{"paper_id":"a0d0010c-0f74-48d6-ae78-1d2b443590b3","body_text":"108 \nSelected Disorders of the Female \nReproductive System \nGary R. Newkirk and Patricia Ann McGuire \nPelvic pain is one of the most vexing problems encoun­\ntered by the family physician. The monetary and psy­\nchosocial costs are unknown but are assumed to be high. \nIn the United States about 40% of all laparoscopies are \ndone for the evaluation and treatment of pelvic pain.! \nEvaluation of Pelvic Pain \nClinical Presentation \nPatients with pelvic pain present with a wide variety of \ncomplaints and physical findings. To better understand \nthe causes of pelvic pain and assist with the initial evalu­\nation it is helpful to distinguish acute pelvic pain from \nchronic pelvic pain. Chronic pelvic pain is present for 6 \nmonths or more and acute pelvic pain for less than 6 \nmonths. Chronic pelvic pain syndrome is characterized \nby incomplete response to treatment, impairment at work \nor home, signs of depression, and pain that is worse than \nwould be expected on the basis of the pathologic process 2 \n(see Chapter 61). \nDiagnosis \nEffective evaluation of pelvic pain begins with a search \nfor organic causes that require immediate therapy. An \nintegrative approach that relates psychological, histori­\ncal, and physical factors from the outset is essential. \nWhen taking the history it is helpful to differentiate acute \nfrom chronic pelvic pain because this distinction refines \nthe differential diagnoses (Tables 108.1, 108.2). A detailed \nhistory is obtained clarifying the location, severity, and \ninciting and relieving factors of the pain. Careful men­\nstrual, pregnancy, and sexual histories are sought. Con­\ntraceptive use, previous pelvic problems or surgery, and \nprevious diagnostic and therapeutic efforts are clarified. \nThe psychosocial history includes clarification of prior \nsexual abuse, personal relationships, and exploration of \nthe patient's efforts to cope with and her fears about the \ncause of pain. \nResearch has shown a high incidence of sexual abuse \nassociated with chronic pain.3 Furthermore, current psy­\nchiatric diagnoses, especially depression, and substance \nabuse correlate with pelvic pain. Rates of childhood or \nadult sexual or physical abuse are as high as 48% in pa­\ntients presenting with chronic pelvic pain. 3 Formal psy­\nchological consultation may be useful for assessing the \npsychiatric contribution to chronic pelvic pain. In most \ninstances a psychiatric diagnosis modifies the patient's \nperception and significance of pelvic pain and rarely is \nthe sole cause for symptoms. \nPhysical Examination \nThe physical examination includes careful abdominal, \nmusculoskeletal, and pelvic examination. In addition to \nthe routine abdominal examination the examiner looks \nfor trigger points in the abdominal wall. The abdominal \nwall has been identified as a common source of pain for \nboth acute and chronic forms of pelvic pain. 4 The abdom­\ninal wall is palpated with the patient's abdominal mus­\ncles stretched (supine) and relaxed (knees bent) so trigger \npoints typical of the myofascial syndrome can be de­\ntected? During the pelvic examination the external gen­\nitalia are examined for signs of sexually transmitted \ndiseases or trauma. The bimanual examination evaluates \nthe introitus, levator sling, vaginal walls, cervix, uterus, \nadnexa, septum and cul-de-sac. The urethra is palpated \nfrom within the vagina, as significant pain in this area \nimplies the urethral syndrome related to chlamydial in­\nfection. The patient is requested to contract and relax the \nR. B. Taylor et al. (eds.), Family Medicine\n© Springer Science+Business Media New York 1998\n\n940 Gary R. Newkirk and Patricia Ann McGuire \nTable 1 OB.1. Causes of Acute Pelvic Pain and Initial \nManagement \nPelvic infection-anti biotics \nPregnancy complications \nEctopic pregnancy-laparotomy \nSpontaneous abortion-may need dilatation and curettage \nSeptic abortion-antibiotics, may need dilatation and \ncurettage \nAdenexal problems \nOvarian torsion-often requ ires laparotomy \nRuptured ovarian cyst-may require surgery \nIntracapsular or extracapsular ovarian hemorrhage-\nmay require surgery \nEndometriosis--specific therapy (see next section) \nAcute degeneration or torsion of a leiomyoma-often \nrequ ires surgery \nNongynecologic causes \nInflammatory bowel disease-specific medical \nmanagement \nUrinary tract stone-may require surgical removal, \nantibiotics \nAcute cystitis-antibiotics \nSexual abuse \nMiscellaneous causes-require specific medical treatment \nSickle cell disease, porphyria, diabetes, systemic lupus \nerythematosus \nHereditary angioneurotic edema \nvagina around the examining fingers to assist in the detec­\ntion of vaginismus. An attempt is made to recreate the \npain on the bimanual examination including palpation \nand movement of the cervix. If pressing on the posterior \nfourchette or bottom of the vagina reproduces the pain, \nthere is a high likelihood that the pain has a significant \npsychological or musculoskeletal origin. Pain from a pel­\nvic organ origin may be noted ventrally or both dorsally \nand ventrally but almost never presents as dorsal back \npain alone. The cul-de-sac is palpated for abnormalities \nsuch as nodules which can be found with endometriosis. \nIn most instances the cervix is screened or cultured for \ngonorrhea and Chlamydia. \nMusculoskeletal dysfunction often contributes to the \nsigns and symptoms of chronic pelvic pain and in many \ncases is the primary factor. s King et al. found that a typical \npattern of faulty posture, termed typical pelvic pain (TPP) \nposture, was found in 75% of patients studied with \nchronic pelvic pain. 6 The posture consists of exaggerated \nlordotic posture of the lumbar spine, anterior tilt of the \npelvis, and kyphosis of the thoracic spine. Referred sources \nof pain must also be considered. 6,7 \nTable 1OB.2. Causes of Chronic and Cyclic Pelvic Pain \nChronic pelvic pain \nEndometriosis \nChronic salpingitis \nSevere pelvic adhesions \nAdenomyosis \nPelvic congestion syndrome \nNongynecologic causes \nMuscu loskeletal \nInflammatory bowel disease \nIrritable bowel syndrome \nDiverticulitis \nInterstitial cystitis \nReferred pain \nPsychological \nCyclic pelvic pain \nMittleschmerz \nPrimary dysmenorrhea \nSecondary dysmenorrhea \nAdenomyosis \nEndometrial polyp \nPedunculated submucous myoma \nPremenstrual tension syndrome \nDiagnostic Studies \nThe initial laboratory evaluation for pelvic pain includes a \npregnancy test if the patient is of reproductive age, com­\nplete blood count (CBC), urinalysis, and erythrocyte sedi­\nmentation rate (ESR). Vaginal probe ultrasonography can \nconfirm intrauterine pregnancies as early as 4 to 5 weeks \nand can assist in the evaluation of women with suspected \nectopic pregnancy. The presence of fluid in the posterior \ncul-de-sac seen on the ultrasound scan suggests a patho­\nlogic process, but this finding has poor specificity. Ultra­\nsonography may also be useful for the patient who is \ndifficult to examine because of obesity, is unable to relax, \nor whose pain prevents palpation during the bimanual \nexamination. Unfortunately, abdominal ultrasonography \nis sometimes overutilized, as the likelihood of positive \nfindings in a patient with completely normal pelvic exam­\nination is low and may contribute to further unnecessary \nimaging and heightened physician and patient anxiety. \nFor example, ovarian cysts are a common finding on ultra­\nsound scans and may be up to 5 cm in diameter; yet they \nare not the source of pain unless careful bimanual palpa­\ntion of these cysts duplicates the pain. \nDiagnostic laparoscopy remains an important tool for \nevaluating pelvic pain. s Laparoscopy is the gold standard \nfor diagnosing such conditions as pelvic inflammatory \ndisease (PID), ectopic pregnancy, and ovarian torsion. The \ncause of chronic pelvic pain in patients under age 30 is \nmost often endometriosis or chronic PID. Older patients \nare most likely to have adenomyosis, leiomyomas, endo­\nmetriosis, or symptoms due to pelvic relaxation. Pelvic \nadhesions are the only finding in 10% to 25% of laparos-\n\n108. Selected Disorders of the Female Reproductive System 941 \ncopies for chronic pelvic pain, but studies are still not \nclear whether adhesions are incidental findings or are the \ncause of the pain. Another benefit of diagnostic laparos­\ncopy is to offer the patient reassurance. In one study that \nfollowed patients with chronic pelvic pain after laparos­\ncopy had excluded pelvic pathology, 22% were pain-free \nat their 6 week follow-up appointment, and 40% reported \ndecreased pain. 9 \nOther diagnostic studies that may aid in the diagnosis \ninclude urine cultures, barium enema, intravenous pye­\nlography, or empiric nerve blocks to help confirm the \norigin of pain (e.g., symptomatic adenomyosis). \nManagement \nManagement of acute pelvic pain is most successful when \na specific diagnosis has been identified. The patient with \nacute, severe pelvic pain and deteriorating clinical condi­\ntion often requires abdominal exploration. In most other \ninstances, a careful history and physical examination in­\ndicate the most likely nonsurgical causes of acute pelvic \npain. Table 108.1 outlines initial management steps for the \nvarious causes of acute pelvic pain. \nNarcotics can be used with acute pelvic pain on a selec­\ntive basis, when the diagnosis is assured, and for a short \ntime. Narcotics should not be used for chronic pelvic \npain. Nonsteroidal antiinflammatory drugs (NSAIDs) are \nthe best choice for long-term causes of pelvic pain. Anti­\ndepressants help with the management of chronic pelvic \npain regardless of whether symptoms of classic depres­\nsion are identified and can be tried on an empiric basis. \nLow dose amitriptyline (25 mg) was significantly more \neffective than placebo in reducing such pain. 10 \nHormone treatment with oral contraceptives, Depo­\nProvera, and gonadotropin-releasing hormone (GnRH) \nanalogs may be helpful in suppressing ovarian function \nto treat conditions such as endometriosis, adenomyosis, \nfibroids, dysmenorrhea, and ovarian cysts. Definitive treat­\nment with antibiotics and the occasional need to drain pel­\nvic abscesses surgically are the main strategies for managing \nPID. \nSeveral studies have reported the importance of a mul­\ntidisciplinary management for treatment of chronic pelvic \npain (CPP). Sexual and marital counseling, family ther­\napy, and behavior modification therapy are interventions \nto be considered. Regular office visits should be sched­\nuled to decrease the patient's need to justify visits by \nexperiencing more pain. The frequency of these visits can \nbe gradually tapered as the patient improves. Realistic \ngoals must be established early regarding the manage­\nment of CPP.ll Adapting and coping with CPP is consid­\nered the therapeutic goal, with complete resolution of \nsymptoms unlikely. \nAdjunctive treatment includes nerve blocks and nerve \ninterruption surgery. Paracervical blocks may have a di­\nagnostic and therapeutic value, as a response to this trial \nof analgesia strongly implies a uterine source for the pel­\nvic pain. Fascial injections were advocated by Ling and \nSlocumb for myofascial origins of pelvic pain. 4 Laser uter­\nine nerve ablation therapy has had mixed results when \nused to manage uterine sources of pain. Patients often \nadamantly demand a hysterectomy, especially when the \nsearch for the etiology of CPP becomes nonproductive. \nInterestingly, in one study looking at the outcome of wo­\nmen undergoing hysterectomy with CPP, 78% showed \nsignificant improvement. 12 \nOther, less traditional therapies for CPP include physical \ntherapy for musculoskeletal dysfunction, stressing manage­\nment through life-long attention to posture, strength, \nand flexibility, transcutaneous electrical nerve stimula­\ntion (TENS) for musculoskeletal abdominal wall or back \npain, acupuncture, and relaxation and biofeedback. \nPrevention \nEarly aggressive management, including hospitalization \nfor controlling acute symptoms and facilitating the initial \nworkup, may be indicated. Furthermore, accurately clari­\nfying the source for acute pelvic pain can lead to effective \nearly management of symptoms with much less chance of \nsymptoms becoming chronic. Initial empiric therapy, such \nas parenteral antibiotics if PID is suspected, and defini­\ntive studies such as laparoscopy are believed to prevent \nchronic sequelae; in general, however, poorly directed \nempiric therapy is to be avoided. In the patient who is \nsexually active, counseling regarding sexually transmit­\nted diseases (STDs) and their prevention is always pru­\ndent. The use of estrogen in postmenopausal women may \nbe helpful for preventing pelvic pain due to vaginismus. \nThe use of NSAIDs for 3 days prior to menstruation and \nduring menses is beneficial in preventing pelvic pain \ncaused by dysmenorrhea. A thorough history early in the \ninvestigation of CPP sufferers, such as clarifying sexual or \nphysical abuse, may avoid extensive medical evaluations \nand unnecessary surgical procedures (see Chapter 27). \nAppropriate posture along with good physical condition­\ning, nutrition, and regular exercise may prevent the mus­\nculoskeletal origins of pelvic pain. \nFamily and Community Issues \nThe multiple causes of pelvic pain make its treatment and \ndiagnoses challenging. Family physicians are uniquely \nqualified to care for patients with pelvic pain by virtue of \ntheir psychosocial evaluation skills, long-term manage­\nment potential, and general ability to coordinate care \nfrom various consultants. Education of the community \nabout sexual abuse, STDs, PID, endometriosis, depres­\nsion, and other factors associated with pelvic pain can be \noffered by the family physician. \nEndometriosis: Diagnosis and Therapy \nThe presence of tissue that is biologically and morpholog­\nically similar to normal endometrium in locations beyond \nthe endometrial cavity is termed endometriosis. 13 Endo-\n\n942 Gary R. Newkirk and Patricia Ann McGuire \nmetriosis affects approximately 7% to 10% of premeno­\npausal women, and its incidence is increasing.14 The prev­\nalence in the general population may be underestimated, \nas not all endometrial lesions exhibit classic morphologic \nfindings at laparoscopy.15 Endometriosis is found in 30% \nto 60% of women who present for infertility evaluation. 16 \nSixty to seventy percent of women with endometriosis are \nnulliparous, and most have a family historyP Endometri­\nosis substantially affects the individual (pain, loss of work \ntime) and the health care system (estimated 582,000 hospi­\ntal days in 1980).18 \nThe pathophysiology of endometriosis remains incom­\npletely characterized and poorly understood. The most \nwidely accepted explanation for endometriosis focuses on \nthe concept of retrograde flow of menstrual fluid back \nthrough the fallopian tubes with implantation of viable \nendometrial tissue in the free pelvis.16 This explanation \ncontrasts with the \"celomic metaplasia theory,\" which ar­\ngues that undifferentiated celomic epithelial cells remain \ndormant on the peritoneal surface until the ovaries pro­\nduce hormones sufficient to stimulate this ectopic tissue.14 \nDespite the controversies surrounding pathophysiology, \nendometriosis remains one of the most common gyneco­\nlogic diseases in women during their reproductive years. \nClinical Presentation \nEndometriosis is rarely life-threatening but frequently be­\ncomes \"life-altering.\" Patients with endometriosis present \na wide range of clinical symptoms, and frequently there is \npoor correlation between these symptoms and the extent \nof endometrial implants within the pelvis. Dysmenorrhea \n(50%), infertility (25-50%), pelvic pain, and dyspareunia \n(20%) and menstrual irregularities (12-14%) are the most \ncommon complaints.1 9 Pain can be diffuse or localized to \nthe organs involved. Other, less common symptoms in­\nclude low back pain, dysuria, hematuria, and diarrhea, \nwhich classically occur before or during menses. De­\nspite classic descriptions of the disease, endometriosis \nmay present with some, none, or all of these symptoms, \nwhich mayor may not correlate with the menstrual cycle. \nTextbooks describe the \"typical\" endometriosis patient as \nin her late twenties or early thirties, Caucasian, and fre­\nquently nulliparous. In reality, endometriosis occurs with \nall races from early adolescence to the perimenopausal \nperiod. \nEndometriosis should also be considered in women ini­\ntially presenting for evaluation of infertility.20 How en­\ndometriosis contributes to infertility is not known, and \nlikely more than one mechanism is involved. Explana­\ntions include altered anatomy, ovulatory dysfunction, \nhormonal abnormalities, autoimmunity, toxic pelvic fac­\ntors, altered sexual functioning, and increased spontane­\nous abortions. 16,19 Even though it appears that the number \nof pelvic implants does not correlate well with the sever­\nity of dysmenorrhea and dyspareunia, the probability of \nsuccessful conception appears to be inversely related to \nthe severity of the disease. 21 \nDiagnosis \nPatients presenting with pelvic pain, dyspareunia, dys­\nmenorrhea, abnormal bleeding, or infertility should prompt \nthe clinician to consider endometriosis as a diagnosis. \nPhysical findings include uterosacral nodularity, retro­\nversion of the uterus, limited pelvic mobility, adnexal \nmasses, and diffuse or focal tenderness. Unfortunately, \nneither the history nor the physical examination confirms \nthe diagnosis of endometriosis. The diagnosis of endome­\ntriosis requires direct visual and histologic confirmation \nobtained during laparoscopy or laparotomy. A uniform \nsystem of classification based on the presence, location, \nand quality of adhesions, endometriomas, and tubal dis­\ntortion has been formulated by the American Fertility \nSociety (AFS). The AFS classifies endometriosis as mini­\nmal, mild, moderate, and severe (stages I-IV, respectively).22 \nDuring laparoscopy or laparotomy, endometriosis may ap­\npear as classic brown lesions that may be focal (e.g., ovar­\nian) or diffuse (e.g., peritoneal). Reddish blue nodules on \nthe peritoneum, uterine ligaments, or pelvic viscera are a \ncommon finding as well. Focal scarring or retraction of \nthe peritoneum, diffuse adhesions, and distortion of uter­\nine, ovarian, and tubal anatomy can be seen. Ovarian \nimplants may result in the formation of an endometrioma. \nThese ovarian masses, or \"chocolate cysts,\" can explain \nthe finding of a tender adnexal mass on pelvic examina­\ntion. The presence of endometriomas are confirmed dur­\ning laparotomy and may constitute the initial finding \nfor endometriosis. Extrapelvic (e.g., vulva, vagina) or \npelvic endometriosis should be considered with any \nmass or lesion that becomes painful in a cyclic fashion \nwith menses. \nComputed tomography (CT), and magnetic resonance \nimaging (MRI) can provide presumptive evidence of en­\ndometriosis but are rarely justified for the initial workup. \nThese expensive imaging studies are not diagnostic, as \nthere is no characteristic appearance or location for en­\ndometriosis implants. Pelvic ultrasonography is not di­\nagnostic either but can be helpful in detecting and \ncharacterizing pelvic pathology if the pelvic examination \nis limited owing to tenderness or obesity. Its common \navailability, lower cost, safety during pregnancy, and non­\nradiographic nature are general features that prompt many \nclinicians to include pelvic ultrasonography in the workup \nof endometriosis. \nA cell surface antigen, CA -125 is found on deri va ti ves \nof celomic epithelium including endometrial tissue. De­\nspite the correlation of CA-125 levels with both the \ndegree of endometriosis and the response to therapy, \nthe sensitivity of this assay is too low for it to be used \nas a screening test. It may be beneficial to utilize this \ntest when evaluating ovarian cystS.23 Screening for other \nproteins, such as placental protein 14 and antibodies to \nendometrial tissue, are currently being investigated \nand may prove to be of clinical benefit as screening \nparameters. 24,25 \n\nlOB. Selected Disorders of the Female Reproductive System 943 \nManagement \nTreatment for endometriosis is preceded by careful confir­\nmation and staging with laparoscopy or laparotomy. Fac­\ntors to consider prior to treatment include the patient's \nage and desire for fertility, the severity of symptoms, and \nthe extent, location, and severity of the disease. Even \nthough there is no universally effective cure for this dis­\norder, treatment options do exist that can provide relief of \nsymptoms. The wide variety of treatments for endo­\nmetriosis betray its poorly defined etiology and patho­\nphysiology. Treatment includes expectant management, \nconservative surgical therapy, medical therapy, extensive \nsurgery with castration, and superovulation therapies for \ninfertility, such as in vitro fertilization or gamete intra­\nfallopian tube transfer (GIFT). With more advanced endo­\nmetriosis, there is a greater likelihood that surgical \nintervention will be required to treat the disease success­\nfully. Surgical removal of both ovaries invariably induces \nremission of the disease but should be reserved for wo­\nmen with advanced endometriosis who are over 35 years \nof age and have completed their family. \nExpectant management, or \"watchful waiting,\" may be \na reasonable management strategy for the younger wo­\nman who desires pregnancy and has mildly symptomatic \nendometriosis. Efforts can then be spent identifying and \ncorrecting any other infertility factors as necessary (see \nEvaluation of the Infertile Couple, below). This approach \nhas been shown to produce pregnancy rates as high as \nthose achieved with medical therapy or conservative sur­\ngery (50%).26 \nConservative surgery for endometriosis entails either \nlaparoscopyor laparotomy and is indicated (1) for confir­\nmation of diagnosis; (2) if fertility is desired, to determine \ntubal occlusion or peritubal, ovarian, pelvic, or ovarian \nadhesions; (3) for aspiration of chocolate ovarian cysts; \nand (4) for evaluation of pelvic pain unrelieved by medical \ntherapy.16 The initial treatment at the time of diagnostic \nlaparoscopy can often be accomplished with electrocoagula­\ntion or laser ablation of implants through the laparo­\nscope. Partial ovarian resection for endometriomas and \nlysis of adhesions are accomplished as necessary. Defini­\ntive surgery includes total hysterectomy and bilateral sal­\npingo-oophorectomy and is indicated in women who do \nnot desire pregnancy and for which all previous medical \nand conservative surgical efforts have failed. \nMedical management of endometriosis includes the use \nof danazol, progestogens, oral contraceptives, and GnRHs. \nThe goals of hormonal therapy are to control symptoms, \nimprove fertility, or both. Most medical regimens involve \ntreatment for at least 6 months, allowing for adequate re­\ngression of implants. Unfortunately, hormonal therapy \ndoes not improve adhesive disease or cause ovarian \nendometriomas to regress. Surgery is required in these \ncircumstances. \nEndometriotic implants behave like normal endome­\ntrial tissue and are supported by ovarian hormonesP \nThe effectiveness of hormonal management takes ad-\nvantage of the biologic response of endometriotic tissue \nto alterations of the hormonal environment. In either a \nhypoestrogenic or a hyperandrogenic environment, en­\ndometriotic implants become atrophic. Danazol (Danocr­\nine), for instance, induces a hyperandrogenic state, and \nGnRH agonists produce a hypoestrogenic state. Both \nagents induce regression of endometriotic implants. Pro­\ngesterone therapy such as medroxyprogesterone acetate \n(Amen, Cycrin, Provera) induces decidual or atrophic \nchanges in endometriotic implants. Finally, administration \nof combined estrogen-progestogen contraceptives (pseudo­\npregnancy regimen) produce an acyclic hormonal en­\nvironment similar to that of pregnancy, which causes \nendometriotic implants to atrophy.28 Table 108.3 summa­\nrizes various treatment strategies, the common drugs \nused for therapy, and their potential side effects. Severe \nendometriosis and infertility often require an organ­\nized treatment plan combining surgical and prolonged \nmedical treatment. \nInfertility associated with endometriosis has now been \ntreated with advanced reproductive techniques including \nadministration of hyperstimulation gonadotropins, in vitro \nfertilization, and GIFT techniques. 29,30 Future promise may \nbe found with selective immunologic suppression of \nperitoneal macrophages with verapamil or pentoxifyl­\nline, which has been found to enhance fertility in animal \nmodels. 31 The family physician assumes a critical role in \nmanaging endometriosis by arranging for appropriate \nconsultation, monitoring medical treatment protocols \nand, providing long-term emotional support to patients \nand families troubled by this chronic condition. \nPrevention \nAt present there are no known effective interventions to \nprevent endometriosis from developing in a given pa­\ntient. A positive family history and deferring childbearing \nlead to a higher likelihood for the development of endo­\nmetriosis. Endometriosis usually recurs despite medical \nor conservative surgical treatmentY Long-term hormonal \ntherapy without surgery can help prevent progression in \nsome patients with severe symptoms. Only definitive \nsurgery such as abdominal hysterectomy with bilateral \nsalpingo-oophorectomy, combined with resection of all \nendometrial implants, yields the highest likelihood for \nresolution of symptoms. The laparoscopic finding of mini­\nmal endometrial disease in a women not desiring pregnancy \ncan frequently be managed with cyclic birth control pills to \nlessen further seeding. More advanced disease usually re­\nquires 6 months of danazol or medroxyprogesterone acetate \nfollowed by cyclic birth control pills.20 \nFamily and Community Issues \nEducation regarding endometriosis ideally begins during \nearly adolescence as part of comprehensive health educa­\ntion. Women should be encouraged to seek medical help \nfor the symptoms of endometriosis. For many women \n\n944 Gary R. Newkirk and Patricia Ann McGuire \nTable 108.3. Major Treatment Modalities for Endometriosis \nMethod Hormonal effect Drug \nBilateral Hypoestrogenic NA \noophorectomy \n(often with \nhysterectomy) \nLaser or electro- NA NA \nfulguration ablation \nof endometrial \nimplants \nGnRH agonist Hypoestrogenic Nafarelin (Synarel) \nLeuprorel in (Lupron) \nAndrogenic agonist Hyperandrogenic Danazol (Danocrine) \nHigh progesterone Hyperprogestational Medroxyprogesterone \n(relative low acetate (Amen, \nestrogen) Curretab, Cyrin, \nProvera) \nContinuous oral Combined Birth control pills \ncontraceptives estrogenic and (many types) \n(pseudopregnancy) progestational \nNA = not available; SC = subcutaneous. \nendometriosis becomes a chronic affliction that requires \nongoing education, treatment, and compassion. If the pa­\ntient requests, the physician should meet with other \nmembers of the family to offer information and address \nquestions or concerns. Patients and families may benefit \nfrom contacting the Endometriosis Association to obtain \neducational materials and information regarding support \ngroups that deal with the impact of this chronic condi­\ntion. 32 Women with documented endometriosis who de­\nsire pregnancy should be counseled regarding its relation \nto infertility so these desires and the timing of childbear­\ning can be discussed. Effectively managing patients with \nendometriosis challenges the family physician to remain \nan informed patient advocate, as comprehensive care fre­\nquently involves referral and familiarity with long-term \ntreatment modalities not routinely used by family physi­\ncians. 33 \nEvaluation of the Infertile Couple \nInfertility is generally diagnosed when pregnancy has not \noccurred in a couple trying to conceive after 1 year of \nunprotected intercourse. It is estimated that nearly 15% of \ncouples in the United States are infertile. 34 The infertility \nrisk doubles for women age 35 to 44 compared to women \nRoute of \nadministration Typical daily dose Problems \nLaparotomy NA Permanent sterility, \nbone loss, meno-\npausal symptoms \nLaparoscopy NA Surgical risks; ? benefit \nor for severe disease, \nlaparotomy recurrence \nNasal 0.4-0.8 mg Bone loss, hot flashes, \nSC 0.5-1.0 mg decreased libido, \nvaginal discharge \nOral 400-800 mg Androgenic side \neffects, weight gain, \nacne, oily skin, \ndeep voice \nOral 30-60 mg Mood changes, \nbloating, break-\nthrough bleeding \nOral e.g., 0.035 mg Oral contraceptive \neth i nylestrad ioll side effects: mood \n1 mg norethindrone changes, weight \n(1-4 per day) gain, bloating \nage 30 to 34; consequently, about one-third of women \nolder than 35 who desire pregnancy experience infertil­\nity.35 \nCouples are seeking professional help for infertility on \na increasing basis, and family physicians are in an ideal \nposition to begin this evaluation. Their familiarity with \npartner's family, medical, and physical histories allow the \nassessment to begin with both partners, which contrib­\nutes to the cost-effectiveness of the family physician's \ninfertility evaluation. The major goals when evaluating \nthe infertile couple include (1) identifying and correcting \ncauses of infertility, (2) providing accurate information for \nthe couple, (3) providing emotional support during and \nafter the evaluation process, and (4) providing counseling \nregarding alternatives should pregnancy be unlikely or \nimpossible. 36 This discussion presents the initial workup \nof the infertile couple, which is sufficient to allow diagno­\nsis in approximately 60% of couples seeking helpP \nThere are various estimates regarding the causes for \ninfertility. Table 108.4 summarizes the experience for in­\nfertile couples in the United States. 36-38 \nInitial Fertility Workup \nA timely and cost-effective approach to evaluating the \ninfertile couple requires initial evaluation of both the male \n\n108. Selected Disorders of the Female Reproductive System 945 \nTable 10B.4. Male and Female Infertility Factors \nMale factors (40% of couples) \nDisorders of spermatogenesis \nObstruction of efferent ducts \nDisorders of sperm motility \nSexual dysfunction \nFemale factors (45% of couples) \nPelvic origin (30-50% of female causes) \nTubal disorders \nUterine disorders \nEndometriosis \nOvulatory origin (40% of female causes) \nEndocrine (adrenal, thyroid, pituitary) disorder \nOvarian: luteal phase defects \nCervical origin (10% of female causes) \nMucous problems \nInfectious problems \nCombined factors (15-30% of couples) \nUnidentifiable factors (15% of couples) \nand female factors for infertility. Table 108.5 summarizes \nan organized approach to the fertility workup.36-39 Both \npartners are scheduled for extended examination times. \nAmple time is afforded to explain the need and methods \nfor the various initial tests and data collection including \n(1) semen analysis, (2) documentation of ovulation, (3) \npostcoital test, and (4) evaluation of tubal patency. The \nexact sequence in which a physician evaluates a couples' \ninfertility varies based on historical and physical findings \nascertained during the initial visit. \nA semen sample is analyzed within 2 hours of ejacula­\ntion after 48 hours of ejaculatory abstinence. Evaluation \nshould be by persons experienced with fertility semen \nanalysis. If an abnormality is found on this initial assess­\nment, two additional semen analyses are performed 2 \nweeks apart. If the abnormality persists, urologic consul­\ntation is appropriate. \nAssessing ovulation can be accomplished by one or \nmore methods: (1) basal body temperature (BBT) assess­\nment; (2) timed serum progesterone levels; (3) urinary LH \nscreening; and (4) endometrial biopsy. The method of re­\ncording BBT data is explained during the initial visit. \nSerum progesterone levels are measured 7 days after esti­\nmated ovulation. Values consistent with ovulation vary \nwith each laboratory, but generally values of more than 15 \nng/ml are consistent with normal ovulatory function and \nlevels under 5 ng/ml imply anovulation. \nEndometrial biopsy, in addition to histologically detect­\ning ovulation, provides timing of the progestational effect \nwith the day of the cycle and can provide information \nregarding ovulation and luteal phase defects. Endome­\ntrial sampling is easily accomplished using small aspira­\ntion catheters (Pipelle, Z-sampler) at as close to 7 days \nTable 10B.S. Evaluation Plan for the Infertile Couple \nInitial visit (extended visit time for both partners) \nComplete medical, family, drug and sexual history \nLaboratory studies \nSexually transmitted disease cultures (especially \nChlamydia, Ureaplasma urealyticum, Neisseria \ngonorrhoeae) \nAssess need for HIV screening \nConsider CBC, FBS, VORL, urinalysis \nMen: semen analysis \nWomen \nPapanicolaou screening \nKOH and wet mount \nFocused stud ies \nThyroid history?-thyroid function tests \nGalactorrhea?-prolactin levels \nAbnormal pelvic examination?-ultrasonography, \nlaparoscopy \nHistory PI D?-hysterosal pi ngography \nEndometriosis I ikely?-Iaparoscopy \nHistory sexual dysfunction?-education, counseling \nOvulatory monitoring (BBT, urinary LH) \nEducation \nAlcohol, drugs, hot tubs, sexual practices/frequency, \ndouching, lubricants \nArrange for postcoital sample analysis with next visit \nSecond visit (midcycle/ovulatory as predicted by BBT \nand/or urinary LH testing) \nReview laboratory studies, semen analysis, ovulatory \nmonitoring data to date \nAnalyze postcoital sample \nConsider and discuss need for endometrial biopsy \nArrange for hysterosalpingography during follicular \nphase (days 7-9). If laparoscopy deemed necessary, \nHSP often accomplished during laparoscopy \nThird visit (midluteal phase of cycle, 7-9 days \npostovulation) \nReview studies to date \nPerform endometrial sampling \nConsider progesterone and prolactin levels if not \nalready done \nConsider HSP or laparotomy; referral often appropriate \nat this time \nCBC = complete blood counts; FBS = fasting blood sugar; LH = \nluteinizing hormone; HSP = hysterosalpingography; BBT = basal \nbody temperature; HIV = human immunodeficiency virus; PIO = \npelvic inflammatory disease. \nafter presumed ovulation as possible (roughly, day 22 of a \n28-day cycle). \nPostcoital testing requires evaluation of the sperm-mucus \ninteraction. The couple is instructed to have intercourse fol­\nlowing 48 hours of abstinence. Pelvic examination is per­\nformed and aspirated cervical mucous is examined within 2 \nto 8 hours of intercourse. Intercourse should occur within \n\n946 Gary R. Newkirk and Patricia Ann McGuire \n24 to 48 hours of presumed ovulation as determined by \nmethods outlined above. The postcoital mucus is exam­\nined by experienced individuals for quantity, clarity, pH, \nspinnbarkeit (ability of cervical mucus to stretch), and the \nnumber, forms, and motility of sperm. Generally, finding \n5 to 10 sperm with linear motility per high power field in \nclear, acellular mucus with more than 8 cm spinnbarkeit \nexcludes cervical factors as a major cause for infertility. \nDuring a subsequent office visit, results of the initial \nlaboratory studies, cultures, and semen analysis are dis­\ncussed. The postcoital sample can be obtained and an \nappointment for the endometrial biopsy, luteal progester­\none and prolactin levels scheduled. The results of these \nstudies are carefully reviewed during the third visit, at \nwhich time a decision is made to pursue hysterosal­\npingography, laparoscopy, hysteroscopy, or laparotomy. \nThe frequency of these visits also facilitates emotional \nsupport and encouragement for the couple. RESOLVE (5 \nWater Street, Arlington, MA 02174), a national nonprofit \ninfertility organization, has chapters throughout the United \nStates and is an excellent resource for support and coun­\nseling groupS.39 \nHysterosalpingography \nHysterosalpingography (HSP) is a safe, high yield proce­\ndure when performed during the early proliferative \nphase of the cycle. During HSP a special catheter is passed \nthrough the vagina into the endocervical canal through \nwhich contrast medium is injected and fluoroscopically \nfollowed through the endometrial and fallopian tube \nlumen. An undiagnosed pelvic mass or PID contraindi­\ncates this procedure, as does an iodine or radiocontrast \ndye allergy. HSP can be performed during laparoscopic \nsurgery as well. The appearance of uterine defects on HSP \nimplicate a uterine cause for infertility, which include \npost-DES uterine abnormalities (T-shaped, hypoplastic \ncavity), intrauterine synechiae (Asherman syndrome), \nsubmucous or large intramural myomas, congenital anom­\nalies, and leiomyomas. \nFurther evaluation of pelvic factors for infertility re­\nquire laparoscopy. Laparoscopy is indicated if HSP is \ncontraindicated or abnormal and is also performed if his­\ntorical (e.g., PID, endometriosis) or physical (e.g., adhe­\nsions, tube/ovarian abnormality) findings implicate a \npelvic cause. Women with endometriosis are twice as \nlikely to be infertile as women without this condition. \nEndometriosis is confirmed and staged by laparoscopy. \nTreatment for endometriosis was discussed earlier in this \nchapter. Finally, laparoscopy is indicated if no other sig­\nnificant cause for infertility is identified. \nOvulatory disorders for infertility include adrenal and \nthyroid disorders. Fasting blood glucose, thyroid func­\ntion, FSH, LH, and prolactin levels assist the evaluation of \nendocrinologic factors for infertility. Drug-related infertil­\nity must also be considered, as a number of medications \ncontribute to disruption of thyroid, adrenal, or ovarian \nfunctioning in both men and women (e.g., antihyperten-\nsive drugs, major tranquilizers, steroids). Therapy for ovula­\ntory factors is directed toward the underlying disorder, \nincluding thyroid replacement for hypothyroidism, bromo­\ncriptine for hyperprolactinemia (with pituitary macro­\nadenoma ruled out), or clomiphene to induce ovulation. \nEvidence supports a possible link between the risk of ovar­\nian cancer in women receiving ovulatory stimulants. 40 \nCervical factors for infertility are assessed initially by \nthe postcoital test. The finding of leukocytes suggests cer­\nvicitis; and cultures for gonorrhea, Ureaplasma urealyti­\ncum, and Chlamydia are useful for directing treatment. \nFinding nonmotile or nonprogressively motile sperm with a \n\"shaking\" pattern suggests sperm antibodies. Miscalcula­\ntion of ovulation timing is suggested by poor quality \ncervical mucus, which is abnormally thick, cloudy, and \ndemonstrates poor spinnbarkeit. A repeat postcoital test is \nnecessary if ovulatory timing is in question. \nDespite comprehensive evaluation 5% to 10% of cou­\nples have no identifiable cause for their infertility. Often \nreferral to infertility centers for consideration of assisted \nreproductive technologies (ART) is necessary (e.g., in \nvitro fertilization, GIFT) and appropriate. Attitudes re­\ngarding adoption and assisted reproductive technologies \nshould be explored. \nOften individual or joint guilt regarding infertility can \nbe underestimated. Family physicians are in an ideal po­\nsition to utilize established trust and comfort with their \npatients to explore potential past history and guilt issues \nthat might relate to infertility. Emotional support remains \na part of every visit. \nToxic Shock Syndrome \nIn 1978 an acute, febrile, exanthematous illness associated \nwith multisystem organ failure became known as the toxic \nshock syndrome (TSS).41 There are currently no definitive \ntests or specific serologic markers for diagnosing TSS. The \ndiagnosis requires the presence of the six clinical criteria, \noutlined in Table 108.6.42,43 TSS should be suspected in all \npatients who present with flu-like symptoms, rash, and \notherwise unexplained hypotension. \nEarly reports indicate that more than 90% of the re­\nported TSS cases involved menstruating females. 44 Be­\ncause of the high correlation of TSS with menstruation \nand tampon use, the perception of TSS as strictly a \"tam­\npon disease\" persists. More recent data reveal that only \nhalf of the reported cases were female, and many of these \ncases were not associated with menstruation. 45 Most cases \nof tampon-related TSS occurred during the teenage years; \n97% of reported patients were white, and 42% were ado­\nlescents.46 Physicians must recognize that TSS can occur \nin nonmenstruating women, men, and children of all \nages. Nonmenstrual cases of TSS occur in males and fe­\nmales equally with various sites and types of infection, \nincluding surgical wounds, burns, abscesses, sinus in­\nfections, bronchopneumonia, tracheitis, empyema, septic \nabortion, intravenous drug injections, pilonidal abscess, \n\n108. Selected Disorders of the Female Reproductive System 947 \nTable 708.6. Toxic Shock Syndrome, Criteria for \nDiagnosis \nConfirmed diagnosis requires that all six criteria be met. \n1. Acute fever \n2. Scarlatin iform rash \n3. Desquamation of palms and soles 1-2 weeks after \nillness onset \n4. Hypotension \n5. Clinical or laboratory evidence of involvement of at \nleast three organ systems: hematologic, gastro­\nintestinal, neurologic, cardiovascular, hepatic, renal, \nmuscular \n6. Other causes excluded (e.g., sepsis, measles, drug or \ntoxic ingestion) \nSource: Data from Todd and Fishaut 41 and Tofte and Williams. 42 \ninsect bites, diaphragm use, and even ear piercing. Inter­\nestingly, menstruation-related TSS affects Caucasians al­\nmost exclusively, whereas non-menstruation-related forms \naffect the races proportionate to the racial! sexual mix of \nthe population. 47 \nPathogenesis \nThe expression of TSS depends on the interaction of sev­\neral bacterial and host factors that are incompletely \nunderstood. In the original studies, patients with TSS \nusually had a source of staphylococcal infection. More \nrecent reports have characterized a streptococcal toxic \nshock-like syndrome caused by toxins elaborated by \ngroup A streptococci. 48,49 Both have in common the pres­\nence of bacteria-related toxins that appear to initiate the \nserious multiorgan syndrome characteristic of these dis­\norders. Toxic shock syndrome toxin-1 (TSST-1) has been \nidentified as one of the significant staphylococcal media­\ntors of pathogenicity in TSS,50 although TSS can occur in \nthe absence of TSST-1. Endotoxin from co-infecting gram­\nnegative or streptococcal bacteria has also been implicated \nin TSS.51 Staphylococcal toxins may interact synergistically \nwith these endotoxins. TSST-1 enhances the release of a \nwide variety of endogenous mediators produced by the \nhost, which partly explains the multiorgan dysfunction \ncharacteristic of this syndrome. Finally, the correlation of \nTSS with vaginal materials such as tampons, barrier \nsponges, or the diaphragm strongly implies an as yet \nuncharacterized relation between foreign materials and \nthe induction and maintenance of this condition. TSS ap­\nparently results from multiple, cumulative effects of pri­\nmary and secondary mediators initiated by the continued \ngrowth of certain bacteria. \nClinical Presentation \nToxic shock syndrome presents with a broad spectrum of \nclinical findings ranging from relatively mild symptom­\natology to a rapidly fatal illness. 42 Mortality is about 3%. \nPatients may progress from onset of symptoms to overt \nmultisystem failure within 48 hours. Hypotension and \npoor tissue perfusion, with nonhydrostatic leakage of \nfluid from the intravascular to the interstitial space, ac­\ncounts for a portion of the multisystem organ failure (renal, \nhepatic, central nervous system, hematologic). Fatal com­\nplications include refractory shock, renal failure, arrhyth­\nmias, intravascular coagulopathy, and respiratory distress \nsyndrome. The initial fever, rash, and malaise of TSS may \nmimic a common viral syndrome early in the disease \nprocess. These symptoms typically progress rapidly to \ninclude high fever (104 OF), pharyngitis, conjunctivitis, di­\narrhea, vomiting, myalgia, and scarlet fever-like rash. \nWithin a matter of hours orthostatic dizziness, fainting, or \novert hypotension may occur; these first symptoms clear­\nly set this syndrome apart from benign infectious pro­\ncesses. The rash of TSS is usually a prominent finding and \ntypically appears as a diffuse scarlatiniform exanthem \nbeginning on the trunk and spreading to the arms and \nlegs with flexural accentuation. Some clinicians have de­\nscribed this rash as having a \"sunburn\" appearance that \nblanches with pressure. \"Strawberry tongue,\" as seen \nwith scarlet fever, is a common finding. Erythema of the \nmucous membranes and intense conjunctival hyperemia \nwithout purulence are characteristic. Generalized non­\npitting edema accompanies the rash in many cases. Des­\nquamation of the hands and feet is commonly seen within \n10 to 21 days after presentation. Reversible patchy alope­\ncia and shedding of fingernails has been described as \nwell. 52 \nToxic shock syndrome is rare in children, but when it \ndoes appear the clinical features of the illness do not \ndiffer appreciably from those described in adults. There \ndoes seem to be a higher likelihood of respiratory in­\nvolvement in children. 50 The differential diagnosis of TSS \nin children includes Kawasaki disease, staphylococcal \nscalded skin syndrome, scarlet fever, Rocky Mountain \nspotted fever, leptospirosis, erythema multiforme, Stevens­\nJohnson syndrome, and measles. \nCommon laboratory findings of TSS reflect widespread \norgan involvement: sterile pyuria; normocytic anemia; \nleukocytosis with left shift; prolongation of the prothrom­\nbin and partial thromboplastin times; an increase in serum \nbilirubin, creatinine, and creatine kinase; hyponatremia; \nhypokalemia; and metabolic acidosis. 53 \nManagement \nHospitalization is necessary for all patients with pre­\nsumed TSS, as the illness may progress from mild to \nlife-threatening within a matter of hours. Supportive \nmeasures tailored to the patient's symptoms are the main­\nstay of therapy.54 A search is made for the potential source \nof the staphylococcal or streptococcal toxin, and cultures \nof any suspected source are obtained. Removal of vaginal \ntampons, pads, sponges, or diaphragms is paramount. \nRecent surgical wounds are explored even if they appear \nnot to be inflamed or infected. All presumed sources of \ntoxin must be thoroughly drained and irrigated. \n\n948 Gary R. Newkirk and Patricia Ann McGuire \nProspective management includes administration of \nlarge volumes of colloid and crystalloid fluids with glu­\ncose (10-20 ml/kg) over the first hour to reestablish vas­\ncular volume. Patients may require 5 to 10 liters of fluid \nduring the first 24 hours to maintain tissue perfusion and \nurinary output. Swan-Ganz catheterization is required for \nsevere cases. After specimens for culture are obtained, \nantistaphylococcal antibiotics (e.g., methicillin, oxacillin, \nnafcillin, first generation cephalosporin, or vancomycin) \nare given intravenously until oral fluids can be tolerated. \nAntibiotics are continued for at least 10 days. Steroid ther­\napy (e.g., methylprednisolone 10-30 mg/kg/day) maybe \ngiven to patients with severe unresponsive shock. Intra­\nvenous immune globulin may be also given to patients \nwho are not improving, although the effectiveness of this \ntherapy has not been proved. \nSigns of adult respiratory distress syndrome (ARDS) \noften develop on the second or third day of treatment \nwith severe TSS. Intubation with continuous positive air­\nway pressure may be required; generally, fluids are not \nrestricted. Acute renal failure may require dialysis. \nRecurrences of TSS are common but generally milder. \nFemale patients who experience TSS are advised to avoid \nthe use of vaginal devices (tampons, sponges, diaphragms). \nProphylactic antistaphylococcal oral antibiotics at the time \nof menses have been recommended for patients experi­\nencing TSS associated with menses. Oral contraceptives \nhave been shown to decrease the risk of TSS recurrence. 44 \nThese approaches have not yet been conclusively sup­\nported by rigorous studies. \nReferences \n1. Peterson HB, Hulka JF, Phillips JM. American Association of \nGynecologic Laparoscopists' 1988 membership survey on \noperative laparoscopy. J Reprod Med 1990;35:587-9. \n2. Nolan TE, Elkins TE. Chronic pelvic pain differentiating an­\natomic from functional causes. Postgrad Med 1993;94:125-8. \n3. Toomey TC, Hernandez JT, Gittlelman DF, Hulka JE Rela­\ntionship of sexual and physical abuse to pain and psycho­\nlogical assessment variables in chronic pelvic pain. Pain \n1993;94:125-8. \n4. Ling FW, Slocumb Je. Use of trigger point injections in \nchronic pelvic pain. Obstet Gynecol Clin North Am 1993; \n20:809-15. \n5. King Baker P. Musculoskeletal origins of chronic pelvic pain. \nObstet Gynecol Clin North Am 1993;20:719-40. \n6. King PM, Myers LA, Ling FW, et a1. Musculoskeletal factors \nin chronic pelvic pain. J Psych Obstet Gynaecol 1991;12:87-\n98. \n7. Basu HK. Major common problems: pelvic pain. Br J Hosp \nMed 1981;26:150. \n8. Vercellini P, Fedele L, Arcaini L, et a1. Laparoscopy in the \ndiagnoses of chronic pelvic pain in adolescent women. J \nReprod Med 1989;34:827. \n9. Baker PN, Symonds EM. The resolution of chronic pelvic \npain. Am J Obstet GynecoI1992;166:835. \n10. McQuay HJ, Carroll D, Glynn CJ: Low dose amitriptyline in \nthe treatment of chronic pain. Anesthesia 1992;47:646-52. \n11. Parsons L, Stovall T. Surgical management of chronic pelvic \npain. Obstet Gynecol Clin North Am 1993;20:765-78. \n12. Stovall TG, Ling FW, Crawford DA. Hysterectomy for chronic \npelvic pain of presumed uterine etiology. Obstet Gynecol \n1990;75:676. \n13. Sampson JA. Perforating hemorrhagic (chocolate) cysts of \nthe ovary, their importance and especially their relation to \npelvic adenomas of the endometrial type. Arch Surg 1921;3: \n245-323. \n14. Saltiel E, Garabedian-Ruffalo SM. Pharmacologic manage­\nment of endometriosis. Clin Pharm 1991;10:518-30. \n15. Rawsn JM. Prevalence of endometriosis in asymptomatic \nwomen. J Reprod Med 1991;36:513-5. \n16. Dawood MY. Endometriosis. In: Gold H, Josimovich JB, edi­\ntors. Gynecologic endocrinology. New York: Plenum, 1987: \n387-404. \n17. Moghissi KS. Office management of endometriosis. In: Sten­\nchever MA, editor. Office gynecology. St. Louis: Mosby-Year \nBook, 1992:413-29. \n18. National Center for Health Statistics, McCarthey E. Inpa­\ntient utilization of short-stay hospitals by diagnosis: United \nStates, 1980. Hyattsville, MD: National Center for Health \nStatistics, 1982. DHSS Publ. no. (PHS) 83-1735. (Vital and \nhealth statistics; series 13: Data from the National Health \nSurvey, no. 74.) \n19. Hurst BS, Rock JA. Endometriosis: pathophysiology, diagno­\nsis, and treatment. Obstet Gynecol Surv 1989;44:297-304. \n20. Endometriosis and infertility. In: Speroff L, Glass RH, Kase \nNG, editors. Clinical gynecology, endocrinology, and infer­\ntility. 4th ed. Baltimore: Williams & Wilkins, 1989;547-63. \n21. Dmowski WP. Endometriosis. In: Glass RH, editor. Office \ngynecology. Baltimore: Williams & Wilkins; 1987:317-36. \n22. American College of Obstetricians and Gynecologists. Man­\nagement of endometriosis. Washington, DC: ACOG, 1985. \nTechnical Bulletin No. 85. \n23. Pittaway DE. CA-125 in women with endometriosis. Obstet \nGynecol Clin North Am 1989;16:237-52. \n24. Koninck PR, Riittinen L, Sepalla M, Cornillie FI. CA-125 and \nplacental protein 14 concentrations in plasma and perioneal \nfluid of women with deeply infiltrating pelvic endometrio­\nsis. Fertil SterilI992;57:523-30. \n25. Badawy SZA, Cuenea V, Freliech H, Stefanu e. Endometrial \nantibodies in serum and peritoneal fluid of infertile patients \nwith and without endometriosis. FertH SterilI990;53:930-2. \n26. Seibel MM. Does minimal endometriosis always require \ntreatment? Contemp Obstet Gynecol 1989;34:27-39. \n27. DiZerega GS, Barber DL, Hodgen GD. Endometriosis: role of \novarian steroids in initiation, maintenance, and suppres­\nsion. Fertil Steril1980;33:649-53. \n28. Barbieri RL. Endometriosis 1990: current treatment ap­\nproaches. Drugs 1990;39:502-10. \n29. 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The Collab­\norative Ovarian Cancer Group: characteristics relating to \novarian cancer risk: collaberative analysis of twelve US \ncase-control studies I-IV. Am J EpidemioI1992;136:1175-220. \n41. Todd I, Fishaut M. Toxic-shock syndrome associated with \nphage-group-I staphylococci. Lancet 1978;2:1116-8. \n42. Tofte RW, Williams DN. Toxic shock syndrome: evidence of \na broad clinical spectrum. JAMA 1981;246:2163-7. \n43. Bryner CL Jr. Recurrent toxic shock syndrome. Am Fam \nPhysician 1989;39:157-64. \n44. Davis JP, Chesney PI, Wand PJ, LaVenture M. Toxic shock \nsyndrome: epidemiologic features, recurrence, risk factors, \nand prevention. N Engl J Med 1980;303:1429-35. \n45. Centers for Disease Control. Summary of notifiable disease, \nUnited States. MMWR 1988;37:40. \n46. Litt IF. Toxic shock syndrome-an adolescent disease. J Ad­\nolesc Health Care 1983;4:270-4. \n47. Reingold AL, Hargrett NT, Dan BB, Shands KN, Strickland \nBY, Broome Cv. Nonmenstrual toxic shock syndrome: a re­\nview of 130 cases. Ann Intern Med 1982;96:871-4. \n48. Gallo UE, Fontanarosa PB. Toxic streptococcal syndrome. \nAnn Intern Med 1990;19:1332-4. \n49. Wolf J, Rabinowitz L. Streptococcal toxic shock like syn­\ndrome. Arch DermatoI1995;131:73-7. \n50. Resnick SD. Toxic shock syndrome: recent developments in \npathogenesis. J Pediatr 1990;116:321-8. \n51. Parsonnet J. Mediators in the pathogenesis of toxic shock \nsyndrome: overview. Rev Infect Dis 1989;2 Suppll:s263-9. \n52. Tofte R, Williams DN. Toxic shock syndrome: clinical and \nlaboratory features in 15 patients. Ann Intern Med 1981; \n94:149-56. \n53. Davis JP, Osterholm MT, Helms CM, et al. Tri-state toxic­\nshock syndrome study: clinical and laboratory findings. J \nInfect Dis 1982;145:441-8. \n54. Todd JK. Therapy of toxic shock syndrome. Drugs 1990;39: \n856-61.","source_license":"CC0","license_restricted":false}