PUBLISHING STAFF Cervical Incompetence; PRESIDENT, GROUP PUBLISHER

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OBSTETRICS AND GYNECOLOGY BOARD REVIEW MANUAL

Obstetrics and Gynecology Volume 8, Part 4 1

PUBLISHING STAFFPRESIDENT, GROUP PUBLISHER

Bruce M. White

EDITORIAL DIRECTORDebra Dreger

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Chapter 1—Cervical Incompetence . . . . . . . . . . . . . . . . . . . . . . .2Contributors: Francis S. Nuthalapaty, MD, and

Matthew F. Davies, MD, FACOG

Chapter 2—Clinical Management of Hirsutism and Virilization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Contributors: Paul B. Marshburn, MD, FACOG, Michelle L.Matthews, MD, and Bradley S. Hurst, MD

Table of Contents

Cover Illustration by Scott M. Holladay

Cervical Incompetence;Clinical Management ofHirsutism and VirilizationSeries Editor: Jordan G. Pritzker, MD, MBA, FACOGAssistant Professor, Albert Einstein College of Medicine, Montefiore Medical Center,Bronx, NY, Obstetrics and Gynecology Faculty Practice, Women’s ComprehensiveHealth Center, Long Island Jewish Medical Center, New Hyde Park, NY

Series Editors and Contributors: Matthew F. Davies, MD, FACOGAssociate Professor of Obstetrics and Gynecology, Residency Program Director, Chief,Division of Women’s Health and Division of Medical Education in Obstetrics andGynecology, Pennsylvania State University College of Medicine, Department ofObstetrics and Gynecology, Milton S. Hershey Medical Center, Hershey, PA

Paul B. Marshburn, MD, FACOGDirector, Division of Reproductive Endocrinology and Infertility, Department ofObstetrics and Gynecology, Carolinas Medical Center, Charlotte, NC

Contributors: Francis S. Nuthalapaty, MDMaternal-Fetal Medicine Fellow, Department of Obstetrics and Gynecology, Universityof Alabama at Birmingham, Birmingham, AL

Michelle L. Matthews, MDAssistant Director, Division of Reproductive Endocrinology and Infertility,Department of Obstetrics and Gynecology, Carolinas Medical Center, Charlotte, NC

Bradley S. Hurst, MDDirector, Assisted Reproduction, Division of Reproductive Endocrinology and Infertility,Department of Obstetrics and Gynecology, Carolinas Medical Center, Charlotte, NC

2 Hospital Physician Board Review Manual

I. INTRODUCTION

Cervical incompetence has commonly been describedas painless cervical dilatation leading to recurrent second-trimester pregnancy loss. This description results from theold all-or-nothing concept that the cervix is either com-pletely competent or incompetent. This concept was fur-ther substantiated by an early study that used digital assess-ment of cervical dilation and length but that failed toidentify a degree of incompetence leading to pretermlabor.1 Therefore, cervical incompetence was considereddistinct from the general process of preterm labor. Sincethat time, the ability to more accurately assess cervicalchanges by using ultrasonography has led to the theorythat cervical incompetence is part of a continuum of pre-term labor.2 In this review, we will discuss the evolution ofour understanding of cervical incompetence as well as thecurrent tools available for diagnosis and management ofthis process. The goals of this review are to describe thepathogenesis, clinical features, diagnosis, and manage-ment of cervical incompetence.

II. ETIOLOGY

NORMAL CERVICAL STRUCTURE

Knowledge of normal cervical structure is essential tounderstanding the factors that may contribute to cervicalincompetence. The female genital tract begins develop-ment at the sixth embryologic week. Invagination of thecoelomic epithelium occurs to form the müllerian (para-mesonephric) ducts.3 The uterine cervix is formed byfusion of the most caudal portions of the müllerianducts.4 Nonpregnant cervical tissue is dense and fibrous;it is composed primarily of cross-linked types 1 and 3 col-lagen, elastic tissue, blood vessels, and, to a lesser degree,smooth muscle.5 The proportion of cervical smooth mus-cle increases from 6% at the external os to 29% at theinternal os.6 The transition from the fibrous to musculartissue at the cervicoisthmic junction extends over a 5- to10-mm zone.7 This muscular and elastic zone is respon-sible for retaining the fetus in utero during pregnancy.8

Normal cervical length during the course of gesta-tion and the process of effacement has been deter-mined by transvaginal ultrasound. In the late secondand early third trimesters, cervical length follows anormal distribution with the 50th percentile at about35 mm and the 10th percentile at 25 mm (Figure 1).9

The process of cervical effacement begins at the inter-nal os and proceeds caudally according to the shapeof the letters T, Y, V, and U as shown in Figure 2.10 Thecorresponding biochemical changes in cervical struc-ture are marked by dissolution of the fibrous collagenmatrix.5

RISK FACTORSCongenital Factors

Factors associated with an increased risk for cervicalincompetence can be divided into 3 general categories:congenital, acquired, or other (Table 1). Congenitalfactors—such as a short cervix because of normal bio-logic variation, müllerian abnormalities, and diethyl-stilbestrol (DES) exposure—are among the bestdefined factors. As illustrated in Figure 1, the risk ofspontaneous preterm birth progressively increases ascervical length decreases, beginning with lengths lessthan the 75th percentile. The association of variousmüllerian abnormalities with adverse pregnancy out-comes is well defined. In this population, the reportedrate of early miscarriage is 25% to 38% and the rate ofpreterm delivery is 25% to 47%. Cervical incompetencelikely contributes to a portion of these adverse preg-nancy outcomes.11 Similarly, women exposed to DES inutero have an increased risk of preterm delivery. Thisincreased risk is likely the result of DES-associated gen-ital tract abnormalities, including alterations in cervicallength and composition.12

Acquired Factors

Acquired factors leading to cervical incompetenceresult from the alteration of cervical structure, througheither trauma or iatrogenic events. Both vaginal andcesarean birth can result in extensive cervical trauma.Overzealous mechanical dilatation of the cervix oncewas thought to be the main cause of cervical incompe-tence.13 The overall incidence of cervical injury during

OBSTETRICS AND GYNECOLOGY BOARD REVIEW MANUAL

Chapter 1—Cervical Incompetence

Francis S. Nuthalapaty, MD, and Matthew F. Davies, MD, FACOG

C h a p t e r 1 — C e r v i c a l I n c o m p e t e n c e

mechanical dilation is approximately 1%. However, thisrisk can be reduced 27-fold when preoperative lami-naria are used and the procedure is performed by anexperienced physician under local anesthesia.14

Cervical cone biopsy may increase the risk for cervicalincompetence. Data indicate that the original length ofthe cervix and the extent of the conization are importantfactors. Women with a cervical length less than the 10th to25th percentile range (Figure 1) may be at higher risk forcervical incompetence and preterm birth after coniza-tion. In conjunction with this, data show that a moreextensive laser conization (> 10 mm) is an independentrisk factor for preterm birth. Therefore, in patients with ahistory of conization, ultrasonographic assessment of cer-vical length can help determine the potential risk of cer-vical incompetence and preterm birth.

Other Factors

Uterine overdistension caused by multifetal gesta-tion and polyhydramnios is a theoretical risk factor forcervical incompetence. As with singleton gestations, themost important risk factor for twin gestations is cervicallength. Women carrying twins have approximatelytwice the likelihood of having a short cervix (≤ 25 mm)as women carrying a single fetus.15 Data on the benefitof cerclage for multiple gestations are mixed.16–18

Elevated serum relaxin levels in the late secondtrimester also have been associated with an increasedrisk of preterm birth.19,20 Relaxin is an insulin-like pep-tide hormone that is secreted primarily by the corpus

luteum and achieves its highest serum levels in preg-nancy. The role of relaxin in preterm birth may be relat-ed to its biologic activity in inducing collagen remodel-ing and softening of the tissues of the birth canal.21

However, clinical trials have failed to establish an asso-ciation between relaxin and cervical length.22

III. CLINICAL PRESENTATION AND DIAGNOSISOF CERVICAL INCOMPETENCE

CLINICAL MANIFESTATIONS

Cervical incompetence can have several distinct clini-cal presentations. The diagnosis may be made in the non-pregnant patient based on a classic history of second-trimester loss that occurs without the recognizable clinicalfeatures of labor (Table 2) or associated intra-amnioticinfection. A thorough history and physical examina-tion are essential to making the appropriate diagnosis(Table 3). In the absence of a firm history, several adju-vant tests (such as Foley catheter traction, Hegar dilatorresistance, and hysterosalpingography) have been de-scribed to help establish the diagnosis. However, thesetests are limited by the fact that they are inaccurate andmay not predict the function of the gravid cervix. For thisreason, they are now of historical significance only.23,24

Nulliparous patients, or patients with a previously un-complicated pregnancy, may present acutely in the sec-ond trimester with advanced cervical dilation and bulging


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Figure 1. Distribution of subjects amongpercentiles for cervical length measured bytransvaginal ultrasonography at 24 weeks ofgestation (solid line). Relative risk of sponta-neous preterm delivery before 35 weeks ofgestation according to percentiles for cervi-cal length (bars) is also shown. The risksamong women with values at or below thefirst, fifth, 10th, 25th, 50th, and 75th per-centiles for cervical length are comparedwith the risk among women with valuesabove the 75th percentile. (Adapted withpermission from Iams JD, Goldenberg RL,Meis PJ, et al. The length of the cervix and therisk of spontaneous premature delivery.National Institute of Child Health andHuman Development Maternal Fetal Medi-cine Unit Network. N Engl J Med 1996;334:569. Copyright © 1996 Massachusetts Medi-cal Society. All rights reserved.)


membranes without symptoms of labor or with only vaguesymptoms of vaginal pressure or discharge. The diagnosisof cervical incompetence in these situations is especiallychallenging because of the potential for unrecognizedpreterm labor symptoms; ruptured membranes; or occultintra-amniotic infection, which may have precipitated thecervical change. Although an early gestational age maysuggest cervical incompetence, exclusion of all other fac-tors is necessary to make the diagnosis.

Finally, patients may present during early pregnancywith either a history or risk factors suggestive of cervicalincompetence. Currently, ultrasonography is the mostimportant adjunct to diagnosis in this situation. Thevalue of endovaginal sonography for predicting sponta-neous preterm birth in high-risk patients has been val-idated in well-designed prospective studies.2,25 A cervi-cal length of less than 25 mm at 16 to 18 weeks ofgestation is a significant predictor of spontaneouspreterm birth before 35 weeks.25 Therefore, pregnantwomen with a pregnancy history suggestive of cervicalincompetence or those with risk factors may benefitfrom serial sonographic evaluation of cervical length.Such information can either reassure patients with riskfactors or help identify those who may benefit fromtherapeutic interventions. It is important to note thatthese studies did not identify a single cutoff for cervicallength that completely discriminated between eventualterm and preterm births. This information substanti-ates the concept that cervical incompetence is not anall-or-none phenomenon but that it occurs along acontinuum of preterm labor.

IV. TREATMENT OPTIONS AND OUTCOMES

There is a great deal of uncertainty regarding theoptimal therapy for cervical incompetence. Currently,the most prevalent approaches are either surgical man-agement with cerclage or close observation. There is,however, a paucity of consistent evidence to support thebenefit of either of these management schemes.

CLINICAL TRIALS

Reports of techniques for surgical management of cer-vical incompetence gained prominence in the biomed-ical literature in the 1950s. In 1955, Shirodkar publishedthe first description of his technique.26 Subsequently in1957, McDonald published his modified technique.27

These 2 techniques soon became the most commonlyused methods of transvaginal cerclage. Shortly after theseinitial descriptions, numerous case series described theuse of these techniques in pregnancies complicated bycervical incompetence. These studies reported a broadrange of perinatal survival rates before (10%–40%) andafter (70%–90%) cerclage placement.27 Typically, eachpatient served as her own historical control, which was theprimary cause of the inconsistent data reported in thesecase series. It is known now that many patients (up to70%) with a history of recurrent pregnancy loss can havea subsequent term pregnancy.28 Additionally, it is knownthat the success rate in untreated pregnancy reported insubsequent randomized trials29–32 is higher than previ-ously observed in retrospective case series. Although theselimitations underscore the need for prospective random-ized trials to assess cerclage efficacy, a sentiment that such


Table 1. Risk Factors for Abnormal Cervical Function

Congenital

Congenitally short cervix

Müllerian abnormalities

In utero DES exposure

Acquired

Cervical laceration during childbirth

Prolonged second stage of labor

Instrumental vaginal delivery

Surgical procedures involving the cervix

Others

Uterine overdistension

Elevated serum relaxin levels

DES = diethylstilbestrol.

T Y

V UFigure 2. Schematic representation of the cervical effacementas it proceeds caudad from the internal os, as indicated by theletters T, Y, V, and U. (Reprinted with permission from CreasyRK, Resnick RR, editors. Maternal fetal medicine. 4th ed. Phila-delphia: WB Saunders; 1999:446.)

A B

C D


trials would be unethical, in light of the retrospective data,delayed their eventual implementation.

At least 5 prospective randomized trials have report-ed on the use of prophylactic cerclage (Tables 4 and 5).Lazar et al29 and Rush et al30 published the first ran-domized trials studying prophylactic McDonald cer-clage in women with historical risk factors. These inves-tigators found no significant reduction in preterm birthin the cerclage group but found a higher rate of inter-vention, such as hospital admission, length of stay,tocolytic use, and puerperal infection.

The largest cerclage trial to date was done by theMedical Research Council/Royal College of Obstetriciansand Gynaecologists.31 This multicenter, prospective ran-domized study involved 1292 women who had a history ofearly delivery or cervical surgery and whose physicianswere unsure whether to recommend cerclage. The cer-clage technique was left to the discretion of the surgeon.A statistically significant reduction in preterm birth before33 weeks was observed in the cerclage group (13% versus17%; P = 0.03). The authors noted that this result was ofmarginal significance and translated into the preventionof one preterm delivery for every 25 women who receivedcerclage. As with the previous studies, an increased rate ofinterventions was observed, such as hospital admission,tocolytic use, and puerperal fever. In an associated sub-group analysis, the beneficial effect of cerclage also ap-peared to be greatest for pregnancies characterized by3 or more second-trimester miscarriages or preterm deliv-eries. The authors suggested that a few women who haveclassic clinical risk factors benefit the most from cerclage.

Recent studies have attempted to incorporate ultrasound-detected cervical changes to determinethe benefit of therapeutic cerclage versus expectantmanagement. Rust and colleagues32 conducted a ran-domized study using ultrasound-defined cervical mea-surements to identify women for therapeutic cerclage.Two groups of women were defined. The first groupincluded women who demonstrated a prolapse of the

fetal membranes into the endocervical canal of morethan 25% of the total cervical length. The secondgroup consisted of women who had a distal cervicallength of less than 2.5 cm. In contrast to previous stud-ies, all 61 women were screened initially for subclinicalinfection with amniocentesis and urogenital culturesand were then treated with an empiric antibiotic (clin-damycin) and oral tocolytic (indomethacin) for 48 to72 hours. After reevaluation with transvaginal ultra-sound, the patients were randomly assigned either totherapeutic McDonald cerclage or to no cerclage. Allpatients were discharged after 24 hours and pre-scribed home bedrest, and they underwent serialultrasonographic assessment. No difference was notedbetween the 2 groups in perinatal outcomes, includ-ing gestational age at delivery, the incidence of pre-term birth, and neonatal morbidity.


Table 2. Clinical Criteria for Cervical Incompetence

Painless dilatation of the cervix

Rupture of membranes in the second trimester withoutprior contractions

Delivery of the fetus after a short and relatively painlesslabor

Loss of one or more pregnancies in the second trimesterassociated with these symptoms

Adapted with permission from Barford DA, Rosen MG. Cervicalincompetence: diagnosis and outcome. Obstet Gynecol 1984;64:159.

Table 3. Key Elements of Evaluation for CervicalIncompetence

Medical history

In utero DES exposure

Family history of habitual abortions and congenital defects

Obstetrical and gynecologic history

Detailed history of all prior abortions

Clinical manifestations

Presence of bleeding and/or contractions

Fetal growth restriction

Congenital fetal anomalies

Previous gynecologic surgery performed on the cervix

History of cervical trauma

Terminations—use or non-use of laminaria

Instrumental vaginal deliveries

Cervical lacerations

Cervical conization or LEEP

Physical examination

Survey congenital anomalies of reproductive tract

Assess cervical dilation/effacement

Assess protruding membranes

Tests

Cervical cultures

Ultrasound

DES = diethylstilbestrol; LEEP = loop electrosurgical excision proce-dure.

Adapted with permission from Golan A, Barnan R, Wexler S, et al.Incompetence of the cervix. Obstet Gynecol Surv 1989;44:96–107.


Given these findings, Rust and colleagues extendedtheir study protocol to 113 patients so they could per-form a risk factor analysis to assess the lack of benefit withcerclage.33 The authors constructed regression modelswith gestational age at delivery and neonatal morbidity,respectively, as the dependent variables. Their analysisshowed that in this population, preterm labor, chorio-amnionitis, and abruption consistently were associatedwith early gestational age at delivery and with increasedneonatal morbidity. Based on these combined data, theauthors proposed that cerclage might not have been ben-eficial because the ultrasound-detected cervical changeswere part of a continuum of preterm birth precipitatedby multifactorial subclinical pathophysiologic processes,such as infection, inflammation, and abruption.

Finally, the most recent prospective cerclage trial byAlthuisius and colleagues34,35 compared prophylacticand therapeutic McDonald cerclage with expectantmanagement in women with clinical risk factors. Thestudy population was divided into 3 groups. The first

group consisted of 77 women with a singleton preg-nancy of less than 15 weeks of estimated gestational age(EGA) and a history of a previous preterm birth before34 weeks of EGA who were suspected of having cervi-cal incompetence or who had previous pretermpremature rupture of the membranes (PROM) at lessthan 32 weeks of EGA. This group was randomlyassigned either to prophylactic cerclage or to observa-tion. The second group consisted of 39 women withthe aforementioned risk factors and additional risk fac-tors, such as a history of cervical cold knife conization,DES exposure, or uterine anomalies. Women managedexpectantly in group 1 and all women in group 2 un-derwent serial transvaginal ultrasound to determinetheir cervical length measurement. Thirty-six womenwho developed a cervical length less than 25 mmbefore 27 weeks of EGA were randomly assigned eitherto therapeutic cerclage or to continued observation.The final group consisted of 10 women meeting crite-ria for either group 1 or 2 who additionally underwentserial transvaginal ultrasound and who were found tohave a cervical length less than 25 mm before 27 weeksof EGA. These women also were randomly assignedeither to therapeutic cerclage or to observation. Allwomen who underwent therapeutic cerclage receivedperioperative indomethacin. Final analysis of thesedata by Althuisius and colleagues showed no differencein preterm birth before 34 weeks of EGA when pro-phylactic McDonald cerclage was compared withexpectant management and therapeutic cerclage, ifindicated (Table 4). However, a significantly decreasedrate of preterm birth before 34 weeks (Table 5) anddecreased composite neonatal morbidity (neonatal


Table 5. Summary of Randomized TherapeuticCerclage Trials

Preterm Birth Before 34-weeks Gestation

Trial n % P Value

Althuisius et al (2001)35

Cerclage (n = 19)* 0 0 0.002

No cerclage (n = 16) 7 44

Rust OA et al (2000)32

Cerclage (n = 31)* 12 39 NS


NS = not significant.

*Patients received McDonald cerclage.

Table 4. Summary of Randomized ProphylacticCerclage Trials

Preterm Birth Before 33-weeks Gestation

Trial n % P Value

Althuisius et al (2000)34


Observation ± cerclage (n = 44) 6 14

MRC/RCOG (1993)31

Cerclage (n = 647) 83 13 < 0.05

No cerclage (n = 645) 110 17

Rush RW et al (1984)30



Lazar P et al (1984)29


No cerclage (n = 238) 1 < 1

MRC/RCOG = Medical Research Council/Royal College of Obste-tricians and Gynaecologists; NS = not significant.

*Patients received McDonald cerclage.

Data from Final report of the Medical Research Council/Royal Collegeof Obstetricians and Gynaecologists multicentre randomized trial ofcervical cerclage. Br J Obstet Gynaecol 1993;100:516–23.


intensive care unit [NICU] admission, neonatal death)were noted in the therapeutic cerclage group whencompared with expectant management.

The different results regarding therapeutic McDonaldcerclage between Rust et al33 and Althuisius et al35 aremost likely explained by the difference in study popula-tions. Rust et al performed cervical length measure-ments in patients with a history of preterm birth, where-as Althuisius et al screened patients with risk factors forcervical incompetence. Althuisius and colleagues pointout that both studies incorporated patients with a shortcervical length, which has been shown to be a risk factorfor preterm birth but not necessarily a risk factor for cer-vical incompetence.

MANAGEMENT OPTIONS

Clinicians who encounter patients with risk factorsfor cervical incompetence have several managementoptions. Most of the data seem to indicate that prophy-lactic cerclage in patients with clinical risk factors doesnot improve perinatal outcomes and leads to more in-terventions.29–32,34 However, prophylactic cerclage maybe a reasonable option for subgroups of patients eitherwith recurrent second-trimester losses or with congeni-tal risk factors (eg, müllerian abnormalities or DES ex-posure).31,36

Patients who elect expectant management may benefitfrom serial transvaginal ultrasonographic assessment ofcervical length as a screening tool for preterm birth.However, the data from the studies by Rust et al andAlthuisius et al are not adequate to support routine cer-clage in patients who develop short cervical length orother ultrasound-based risk factors. An upcoming coop-erative trial sponsored by the NICHHD (National Instituteof Child Health and Human Development) Maternal-Fetal Medicine Units Network will assess ultrasound-indicated therapeutic cerclage and may provide moredefinitive data on this topic.

V. MANAGEMENT ISSUES REGARDING CERCLAGE

CLASSIFICATION

As previously stated, cerclage procedures are classifiedas either prophylactic or therapeutic. Prophylactic cer-clage generally refers to cerclage in patients before anyclinical evidence of cervical change. It is most commonlyperformed in the early second trimester to avoid unnec-essary procedures in patients who might experience aspontaneous first trimester abortion. Preconception pro-phylactic cerclage placement is associated with an infertil-

ity rate as high as 50%;27 therefore, this practice is nolonger used. Therapeutic cerclage can be further subclas-sified into either urgent or emergent (rescue) cerclage.Urgent cerclage generally refers to cerclage in patients withpreclinical evidence of cervical change as detected byultrasound. In contrast, emergent cerclage generally refersto cerclage in patients who have more advanced cervicalchanges that are obvious on physical examination.

SURGICAL CONTRAINDICATIONS

Contraindications to cervical cerclage are divided into3 major categories.37 The first category is high-maternalrisk and includes active bleeding from abruption and/orplacenta previa, PROM, or active infection such as chor-ioamnionitis. The second category of contraindicationsto cerclage placement is the presence of non-reassuringfetal status or a fetal anomaly that is incompatible withlife. This area can be clear cut (such as anencephaly) butmay be more controversial (as with diaphragmatic her-nia). The third category is definitive preterm labor. Al-though seemingly straightforward, there are gray areaswhere care must be individualized. For example, cerclageplacement between 24 and 26 weeks (and beyond) israrely done because survival of the fetus at and beyondthese time periods exceeds 50%.38,39 In fact, bedrest at25 weeks of gestational age without cerclage has resultedin good outcomes.40 Hydramnios is a relative contraindi-cation; however, if membranes are not in the way, cer-clage may be attempted.

PREOPERATIVE EVALUATION

In light of these factors, a few basic preoperative eval-uations are prudent before proceeding with cerclageplacement. In the case of prophylactic cerclage, pa-tients should be offered a basic ultrasound examinationto confirm fetal viability and to rule out obvious fetalabnormalities. If they are at risk, patients should under-go cultures for gonorrhea and chlamydia. Treatment ofpositive cultures should be completed before surgery.

Several additional concerns are specific to patientswho may undergo emergent cerclage. As previously dis-cussed, cervical incompetence often is a manifestationof several pathophysiologic processes. Therefore, it isessential to thoroughly evaluate all patients for evidenceof preterm labor, PROM, intra-amniotic infection, andabruption before proceeding with cerclage placement.In addition, many patients will manifest prolapsedmembranes into the cervical os or vagina, which can beconsidered a relative contraindication for cerclagebecause of the high risk for procedure-related PROM.

The membranes must be reduced into the uterusbefore cerclage can be performed. Salvage procedures



that are done when the membranes protrude throughthe os and into the vagina (ie, prolapsed membranes)have various success rates; early reports revealed a suc-cess rate of less than 50%.41,42 The first step in accom-plishing membrane reduction is placing the patient insteep Trendelenburg’s position. Several techniques toaid in the reduction of prolapsed membranes have beendescribed. These methods include use of a large Foleycatheter43 to push the membranes into the uterus andhold them in place during the procedure; amnioreduc-tion to decrease amniotic fluid volume and therebyreduce tension on the membranes;44 the placement oftraction sutures into the lateral cervix45 to pull the cervixforward over the membranes; and the gradual overdis-tension of the bladder with saline through a trans-urethral catheter to push the lower uterine segment outof the pelvis.46 Cerclage should be attempted only if suc-cessful membrane reduction has been achieved.

PERIOPERATIVE CAREAntibiotic and Tocolytic Prophylaxis

Attention to several issues can help maximize the peri-operative care of patients undergoing cervical cerclage.Perioperative prophylactic antibiotic treatment is gener-ally recommended for emergent cerclage proceduresbecause of the significant risk for chorioamnionitis. Incontrast, there is a lack of consistent evidence to recom-mend routine perioperative antibiotics for urgent proce-dures.47,48 For example, in the cerclage trials discussedpreviously,32,35 antibiotic regimens can vary from no treat-ment to a single preoperative dose to prolonged postop-erative treatment. In general, perioperative antibioticsare not indicated for prophylactic cerclage procedures.However, antibiotic prophylaxis is warranted for sched-uled cerclage procedures in women with cervicitis.

Perioperative tocolytics are often used during thera-peutic cerclage procedures. Cerclage procedures canincrease the levels of circulating prostaglandins;49 there-fore, indomethacin (a prostaglandin synthetase inhibitorand commonly used tocolytic) can be administered pre-operatively to reduce uterine activity. There is, however,insufficient evidence to support routine use of tocolytics.Perioperative tocolytics are not indicated for prophylac-tic cerclage procedures.

Anesthesia

A regional anesthetic is preferred for cerclage proce-dures. Regional anesthesia can provide excellent paincontrol and relaxation of the lower extremities for posi-tioning, without the risk of strain on the cerclage sutureand the fetal membranes, which can result when patientsexperience Valsalva while waking from general anesthesia.

POSTOPERATIVE CARE

Most prophylactic and therapeutic (urgent) cerc-lage procedures can be performed as outpatient pro-cedures. After the procedure, many clinicians initiallyrecommend reduced activity and pelvic rest for 5 to7 days, which can be modified as necessitated by clini-cal progress. Because emergent cerclage proceduresare associated with increased perioperative risks andpossibile subsequent labor progression, postoperativecare of these patients must be individualized. Con-servative management typically includes bedrest andpelvic rest until 32 to 34 weeks of gestation.

VI. CERCLAGE TECHNIQUES

Currently, only 3 cerclage procedures are commonlyused: the McDonald cerclage, the Shirodkar technique,and the transabdominal cervicoisthmic cerclage. Num-erous modifications for each procedure have been de-scribed in the biomedical literature;50 therefore, a gener-al approach is presented here. The McDonald cerclage isthe most commonly used technique of transvaginal cer-clage because of its simpler surgical approach. Both theShirodkar and McDonald techniques are initiated inmuch the same way in regard to positioning of the pa-tient and sterile preparation.

McDONALD CERCLAGE

In the McDonald technique, the cervix is grasped fortraction with ring forceps and gently pulled into the prox-imal vagina. A large, nonabsorbable suture is then used toperform a purse-string closure of the cervix. Typically,4 to 5 circumferential bites are taken into the cervical stro-ma, beginning anteriorly at the cervico-vaginal junction(Figure 3). Posteriorly, the bites are taken more proxi-mally to theoretically capture the uterosacral ligaments.The suture ends are tied to close the internal os, and thefree ends are left long in order to help with identificationfor removal. McDonald’s original procedure was per-formed with No. 4 silk suture on a Mayo needle; however,modifications using 5-mm polyester (Mersilene) tape,No. 2 Mersilene thread, or braided nylon on a double-loaded needle are more common today.

MODIFIED SHIRODKAR CERCLAGE TECHNIQUE

The major difference between the McDonald andShirodkar techniques is that the latter involves submu-cosal placement of the cerclage suture. In order toaccomplish this type of placement, the vaginal mucosamust be incised anteriorly and posteriorly and then dis-section is performed up to the internal os. The suture



material is then placed in 2 bites into the cardinal-uterosacral ligament complex bilaterally at 9 o'clock and3 o'clock. An important element of this procedure is notto take the bites too deeply in order to minimize the riskof encroachment on the fetal membranes and possiblerupture. The suture is tied anteriorly, and the mucosalincisions may then be closed with fine absorbable suture.Shirodkar’s original description used maternal fascia lataas the suture material.26 Today, synthetic materials similarto those described for the McDonald procedure can beused.

TRANSABDOMINAL CERVICOISTHMIC CERCLAGE

The transabdominal cervicoisthmic cerclage proce-dure is reserved for a select group of patients. The orig-inal procedure was advocated for patients with a cervix

that was either congenitally short or surgically dam-aged, preventing transvaginal cerclage.51 This tech-nique requires laparotomy along with dissection of thevesicouterine peritoneum and uterine vessels to identi-fy the uterine isthmus, around which the cerclage tapeis placed. Although, transvaginal cerclage is typicallyremoved at or near term in the outpatient setting, trans-abdominal cerclage is typically left in situ; thus, patientsrequire a second laparotomy for subsequent cesareandelivery. Because of the complexity and increased sur-gical risks of this procedure, it should only be perform-ed by experienced operators.

SURGICAL COMPLICATIONS

Complications associated with cerclage are related toeither the procedure or delivery (Table 6). In general, allcomplications encountered with cerclage are increasedat later gestational ages and in patients with advancedcervical dilation.

Premature Rupture of Membranes

The major procedure-related complication with cer-clage is membrane rupture. PROM may be the result ofan iatrogenic puncture at the time of surgery. The over-all rate of preterm PROM has been reported to be ashigh as 38%.47 Although the risk of perioperative PROMis minimal during prophylactic cerclage, this risk increas-es with advancing dilation and gestational age.8 The cer-clage should be removed immediately should perioper-ative PROM occur.

A particular area of controversy is management ofthe patient who experiences PROM remote from thecerclage procedure. There is no consensus in the bio-medical literature as to whether the cerclage should beremoved immediately or be left in place and its effecton maternal and neonatal infectious morbidity.52–57

Obviously, the cerclage must be removed if there is anyclinical evidence of infection. However, in the absence


Figure 3. McDonald cerclage. Without mucosal incisions, thestitch is used to encircle the cervix in 4 to 6 bites. Anteriorly, thesuture is placed as close to the cervicovesical reflection as pos-sible. Posteriorly, the bites are taken as high as possible withouttraversing the pouch of Douglas. As shown in the schematicinset, the needle is guided into the cervical stroma beneath thelateral vasculature with care to avoid the endocervical canal.(Reprinted with permission from Hankins GDV, Clark SL,Cunningham FG, Gilstrap LC 3rd, editors. Operative obstetrics.East Norwalk (CT): Appleton and Lange; 1995:581.)

Table 6. Complications of Cerclage

PROM = premature rupture of the membranes.

Data from Creasy RK, Resnick RR, editors. Maternal fetal medicine.4th ed. Philadelphia: WB Saunders; 1999:458.

Procedure related

PROM

Chorioamnionitis

Suture displacement

Maternal soft tissue injury

Bleeding

Delivery related

Cesarean delivery

Cervical laceration

Cervical dystocia

Fistula

Uterine rupture


of this finding, the cerclage may be left in place withclose expectant management at very early gestations(< 28 weeks) when a prolongation of the pregnancy foreven a few days may vastly improve fetal outcome.Beyond this gestational age, the risks of maternal andfetal morbidity probably outweigh any benefit from pro-longed pregnancy and, therefore, the cerclage shouldbe removed.58

Other Complications

Suture displacement occurs less frequently thanPROM and chorioamnionitis.59,60 There are only anec-dotal reports of repeat procedures, many with suturedisplacement diagnosed before 25 weeks of EGA.60,61

Surprisingly, the outcome was very good in many cases.Given the lack of good studies in this area, managementmust be individualized in these cases.

Another complication of cerclage can be labor abnor-malities, such as laceration and bleeding or cervical scar-ification and dystocia. Finally, a higher cesarean sectionrate was noted in patients with cerclage; one groupreported 3 cases of uterine rupture during labor becausethe Shirodkar cerclages could not be removed in time.62

For some patients, a cesarean section may need to be per-formed for other obstetrical reasons, and the decision toleave the cerclage in place must be individualized.

If the patient desires a future pregnancy, the physi-cian may want to leave the cerclage in place because thesuture is entirely re-epithelialized, obviating the needfor a repeat procedure during that gestation. However,this benefit must be weighed against the high infertilityrate (50%) if the cerclage is left in place.41 When thepatient is done with childbearing, it is recommendedthat the cerclage be removed to prevent potential long-term sequelae from the permanent suture materialeroding into neighboring structures (eg, bladder cal-culi, trigonitis, urinary tract fistula).63–66

Complications of Transabdominal CervicoisthmicCerclage

Transabdominal cerclage has distinct complicationswhen compared with the modified Shirodkar andMcDonald procedures. First, transabdominal cerclagenot only requires laparotomy for placement but also forremoval and delivery of the fetus. Second, hysterotomywill probably be required even if there is a fetal death orsome other indication for pregnancy termination. Third,hemorrhage may develop from passing the needlesthrough a more vascular region of the uterine isthmus.Finally, the procedure has a high fetal loss rate of 5%.67

VII. SUMMARY POINTS

• Previously, the cervix was considered to be either com-pletely competent or incompetent. However, the cur-rent concept is that cervical incompetence should beconsidered a part of the continuum of preterm labor.

• A thorough history and physical examination are themost important tools in diagnosing cervical incom-petence.

• Endovaginal sonography in the second trimester canbe a useful adjunct for predicting spontaneous pre-term birth in high-risk patients.

• In patients with a classic history who clearly have cer-vical incompetence, scheduled cerclage has a low rateof complications but also an uncertain benefit.

• Data indicate that prophylactic cerclage in patientswith clinical risk factors does not improve perinataloutcomes and leads to more interventions. However,prophylactic cerclage may be a reasonable option forsubgroups of patients either with recurrent second-trimester losses or with congenital risk factors.

• Cerclage placement between 24 and 26 weeks of ges-tational age (and older) is rarely done because survivalof the fetus at and beyond these time periods exceeds50%. In fact, bedrest at 25 weeks of gestational agewithout cerclage has resulted in good outcomes.

• The McDonald cerclage technique is the most com-monly used procedure.

• Contraindications to cervical cerclage include activebleeding from abruption and/or placenta previa, pre-mature rupture of the membranes, or active infectionsuch as chorioamnionitis.

• The use of antibiotics does not appear to be warrant-ed for scheduled cerclages but is prudent for urgentand emergent cases.

REFERENCES

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2. Iams JD, Johnson FF, Sonek J. Cervical incompetence asa continuum: a study of ultrasonographic cervical lengthand obstetric performance. Am J Obstet Gynecol 1995;172:1097–103.

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4. Crosby WM, Hill EC. Embryology of the Müllerian ductsystem. Obstet Gynecol 1962;20:507.

5. Minamoto T, Arai K, Hirakawa S, Nagai Y. Immuno-histochemical studies on collagen types in the uterinecervix in pregnant and nonpregnant states. Am J ObstetGynecol 1987;156:138–44.

6. Rorie DK, Newton M. Histologic and chemical studies ofthe smooth muscle of the human cervix and uterus. AmJ Obstet Gynecol 1967;99:466–9.

7. Danforth DN. The fibrous nature of the human cervixand its relation to the isthmic segment in gravid and non-gravid uteri. Am J Obstet Gynecol 1947;53:541.

8. Creasy RK, Resnick RR, editors. Maternal fetal medicine.4th ed. Philadelphia: WB Saunders; 1999.

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13. Lash AF, Lash SR. Habitual abortion: the incompetentinternal os of the cervix. Am J Obstet Gynecol 1950;59:68.

14. Schulz KF, Grimes DA, Cates W Jr. Measures to preventcervical injury during suction curettage abortion. Lancet1983;1:1182–5.

15. Goldenberg RL, Iams JD, Miodovnick M, et al. Thepreterm prediction study: risk factors for twin gestations.National Institute of Child Health and Human Devel-opment Maternal-Fetal Medicine Units Network. Am JObstet Gynecol 1996;175(4 Pt 1):1047–53.

16. Eliman A, Figueroa R, Nigam S, et al. Perinatal outcomeof triplet gestation: does prophylactic cerclage make adifference? J Matern Fetal Med 1999;8:119–22.

17. Goldman GA, Dicker D, Peleg D, Goldman JA. Is electivecerclage justified in the management of triplet and quadru-plet pregnancy? Aust N Z J Obstet Gynaecol 1989;29:9–12.

18. Mordel N, Zajicek G, Benshushan A, et al. Elective sutureof uterine cervix in triplets. Am J Perinatol 1993;10:14–6.

19. Vogel I, Salvig JD, Secher NJ, Uldbjerg N. Associationbetween raised serum relaxin levels during the eigh-teenth gestational week and very preterm delivery. Am JObstet Gynecol 2001;184:390–3.

20. Weiss G, Goldsmith LT, Sachdev R, et al. Elevated first-trimester serum relaxin concentrations in pregnant

women following ovarian stimulation predict prematu-rity risk and preterm delivery. Obstet Gynecol 1993;82:821–8.

21. Bani D. Relaxin: a pleiotropic hormone. Gen Pharmacol1997;28:13–22.

22. Iams JD, Goldsmith LT, Weiss G. The preterm predictionstudy: maternal serum relaxin, sonographic cervicallength, and spontaneous preterm birth in twins. J SocGynecol Investig 2001;8:39–42.

23. Bergman P, Svenerund A. Traction test for demonstrat-ing incompetency of the internal os of the cervix. Am JObstet Gynecol 1954;68:1261.

24. Golan A, Barnan R, Wexler S, et al. Incompetence of theuterine cervix. Obstet Gynecol Surv 1989;44:96–107.

25. Owen J, Yost N, Berghalla V, et al. Mid-trimester endo-vaginal sonography in women at high risk for sponta-neous preterm birth. JAMA 2001;286:1340–8.

26. Shirodkar VN. A new method of operative treatment forhabitual abortion in the second trimester of pregnancy.Antiseptic 1955;52:299.

27. Harger JH. Cervical cerclage: patient selection, morbidi-ty, and success rates. Clin Perinatol 1983;10:321–41.

28. Tho PT, Byrd JR, McDonough PG. Etiologies and subse-quent reproductive performance in 100 couples withrecurrent abortion. Fertil Steril 1979;32:389–95.

29. Lazar P, Gueguen S, Dreyfus J, et al. Multicenter con-trolled trial of cervical cerclage in women at moderaterisk of preterm delivery. Br J Obstet Gynaecol 1984;91:731–5.

30. Rush RW, Isaacs S, McPherson K, et al. A randomizedcontrolled trial of cervical cerclage in women at high riskof spontaneous preterm delivery. Br J Obstet Gynaecol1984;91:724–30.

31. Final report of the Medical Research Council/Royal Col-lege of Obstetricians and Gynaecologists multicentre ran-domized trial of cervical cerclage. Br J Obstet Gynaecol1993;100:516–23.

32. Rust OA, Atlas RO, Jones KJ, et al. A randomized trial ofcerclage versus no cerclage among patients with ultrason-agraphically detected second-trimester preterm dilatationof the internal os. Am J Obstet Gynecol 2000;183:830–5.

33. Rust OA, Atlas RO, Reed J, et al. Revisiting the shortcervix detected by transvaginal ultrasound in the secondtrimester: why cerclage therapy may not help. Am JObstet Gynecol 2001;185:1098–105.

34. Althuisius SM, Dekker GA, van Geijn HP, et al. CervicalIncompetence Prevention Randomized Cerclage Trial(CIPRACT): study design and preliminary results. Am JObstet Gynecol 2000;183:823–9.

35. Althuisius SM, Dekker GA, Hummel P, et al. Final resultsof the Cervical Incompetence Prevention Randomized



Cerclage Trial (CIPRACT): therapeutic cerclage with bedrest versus bed rest alone. Am J Obstet Gynecol 2001;185:1106–12.

36. Speroff L, Glass RH, Kase NG. Clinical gynecologicendocrinology and infertility. 5th ed. Baltimore: Williams& Wilkins; 1994:841–51.

37. Hankins GDV, Clark SL, Cunningham FG, Gilstrap LC3rd, editors. Operative obstetrics. East Norwalk (CT):Appleton and Lange; 1995.

38. Gilstrap LC 3rd, Hauth JC, Bell RE, et al. Survival andshort-term morbidity of the premature neonate. ObstetGynecol 1985;65:37–41.

39. Cooper RL, Goldenberg RL, Creasy RK, et al. A multi-center study of preterm birth weight and gestationalage–specific neonatal mortality. Am J Obstet Gynecol1993;168(1 Pt 1):78–84.

40. Levine RU, Berkowitz KM. Conservative management andpregnancy outcome in diethylstilbestrol-exposed womenwith and without gross genital tract abnormalities. Am JObstet Gynecol 1993;169:1125–9.

41. Harger JH. Comparison of success and morbidity in cer-vical cerclage procedures. Obstet Gynecol 1980;56:543–8.

42. McDonald IA. Cervical incompetence as a cause of spon-taneous abortion. In: Bennett MJ, Edmonds DK, editors.Spontaneous and recurrent abortion. London: BlackwellScientific; 1987:168.

43. Holman MR. An aid for cervical cerclage. Obstet Gynecol1973;42:468–9.

44. Goodlin RC. Cervical incompetence, hourglass mem-branes, and amniocentesis. Obstet Gynecol 1979;54:748–50.

45. Olatunbosun OA, Dyck F. Cervical cerclage operation fora dilated cervix. Obstet Gynecol 1981;57:166–70.

46. Sheerer LJ, Lam F, Katz M. A new technique for cervicalcerclage in the presence of prolapsed fetal membranes.In: Abstracts of the seventh annual meeting of the So-ciety of Perinatal Obstetricians. Lake Buena Vista, CA.1987:144.

47. Treadwell MC, Bronsteen RA, Bottoms SF. Prognostic fac-tors and complication rates for cervical cerclage: a reviewof 482 cases. Am J Obstet Gynecol 1991;165:555–8.

48. Charles D, Edwards WR. Infectious complications of cer-vical cerclage. Am J Obstet Gynecol 1981;141:1065–71.

49. Novy MJ, Ducsay CA, Stanczyk FZ. Plasma concentrationsof prostaglandin F2 alpha and prostaglandin E2 metabo-lites after transabdominal and transvaginal cervical cer-clage. Am J Obstet Gynecol 1987;156:1543–52.

50. Shortle B, Jewelewicz R. Clinical aspects of cervical incom-

petence. Chicago: Yearbook Medical Publishers; 1989.

51. Benson RC, Durfee RB. Transabdominal cervicouterinecerclage during pregnancy for the treatment of cervicalincompetency. Obstet Gynecol 1965;25:145.

52. Yeast JD, Garite TR. The role of cervical cerclage in themanagement of preterm premature rupture of the mem-branes. Am J Obstet Gynecol 1988;158:106–10.

53. Dubouloz P, Maye D, Beguin F. [Cerclage and infection.Clinical and therapeutic study.] [Article in French.]J Gynecol Obstet Biol Reprod (Paris) 1980;9:671–4.

54. Kuhn RJP, Pepperell RJ. Cervical ligation: a review of 242pregnancies. Aust N Z J Obstet Gynaecol 1977;17:79.

55. Dunn LJ, Robinson JC, Steer CM. Maternal death fol-lowing suture of incompetent cervix during pregnancy.Am J Obstet Gynecol 1959;78:335–9.

56. Lipshitz J. Cerclage in the treatment of incompetentcervix. S Afr Med J 1975;49:2013–5.

57. Barth WH Jr. Cervical incompetence and cerclage: un-resolved controversies. Clin Obstet Gynecol 1994;37:831–41.

58. O’Connor S, Kuller JA, McMahon MJ. Management ofcervical cerclage after preterm premature rupture ofmembranes. Obstet Gynecol Surv 1999;54:391–4.

59. Newton M, Newton ER. Complications of obstetric opera-tions. In: Complications of gynecologic and obstetric man-agement. Philadelphia: Saunders; 1988:229.

60. Aarnoudse JG, Huisjes HJ. Complications of cerclage.Acta Obstet Gynecol Scand 1979;58:255–7.

61. Schulman H, Farmakides G. Surgical approach to failedcervical cerclage. A report of three cases. J Reprod Med1985;30:626–8.

62. Peters WA 3rd, Thiagarajah S, Harbert GM Jr. Cervicalcerclage: twenty years’ experience. South Med J 1979;72:933–7.

63. Ben-Baruch G, Rabinovitch O, Madjar I, et al. Urethro-vaginal fistula—a rare complication of cervical cerclage.Isr J Med Sci 1980;16:400–1.

64. Bates JL, Cropley T. Complications of cervical cerclage.Lancet 1977;2:1035.

65. Ehrenpreis MD, Alarcon JA, Firfer R. Case profile: largebladder calculus—post cervical cerclage. Urology1986;27:366–7.

66. Hortenstine JS, Witherington R. Ulcer of the trigone: alate complication of cervical cerclage. J Urol 1987;137:109–10.

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Copyright 2002 by Turner White Communications Inc., Wayne, PA. All rights reserved.


C h a p t e r 2

I. INTRODUCTION

Women seek clinical evaluation for excessive hairgrowth because they have concerns about their cosmeticappearance, reproductive function, and general health.Hirsutism is defined as excessive hair growth in womenthat occurs in specific androgen-sensitive areas of thebody, including the face, chest, upper and lower back,buttocks, inner thigh, and the external genitalia.1

Approximately 5% to 8% of the female population hassome form of hirsutism.2 Although hirsutism is usually aclinical sign of a benign condition, it occasionally is asso-ciated with signs of virilization, such as clitoromegaly,deepening of the voice, temporal hair loss, and loss offemale body contour. A serious underlying disorder, suchas an ovarian or adrenal tumor, is more likely to existwhen hirsutism coexists with virilization. In addition tosymptoms of excessive hair growth, women with hirsutismoften present with disorders of menstruation and are atrisk for development of endometrial cancer and infertili-ty secondary to infrequent or absent ovulation. This arti-cle will define the broad categories of hirsutism and viril-ization in women and provide a systematic approach todiagnosis. A central theme will be to distinguish benigncauses of hirsutism from life-threatening causes and toinstitute specific therapy in a logical sequence.

II. BIOLOGY OF HAIR GROWTH

Scalp hair has long been considered a source of beau-ty for women. However, in the United States, most otherhair (excepting pubic hair) is considered to be unat-tractive and is removed. Knowledge of the physiology ofhair growth and the expected patterns of hair distribu-tion for women is useful when discussing perceivedexcess hair growth. The number of hairs per unit area ofskin is determined by genetic factors and is fixed beforebirth. Persons of Caucasian, African, and Mediterraneandescent have a higher density of hair growth in non-scalp regions than do persons of Eastern Asian andNordic origin. Within a given racial group, the number

of hair follicles per unit of body surface area does not dif-fer between men and women. In fact, hirsutism is not anincrease in the number of hair follicles but an alterationin their character. Hirsutism occurs when androgensaffect the pilosebaceous unit by increasing the pigmen-tation, thickness, and growth of steroid-sensitive hair.

There are 3 types of hair: (1) lanugo, which is the fine,short hair covering the body of the fetus and newborn;(2) vellus, which is fine, short, unpigmented hair; and(3) terminal, which is the long, coarse, pigmented hair.3

Hair in the axilla and midline region, with the exceptionof scalp hair, is generally sex-hormone responsive. An-drogens (testosterone and dihydrotestosterone [DHT])stimulate sex-hormone responsive hair growth, and estro-gens (17 β-estradiol and estrone) inhibit it.4 Excess andro-gen production stimulates facial and body vellus hairs todevelop into long, coarse, pigmented terminal hairs. Inthe scalp, androgens convert terminal hairs to vellus hairs,eventually resulting in temporal balding.4 Pregnancyinduces a state of both increased estrogen and proges-terone secretion and thus increases synchrony of hairgrowth.5 Such hormonal synchronization may lead toperiods of growth and shedding of hair that may result inthe perception of hair loss.

Hirsutism and virilization develop secondary toincreased secretion of androgens by the ovary or theadrenal glands or to exogenous androgens. The contri-butions from the ovary and the adrenal gland to circu-lating androgen levels in normal women are summarizedin Figure 4.1 In women, circulating testosterone is derivedfrom (1) direct testosterone secretion by the ovary and(2) from extraglandular conversion of androstenedione(produced by the adrenal gland and ovary) into testos-terone, which occurs in fat tissue. In addition, the adren-al gland secretes dehydroepiandrosterone (DHEA) andits sulfated congener (DHEAS).6 In most hirsute women,the amount of DHEAS, testosterone, and androstene-dione at the level of the hair follicles is increased: all ofthese androgenic precursors can be converted into DHT,which is a more potent androgen. Consequently, the vel-lus follicles become terminal hair follicles in larger num-bers in androgen-sensitive areas of the skin, therebyincreasing the diameter, pigmentation, and apparent

Chapter 2—Clinical Management ofHirsutism and Virilization

Paul B. Marshburn, MD, FACOG, Michelle L. Matthews, MD, and Bradley S. Hurst, MD


C h a p t e r 2 — M a n a g e m e n t o f H i r s u t i s m a n d V i r i l i z a t i o n

density of hairs. Other women appear to have an in-creased sensitivity of the pilosebaceous unit to normalserum levels of androgen. The mechanism for increasedhair follicle sensitivity is believed to be secondary to anincrease in the activity of 5 α-reductase, the enzyme re-sponsible for converting testosterone to the more potentandrogen DHT.7,8

CASE PATIENT 1 PRESENTATION

Patient 1 is a 26-year-old woman who is gravida 0 andparity 0. She relates a history of increasing growth of facialand lower abdominal hair since menarche at age 11 years.The excessive hair and facial acne are distressing to her;she asks whether these symptoms are associated with anyhealth problems. Patient 1 has had irregular periods sincemenarche, with an average of 2 heavy menstrual periodsper year. The facial hair has been managed by shaving 1 to2 times per week, but she is unhappy with the inconve-nience and the cosmetic result. She always has been over-weight and has difficulty with exercise and diet becauseshe feels she has no energy. There is no history of anyvoice change or any loss of hair from her head. She is anonly child. Her mother is obese with coronary atheroscle-rotic heart disease and type 1 diabetes mellitus. Patient 1is of Italian descent and is not taking any medicines orherbal supplements.

Her physical examination indicates a blood pressureof 140/88 mm Hg, weight of 205 lb, height of 5 ft 2 in,a body mass index of 37, and a waist-to-hip circumfer-ential ratio of 0.86. Her skin generally has a brownish,cutaneous discoloration on the back of her neck, underher arms, and in the intertriginous folds of the groin.Further skin evaluation indicates modest facial acneand significant hair on the upper lip, chin, periumbili-

cal, and periareolar regions with a male-type, diamond-shaped escutcheon. The Ferriman-Gallwey score ratingthe degree and location of body hair for patient 1 is12 (Figure 5); a normal score is 8 or less.9,10 She hasgrossly normal muscle mass. Her scalp hair has a nor-mal female distribution and thickness without temporalbalding. Head, nose, and throat are normal with nopalpable abnormality of the thyroid gland. Her breastshave no masses, nipple discharge, or skin change ex-cept for the periareolar hair. Cardiovascular examina-tion is normal. The abdomen is obese, and no striae ororganomegaly are noted. Pelvic examination shows aTanner Stage 5 pubic hair distribution (the pubic hairdoes extend onto the thighs). The clitoris is prominentbut within normal limits, with the glans of the clitorismeasuring 0.3 × 0.4 cm. The vagina is rugose, normalin appearance, and well estrogenized. The cervix showsclear estrogenized mucus. The uterus is mid-plane;mobile; and of normal size, shape, and consistency. Theovaries are palpable but are mobile, nontender, sym-metrical, and regular in shape and consistency. A recto-vaginal examination suggests that she does not have anovarian tumor.

III. CLASSIFICATION FOR HIRSUTISM AND VIRILIZATION

The clinical management of women with hirsutismand virilization is facilitated by a classification that allowsa systematic and orderly approach to the problem(Table 7).1 This classification lists the most commoncauses of hirsutism and virilization based on the sites ofandrogen production (ovary and adrenal gland).

Figure 4. Testosterone and dihydrotestos-terone induce increased hair growth in re-sponsive areas. These androgens arise fromboth the ovaries and the adrenal glands,either from conversion via androgen pre-cursors or from direct formation in theovaries. DHEA = dehydroepiandrosterone;DHEAS = dehydroepiandrosterone sulfate.(Adapted with permission from Carr BR.Disorders of the ovary and female repro-ductive tract. In: Wilson JD, Foster DW,editors. Williams’ textbook of endocrin-ology. 9th ed. Philadelphia: Elsevier Science;1998:795–9. Copyright 1998 Elsevier Sci-ence. All rights reserved.)

90%–95% Plasma DHEAand DHEAS

Probablynegligible

75% Plasmatestosterone

25%

50%

50%Ovary

Plasmaandrostenedione

Adrenal gland

Conversion fromprehormones

(androstenedione,DHEA, and

DHEAS)



Site Grade and Definition (Enter Numerical Grade in Box)1 2 3 4

A small moustacheat outer margin orcovering less thanhalf of upper lip

Scattered terminalhairs with smallconcentrations

Scattered terminalhairs with smallconcentrations

Scattered hairswith small concen-trations

More terminalhairs but still scat-tered

With greater later-al extension

More than this;coverage stillincomplete

More than this;coverage stillincomplete

Both terminal cir-cumareolar hairsand midline hairs

More terminalhairs still midline

A midline streak ofterminal hair

Lateral extensionof terminal hair toedge of glutealcleft

A moustache ex-tending halfwayfrom outer marginor halfway up lip

Light coverage ofentire area

Complete but lightcoverage

Light coverage ofentire area


Three-quartercoverage



Three-quartercoverage

Half coverage

A midline band ofterminal hair notmore than 1/2 widthof pubic hair at base

Three-quartercoverage of but-tocks

A moustache ex-tending to midlineand covering mostof upper lip

Dense coverage ofentire area

Complete andheavy coverage

Complete anddense coverage ofentire area

Complete anddense coverage

Complete cover-age



Complete cover-age

Full coverage

An inverted V-shaped growth1/2 width of pubichair at base

Complete cover-age of buttocks

Upper lip

Sideburnarea

Chin

Lower jawandupper neck

Upper back

Lower back

Upper arm

Thigh

Chest

Upper abdomen

Lowerabdomen

Perineum

A few terminalhairs at outer mar-gin or scatteredover upper lip

A few scatteredterminal hairs


A few scatteredhairs


Some sacral hair(area of coverage< 4 cm wide)

Sparse growthaffecting not morethan 25% of limb

Sparse growthaffecting not morethan 25% of limb

Terminal circum-areolar hairs ormidline hairs

A few midline ter-minal hairs

A few midline ter-minal hairs alonglinea alba

Perianal terminalhair

Column subtotals

Figure 5. The Ferriman-Gallwey method for scoring the degree of hirsutism in regions of the body with sex hormone responsivehair growth. The normal Ferriman-Gallwey score is 8 or less. (Data from Ferriman D, Gallwey JD. Clinical assessment of body hairgrowth in women. J Clin Endocrinol Metab 1961;21:1440–7; and The evaluation and treatment of androgen excess. Birmingham (AL):American Society for Reproductive Medicine; 2000. ASRM technical bulletin. Available at http://www.asrm.org/Media/Practice/practice.html#Guideline.)

Total score

OVARIAN HYPERANDROGENISM Polycystic Ovarian Syndrome

The most frequent ovarian cause of hirsutism is hyper-androgenism with chronic anovulation, commonly

referred to as polycystic ovarian syndrome (PCOS).11

This condition is diagnosed clinically and is character-ized by an association between the presence of polycysticovaries and infrequent or absent menses as well as somesign of hyperandrogenism, most commonly hirsutism,acne, or oily skin. PCOS often is associated with obesity.

The onset of hirsutism in PCOS usually occurs aroundthe time of menarche and results in a slow rate of pro-gression of the hirsutism, without signs of virilization.About 30% of women with PCOS have evidence of glu-cose intolerance relating to insulin resistance.12 Insulinresistance results in a higher serum insulin level that stim-ulates ovarian thecal cells to enhance production oftestosterone. The binding hormone for androgens (sex-hormone binding globulin [SHBG]) is reduced by in-sulin, causing higher amounts of “free” testosterone.Some women with PCOS have severe insulin resistanceaccompanied by the skin condition termed acanthosisnigricans (cutaneous brown discoloration on the back ofthe neck, groin, and axilla); this constellation of symp-toms is known as hyperandrogenism–insulin resistanceacanthosis nigricans (HAIR-AN) syndrome.13

Hyperthecosis

Hyperthecosis is a benign condition in which islandsof ovarian luteinized thecal cells produce higher levelsof testosterone than in typical PCOS, although there isoverlap with some aspects of PCOS.6 Patients with hyper-thecosis may, in fact, have progression of hirsutism to vir-ilization.

Ovarian Tumors

Androgen-producing ovarian tumors are rare andtypically are associated with rapid progression of viriliza-tion, in addition to hirsutism, and can occur at any age.In greater than 80% of patients, a unilateral adnexalmass is palpable on pelvic examination.11 Furthermore,serum testosterone levels are higher (typically > 2 ng/mL[3.5 nmol/L]) in patients with androgen-producingovarian tumors than in those with PCOS or hypertheco-sis. Virilizing ovarian tumors are derived from sex cord orstromal cells and include Sertoli-Leydig cell, hilar cell,lipoid cell, and adrenal rest tumors.14,15 Luteomas andtheca-lutein cysts are benign ovarian tumors associatedwith pregnancy.16 The luteoma of pregnancy is morecommonly unilateral than the theca-lutein cysts and canresult in virilization of the female fetus.

ADRENAL DISORDERSCongenital Adrenal Hyperplasia

Hirsutism and virilization associated with adrenal dis-orders are less common than ovarian hyperandrogenism.



Table 7. Classification of Hirsutism and Virilization

Ovarian

Polycystic ovarian syndrome

Hyperthecosis

Neoplasms

Sex cord tumors

Germ cell tumors

Hilar cell tumors

Adrenal rest tumors

Mixed germ cell and gonadal tumors

Tumors with functioning stroma

Pregnancy associated

Luteoma

Hyperreactio luteinalis

Adrenal

Congenital adrenal hyperplasia/adult-onset adrenal hyperplasia

21-Hydroxylase deficiency

11 β-Hydroxylase deficiency

3 β-Hydroxysteroid dehydrogenase deficiency

Neoplasms

Adenomas

Carcinomas

Cushing’s syndrome

Drugs

Phenytoin

Diazoxide

Anabolic steroids

Progestogens (19-norsteroid derivatives)

Danazol

Idiopathic

Miscellaneous

Hyperprolactinemia

Acromegaly

Menopause

Adapted with permission from Carr BR. Disorders of the ovary and fe-male reproductive tract. In: Wilson JD, Foster DW, editors. Williams’textbook of endocrinology. Philadelphia: Elsevier Science; 1998:796.Copyright 1998 Elsevier Science. All rights reserved.

The most common disorder associated with adrenal viril-ization is congenital adrenal hyperplasia (CAH).17 Mostcases of CAH are detected at birth, but a less severe formmay present initially in adulthood with the sign of hir-sutism.18 The adult-onset form of CAH, called late-onsetcongenital adrenal hyperplasia (LOCAH), occurs in ap-proximately 5% of women with hirsutism. LOCAH resultsfrom a mild deficiency of 21- or 11-hydroxylase activity,the adrenal enzyme necessary for cortisol production. InCAH, hirsutism and chronic ovulatory dysfunction resultfrom increased androgen levels, derived from the diver-sion of high levels of 17-hydroxyprogesterone (17-OHP)to the androgen synthetic pathway. LOCAH is found mostcommonly in certain ethnic groups that include Ash-kenazi Jews, Hispanics, Italians, and Yugoslavs (note thatYugoslavia does not exist anymore and is now a co-joinedstate of Serbia and Montenegro).19

Other Adrenal Conditions

Women with Cushing’s syndrome may develop hir-sutism, amenorrhea, and polycystic ovaries.6 The hyper-cortisolism of Cushing’s syndrome produces truncal obe-sity, dorsal fat hump, muscle weakness, facial plethora,easy bruising, purple abdominal striae, and hirsutism.Less commonly, women with acromegaly (caused bygrowth hormone excess) or hyperprolactinemia mayexhibit mild hirsutism. Adrenal tumors (adenomas orcarcinomas) are rarely the etiology of hirsutism but arecommonly associated with virilization. Constitutionalsigns of wasting and/or Cushingoid signs or symptomsmay accompany the finding of adrenal carcinoma.

MEDICATIONS

Various medications may be associated with hir-sutism in women.1 Those drugs commonly cited in-clude danazol, phenothiazides, phenytoin, diazoxide,and 19-nortestosterone compounds.20 Androgens(anabolic steroids) also can be taken for increasingmuscle mass for body building purposes or for treat-ing diminished sexual drive. A slight increase in facialhair growth may be noticed by menopausal women;however, this is a normal physiological response to achange in the estrogen/androgen ratio.

IDIOPATHIC

Hirsutism in women with regular menstrual cyclessuggests an entity referred to as idiopathic hirsutism. Inthis case, serum testosterone levels are normal but the5 α-reductase activity in the hair follicle is increased. Aspreviously mentioned, this increased enzyme activityconverts testosterone into the more potent endogenousandrogen, DHT.

IV. LABORATORY EVALUATION

GENERAL PRINCIPLES

The laboratory evaluation should be oriented toward(1) excluding life-threatening causes associated with hir-sutism and virilization, and (2) directing the clinician tospecific treatment recommendations. A summary diag-nostic algorithm for the management of hirsutism andvirilization is presented in Figure 6.

The initial hormonal screening should include mea-suring serum levels of total testosterone, DHEAS, pro-lactin, and thyroid-stimulating hormone (TSH). TheTSH and prolactin levels can be used to exclude coinci-dental ovulatory dysfunction resulting from thyroid orprolactin abnormalities in the patient with hirsutism. Aslight elevation of serum prolactin may be present withPCOS; this finding in PCOS is secondary to tonically ele-vated levels of estrogen. The total serum testosterone is usually elevated in the ovarian causes of hirsutism.Most cases of hirsutism and/or virilization associatedwith an elevated serum testosterone greater than2 ng/mL (3.5 nmol/L) and normal DHEAS are of ovar-ian origin. If an adnexal mass is not palpable on pelvicexamination, then radiologic examination of the pelviswith a sonogram or CT scan will help localize an ovariantumor. If a sonogram or CT of the pelvis fails to identifya discrete mass in the ovaries, then a selective samplingof venous blood that drains each ovary can help to iden-tify the source of high testosterone production.

DHEAS is derived primarily from the adrenal glandand is elevated in cases of hirsutism of adrenal origin.Sebaceous gland activity appears to be stimulated byDHEA and DHEAS, which can be converted at the hairfollicle to testosterone and DHT.21 If plasma DHEAS isgreater than 7 µg/mL (19 µmol/L), then a computedtomography (CT) scan of the adrenal glands should bedone to rule out the presence of a tumor.

A 17-OHP level is obtained in the preovulatory phaseof the menstrual cycle if LOCAH is suspected. The 17-OHP level will be elevated with LOCAH. Borderlinelevels between 2 and 8 ng/mL warrant an adrenocor-ticotropic hormone stimulation test to determine if thisprecursor for androgen synthesis remains elevated.Basal levels of 17-OHP greater than 8 ng/mL confirmthe diagnosis of LOCAH.

Screening for diabetes is a cost-effective test in hirsutepatients. An initial glucose tolerance test (GTT) should be performed in all patients with evidence of acantho-sis nigricans. The American Diabetes Association pro-vides diagnostic criteria for insulin resistance and type 2



18H

ospital P

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Manual

Ch

ap

ter

2—

Ma

na

ge

me

nt o

f Hir

su

tism

an

d V

iriliz

atio

n

Figure 6. Diagnostic algorithm for management of hirsutism and/or virilization. CAH = congenital adrenal hyperplasia; CAT = computed axial tomography; cath = catheterization;CT = computed tomogram; DHEAS = dehydroepiandrosterone sulfate; 17-OHP = 17-hydroxyprogesterone; PCOS = polycystic ovarian syndrome; T = testosterone; TSH = thyroid-stimulating hormone. (Adapted with permission from Carr BR. Disorders of the ovary and female reproductive tract. In: Wilson JD, Foster DW, editors. Williams’ textbook ofendocrinology. 9th ed. Philadelphia: Elsevier Science; 1998: 795–9. Copyright 1998 Elsevier Science. All rights reserved.)

LaparotomyNormal

Manage for benign hirsutismand hyperandrogenism

Abormal

Manage for hyperprolactinemia, hypothyroidism,glucose intolerence, and late-onset CAH

Consider:1) Ovarian/adrenal vein cath studies2) Ovarian wedge/biopsy

Rules out adrenal tumor: Follow algorithm for T

andCushing’s syndrome

Abnormal

Follow algorithmfor T, DHEAS

Normal

Further diagnostic tests

Check T, 17-OHP

Surgery

+–

Plasma T, DHEAS

< 7 µg/mL > 7 µg/mL

> 2 ng/mL

Ovarian tumor

Plasma T Plasma DHEASSigns or symptoms of Cushing’s syndrome

< 2 ng/mL

SonogramCT scanTSH, prolactin, 17-OHP, fasting blood sugar

PCOS (hyperandrogenism, chronic anovulation)

24-hr urinary free cortisolor overnight

dexamethasone (1 mg)suppression test

Normal pelvic Palpable mass

CAT scan +–

Adrenal tumor

diabetes using an oral GTT. A fasting blood glucose levelgreater than 110 mg/dL or a 2-hour level greater than140 mg/dL after a 75-g glucose load indicates glucoseintolerance and insulin resistance. A fasting value of126 mg/dL or more (or a 2-hour value of ≥ 200 mg/dL)is consistent with diabetes mellitus. An elevated fastinginsulin level in the presence of apparently normal glucosetolerance should prompt counseling about susceptibilityfor type 2 diabetes mellitus.

FURTHER PRESENTATION OF PATIENT 1

Patient 1 has a hirsutism score of 12, which is abovethe normal range for the Ferriman-Gallwey scoring sys-tem (normal, 8). Her hyperandrogenemia has not ledto virilization, and her hirsutism has progressed slowlysince menarche. This age onset of the hirsutism andlack of any evidence of rapidly progressive hirsutism orvirilization diminishes a concern for adrenal or ovariantumors. No history of exogenous androgen adminis-tration is given. She has no other obvious history, signs,or symptoms of endocrinopathies (eg, Cushing’s syn-drome, hyperprolactinemia, or acromegaly). Her signsof the cutaneous brown discoloration on the back ofher neck, groin, and axilla are suspicious for acantho-sis nigricans, which may indicate hyperinsulinemia.Her Italian ancestry is pertinent because this ethnicgroup has a hereditary predisposition for increasedhair density and LOCAH.

Laboratory Results

Results of blood tests for patient 1 are shown inTable 8. LOCAH and other primary endocrinopathiesare ruled out. Laboratory testing and physical exami-nation lead to the overall clinical impression that pa-tient 1 has the HAIR-AN syndrome.

V. TREATMENT

The goal of treatment for hirsutism is to interruptthe steps leading to the increased androgen expressionat the pilosebaceous unit. Typically, the patient wantstreatment of her hirsutism as well as information aboutcontraception, reproductive health, and managementof abnormal uterine bleeding. Benign causes of hir-sutism can be treated effectively by medical and physicalmethods. Hirsutism secondary to endocrinopathiesand tumors can typically be recognized by the rapidprogression of hair growth as well as by virilizing signsand symptoms; these patients should be referred to agynecologic oncologist or general surgeon (in the caseof adrenal tumor) for prompt management.

SURGICAL TREATMENT

Androgen-producing tumors of the adrenal gland or ovary require excision, except in the special case of pregnancy-associated ovarian tumors (luteoma, theca-lutein cyst). Female fetuses rarely are virilized because pla-cental aromatase converts testosterone to estrogens; thus,these tumors typically do not require excision. Unless met-astatic disease is present, surgery will stop progression ofmost signs and symptoms of hirsutism/virilization. Thesepatients should be referred to a gynecologic oncologist formanagement. Intermenstrual or irregular uterine bleed-ing warrants an endometrial biopsy to rule out endome-trial neoplasia, especially in women older than 35 years.Virilizing ovarian or adrenal tumors rarely occur; thus, thepatient usually has a benign disorder.

LIFESTYLE MODIFICATION

Many of these patients are obese, and obesity direct-ly contributes to their condition. Obese patients whosuccessfully decrease their total body weight by as littleas 10% to 15% may be rewarded with improvement inunwanted hair growth and return of normal menses.22

Such weight loss increases SHBG, thereby decreasingfree testosterone levels and diminishing the hyperinsu-linemic effect on the ovary.

MEDICAL THERAPYHyperinsulinemia

The constellation of signs and symptoms includinghyperandrogenism, chronic anovulation, obesity, hyper-tension, dyslipidemia, and hyperinsulinemia has beentermed syndrome X,23 which has a broad spectrum ofexpression. Clinical signs consistent with hyperinsuline-mia include acanthosis nigricans and centripetal obesity



Table 8. Laboratory Evaluation for Patient 1

Test Patient 1 Normal Range

Total testosterone, ng/mL 1.08 0.55–0.85

Prolactin, ng/mL 18 5–20

TSH, µIU/mL 1.7 0.5–4.6

DHEAS, µg/dL 252 65–380

17-OHP, ng/mL 0.8 0.3–1.0

Fasting glucose, mg/dL 140 < 100

2-Hour glucose (after 75-g 164 < 140glucose load), mg/dL

Fasting serum insulin, 56 5–25µIU/mL

DHEAS = dehydroepiandrosterone sulfate; 17-OHP = 17-hydroxypro-gesterone; TSH = thyroid-stimulating hormone.

as indicated by a waist-to-hip ratio of greater than 0.85.Screening with GTT is indicated in these patients be-cause of the high incidence of type 2 diabetes mellitus.Hyperinsulinemic women with type 2 diabetes mellitusmay be treated with weight loss and insulin-sensitizingagents such as metformin. A study indicated that a med-ication that improves insulin sensitivity (eg, rosiglita-zone, pioglitazone) lowered the free testosterone leveland lessened hirsutism in these patients.24

Oral Contraceptive Pills

Oral contraceptive pills (OCPs) are by far the mosteffective and widely used medicine to treat benign ovar-ian causes of hirsutism, including PCOS. These hor-monal preparations decrease bioavailable testosteroneby inhibiting luteinizing hormone secretion from thepituitary gland, thereby diminishing stimulation of an-drogen production by ovarian thecal cells and by in-creasing SHBG. An OCP containing 30 to 35 µg of ethinyl

estradiol with one of the newer progestins (norgestimate,gestodene, desogestrel) is recommended because theseprogestins possess minimal androgenic activity.25 A recentstudy indicated that an OCP containing 30 µg of ethinylestradiol and desogestrel was effective in controlling hy-perandrogenism and hirsutism while ameliorating insulinresistance and increasing high-density lipoprotein levels.26

If insufficient reduction of hirsutism is achieved after6 months of OCP use, then antiandrogen therapy shouldbe considered.

Anti-Androgen Medications

Currently, the topical agent eflornithine hydrochlo-ride (Vaniqa) is the only drug approved in the UnitedStates and Canada to specifically treat hirsutism (see nextsection “Hair Growth Inhibition”). Nevertheless, severalanti-androgen drugs approved for other uses are effec-tive in the treating hyperandrogenism. Most of theseagents exert their action by blocking the synthesis ofandrogens or by antagonizing the androgen receptor atthe pilosebaceous unit. These medications alwaysshould be used concomitantly with strict contraceptionbecause anti-androgen medications may cause femi-nization of a male fetus during pregnancy. Spirono-lactone is the most commonly used anti-androgen agentalong with OCPs to treat hirsutism in the United States.Spironolactone is a potassium-sparing antihypertensivethat acts as an anti-androgen at the androgen receptor.Spironolactone also inhibits an enzyme that is requiredfor biosynthesis of androgens in gonadal and adrenalsteroid-producing cells.27,28 An initial daily dose of100 mg (50 mg twice daily) of spironolactone is recom-mended to treat hirsutism.29 Serum sodium and potassi-um levels should be checked periodically when spirono-lactone is used, and medications or supplements thatincrease serum potassium should be avoided.

Flutamide acts as an antagonist at the androgenreceptor and is a mild inhibitor of androgen biosynthe-sis.29 Flutamide requires careful monitoring during itsuse because of the rare liver toxicity. Finasteride inhibitsthe enzyme 5 α-reductase thereby lowering DHT levelsat the hair follicle. The expense of finasteride and itslack of superior effectiveness over other pharmacologictherapy precludes its routine use.29 Gonadotropin-releasing hormone analogues (GnRH-a) decrease ovar-ian androgen production by suppressing pituitaryluteinizing hormone release; amenorrhea and vasomo-tor symptoms result from decreased secretion of ovari-an estrogen. One study failed to prove a greater effec-tiveness of GnRH-a alone or combined with OCPswhen compared with OCP use alone.30 The expenseand lack of superior results limits the use of GnRH-a.



Table 9. Medical and Surgical Treatment Options forHirsutism and Virilization

Etiology Treatment

Ovarian sources

PCOS, idiopathic

Hyperthecosis

Neoplasms

Adrenal

Congenital adrenal hyper-plasia (classical and late onset)

Neoplasms

Other primary endocrin-opathies (eg, Cushing’s syndrome, acromegaly)

Drugs

OCPs = oral contraceptive pills; PCOS = polycystic ovarian syndrome.

*Luteomas and theca-lutein cysts of pregnancy may be managed ex-pectantly; refer to gynecologic oncologist for management.

First line: OCPs, spironolac-tone, weight loss, eflor-nithine HCl, possible met-formin if glucose intolerant.

Second line: other anti-androgen therapy (seetext).

As with PCOS, possiblebilateral ovarian removalif childbearing completed.

Surgical removal*

Corticosteroid therapy(possible mineralocorti-coid therapy for classical)

Surgical removal

Treat primary disorder

Modify or discontinueintake

Hair Growth Inhibition

Eflornithine hydrochloride is a topical agent that hasbeen approved by the US Food and Drug Administrationfor treating unwanted facial hair. This therapeutic agentinhibits the enzyme ornithine decarboxylase thereby re-tarding the proliferation of hair matrix cells. Prospective,placebo-controlled, phase 2 clinical trials suggest thateflornithine is effective, but this medication must be usedcontinuously for control of hirsutism.31 Sufficient timeshould be allowed for a woman to respond to medicaltherapy (approximately 6 months) because medicinesaffect only new hair growth. A summary of the medical

and surgical treatment options for hirsutism and viriliza-tion is presented in Table 9.

HAIR REMOVAL

Physical methods for temporary hair removal includeshaving, depilatories, waxing, or tweezing. Permanentmethods of hair removal include electrolysis and laser epi-lation (Table 10). For many years, electrolysis was the onlypermanent method of long-term hair removal; however,hair regrowth after treatment is as high as 50%.32 Newlydeveloped techniques of laser-assisted hair removal havebeen introduced and have shown promising results.



Table 10. Mechanical Methods for Removal of Unwanted Hair

PermanentMethod Mechanism Side Effects Removal Cost Notes

Physical epilation

Shaving

Plucking

Waxing

Depilatories

Electrosurgical epilation

Galvanic and thermolytic electrolysis

Laser-assisted hair removal

Photodynamic therapy and selective thermolysis

Excision of hairshaft

Removal of hairshaft

Removal of hairshaft

Hair breakdown bydissolving disul-fide bonds

Current producessodium hydrox-ide in the hairfollicle causingdestruction

Selective thermoly-sis of hair follicleby laser energycoupling withmelanin

No

No

No

No

Yes

Yes

$

$

$$

$$

$$$$

$$$$

Skin irritation, stub-ble, cuts, must bedone daily

Discomfort, ingrownhairs, hyper-pigmentation

Uncomfortable (notuseful for face),skin irritation, fol-liculitis

Irritation, contactdermatitis

Time consuming,uncomfortable,short-termedema, rarehyper- or hypo-pigmentation, rareskin blistering

Time consuming,uncomfortable,short-termedema, and ery-thema. Rarelyscarring, or hypo- or hyper-pigmentation

Does not affecthair growth

Response is vari-able; some hairsremain thinner,others coarser

Some hair tooshort for removal

Can settle into hairfollicles givinglonger-lastingresults

Shave before totreat only hairs ingrowing phase;transformation ofvellus to darkerterminal hair canoccur; multiplesessions required

Time efficient, lessdiscomfort; rubyand Alexandritelasers work beston light skin withdarkly pigmentedhair; multiple ses-sions required

Laser-selective thermolysis of the hair follicle is achievedbecause melanin couples with monochromatic laser wave-lengths and induces selective damage to hair follicles.33,34

The best candidates for laser epilation are individuals withdark hair and relatively fair skin. Typically, several laser-treatment sessions several months apart are needed toachieve 80% to 90% permanent hair removal, but thetreatment sessions are relatively quick with a minimum ofdiscomfort and side effects.33 Direct comparisons of vari-ous laser hair removal systems, however, are not yet avail-able. Further studies need to be performed to determineideal laser parameters and regimens to maximize safety,reliability, and effectiveness.

VI. MANAGEMENT OF PATIENT 1

As previously discussed, patient 1 has the HAIR-ANsyndrome; she does not have specific adrenal, thyroid,or pituitary endocrinopathy. This special category ofPCOS requires tailored therapy to address issues of gen-eral health along with cosmesis. Patient 1 should loseweight using both diet and exercise to improve symp-toms caused by diabetes. She should also receive thera-py for insulin resistance along with hormonal therapyfor hirsutism and her abnormal menses.

After dietary consultation, she initiates a low-calorie,low fat diet with the judicious use of complex carbohy-drates; aerobic exercise is instituted. She requires met-formin (500 mg 3 times daily) to manage type 2 diabetes.An OCP with a low androgenic progestin is administeredto induce regular menses (protecting her from endome-trial hyperplasia) and to ameliorate hirsutism and acne.She is reassessed every 3 months. After 6 months of OCPtreatment, the patient should be evaluated to determinewhether spironolactone, eflornithine hydrochloride, orphysical means of permanent hair removal are warranted.Ovulation induction with an agent, such as clomiphenecitrate, may be necessary for patient 1 to achieve a preg-nancy.35 She understands that no anti-androgenic treat-ment should be taken when attempting conception.

VII. SUMMARY POINTS

• Hirsutism is the result of androgen-induced increasesin the hair shaft diameter, pigmentation, and growthof midline/facial hair; it is not an increase in the num-ber of hair follicles/body surface area.

• The ovary is the most common source of testos-terone production; however, the peripheral conver-sion of androgen precursors (primarily androstene-

dione, DHEA, and DHEAS) of ovarian and adrenalorigin contributes to the total pool of testosterone.

• Although rare, rapidly progressive hirsutism coexis-tent with virilization suggests a serious underlyingdisorder such as an ovarian or adrenal tumor.

• PCOS is the most common cause of hirsutism and isdescribed by hyperandrogenism and chronic anovu-lation. Cyclic OCPs will regulate menses, help pro-tect from the increased risk of endometrial hyper-plasia, and offer the best and most effective first-linetreatment for hirsutism and acne in these patients.

• Hyperinsulinemia often accompanies PCOS. Use ofinsulin-sensitizing medications for glycemic controlin type 2 diabetes can help to improve hirsutism.

• Endocrinopathic conditions (eg, Cushing’s syndrome,acromegaly, congenital adrenal hyperplasia) are rarelythe cause of hirsutism. The history or specific signs andsymptoms of these diseases should prompt additionaldiagnostic testing to direct therapy.

• Anti-androgen medications (eg, spironolactone, flu-tamide, finasteride) are not approved by regulatoryagencies in the United States or Canada for the treat-ment of hirsutism. These agents, while effective inmanaging hirsutism, should be held in reserve forrecalcitrant cases. Strict contraception should alwaysbe followed when using these therapeutic agents.

• Sufficient time should be allowed for response tomedical therapy (approximately 6 months) to opti-mize physical methods (eg, electrolysis, laser epila-tion) to control unwanted body hair.

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PUBLISHING STAFF Cervical Incompetence; PRESIDENT, GROUP PUBLISHER

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