to achieve and maintain an erec-tion For women, however, sexual response is much more complex, involv-ing social, psychological, neurologic, vascular, and hormonal processes andincludes complex interaction of sexual stimulation, the central nervous sys-tem, the peripheral neurovascular system, and hormonal influences, whichare not understood completely[9–11] Female sexual dysfunction (FSD) istherefore a complex problem with neurovascular, psychosocial, and endo-crine etiologies

Sexual dysfunction

Sexual dysfunction is recognized as a widespread problem, but data arescarce as to the prevalence, which ranges from 25% to 63% of women de-pending on the source and definition used An early study of sexual dysfunc-tion in the United States analyzed data from the National Health and SocialLife Survey The survey was based on a probability sample of sexual behav-ior in a 1992 cohort of 1749 women and 1410 men aged 18 to 59 years and

noted a prevalence of sexual dysfunction in 43% of women and 31% of men

[12] Low libido was the most common complaint reported in 51% of spondents, followed by problems with arousal in 33%, and pain disorders

re-in 16% Sexual dysfunction was more common re-in women as comparedwith men (43% versus 31%), and was associated with younger age (18 to

39 years), less education, and unmarried status Importantly, in this study,sexual dysfunction was linked to poor physical and emotional health andsignificantly impacted quality of life These data, however, are limited bylack of information on individuals greater than 59 years of age, and whetherthe sexual dysfunction was problematic or a cause of distress to the affectedindividual Recent studies have addressed sexual practices in a more inclu-sive population up to age 79 years and have reported on sexual dysfunction

in about 35% of participants[4,5] In one study[4], 71% of women were ually active, and 33% of the sexually active women were classified with FSD

sex-by the answer of ‘‘somewhat of a problem’’ or ‘‘very much a problem’’ in atleast one of the four domains studied including lack of interest, lack of en-joyment, difficulty in arousal, or difficulty in orgasm When women not sex-ually active were included in those with sexual dysfunction, then the overallprevalence of FSD in this study was 45%[4]

The definition of FSD is problematic, and may be defined better by what

it is not, rather than what it is Media attention and progress in the ceutical treatment of male erectile dysfunction have focused attention on fe-male sexuality This scrutiny may have created an artificial standard ofexpected female sexual function that if not attained is labeled a dysfunction

pharma-A less than perfect sex life becomes FSD when it causes personal distress asdetermined by the affected women, and not necessarily her partner[13] Thediagnosis of FSD requires that the symptom be persistent, pervasive, andcause personal distress to the woman Symptoms that bother the woman’spartner but are not distressful to the woman herself, such as lack of thewoman’s interest in sex, are not classified as her sexual dysfunction.FSD has been classified into four areas by an international consensusconference: problems with arousal, orgasm, desire, and pain (Box 1) [14].Women may have symptoms that fall into more than one dysfunction cate-gory Sexual arousal disorder (FSAD) is defined as the persistent or recur-rent inability to attain or maintain sexual excitement, with an emotionallessening of excitement or sensation Orgasmic disorder (FOD) is defined

as the difficulty or inability to reach orgasm after sufficient sexual tion and arousal Sexual desire disorders are divided into two categories: hy-poactive sexual desire disorder (HASDD), which involves the lack of desirefor sexual activity and/or a deficiency or absence of sexual thought and fan-tasies, and sexual aversion disorder, defined as the fear and avoidance ofsexual thought and situations Sexual pain disorders are subdivided intothree categories: dyspareunia, vaginismus, and noncoital sexual pain disor-der The first type of FSD pain disorder is dyspareunia, or genital pain thatoccurs with intercourse Vaginismus, the second type of sexual pain

stimula-disorder, involves involuntary muscle spasms of the lower third of thevagina that interferes with intercourse The last category is noncoital sexualpain disorder, defined as genital pain that occurs with any type of noncoitalsexual stimulation FSD can be characterized further as primary or second-ary, and persistent, versus situational The etiology may be physical or psy-chological, a combination, or the cause may be unknown.

Assessment of female sexual dysfunction

The approach to the treatment of FSD involves identification of womenwho have the problem, identification and treatment of causes of pain, iden-tification of the class of sexual dysfunction, and treatment tailored to theindividual patient as well as her partner The most common reason healthcare providers fail to question their patients about possible FSD is because

of a lack of time [15] Plouffe [16], however, has demonstrated that threesimple questions are as effective as lengthy interviews to screen for sexualproblems Screening questions for female sexual function include[16]:

 Are you sexually active?

 Are there any problems?

 Do you have pain with intercourse?

An intake questionnaire with these three questions may be helpful for ficiency and privacy The nature of the sexual problem is characterized asbeing associated with arousal, desire, problems with orgasm, or symptoms

ef-of pain In addition, the history should focus on the duration ef-of the problem(primary or secondary) and the psychosocial factors involved, such as anyrecent life changes or stressors There are several female sexual function

Box 1 Classification of female sexual dysfunction

Sexual arousal disorder

Orgasmic disorder

Sexual desire disorders

 Hypoactive sexual desire disorder

 Sexual aversion disorder

Sexual pain disorders

 Dyspareunia

 Vaginismus

 Noncoital sexual pain disorder

Data from Basson R, Berman J, Burnett A, et al Report of the international sensus development conference on female sexual dysfunction: definitions and classifications J Urol 2000;163:888–93.

con-questionnaires that can be useful, such as the Female Sexual Function Index(FSFI, available atwww.fsfi-questionnaire.com), which has been validatedbased on Diagnostic and Statistical Manual of Mental Disorders, FourthEdition (DSM-IV) diagnoses of HASDD, FSAD, and FSOD[17] A totalFSFI score of 26 or less is considered at risk for sexual dysfunction.Medical history is important, as chronic illnesses or medications that af-fect neurologic, endocrine, vascular, or psychological function can impact

on sexual function[18,19] Examples of illnesses that may affect sexual tion include spinal cord injuries, thyroid disease, diabetic neuropathy, surgi-cal or medical castration with accompanying marked decreased estrogenand testosterone levels, cardiovascular disease, and depression Medicationscan interfere with sexual function by alteration of mood and libido, such asantidepressants, antipsychotics, and sedatives, by alteration of blood flow tothe genitals decreasing arousal and/or lubrication, such as certain antihyper-tensives or antiestrogens, or by increasing sex hormone-binding globulinsand therefore decreasing free testosterone levels such as with oral contracep-tives Illicit drug use and alcoholism also are associated with FSD Excessivetobacco abuse may lead to vascular insufficiency and decreased genitalblood flow Difficult vaginal delivery or vaginal surgery may cause denerva-tion or dyspareunia Surgical castration is another common interventionthat may affect sexual function adversely, particularly in premenopausalwomen Bilateral oophorectomy is the most common prophylactic opera-tion performed with removal of otherwise healthy tissue

func-The physical manifestations of the normal female sexual response cycleare the result of increased blood flow (engorgement) that occurs in the pelvisand breasts, and increased muscle tension in the body Vaginal increases inblood flow result in increased vaginal secretions, which are important for lu-brication, and are estrogen-dependent Low estrogen levels are associatedwith significant decreases in clitoral, vaginal, and urethral blood flow andhistologic changes of thin mucosal layers Thus, any medical illness or med-ication that interferes with this complex process can contribute to sexualdysfunction

An evaluation for possible need for psychotherapy is important, based onthe patient’s current life stressors, social situation and relationships, history

of psychiatric illnesses, and history of sexual trauma Determination of ual partner involvement in the FSD is crucial The physical examination fo-cuses on general health and on the identification of treatable causes of pain.Additionally, women who have incontinence and prolapse have lower sexualfunction scores than women without these problems[20]

sex-Routine laboratory testing is not recommended unless a hormonal mality is suspected, and it includes screening for prolactinoma, thyroiddysfunction, and adrenal disorders There is some suggestion that freetestosterone levels less than the lowest quartile may be associated withFSD or androgen insufficiency syndrome [18,21] Androgen insufficiencysyndrome, with symptoms of decreased sexual interest and well-being,

abnor-fatigue, persistent postmenopausal vasomotor symptoms despite estrogenreplacement, and lack of motivation recently has been postulated Normalrange of testosterone levels have not been established in women, however,and testosterone levels do not correlate with libido, so random values areworthless in the evaluation of FSD[18,19] If adrenal insufficiency is sus-pected, measurement of dehydroepiandrosterone sulfate (DHEAS) is usefulbecause of isolated adrenal production [21] Although estrogen deficiencyand urogenital atrophy can contribute to FSD, including dyspareunia andvascular insufficiency, measurement of estrogen levels is also not useful

[10,19] Progesterone appears to have little impact either alone or with gen on female sexual function[10]

estro-Treatment of female sexual dysfunction

The advent of new therapies for male sexual erectile dysfunction and themedia attention it has received have led to widespread attention of FSD.The treatment of sexual dysfunction in the female, however, is more com-plex than the male Male sexual dysfunction mainly involves the arousalstage of the sexual response and problems with erection or premature ejac-ulation In the case of erectile disorders, pharmaceutical interventions thatincrease penile blood flow have proven efficacy Female sexual dysfunctionless commonly occurs in the arousal phase of the sexual response, with morewomen reporting difficulties with libido and orgasm[12] Because the femalesexual response is more complex involving neurovascular, endocrine andpsychosocial factors, simply increasing clitoral and vaginal blood flowwith pharmaceutical agents usually does not result in improved desire,arousal, or orgasm

Education of women who have sexual problems about average sexualbehaviors and frequencies as well as determination of whether their ownpersonal sexual practices are distressing to them can be very helpful Specifi-cally, media portrayals do not accurately represent the average Americanexperience in terms of sexual activity and quality of sexual experience Inaddition, it is important that women know that there is no medically ex-pected level of sexual activity or function, and that lack of libido or ability

to climax does not represent a sexual dysfunction as long as the woman periences no personal distress Other information that is useful is that aboutonly 20% of women experience orgasm with vaginal intercourse and thatmost require clitoral stimulation to climax Not all women experienceorgasm with every sexual encounter; only 30% of women climax withalmost every sexual activity [7,8] An anatomy lesson regarding clitorallocation and techniques for stimulation such as the vibrator may be helpful

ex-in givex-ing the woman with psychosocial barriers medical permission to treather sexual problems in this way[22]

Exploration for any recent significant physical or social changes such aschildbirth, menopause, work status, or a death should be made as these life

events can affect sexual function negatively Optimal female sexual healthincorporates physical, mental, and emotional aspects, and these are the con-text in which a woman experiences desire, arousal, and orgasm No medicaltreatment will improve a bad situation or relationship Psychosocial inter-vention may be necessary based on the woman’s relationship, current lifestressors, and sexual problems Women who have sexual aversion disorder,primary FOD, and noncoital pain disorder and those who have history ofsexual abuse usually require psychotherapy.

Alteration of contributors to FSD, such as smoking, excess alcohol or licit drug use, obesity, and optimal treatment of medical diseases that canaffect FSD such as hypertension and diabetes are also part of management.Simple things, including exercise, a healthy diet, and adequate rest, improvephysical and mental, and therefore sexual health The woman and her part-ner need to improve communication and reduce relationship strains whenpresent, as a strong impetus for female sexuality is intimacy [21] Sensatefocus is a technique that can be used by couples to resolve sexual problemsand improve intimacy through communication regarding what is pleasur-able [22] This technique aims to make both partners aware of what eachfinds enjoyable and to reduce anxiety about performance Initially, inter-course is banned, and the focus is on the sensation of nongenital touching,with mutual pleasure the goal Gradually, the level of intimacy is advancedwhen both partners are comfortable, to mutual touching to include the gen-itals, and finally to intercourse with the same focus of pleasure and enjoy-ment that was learned in the first levels

il-Sexual activity is often begun by women to improve emotional closenesswith their partners, and this can impact libido Scheduling date nights andtime for sexual relations can be effective even when desire is not apparent.Remind patients that for women, desire does not always precede arousal,and making protected time for intimacy can improve sexual function[21]

Medications

The effects of systemic hormone therapy (HT) on female sexual functionare inconsistent in randomized controlled trials (RCTs), including placebo-controlled trials [10,18,21] Estrogen improves vaginal and clitoral bloodflow, improving lubrication Dyspareunia caused by atrophy is treatedbest by vaginal estrogen, either delivered as a cre`me, tablet, or ring Proges-terone can ameliorate these changes and cause persistent dryness and dys-pareunia depending on type of progesterone used [18] The ability ofsystemic HT to enhance sexual arousal, desire, and ability to achieve orgasm

is not definitive Studies from the 1970s did not find any changes in tion, orgasm, or frequency of sexual intercourse or masturbation[18] Morerecent RCTs have reported beneficial effects of estrogen therapy (ET) onsexual desire, enjoyment, orgasmic frequency, and vaginal lubrication, but

satisfac-no difference in coital frequency[18] Another study evaluating transdermalestrogen noted improvement in satisfaction, increase in sexual activity andvaginal lubrication, decreased dyspareunia, but no change in arousal or or-gasm frequency[18] Many experts do initiate systemic HT in the absence ofcontraindications in postmenopausal women who have FSD[21].

The role of androgens in the treatment of FSD is controversial terone has been linked to sexual desire[10,18,19,21] Androgen levels grad-ually decrease with age starting at about 30 years, but there is no abruptdrop at the time of menopause Ovarian and adrenal production of andro-gens continue into the menopause, with levels about half of peak levels[21].The data on testosterone use for the treatment of FSD are limited, however,with few RCTs and no information on long-term use The best studies comefrom the treatment of postmenopausal and surgically castrated women eval-uated in RCT[23–26] The addition of testosterone, either oral or transder-mal to ET resulted in significant improvement in sexual function, includingdesire, arousal, and orgasm, compared with ET alone Some patients with-drew secondary to adverse effects [23], however, and supraphysiologictestosterone levels were reported [26] The use of androgens in premeno-pausal women who have FSD has been poorly studied One small RCT re-ported improvement in arousal with use of testosterone gel administered

Testos-4 to 8 hours before planned sexual activity compared with placebo[27] menopausal women who have serum-free testosterone levels below the low-est quartile of normal range and who have symptoms of androgeninsufficiency including FSD may be offered testosterone but need to becounseled on the absence of efficacy data and safety Blood levels should

Pre-be monitored to achieve physiologic levels in the mid–upper level of normalrange [10,18,21] Transdermal testosterone may minimize the adverse ef-fects Because testosterone can affect lipid profile negatively and cause liverdamage, it may be prudent to evaluate liver function and lipids at regularintervals Long-term adverse effects of testosterone therapy that are irre-versible include clitoral enlargement, voice changes, and male pattern bald-ness, but these complications are rare with physiologic levels [21] Otherandrogens such as DHEAS and dehydroepiandrosterone (DHEA) havebeen used to treat FSD but with very limited evidence for effectiveness.One small uncontrolled study reported an improvement in desire, arousal,satisfaction, and orgasm in pre- and postmenopausal women with decreasedandrogen levels and libido treated with DHEA[28] DHEA is available as

a nutritional supplement, and although not regulated by the FDA, it can beused to treat premenopausal women with androgen insufficiency at a dose

of 50 mg/d after counseling regarding the experimental nature of this use

[21]

Tibolone is a synthetic steroid with estrogenic, progesterogenic, and drogenic properties, with possible positive effect on sexual function used inEurope for more than 20 years[10,21] In a recent RCT, tibolone was shown

an-to increase clian-toral circulation and sexual function scores significantly as

compared with conventional HT in postmenopausal women who had FSD

[29]

Medications used to treat male erectile dysfunction such as sildenafil alsohave been studied in women who have FSD These medications increasegenital blood flow by inhibition of phosphodiesterase, thereby facilitatingnitric oxide-mediated relaxation of clitoral and vaginal smooth muscle Inwomen, increased vaginal and clitoral blood flow and increased lubricationand engorgement caused by sildenafil did not translate into consistently im-proved sexual function in several large trials of women with FSD [19,21].There does not appear to be any clear benefit to the use of sildenafil inwomen FSD In women with isolated FSAD who have low vaginal engorge-ment as measured by vaginal pulse amplitude with photoplethysmography,however, a few RCTs have reported significantly increased subjectivearousal and perception of genital arousal [21,30,31] Women who benefitfrom this class of drugs may be those who have deficient genital engorge-ment, especially those who have a specific underlying cause of FSAD,such as type 1 diabetes, and not those who have deficient subjective arousal

[21,32]

Other medications used to treat HASDD, FSAD, and FOD include ical and oral medications Arginmax is an oral nutritional supplement con-taining L-arginine, a precursor for nitric oxide, which facilitates genitalsmooth muscle relaxation, damiana, ginseng, ginkgo, multivitamins andminerals [21,33] Two small, placebo-controlled RCTs both conducted bythe same authors noted significantly improved desire, orgasm, sexual fre-quency, and clitoral sensation, including increased sexual function scores us-ing the FSFI in women randomized to Arginmax [33,34]

top-Zestra is a botanical massage oil composed of PA-free borage seed oil,evening primrose oil, angelica extract, coleus extract, vitamin C, vitamin

E, and natural fragrances to applied to the vulva before sexual activity.One small RCT in 20 women, 10 who had FSAD, reported significantimprovement in arousal, desire, orgasm, and sexual pleasure as comparedwith placebo [35]

Avlimil is a tablet advertised on the Internet and magazines as a ‘‘dailysupplement shown to promote better blood flow and increased muscularrelaxation for an improved libido and a healthier, more energetic sexualresponse.’’ Although the company reports significant improvement in sexualfunction in a RCT, there are no studies published in peer-reviewed journalsusing this product, which contains multiple herbs The US Federal TradeCommission has charged the marketers of Avlimil in making false andunsubstantiated claims Avlimil’s ingredients are substantially differentfrom the formula used in the clinical trial cited in advertisements

Alprostadil, a prostaglandin topically applied to the genitals, is under vestigation to treat FSD Alprostadil increases genital vasocongestion, lubri-cation, and some indices of sexual arousal, but results are inconsistent, withnot all trials demonstrating significant benefit compared with control[36]

in-There are ongoing clinical trials that will help to determine if alprostadil isbeneficial for FSD, however.

In summary, women who have sexual dysfunction may have problemsthat overlap the different stages of sexual function, arousal, desire, orgasm,

or pain Management involves assessment of the level of dysfunction, cation of average sexual practices, ways to improve intimacy, treatment ofpain, evaluation for psychotherapy depending on current and past relation-ships and life stressors including history of sexual abuse, and medicalmanagement when indicated Hormone replacement therapy, includingtestosterone, may be used in postmenopausal woman, but the role of andro-gens in premenopausal women who have sexual dysfunction remains underinvestigation Primary orgasmic disorder, sexual aversion disorder, and non-coital sexual pain disorder are difficult to treat and generally require psychi-atric referral and long-term counseling

edu-Sexual function in women with pelvic floor disorders

Pelvic floor disorders, including urinary and anal incontinence and pelvicorgan prolapse, are common and have a negative impact on the sexual func-tion of women[20] In a large national survey of sexual function, urinarytract symptoms were associated with increased rates of arousal and sexualpain disorders[12] In another epidemiologic study that evaluated womenundergoing hysterectomy, urinary incontinence was associated with lowlibido, vaginal dryness, and dyspareunia, but pelvic organ prolapse wasnot associated with any sexual complaints measured [37] Coital inconti-nence, or loss of urine with sexual intercourse, can be particularly trouble-some to patients and occurs either with vaginal penetration in womenwho have stress incontinence or with orgasm in women who have overactivebladder symptoms [38] The effects of pelvic organ prolapse and urinaryincontinence as well as vaginal anatomy on sexual function have been eval-uated in two studies by the same authors[39,40] Although increasing grade

of prolapse predicted interference with sexual activity, prolapse itself did notaffect frequency of intercourse or subjective satisfaction Sexual activity wasnot correlated with vaginal length or introital caliber, and no associationwas noted between anatomy and complaints of dyspareunia More ad-vanced stages of prolapse have been associated with reports of impairment

in sexual life and increased rates of abstinence [41] Multiple studies haveshown that surgical treatment of the underlying pelvic floor disorder, eitherprolapse or stress urinary incontinence, improves sexual function as mea-sured by a condition-specific validated questionnaire[42–44] Not all studiesreport an improvement, however, A recent publication reported no differ-ence in sexual function following vaginal surgery for prolapse and stress uri-nary incontinence, but these authors used a validated questionnaire, whichwas not specific for pelvic floor disorders[45]

Sexual function after hysterectomy

Hysterectomy is the most common major gynecologic surgery, and there

is popular belief of adverse effect on sexual function Older studies that ported the effects of hysterectomy on sexual function did not use validatedquestionnaires or prospective design Multiple prospective studies havedemonstrated a positive effect of total and subtotal abdominal and vaginalhysterectomy on sexual function [46–49] RCTs have shown no benefit forsexual function by cervical preservation with subtotal (supracervical) hyster-ectomy[49]

re-Pregnancy and childbirth

Sexual dysfunction is common after childbirth, but generally is addressedpoorly by providers Up to 86% of women report sexual problems in thefirst 3 months after childbirth [50,51] At 6 months postpartum, 18% to30% of women still experience sexual problems, mostly related to dyspareu-nia[52] Fortunately, most women resume prepregnancy orgasmic functionand sexual intercourse without severe pain by 6 months postpartum [53].Risk factors for postpartum sexual dysfunction include continued breastfeeding and severity of genital tract trauma sustained at childbirth[53,54]

At 6 months postpartum, women who have severe perineal lacerationsinto the anal sphincter are 270% more likely to report pain with intercoursethan women who delivered without laceration[54] Compared with sponta-neous vaginal delivery, assisted vaginal delivery is associated with postpar-tum sexual dysfunction, but the effect of cesarean delivery on sexualfunction is not consistent [51,53] Prevention of severe laceration at child-birth and increased communication postpartum with women, especiallythose who are breast feeding, would improve the detection and subsequenttreatment of FSD in this young population

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[20] Rogers RG, Villarreal A, Kammerer-Doak DN, et al Sexual function in women with and without urinary incontinence and pelvic organ prolapse Int Urogynecol J Pelvic Floor Dys- funct 2001;12:361–5.

[21] Pauls RN, Kleeman SD, Karram MM Female sexual dysfunction: principles of diagnosis and therapy Obstet Gynecol Surv 2005;50:196–206.

[22] Bachmann GA, Coleman E, Driscoll CE, et al Patients with sexual dysfunction: your ance makes a difference Patient Care 1999;99–123.

guid-[23] Shrifen JL, Braunstein GD, Simon JA, et al Transdermal testosterone treatment in women with impaired sexual function after oophorectomy N Engl J Med 2000;343:682–8 [24] Lobo RA, Rosen RC, Yang HM, et al Comparative effects of oral esterified estrogens with and without methyltestosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive sexual desire Fertil Steril 2003;79:1341–52 [25] Sarrel P, Dobay B, Wiita B Estrogen and estrogen–androgen replacement in postmeno- pausal women dissatisfied with estrogen-only therapy J Reprod Med 1998;43:847–56 [26] Floter A, Nathorst-Boos J, Carlstrom K, et al Addition of testosterone to estrogen replace- ment therapy in oophorectomized women: effects on sexuality and well-being Climacteric 2002;5:357–65.

[27] Chudakov B, Ben Zion IZ, Belmaker RH Transdermal testosterone gel prn application for hypoactive sexual desire disorder in premenopausal women J Sex Med 2007;4:204–8 [28] Munarriz R, Talakoub L, Flaherty E, et al Androgen replacement therapy with dehydroe- piandrosterone for androgen insufficiency and female sexual dysfunction J Sex Marital Ther 2002;28(Suppl 1):165–73.

[29] Nappi RE, Ferdeghini F, Sampaolo P, et al Clitoral circulation in postmenopausal women with sexual dysfunction: a pilot randomized study with hormone therapy Maturitas 2006; 55:288–95.

[30] Caruso S, Intelisano G, Lupo L, et al Premenopausal women affected by sexual arousal order treated with sildenafil: a double-blind, placebo-controlled study BJOG 2001;108: 623–8.

dis-[31] Berman JR, Merman LA, Toler SM, et al Sildenafil study group Safety and efficacy of denafil citrate for the treatment of female sexual arousal disorder: a double-blind placebo- controlled study J Urol 2003;170:2333–8.

sil-[32] Caruso S, Rugolo S, Agnello C, et al Sildenafil improves sexual functioning in premenopausal women with type 1 diabetes who are affected by sexual arousal disor- der: a double-blind, crossover, placebo-controlled pilot study Fertil Steril 2006;85(5): 1496–501.

[33] Ito TTY, Trant AS, Polan ML A double-blind placebo-controlled study of Arginmax, a tritional supplement for enhancement of female sexual function J Sex Marital Ther 2001;27: 541–9.

nu-[34] Ito TY, Polan ML, Whipple B, et al The enhancement of female sexual function with max, a nutritional supplement, among women differing in menopausal status J Sex Marital Ther 2006;32(5):369–78.

Argin-[35] Ferguson DM, Steidle CP, Singh GS, et al Randomized, placebo-controlled, double-blind crossover trial of the efficacy and safety of Zestra for women in women with and without fe- male sexual arousal disorder J Sex Marital Ther 2003;29(Suppl 1):33–44.

[36] Kielbasa LA, Daniel KL Topical alprostadil treatment of female sexual arousal disorder Ann Pharmacother 2006;40(7–8):1369–76.

[37] Handa VL, Harvey L, Cundiff GW, et al Sexual function among women with urinary tinence and pelvic organ prolapse Am J Obstet Gynecol 2004;191(3):751–6.

incon-[38] Barber MD, Dowsett SA, Mullen KJ, et al The impact of stress urinary incontinence on ual activity in women Cleve Clin J Med 2005;72(3):225–32.

sex-[39] Weber AM, Walters MD, Schover LR, et al Vaginal anatomy and sexual function Obstet Gynecol 1995;86(6):946–9.

[40] Weber AM, Walters MD, Schover LR, et al Sexual function in women with uterovaginal prolapse and urinary incontinence Obstet Gynecol 1995;85(4):483–7.

[41] Ellerkmann RM, Cundiff GW, Melick CF, et al Correlation of symptoms with location and severity of pelvic organ prolapse Am J Obstet Gynecol 2001;185:1332–8.

[42] Rogers RG, Kammerer-Doak DN, Darrow A, et al Does sexual function change after gery for stress urinary incontinence and/or pelvic organ prolapse? A multicenter prospective study Am J Obstet Gynecol 2006;195(5):e1–4.

sur-[43] Jha S, Moran P, Greenham H, et al Sexual function following surgery for urodynamic stress incontinence Int Urogynecol J Pelvic Floor Dysfunct 2007;18:845–50.

[44] Handa VL, Zyczynski HM, Brubaker L, et al Sexual function before and after pexy for pelvic organ prolapse Am J Obstet Gynecol 2007;197(6):629 e1–6.

sacrocolpo-[45] Pauls RN, Silva WA, Rooney CM, et al Sexual function after vaginal surgery for pelvic organ prolapse and urinary incontinence Am J Obstet Gynecol 2007;197:622 e1–7 [46] Roovers JP, van der Bom JG, van der Vaart CH, et al Hysterectomy and sexual well-being: prospective observational study of vaginal hysterectomy, subtotal abdominal hysterectomy, and total abdominal hysterectomy BMJ 2003;327:774–8.

[47] Thakar R, Sultan AH Hysterectomy and pelvic organ dysfunction Best Pract Res Clin Obstet Gynaecol 2005;19:403–18.

[48] Ghielmetti T, Kuhn P, Dreher EF, et al Gynaecological operations: do they improve sexual life? Eur J Obstet Gynecol Reprod Biol 2006;129:104–10.

[49] Kuppermann M, Summitt RL Jr, Varner RE, et al Sexual functioning after total pared with supracervical hysterectomy: a randomized trial Obstet Gynecol 2005;105: 1309–18.

com-[50] Barrett G, Pendry E, Peacock J, et al Women’s sexual health after childbirth Br J Obstet Gynaecol 2000;107:186–95.

[51] Hicks TL, Goodall SF, Quattrone EM, et al Postpartum sexual functioning and method of delivery: summary of the evidence J Midwifery Womens Health 2004;49:430–6.

[52] Glazener CMA Sexual function after childbirth: women’s experiences, persistent morbidity and lack of professional recognition Br J Obstet Gynaecol 1997;104:330–5.

[53] Connolly A, Thorp J, Pahel L Effects of pregnancy and childbirth on postpartum sexual function: a longitudinal prospective study Int Urogynecol J Pelvic Floor Dysfunct 2005; 16:263–7, Signorello LB.

[54] Signorello LB, Harlow BL, Chekos AK, et al Postpartum sexual functioning and its tionship to perineal trauma: a retrospective cohort study of primiparous women Am J Ob- stet Gynecol 2001;184:881–90.

rela-New Forms of Contraception

Kristen A Plastino, MDa,*, 1

, Patricia J Sulak, MDb,2

a Department of Obstetrics & Gynecology, University of Texas Health Science Center

at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA

b Department of Obstetrics & Gynecology, Texas A&M University System Health Science Center College of Medicine, Scott & White Hospital, 2401 S 31st St., SLAB,

Rm 109, Temple, TX 76508, USA

The United States unfortunately has one of the highest unintended nancy and abortion rates in developed countries [1], even though highlyeffective reversible methods are available, some approaching or equalingthe efficacy of sterilization In addition to decreasing a woman’s risk of preg-nancy, many of the hormonal methods reduce monthly menstrual symp-toms, regulate cycles, improve complexion, and decrease cancer risks.Women can expect more from their contraception besides birth controland have many more options today than in the past

preg-New formulations of combined estrogen and progestin regimens have viated from the standard regimen of 21 active pills and 7 days of placebos todecrease monthly hormone-withdrawal symptoms and withdrawal bleeding.Also, women are using hormonal contraceptives for noncontraceptive ben-efits such as reducing the risk of ovarian and endometrial cancer A variety

de-of delivery systems, including oral, intramuscular, transdermal, nal, intrauterine, and subdermal methods, also are available to assist withcompliance and side effects Permanent contraception is available as anin-office procedure in which tubal occlusion devices are placed hysteroscopi-cally with minimal postoperative pain

* Corresponding author.

E-mail address: plastino@uthscsa.edu (K.A Plastino).

0889-8545/08/$ - see front matter Published by Elsevier Inc.

35 (2008) 185–197

for 20 days each month[2] All the patients failed to ovulate during ment [2] Rock and his colleagues had discovered a reversible method tocontrol fertility Following this discovery, pharmaceutical companies devel-oped various combinations of OCPs In the late 1970s the relationship be-tween steroid dose and adverse cardiovascular events was noted, resulting

treat-in dramatic lowertreat-ing of estrogen and progesttreat-in doses and eventual removal

of high-dose formulations from the market The approach remains, after

40 years, to use the lowest doses of steroids to provide the most effectivecontraception

The standard regimen of hormonal contraception has been 21 days of trogen and progestin components followed by 7 hormone-free days (the 21/7regimen) This regimen mimicked the average cycle length of 28 days, en-sured a nonpregnant state, and allowed a brief drug holiday As hormonedoses continued to decrease over 40 years, however, decreased pituitary-ovarian suppression and increased monthly hormone-withdrawal symptomswere noted during the 7-day hormone-free interval (HFI) In 1997 a studywas published suggesting extending the duration of active oral contraceptivepills to manage hormone-withdrawal symptoms [3] such as menstrualmigraines These symptoms were described in more detail in 2000 whenmore than 250 women, receiving combined OCPs containing 35 mg or less

es-of ethinyl estradiol (EE), recorded symptoms in daily diaries while takingthe 21 active pills and during the 7-day HFI Pelvic pain, headaches, breasttenderness, bloating, and the use of pain medications were all significantlyhigher during the 7-day HFI than during the 21 active-pill days (Table 1)[4]

In addition to increased hormone-withdrawal symptoms during the HFI,greater pituitary-ovarian activity was noted with low-dose 21/7 regimens.Sullivan and colleagues[5]in 1999 randomly assigned 58 women to standard21/7 regimen or to a 24/4 regimen with 24 active pills and only a 4-day HFI.Six of the cycles in the 21/7 group had luteinized unruptured follicles, andone ovulation occurred; neither of these occurred with the 24/4 regimen.Serum hormone measurements also confirmed incomplete pituitary-ovariansuppression with increases in follicle-stimulating hormone and estradiolnoted during the 7-day HFI, a finding that was reduced dramatically withthe 4-day HFI regimen

Table 1

Hormone-withdrawal symptoms in oral contraceptive users

Symptom 21 Active pills (%) 7 Hormone-free pills (%) P-value

Data from Sulak PJ, Scow RD, Preece C, et al Hormone withdrawal symptoms in oral traceptive users Obstet Gynecol 2000;95:261.

con-Since the 1970s, it has been common practice to use OCPs to suppress theformation of ovarian cysts Early studies, with higher-dose formulations of

50 mg of EE or greater, demonstrated a 40% to 70% reduction in the tion of these cysts[6] Because estrogen and progestin dosing in OCPs hasdecreased, this suppression has been limited Holt and colleagues [7]per-formed a case-control study of 18- to 39-year-old women taking 35-mg EEmonophasic OCPs or less-than-35-mg EE monophasic and multiphasicOCPs over 6 months She concluded that low-dose monophasic and multi-phasic OCP use with a 7-day HFI had little or no effect on the development

forma-of functional ovarian cysts [7] Therefore, as OCP dosing has decreased,many reasons have surfaced to modify the 21/7 contraception regimen, in-cluding common hormone-withdrawal symptoms, development of func-tional ovarian cysts, and possible ovulation with unintended pregnancy

Of importance, the monthly withdrawal bleeding is artificial, unnecessary,has no health benefits, and can be associated with other symptoms Severalmodifications of the 21/7 regimen have been approved by the Food andDrug Administration (FDA) that provide greater pituitary-ovarian suppres-sion Some of these newer formulations can alter the frequency ofmenstruation

Around the world, most women want to menstruate monthly or at least

to menstruate a few times per year [8–10] Patient desires regarding strual frequency must be elicited to decide which type of OCP will fit theirneeds The ideal regimen for patients who prefer the reassurance of monthlybleeding is to shorten the HFI and increase the number of active-pill days.Multiple studies have been documented decreased endogenous ovarian hor-mone levels if the HFI is 3 or 4 days instead of 7 days[11–13] Willis andcolleagues[11]administered a standard 21/7 regimen and then randomly as-signed the same patients to either a 21/3 or 21/4 regimen Blood sampleswere obtained daily surrounding the HFI to measure follicle-stimulatinghormone, luteinizing hormone, estradiol, and inhibin-B Greater pituitaryand ovarian suppression were seen with the shortened HFI Hormone levelsdid not differ between the 3- and 4-day HFI groups Schlaff and colleagues

men-[12]compared three groups of patients taking (1) a standard 21/7 regimen of

EE, 20 mg, and levonorgestrel, 100 mg; or (2) a continuous regimen of

28 days of EE, 20 mg, plus desogestrel, 150 mg, with no HFI; or (3)

21 days of EE, 20 mg, plus desogestrel, 150 mg, with 2 placebo days and

5 days of EE, 10 mg Subjects using the oral contraceptive with a 7-dayHFI experienced the least suppression The FDA has approved two oralcontraceptives that shorten the HFI to 4 days and increase the active com-ponent to 24 days One contains 20 mg of EE and 3 mg of drospirenone Theother contains 20 mg of EE and 1 mg of norethindrone

Knowing that some women may want fewer scheduled withdrawal bleeds

in a year and that the HFI and withdrawal bleeding during this time isunnecessary, many practitioners used extended regimens in an off-label fash-ion In 2003 the FDA approved the first extended regimen, levonorgestrel,

0.15 mg, and EE, 0.03 mg, consisting of 84 combined active pills and a 7-dayHFI This 91-day cycle induced four withdrawal bleeds per year but was as-sociated with breakthrough bleeding and spotting Earlier studies reportedthe use of a 21/2/5 regimen in which there were 21 days of EE (20 mg)plus desogestrel (150 mg), 2 placebo days, and 5 days of low-dose EE(10 mg) Greater ovarian suppression was noted with the 21/2/5 regimenthan with the typical 21/7 dosing, and improved bleeding profiles alsowere observed [14] This experience led to the development of an FDA-approved continuous OCP regimen in 2006 This regimen contained 150

mg of levonorgestrel and 30 mg of EE for 84 days followed by 7 days oflow-dose EE (10 mg), again allowing four withdrawal bleeds per year butimproving the bleeding profile A prospective, randomized study of 21/7,84/7, and 84/7 EE regimens confirmed greater pituitary-ovarian suppressionwith low-dose EE added to the 7-day interval[15]

As women age, they tend to desire less monthly bleeding [8–10] mens have been designed to eliminate monthly menses entirely Practitionershave been prescribing continuous regimens off-label for years Small studieswith continuous OCPs have reported 49%, 68%, and 88% of women with

Regi-no bleeding during 2-month, 6-month, and 12-month cycles, respectively

[16] Other studies have shown a similar reduction in sanitary protectionuse and significantly less bloating and menstrual pain[17] Currently there

is only one FDA-approved product (90 mg of levonorgestrel and 20 mg of

EE daily) for patients who do not want scheduled monthly bleeding)

Vaginal ring

The vaginal contraceptive ring has been studied for 30 years[2] The onlyone currently available in the United States comes in one size, 54 mm in di-ameter and 4 mm in thickness It releases 15 mg of EE and 120 mg of etono-gestrel per day It is approved for use in the vagina for 21 days and thenshould be removed for 7 days, in a typical 21/7 regimen There is enoughsteroid hormone in the ring to inhibit ovulation for more than 21 days, how-ever[18] Barreiros and colleagues[19]prospectively evaluated 75 volunteersusing a 15-mg EE/120-mg etonogestrel ring for 84 days followed by a 7-dayHFI Eighty-five percent of patients had adequate menstrual patterns.Miller and colleagues[20]also compared bleeding patterns and the tolerabil-ity of continuous use of the same contraceptive ring Bleeding days werereduced, but breakthrough spotting (BTS) was increased, as in continuousOCP dosing

Breakthrough bleeding

The most common side effect of these extended contraceptive regimens, cluding the 91-day and 365-day cycles, is breakthrough bleeding (BTB) The

in-occurrence of BTB or BTS is not predictable and, if not managed correctly,can lead to discontinuation Instituting an abbreviated HFI has been shown

to be effective in managing BTB In a retrospective study, patients instructed

to take a 3- to 4-day HFI for BTB rarely discontinued oral contraceptivesbecause of bleeding[21] This management also was studied prospectively

If more than 7 days of BTB/BTS occurred while using extended oral ceptive regimens, patients were assigned randomly a 3-day HFI or to continu-ing the extended regimen Patients must have taken a minimum of 21consecutive active pills before a 3-day HFI could be instituted to ensure con-traceptive efficacy Randomization to a 3-day HFI was more effective (P !.001) than continuing the extended regimen in resolving the BTB/BTS[22].Noncontraceptive uses of combined contraceptives

contra-Overall, many patients accept OCPs as their method of contraception, andwomen use OCPs for other indications The most common noncontraceptiveuse of estrogen and progestin contraceptives is to control menstrual cyclebleeding Menorrhagia[23], dysfunctional uterine bleeding [24], treatment

of anemia caused by menses, and a reduction in menstrual frequency for orders such as von Willebrand’s syndrome[25]are all off-label uses of OCPs.Management of pelvic pain caused by dysmenorrhea, of ovulatory pain, and

dis-of endometriosis, as well as skin conditions such as acne and hirsutism[26],also are common indications for oral contraceptive use As women are delaychild bearing, the risks of ovarian and endometrial cancer increase Estrogenand progestin contraceptives have been shown consistently to help preventovarian and endometrial cancer in epidemiologic findings [27] There issome evidence that colon cancer may be reduced in OCP users as well[28].Newer continuous estrogen and progestin regimens also have shown multiplebenefits, including reductions in bleeding[16,17,22], pelvic pain[17], menstru-ation-associated headaches[29], and premenstrual symptoms[30]

Several studies have noted that 21/7 OCP regimens often show little or noimprovement in premenstrual symptoms and actually may induce symptoms

[31–33] Modifying the 21/7 regimen to a 24/4 or continuous regimen does crease premenstrual-type symptoms[30] Today, data support the use of OCPsfor signs and symptoms of premenstrual syndrome and premenstrual dys-phoric disorder (PMDD)[34,35] Therefore, patients requesting contracep-tion and having a history of PMDD should be offered OCPs because theywill reduce the risk of pregnancy and now have been shown to decrease thesigns and symptoms of premenstrual syndrome and PMDD significantly Atthis time, the FDA has approved only one OCP for the indication of PMDD.Adverse effects

de-In most patients, the benefits of combination contraceptive regimensoutweigh the rare risks, but patients must be screened carefully for

contraindications to combination contraceptives (Box 1)[2] Venous boembolic events are increased in OCP users, but the incidence has de-creased with formulations containing 35 mg of EE or less Patientsexperiencing a venous thromboembolic event while taking OCPs should

throm-be screened for the presence of a hypercoagulable state Arterial events cluding cerebrovascular accidents and myocardial infarctions are extremelyrare in OCP users and usually occur in the presence of risk factors such ashypertension and smoking [36] Also, the risk of gallbladder disease in-creases in current and long-term users of estrogen and progestin contracep-tion The same authors concluded that body mass index remains thestrongest predictor of symptomatic gallstones among young women [37].The risk of breast cancer in OCP users is confusing A retrospective study

in-of BRCA1- and BRCA2-positive breast cancer survivors revealed no dence that OCP use for at least 1 year increases the risk of breast cancer be-fore age 50 years BRCA2 mutation carriers who used OCPs for at least

evi-5 years did have an increased risk of breast cancer, however [38] A analysis published in October, 2006 supported the belief that the risk ofpremenopausal breast cancer is increased, especially with use before a firstfull-term pregnancy in parous women [39] Finally, a study in 2002 inter-viewed 4575 women who had breast cancer and 4682 controls The relativerisk (RR) of breast cancer was estimated using conditional logistic regres-sion For women currently using OCPs, the RR was 1.0, and for thosewho had previously used OCPs, the RR was 0.9 Also, the use of OCPs

meta-by patients who had a family history of breast cancer was not associatedwith an increased risk of breast cancer The authors concluded that among

Box 1 Absolute contraindications to the use

Markedly impaired liver function

Known or suspected breast cancer

Undiagnosed abnormal vaginal bleeding

Known or suspected pregnancy

Smokers over age 35 years

Severe hypercholesterolemia or hypertriglyceridemia

Elevated blood pressure

Data from Speroff L A clinical guide for contraception 4th edition Portland (OR): Lippincott Williams & Wilkins; 2005.

women aged 35 to 64 years current or former OCP use was not associatedwith a significantly increased risk of breast cancer[40] Therefore, data re-garding breast cancer remain conflicting but seem to indicate no increasedrisk of breast cancer in OCP users or previous users.

Contraceptive users want to know about these risks but also want toknow less life-threatening side effects such as weight gain Many studieshave concluded that there is no increase in weight among users of combina-tion oral contraceptives[41–44] Self-reported side effects in women takingOCPs were evaluated over 6 months, and subjects reported no change inweight [41] A prospective, randomized, observational study evaluated

145 women taking OCPs and 218 controls Again, there was no relation tween OCP use and weight gain[42] Finally, Lloyd and colleagues[44]eval-uated 9 years of longitudinal data from 66 women and reported there was noassociation between OCP use and weight gain or increased body fat As dis-cussed previously, many side effects associated with OCP use, such as head-aches, bloating, and breast tenderness, may be seen during the 7-day HFI.These side effects may be reduced with newer formulations that modify oreliminate the HFI[3,4,29,30]

be-Quick-start method

The classic counseling for starting OCP use has been to have the patientstart taking the pills on the Sunday after her menses begin or on Sunday ifher menses begin on that day The reasoning behind this method was toavoid giving contraceptive hormones to a pregnant patient It now is knownthat exposure to contraceptive hormones early in pregnancy is not harmful

[45] Having a patient start using a contraceptive method 3 weeks after theprescription is written gives the patient a long exposure time without any re-duction in risk of pregnancy The quick-start method, which was described

by Westoff and colleagues[46], allows the woman to swallow her first pill inthe clinic after proper counseling and a negative sensitive urine pregnancytest The patient then is given a prescription for the remainder of the packs.Women who were assigned randomly to quick start were three times morelikely than women who started OCP use following a traditional method

to continue OCP use until the second pack

Levonorgestrel intrauterine system

Patients who want reversible contraception and do not want to take

a daily pill or who have contraindications to OCPs have many other tions The levonorgestrel intrauterine system contains a steroid reservoirthat delivers 20 mg of levonorgestrel per day to the endometrium and sur-rounding tissues The contraceptive action of the system is threefold There

op-is a foreign body reaction to the endometrium and thickening of cervical

mucous causing a spermicidal environment, and the progestin causes a ualized endometrium unfavorable to implantation Finally, the intrauterinesystem produces low serum concentrations of progestin, but most womenare ovulatory after the first year of use[2] It is highly effective, with a failurerate of 0.1% per year[2] About 50% of women become amenorrheic 1 yearafter insertion [47,48], allowing noncontraceptive benefits including thetreatment of menorrhagia and dysmenorrhea caused by fibroids, adenomyo-sis, and endometriosis[49,50] The levonorgestrel intrauterine system is rec-ommended for women who have had at least one child, are in a stable,mutually monogamous relationship, have no history of pelvic inflammatorydisease, and have no history of ectopic pregnancy or condition that wouldpredispose them to ectopic pregnancy[51] It is FDA approved for use up

decid-to 5 years and then should be removed or replaced

of action is inhibition of ovulation It also works by increasing the thickness

of the cervical mucus, providing a sperm barrier and causing atrophy of theendometrium, which may prevent implantation if fertilization were to occur.Despite the ovulatory inhibition, follicular development does occur, pre-venting a hypoestrogenic state; therefore, bone metabolism is not affectedadversely The etonogestrel implant is a highly effective method of birth con-trol with a 0.01% failure rate during the first year of use[2] In fact, etono-gestrel concentrations are affected very little by body weight, and failurerates do not increase with increasing body weight [2] The implant must

be inserted and removed by a trained clinician The most common side effect

is a change in bleeding pattern [52], which tends to be the most commoncause for early discontinuation[53,54] Amenorrhea occurs in 20% of eto-nogestrel users during the first year of use and in up to 40% of users afterthe first year, however[55,56] The metabolic effects of the implant on liverfunction, cholesterol, clotting, and insulin resistance are minimal and arenot clinically significant[57–62] Fertility returns rapidly following implantremoval, and pregnancy rates are usually no different from those in patientsdiscontinuing any other contraceptive method[63]

Vaginal sponge

For patients who choose to use a nonhormonal option, the vaginalsponge has returned to the market with FDA approval The soft,

1.75-inch by 0.5-inch nonprescription sponge contains the spermicide oxynol-9 It can be inserted hours before a woman has intercourse andcan remain in her body for up to 24 hours without needing additional sper-micide with each act of sexual intercourse By wetting the sponge thoroughlywith tap water before insertion, leaving it in place for 6 hours after the lastact of intercourse, and having it in place every time intercourse occurs,women can expect a use-effectiveness rate of 84% to 87%, dependingwhether the woman is parous Toxic shock syndrome has been reportedwith use, and therefore use of the sponge is contraindicated during menstru-ation Another precaution is to ensure that women do not leave the sponge

non-in place for longer than 30 hours[64,65]

Permanent contraception

Nonhormonal contraceptive options also include barrier methods, thecopper intrauterine device, natural family planning, and permanent options.Permanent options should be considered only when the patient is certainthat she does not desire any further childbearing Tubal occlusion via theabdominal approach has been popular since the 1960s, with 27% of womenundergoing such a procedure and typical first-year failure rates of 0.4%[2].Another permanent option includes tubal occlusion via the transcervicalapproach, which was described first in the mid-nineteenth century usingchemical cautery[66] Since then, chemical, mechanical and thermal occlu-sion methods have been tried An hysteroscopically placed hybrid metallicand fiber coil is another permanent birth control device A rapidly expand-ing outer coil anchors the device in place while the polyethylene terephthal-ate fibers promote luminal fibrous tissue growth over 3 months The devicecan be placed hysteroscopically in the office with a paracervical block with

or without intravenous sedation Postoperative pain is minimal immediatelyand 4 weeks following the procedure[67] A hysterosalpingogram must beperformed at 3 months to assess tubal occlusion, and another method ofcontraception must be used during this 3-month period Bilateral tubal oc-clusion has been demonstrated in 96% and 99.5% of women at 3 and

12 months, respectively[66] A similar device is currently undergoing opment, and another hysteroscopically placed tubal occlusion device isawaiting FDA approval It combines controlled thermal injury to the inter-stitial portion of the fallopian tube and insertion of a silicone matrix withinthe tubal lumen to cause tissue growth inside the tubal lumen producing oc-clusion The transcervical approach has good occlusion rates, high patientacceptability, and can be done in an outpatient setting[66]

devel-Male hormonal methods

Men have few options to control their fertility Condoms and withdrawalare required with each act of intercourse and can be cumbersome,

unpleasant, and have high failure rates Vasectomy has a high success ratebut is permanent Male hormonal manipulation is difficult because sper-matogenesis is constant, not cyclic like ovulation Research currently is fo-cusing on hormonal methods (eg, stimulating OCPs) for men to inhibitspermatogenesis via the hypothalamic-pituitary axis, but add-back hor-mones may be necessary.

A Cochrane Database of Systematic Reviews search of 30 studies in 2007concluded that no male hormonal contraceptive is ready for clinical use Theprimary focus was on sperm counts Multiple hormonal regimens were usedincluding levonorgestrel implants with injectable testosterone or transder-mal testosterone, desogestrel, norethisterone enanthate, and 7-alpha-methyl-19-nortesterone The major differences between the studies werethe dosage form and dose of testosterone and the amount of add-back ther-apy Finally, the investigators suggested that trials with more detailed meth-odologic requirements, including randomized, controlled trials, and trialswith more power were needed before any male hormonal contraceptive istaken to market[68]

Summary

Women have many options regarding contraception New formulations,products, and dosing give women options to improve compliance, monthlywithdrawal bleeding, and satisfaction with the contraceptive choice A pa-tient’s desire for a long- or short-term method, for one that is reversible

or permanent, and her belief that she can be compliant with the methodall factor into the choice of contraceptive method Practitioners must discusscoexisting conditions, contraindications, and whether the patient desiresscheduled monthly bleeding or if she will tolerate unscheduled bleeding Fi-nally, cost and coverage by insurance tends to be one of the most importantfactors in choosing the method of contraception Patients have manychoices and want more than just birth control

regi-[6] Functional ovarian cysts and oral contraceptives Negative association confirmed surgically.

A cooperative study JAMA 1974;228:68–9.

[7] Holt VL, Cushing-Haugen KL, Daling JR Oral contraceptives, tubal sterilization, and tional ovarian cyst risk Obstet Gynecol 2003;102:252–8.

func-[8] Shields WC What women don’t know about contraception Health Sex 1996;5:6–7 [9] den Tonkelaar I, Oddens BJ Preferred frequency and characteristics of menstrual bleeding

in relation to reproductive status, oral contraceptive use, and hormone replacement therapy use Contraception 1999;59:357–36.

[10] Wiegratz I, Hommel HH, Zimmermann T, et al Attitude of German women and ogists towards long-cycle treatment with oral contraceptives Contraception 2004;69: 37–42.

gynecol-[11] Willis SA, Kuehl TJ, Spiekerman AM, et al Greater inhibition of the pituitary-ovarian axis

in oral contraceptive regimens with a shortened hormone-free interval Contraception 2006; 74:100–3.

[12] Schlaff WD, Lynch AM, Hughes HD, et al Manipulation of the pill-free interval in oral traceptive pill users: the effect on follicular suppression Am J Obstet Gynecol 2004;190: 943–51.

con-[13] Spona J, Elstein M, Feichtinger W, et al Shorter pill-free interval in combined oral ceptives decreases follicular development Contraception 1996;54:71–7.

contra-[14] Killick SR, Fitzgerald C, Davis A Ovarian activity in women taking an oral contraceptive containing 20 microg ethinyl estradiol and 150 microg desogestrel: effects of low estrogen doses during the hormone-free interval Am J Obstet Gynecol 1998;179:S18–24.

[15] Vandever M, Kuehl T, Sulak PJ, et al Evaluation of pituitary-ovarian axis suppression with three oral contraceptive regimens Contraception 2008;77:162–70.

[16] Miller L, Hughes JP Continuous combination oral contraceptive pills to eliminate drawal bleeding: a randomized trial Obstet Gynecol 2003;101:653–61.

with-[17] Kwiecien M, Edelman A, Nichols MD, et al Bleeding patterns and patient acceptability of standard or continuous dosing regimens of a low-dose oral contraceptive: a randomized trial Contraception 2003;67:9–13.

[18] Dieben TO, Roumen FJ, Apter D Efficacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring Obstet Gynecol 2002;100:585–93.

[19] Barreiros FA, Guazzelli CA, de Araujo FF, et al Bleeding patterns of women using extended regimens of the contraceptive vaginal ring Contraception 2007;75:204–8.

[20] Miller L, Verhoeven CH, Hout J Extended regimens of the contraceptive vaginal ring: a domized trial Obstet Gynecol 2005;106:473–82.

ran-[21] Sulak PJ, Carl J, Gopalakrishnan I, et al Outcomes of extended oral contraceptive regimens with a shortened hormone-free interval to manage breakthrough bleeding Contraception 2004;70:281–7.

[22] Sulak PJ, Kuehl TJ, Coffee A, et al Prospective analysis of occurrence and management of breakthrough bleeding during an extended oral contraceptive regimen Am J Obstet Gynecol 2006;195:935–41.

[23] Davis A, Godwin A, Lippman J, et al Triphasic norgestimate-ethinyl estradiol for treating dysfunctional uterine bleeding Obstet Gynecol 2000;96:913–20.

[24] Kriplani A Medical management of dysfunctional uterine bleeding Int J Gynaecol Obstet 2001;75:199–201.

[25] Kadir RA, Sabin CA, Pollard D, et al Quality of life during menstruation in patients with inherited bleeding disorders Haemophilia 1998;4:836–41.

[26] The ESHRE Capri Workshop Group Noncontraceptive health benefits of combined oral contraception Hum Reprod Update 2005;11:513–25.

[27] La Vecchia C, Altieri A, Franceschi S, et al Oral contraceptives and cancer: an update Drug Saf 2001;24:741–54 Program interference.

[28] Fernandez E, La Vecchia C, Balducci A, et al Oral contraceptives and colorectal cancer risk:

a meta-analysis Br J Cancer 2001;84:722–7.

[29] Sulak P, Willis S, Kuehl T, et al Headaches and oral contraceptives: impact of eliminating the standard 7-day placebo interval Headache 2007;47:27–37.

[30] Coffee A, Kuehl T, Willis S, et al Oral contraceptives and premenstrual symptoms: ison of a 21/7 and extended regimen Am J Obstet Gynecol 2006;195:1311–9.

compar-[31] Graham CA, Sherwin BB A prospective treatment study of premenstrual symptoms using

a triphasic oral contraceptive J Psychosom Res 1992;36:257–66.

[32] Backstrom T, Hansson-Malmstrom Y, Lindhe BA, et al Oral contraceptives in strual syndrome: a randomized comparison of triphasic and monophasic preparations Con- traception 1992;46:253–68.

premen-[33] Joffe H, Cohen LS, Harlow BL Impact of oral contraceptive pill use on premenstrual mood: predictors of improvement and deterioration Am J Obstet Gynecol 2003;189:1523–30 [34] Yonkers KA, Brown C, Pearlstein TB, et al Efficacy of a new low-dose oral contracep- tive with drospirenone in premenstrual dysphoric disorder Obstet Gynecol 2005;106: 492–501.

[35] Pearlstein TB, Bachmann GA, Zacur HA, et al Treatment of premenstrual dysphoric der with a new drospirenone-containing oral contraceptive formulation Contraception 2005;72:414–21.

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[37] Grodstein F, Colditz GA, Hunter DJ, et al A prospective study of symptomatic gallstones in women: relation with oral contraceptives and other risk factors Obstet Gynecol 1994;84: 207–14.

[38] Haile RW, Thomas DC, McGuire V, et al BRCA1 and BRCA2 mutation carriers, oral traceptive use, and breast cancer before age 50 Cancer Epidemiol Biomarkers Prev 2006;15: 1863–70.

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pre-[40] Marchbanks P, McDonald J, Wilson H Oral contraceptives and the risk of breast cancer.

[48] Hidalgo M, Bahamondes L, Perrotti M, et al Bleeding patterns and clinical performance of the levonorgestrel-releasing intrauterine system (Mirena) up to two years Contraception 2002;65:129–32.

[49] Peterson HB, Curtis KM Clinical practice Long-acting methods of contraception N Engl

J Med 2005;353:2169–75.

[50] Milsom I, Andersson K, Andersch B, et al A comparison of flurbiprofen, tranexamic acid, and a levonorgestrel-releasing intrauterine contraceptive device in the treatment of idio- pathic menorrhagia Am J Obstet Gynecol 1991;164:879–83.

[51] Mirena [package insert] Bayer Healthcare Pharmaceuticals (ed), Wayne, NJ, 2006 [52] Power J, French R, Cowan F Subdermal implantable contraceptives versus other forms of reversible contraceptives or other implants as effective methods of preventing pregnancy Cochrane Database Syst Rev 2007;(1):CD001326.

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a single-rod hormonal contraceptive implant (Implanon) in healthy women in China Eur

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[57] Cagnacci A, Tirelli A, Cannoletta M, et al Effect on insulin sensitivity of Implanon vs GnRH agonist in women with endometriosis Contraception 2005;72:443–6.

[58] Biswas A, Biswas S, Viegas OA Effect of etonogestrel subdermal contraceptive implant planon) on liver function testsda randomized comparative study with Norplant implants Contraception 2004;70:379–82.

(Im-[59] Biswas A, Viegas OA, Roy AC Effect of Implanon and Norplant subdermal contraceptive implants on serum lipidsda randomized comparative study Contraception 2003;68:189–93 [60] Dorflinger LJ Metabolic effects of implantable steroid contraceptives for women Contra- ception 2002;65:47–62.

[61] Biswas A, Viegas OA, Coeling Bennink HJ, et al Implanon contraceptive implants: effects

on carbohydrate metabolism Contraception 2001;63:137–41.

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[64] McClure DA, Edelman DA Worldwide method effectiveness of the Today vaginal ceptive sponge Adv Contracept 1985;1:305–11.

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[66] Abbott J Transcervical sterilization Curr Opin Obstet Gynecol 2007;19:325–30 [67] Syed R, Levy J, Childers ME Pain associated with hysteroscopic sterilization JSLS 2007;11: 63–5.

[68] Grimes DA, Lopez LM, Gallo MF, et al Steroid hormones for contraception in men Cochrane Database Syst Rev 2007;(1):CD004316.

Human Papilloma Virus – Prevention

and Treatment

Maria Lina Diaz, MDSection of Ambulatory Gynecology, Cleveland Clinic Florida,

2950 Cleveland Clinic Blvd., Weston, FL 33331, USA

The accumulated wealth of information and knowledge regarding therelationship between the human papilloma virus (HPV) and many diseasescontinues to expand This has been fueled in part by the development ofvaccines, which for the first time in history offer primary prevention againstmany HPV-related diseases The burden of HPV infections and their conse-quences is a serious concern worldwide in terms of costs to society andhuman suffering It is estimated that 20 million Americans and 630 millionpersons worldwide are infected with HPV [1] HPV is a double-strandedDNA virus Over 100 strains have been discovered in people, approximately

35 strains having affinity for genital sites [2] Two general categories ofgenital HPV are high-risk HPV and low risk-HPV The low-risk strainsare responsible for genital warts and recurrent respiratory papillomatosis(RRP), as well as low-grade cervical lesions Two types, 6 and 11, accountfor over 90% of genital warts and most cases of RRP[3] Of the approxi-mately 15 risk HPV types, two strains, 16 and 18 were found to be respon-sible for approximately 70% of cervical cancers worldwide in a 1995 study

of five geographic areas by the International Agency for Research onCancer [4] HPV also is implicated in other cancers in men and women.Genital HPV-related cancers include vaginal, vulvar, penile, and anogenitalcancers [5] Nongenital HPV-related cancers include some head and neckcancers[6] This article reviews gynecologic HPV-related disease, with par-ticular emphasis on prevention and on general guidelines for the treatment

of each condition A full discussion of oncological treatments for variousHPV-related malignancies is not included Because many genital HPV-related diseases share the same prevention strategies, these strategies arediscussed jointly in some sections

E-mail address: diazm2@ccf.org

0889-8545/08/$ - see front matter Ó 2008 Elsevier Inc All rights reserved.

35 (2008) 199–217

Cervical cancer

Women in the United States have enjoyed a steady decline in cervicalcancer incidence since the introduction of the Pap smear in the 1950s [7].The natural history of cervical cancer, which includes a long period of tran-sition from precancer states to cancer, allows for ample opportunity todetect the precancer state and treat it Once detected by patient participation

in an organized screening and surveillance program, cervical precancerousconditions, also known as cervical intraepithelial neoplasia (CIN), can betreated with straightforward procedures These procedures are 90%–95%effective in treating precancer conditions of the cervix and in many casescan be performed in the office with little associated morbidity The Ameri-can Cancer Society predicts 11,070 cases of cervical cancer will occur in

2008 and that 3,870 women will die from this disease the same year[8] Sixtypercent of cervical cancers diagnosed in the United States are in women whohave either never been screened or have not been screened in the past 5 years

[9] Limitations to screening therefore significantly impact the incidence ofcervical cancer and can affect women of lower socioeconomic status Lowersocioeconomic status may be linked to lower educations levels, recent immi-gration to the United States, and other racial issues It is important to re-member, however, that in developing countries the same reduction incervical cancer has not been observed In developing countries, cervical can-cer is one of the top two causes of death in women[10] Alarmingly, in 2004,the World Health Organization predicted a steady increase of cervical can-cer worldwide and estimated that by the year 2050, the annual incidence ofnew cervical cancer cases would be 1 million The contrast between devel-oped and developing countries in cervical cancer incidence is simply theimplementation of an organized Pap smear screening program with appro-priate surveillance It is understood that the necessary prerequisite for thedevelopment of cervical cancer is the presence and the persistence of HPV

[11] There are several well-known risk factors for cervical cancer Many

of these risk factors have been established in numerous studies and includeearly age at onset of sexual activity, multiple sexual partners, having a high-risk sexual partner, and high parity Another risk factor for the development

of cervical cancer is a history of sexually transmitted diseases, specificallyChlamydia trachomatis [12] and herpes simplex virus [13] It has been de-bated whether these sexually transmitted diseases are independent markers

of sexual activity (a known risk factor for cervical cancer) or act alongthe lines of a cocarcinogen through the modulation of the host immunesystem Cigarette smoking also has been shown to be a risk factor for cer-vical cancer through its possible role as a cocarcinogen [14] The long-term use of oral contraceptive pills has been implicated as a cofactor inthe development of cervical cancer [15], particularly adenocarcinoma ofthe cervix [16], but the relationship is not observed with CIN [17] Theuse of oral contraceptive pills therefore should not be denied to otherwise

appropriate candidates based on concerns regarding this relationship munosuppression is also a risk factor for the development of cervical cancer,and increased incidence of cervical cancer is observed in women who haveHIV infection[18]and in transplant recipients[19].

Im-Clinical symptoms associated with cervical cancer include abnormalvaginal bleeding, postcoital bleeding, and vaginal discharge Pelvic or lowerback pain with radiation to the lower extremities is also concerning, as is thepresence of significant bowel or urinary symptoms The diagnosis of cervicalcancer sometimes is made by cytology, colposcopy, or histology of colpo-scopy-directed biopsies In advanced cases, the diagnosis may be madeclinically, particularly when the cervix has been replaced by tumor Thehistopathology of cervical cancer is such that 80% of cervical cancers aresquamous cell carcinomas, with 15% adenocarcinomas and the remaining3% to 5% adenosquamous [20] The staging of cervical cancer is based

on clinical criteria The most widely used staging system for cervical cancer

is The International Federation of Gynecologists and Obstetricians System(FIGO) This system allows clinical evaluation through physical examina-tion, the use of colposcopy and histology from endocervical curettage andconization, hysteroscopy, cystoscopy, proctoscopy, intravenous pyelogram,and radiographic examination of the lungs and the skeleton[21] Treatment

of cervical cancer depends on the stage of the malignancy and other factorssuch as patient comorbidities Surgical approaches include radical hysterec-tomy with lymphadenectomy Radiotherapy also has been a mainstay in thetreatment of advanced disease Detailed discussion of the treatment of cer-vical cancer is beyond the scope of this treatise

Cervical intraepithelial neoplasia

HPV has been associated with cytologic abnormalities and the ment of CIN Traditionally, CIN has been divided into three histologiccategories, CIN 1, CIN 2, and CIN 3, based on the degree of involvement

develop-of abnormal cells in the epithelium These categories formerly were referred

to as mild, moderate, and severe dysplasia respectively It is important todifferentiate between cytologic abnormalities (low-grade intraepithelialsquamous lesions [LSIL] and high-grade intraepithelial squamous lesions[HSIL]) and histologic abnormalities (CIN) Treatment based on cytologyalone without a colposcopic evaluation should be avoided In some cases,however, it is acceptable to see and treat, bypassing the colposcopic-directedbiopsy step This approach usually is considered for women who are at risk

to be lost to follow-up and demonstrate a high-grade lesion on colposcopicexamination [22] The 2006 Consensus Guidelines for the Management ofWomen with Cervical Intraepithelial Neoplasia or Adenocarcinoma InSitu[23]provides specific guidelines for treatment based on patient charac-teristics and histologic diagnosis It is understood that CIN 1, particularly

when preceded by the cytologic diagnosis of atypical squamous cell malities (ASC) or LSIL usually is not associated with occult CIN 2, 3 There-fore conservative management is recommended, particularly in adolescentpatients This conservative approach to CIN 1 also is advised when notingthe high regression rates of these lesions[24] The treatment of precancerousconditions of the cervix therefore generally is recommended for treating CIN

abnor-2 and 3 There are no medical treatments for CIN If CIN abnor-2 or 3 has beendocumented with histology (or in some cases colposcopy), accepted methodsfor treatment include ablative procedures and excisional procedures Ablativetherapy includes cryosurgery and carbon dioxide laser ablation, while exci-sional procedures include conization techniques such as LEEP (loop electro-surgical excision) or LLETZ (large loop excision of the transformation zone)and conization, which can be performed with either a scalpel or with laser.When considering ablative treatments, general principles to consider includeabsence of cervical disease in the canal, complete visualization of the lesion,and a clear consensus that invasive disease is not present, as well as concor-dance between cytology and histology It is helpful to stain the cervix withLugol’s solution (an iodine-based contrast solution) to identify the nonstain-ing area and assist in selecting the appropriately sized cryoprobe A nitrogentank with a vaginal probe generally is used A commonly used cryosurgerytechnique is the 3-5-3 freeze cycle With this method, the cervix is treatedfor 3 minutes twice with an intervening 5-minute thaw cycle Through ade-quate visualization of the lateral vagina by selection of an appropriately sizedspeculum and sometimes through the use of tongue depressors to protect thevaginal wall, injury to the lateral vaginal side walls is prevented The patientmay experience mild-to-moderate cramping and occasionally a vasovagal re-action Pretreatment with oral nonsteroidal anti-inflammatory agents is use-ful Postprocedure, patients frequently note copious watery discharge forseveral weeks A concern regarding cryoablation is the regression of the trans-formation zone, making subsequent colposcopic examinations more chal-lenging Carbon dioxide laser ablation also may be used to treat CIN 2 or

3, although expertise in the use of laser is a prerequisite to using this modality.LEEP or LLETZ procedure is an accepted excisional procedure for CIN

2 or 3 This procedure, frequently performed in an outpatient setting, istolerated by most patients The use of Lugol’s staining after the cervix hasbeen exposed sufficiently with a Teflon-coated speculum helps identify thenonstaining area and assists in the selection of the appropriately sizedloop The cervix is infiltrated circumferentially with approximately 10 cc of1% lidocaine and epinephrine in a ratio of 1 to 1000 The speculum shouldhave an attachment for suction of the plume generated during the electro-surgical process A dispersive pad must be applied to the patient and usually

is placed on the anterolateral thigh An electrosurgical generator withfeatures to allow for blending of current is necessary The generator is setbetween 30 and 40 W on the blend setting for the initial pass to removethe transformation zone Additional passes may be necessary if the lesion

is large or to remove an additional endocervical specimen Endocervicalcurettage then can be performed, followed by coagulation with the ballattachment on coagulation current between 30 and 40 W Monsel’s solution

or paste (ferric subsulfate) can be placed in the LEEP crater to furthersecure hemostasis The patient is advised to avoid intercourse for 4 weeks

to prevent trauma to the operative site A follow-up appointment should

be scheduled in 6 weeks to assess healing of the cervix, review the pathologyreport, and schedule appointments for future surveillance

Cold knife conization procedures require the use of a general anesthetic in

a surgical setting This procedure has been reserved for cases in which thepotential thermal artifact at the margin of the conization specimen sometimesnoted with LEEP should be avoided for more accurate pathologic interpreta-tion Such cases include suspected microinvasion or adenocarcinoma of thecervix With the patient fully anesthetized, and the cervix well exposed, staysutures are placed at 3 and 9 o’clock to minimize blood flow through thearea The cervix is infiltrated circumferentially with a vasoconstrictive agentsuch as vasopressin or epinephrine, which can be mixed with a local anes-thetic The application of Lugol’s solution is helpful in delineating thenonstaining area A scalpel on a long handle then is used to carve out acone-shaped specimen Many times, long scissors are used to complete theexcision of the specimen, which traditionally has been sutured at a designatedlocation to allow for orientation during histologic evaluation Many clini-cians submit endocervical curettage after excising the cone specimen Therisk of hemorrhage is the most concerning risk associated with this procedure.Bleeding may be addressed with cautery and suturing of the conization bedand with the application of Monsel’s solution or the application of anoxidized cellulose hemostatic agent held in place by tying the stay sutures

in the midline Subsequent pregnancy complications in patients treatedwith LEEP and cold knife conizations include preterm delivery, low-birth-weight infants, and premature rupture of membranes[25] Patients should

be counseled regarding these risks and can be monitored closely for thesecomplications when they conceive Hysterectomy for CIN disease generally

is not recommended but may be considered if other coexisting gynecologicconditions are present and the patient does not desire future childbearing Ir-respective of treatment modality, it has been observed that success rates areapproximately 90%[26] Several post-treatment follow-up options are avail-able, including repeating high-risk HPV DNA test at 12 months versus re-peating cytology at 6 and 12 months[23]

Prevention strategies for cervical intraepithelial neoplasia

and cervical cancer

Prevention of cervical cancer and CIN may be viewed as two-pronged,with primary and secondary components Primary prevention includesprophylactic vaccination but also can include lifestyle modification As

discussed earlier, there are several known risk factors for the development ofcervical cancer that patients should be educated about, because they may bemodifiable Delaying first intercourse until age 21 affords protection fromcervical cancer by allowing maturation of the transformation zone, making

it less vulnerable to HPV effect Limiting the number of sexual partners isalso important for prevention, as high number of sexual partners is a riskfactor for cervical cancer Avoidance of tobacco use should be emphasized

to women of all ages, not only for general health concerns but also becausetobacco is a known cofactor for the development of cervical cancer Finally,use of latex or vinyl condoms with each and every sexual encounter should

be emphasized to patients who are not in stable mutually monogamousrelationships Although it was initially thought that condoms afforded little

if any protection from HPV transmission, a recent study of newly sexuallyactive college students demonstrated significant protection from HPV infec-tions and CIN in those young women whose partners consistently usedcondoms [27] Additionally, as other sexually transmitted diseases (STDs)have been implicated as cofactors in the development of cervical cancer,the use of condoms should protect against that variable also

The recent breakthrough of the HPV vaccine, the quadrivalent vaccineapproved by the US Food and Drug Administration (FDA) in June 2006,represents the first time in history that girls and women are offered primaryprevention against cervical cancer and other HPV-related diseases Thecurrent available vaccine offers protection from four strains of HPV: 6, 11,

16, and 18 The quadrivalent vaccine was approved by the FDA for theprevention of cervical cancer; cervical precancers (CIN) 2/3 and adenocarci-noma in situ [AIS]; vulvar precancers (vulvar intraepithelial neoplasia [VIN])2/3; and (vaginal precancers vaginal intraepithelial neoplasia [VaIN]) 2/3caused by HPV types 16 and 18 The quadrivalent vaccine also was approvedfor the prevention of genital warts and CIN caused by HPV types 6 and11.The vaccine is approved for girls and women ages 9 to 26 The land-mark study in the development of the HPV vaccine was the proof of prin-ciple study that proved that HPV 16 infections could be prevented insubjects receiving three vaccinations of a monovalent HPV 16 virus-likeparticle (VLP) given on day 0, month 2, and month 6[28] The quadriva-lent HPV phase 2 study demonstrated efficacy in the prevention of HPV6-, 11-, 16-, and 18-related infections; genital warts; and CIN in womenreceiving three doses of HPV 6, 11, 16, and 18 VLPs [29] An extensiontrial of the quadrivalent phase 2 trial demonstrated continued efficacy ofthe vaccine over an additional 2 years[30] Phase 3 trials of the quadriva-lent vaccine, also known as the Future 1 [31] and 2 [32] trials, similarlydemonstrated efficacy and tolerability of the quadrivalent vaccine Thesestudies demonstrated that vaccine efficacy was higher in subjects naı¨ve

to HPV infections studied, but some protection also was observed insubjects who had baseline HPV infections at the onset of the study Thereare ongoing studies in older female populations addressing safety and

efficacy, keeping in mind that lower efficacies may be noted As of the date

of this publication, the bivalent HPV vaccine has not been approved bythe FDA The bivalent vaccine protects against HPV types 16 and 18 Aphase 2 placebo-controlled randomized clinical trial of over 1000 womenages 15 through 25 vaccinated day 0, month 1, and month 6 was 92% ef-ficacious against incident HPV 16 and 18 infections [33] The study alsodemonstrated 100% efficacy in persistence of these two types Addition-ally, a subset of these women has been studied for up to 4.5 years, andefficacy against infections from HPV 16 and 18 has remained intact[34].The Advisory Committee on Immunization Practices has recommendedthat the quadrivalent HPV vaccination programs target females 11 to 12 years

of age [35] Vaccination may begin as early as 9 years of age Catch-upvaccines may be given through the age of 26 years The vaccine can be admin-istered irrespective of HPV status, and HPV DNA testing is not recommen-ded before vaccination[36] The vaccine is administered in a 6-month period,with the following schedule: day 0, month 2, and month 6 The main adverseeffect is irritation at the injection site, (deltoid or anterolateral thigh) and mayinclude pain, swelling, or erythema[37] Contraindications to quadrivalentvaccine administration include allergy or sensitivity to vaccine components,particularly aluminum or yeast A history of blood dyscrasia (which couldlead to hematoma formation at the injection site) is also a contraindication.Protection from HPV strains 16 and 18 has been predicted in vaccination-modeling studies to reduce the rates of cervical cancer by 60% and reduce therisk of cervical cancer related to HPV 16 or 18 by 91% to 95%[38] Studiesappear promising that cross-protection against other high-risk HPV strainsmay be afforded by the HPV vaccines Once specifics of cross-protection areclarified, these figures may be adjusted Cost-effectiveness of vaccination isbalanced against the savings in reduction of disease The cost of continued sec-ondary screening must be factored into this equation, as secondary screening(ie, Pap smears) must not be abandoned in vaccinated populations, keeping inmind that other high-risk HPV strains also may cause disease The cost of

a booster also must be factored into the cost-effectiveness of a vaccine rently, it is unknown if a booster to promote continued immunologic protec-tion will be needed The success of vaccination campaigns is dependent on

Cur-a host of fCur-actors thCur-at include but Cur-are not limited to Cur-accessibility Cur-and Cur-affordCur-abil-ity of vaccines, completion of the entire vaccination protocol, and patient ed-ucation and acceptance of the vaccine

affordabil-Secondary prevention of cervical cancer

As mentioned in previous sections, screening for cervical cancer withcytology has had a dramatic impact on the incidence of cervical cancer inthe United States Until 2006, screening programs were the only tool forpreventing cervical cancer Despite the promise of further disease preventionthrough primary vaccination programs, screening cannot be abandoned, as