GYNECOLOGIC PAIN SYNDROMES
| ENDOMETRIOSIS: DIAGNOSIS AND TREATMENT —Linda C. Giudice, MD, PhD, Professor and Chair, Department
of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, Medical
School
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| General considerations: definition—presence of endometrial glands and stroma outside uterine cavity; 54% of
surgeons studied made correct diagnosis visually (compared to those doing biopsy of suspected lesions); sites of
disease—most commonly found in peritoneum; can be found in pleural cavity, liver, kidney, gluteal muscle, or
bladder; possible in men with high levels of estrogen; pathogenesis—believed to originate from retrograde menstruation;
some evidence it may be derived from coelomic metaplasia; fragments of menstrual blood attach to peritoneum;
can invade peritoneum and establish blood supply, resulting in suboptimal immune response (implants not
adequately cleared, resulting in their survival and growth); epidemiology—occurs in women 12 to 80 yr of age;
time to diagnosis in United States 11 yr, 8.5 yr in United Kingdom; estrogen-dependent disorder; no racial or socioeconomic
predilection; occurs in families; evidence it may be caused by, or correlated with, presence of dioxin and
other environmental contaminants; prevalence—6% to 10% of women of reproductive age and 50% to 60% of
women with pelvic pain have endometriosis; primary indication for hysterectomy between 1965 and 1984; in 2004,
inpatient hospital costs for diagnosis of endometriosis totaled $3 billion
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| Signs and symptoms: cyclic pelvic pain (most common); dysmenorrhea, dyspareunia, dysuria, and dyschezia; referred
musculoskeletal pain to flanks, low back, and thighs; infertility—mechanical blockage of sperm/egg
union, especially in severe disease with adhesions; disruption of normal pelvic anatomy; decreased fecundity—
reason unknown; postulated that toxicity to embryo results from inflammatory milieu in pelvic cavity (may affect
egg, sperm, embryo, and endometrium); associated disorders—malignancies and compromise of immune
system (not clearly defined); physical examination—pain or induration of nonpalpable lesion, uterine or adnexal
fixation, adnexal mass or tender nodules along uterosacral ligaments; 3 types of endometriosis—pelvic/ peritoneal,
rectovaginal, and ovarian; unclear if all have same origin
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 | Clinical appearance: early active lesions—clear to bright; papular excrescences or vesicles; ≈33% synchronous
with eutopic endometrium; advanced active lesions—black, brown, purple, red, or green; represents heme degradation
products as foci undergoing hemorrhage and fibrosis; dormant and healed lesions—white or calcified;
represent remnants of glands embedded in fibrous tissue; ovaries—common site for implants; different histologic
findings possible in same cyst; endometriomal spread can result in invasion of functional cyst; endometriomas
might originate from metaplasia of coelomic epithelium of cyst wall; simple ovarian implants behave
similarly to peritoneal implants
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| Diagnostic modalities: biopsy requires endometrial glands and stroma; surgery and visualization only way to
make diagnosis; computed tomography (CT)—limited differentiation between benign and malignant lesions; limited
differentiation between loop of bowel and adnexal structures; ultrasonography (US)—inadequate differentiation
between benign and malignant lesions; magnetic resonance imaging (MRI)—detects images as small as 3
mm; excellent sensitivity and specificity between benign and malignant lesions
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| Endometriosis and infertility
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| Hypotheses: immunologic or inflammatory responses—increased activity of monocytes and natural killer cells;
distortion of normal anatomy—obstruction of fallopian tubes; other hypotheses—ovulatory dysfunction (luteal
phase deficiency), decreased endometrial receptivity, effects on sperm function, and embryo or oocyte toxicity
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| Implantation: complex interaction between embryo and endometrium; evidence suggests uterine lining in some
women with endometriosis may be compromised for interaction with embryos
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| Molecular definition: insight into molecular markers of window for uterine receptivity for implantation; genes relevant
to implantation failure identified in women with endometriosis; dysregulation of genes in implantation
failure has resulted in identifying infertility phenotype and subsequently more insight into pathogenesis of endometriosis
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| Donor sperm function: increased pregnancy rates and decreased pregnancy rates shown in studies in women with
endometriosis; increased phagocytosis of sperm questionable; conflicting data on whether peritoneal fluid of
women with endometriosis affects sperm motility
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| Embryo response: toxic reaction seen in embryos and oocytes exposed to endometriotic peritoneal fluid; found
only in women with both endometriosis and infertility
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| In vitro fertilization (IVF) outcomes: poor oocyte quality implicated; granulosa cells aspirated during IVF have
higher rates of apoptosis, more alterations of cell cycle, and more evidence of oxidative stress; lower likelihood
of implantation; data for outcomes of IVF cycles show patients with endometriosis have rates similar to those
with male-factor infertility and unexplained infertility
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| Management: probability of pregnancy—patients without significant anatomic disease can conceive spontaneously;
monthly probability of pregnancy 0.14% to 0.45%; with significant anatomic disease, depends on extent of
mechanical distortion and tubal obstruction; medical therapy—efficacy of progestins, danazol, or gonadotropin-
releasing hormone (GnRH) agonist does not enhance fertility; not useful in infertility with asymptomatic endometriosis;
mechanism of infertility different from that of pain associated with endometriosis; meta-analysis of
962 cycles with hyperstimulation and intrauterine insemination (IUI)—pregnancy rates per cycle for stages I
and II 15%; for stages III and IV 8%; similar to statistic for untreated patients with minimal disease; laparoscopic
surgery—includes excision, drainage, and ablation and resection of cyst wall; at 36-wk follow-up, laparoscopy
alone, or ablation and resection of implant, associated with marked increases in fertility and pregnancy
rates and an increased probability of pregnancy for women with minimal to mild disease; significant increase in
fertility also seen (although studies not well controlled) with moderate-to-severe disease; 2 studies showed pain
relief and improved symptoms over 6 mo, but no difference in pregnancy rates; minimal to mild disease generally
treated at time of laparoscopy because of theoretic concern that significant inflammation decreases fertility
(data controversial)
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| Chronic pelvic pain (CPP): accounts for ≈10% of gynecologic outpatient visits; 1 in 5 gynecologic laparoscopies
performed for CPP; 15% to 20% of hysterectomies performed solely or in part for CCP; unlikely that CPP due exclusively
to endometriosis; endometriosis observed in at least one third to one half of women with CPP; most sites
of endometriosis in pelvis; mechanisms by which endometriosis causes pain not fully understood (possible that inflammatory
response irritating to nerves); patient can have adnexal or central pain (presacral or uterosacral neurectomy
controversial); pain may originate from disorder in another organ (eg, bladder, ureter, bowel, diaphragm,
appendix); gastrointestinal (GI) work-up; consider history of psychologic trauma or abuse as possible cause of pain
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| Health risks associated with endometriosis: ovarian cancer—prevalence of endometriosis 20% to 25% in
women with endometrioid, clear cell, or serous mucinous ovarian cancer; synchronous incidence of endometriosis,
with clear cell and endometrioid ovarian carcinoma suggests malignant transformation; possible culprits include
some tumor suppressor genes, increased prevalence of mutations in tumor suppressor genes in atypical endometriosis
and ovarian cancer associated with endometriosis, and endometriotic cysts have loss of heterozygosity and
partial deletions of chromosomes; other malignancies—20876 women hospitalized with diagnosis of endometriosis
had 2.5- to 6-fold increased risk for ovarian cancer, non-Hodgkin’s lymphoma, and breast cancer (breast cancer
controversial); data show higher prevalence of dysplastic nevi, malignant melanoma, and non-Hodgkin’s lymphoma
in women with endometriosis; early malignancy detection in women with endometriosis—important; recommended
practices include annual history and physical examination, appropriate laboratory tests and imaging
studies, and promotion of health maintenance (without alarming patient); immunologic disorders—data show increased
incidence of chronic fatigue syndrome, irritable bowel syndrome, atopy, asthma, food allergies, lupus, and
Sjögren’s syndrome (based on subject recall and self-reporting of symptoms and diagnoses)
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| Future directions in endometriosis research: biomarkers, serum or plasma markers, imaging techniques, and
genetic markers
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| Conclusion: treatment should be targeted to goals of patient; associated disorders should be evaluated for early detection
and treatment; therapies on horizon (to be used adjunctively with surgery or with contraceptive steroids) include
selective estrogen receptor modulators (SERMs), selective progesterone receptor modulators (SPERMs),
aromatase inhibitors, antiangiogenic factors, immunosuppressants, and antioxidants
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| VULVAR PAIN SYNDROMES: A PRACTICAL APPROACH —Mark D. Walters, MD, Vice-Chairman and Head,
Section of General Gynecology and Urogynecology/Reconstructive Pelvic Surgery, Department of Gynecology and
Obstetrics, The Cleveland Clinic Foundation, Cleveland, OH
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| Vulvodynia: vulvar discomfort, most often characterized as burning pain, occurring in absence of relevant visible
findings or specific clinically identifiable neurologic disorder; patient has one of several kinds of characteristic pain
in vulva (from hymen to labia majora) with no identifiable cause; pain chronic; categorized by 2 subtypes, localized
(vulvar vestibulitis) and generalized (pure pain syndrome); prevalence—unknown; one study showed 15% of
women in general obstetric/gynecology practice experienced chronic vulvar pain at some point in lifetime; in specialty
practice, ≈60% of patients have localized pain type, and ≈40% have generalized pain; patients with localized
vulvodynia tend to be younger, whereas patients with generalized vulvodynia span all age ranges
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| Localized vulvodynia (vulvar vestibulitis): severe pain on vestibular touch or attempted vaginal entry; dyspareunia,
or tenderness to pressure on physical examination, localized within vulvar vestibule, usually over Bartholin
glands (at 4- and 8-o’clock positions); physical findings show vestibular erythema (may not be part of
pathophysiology)
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| Generalized vulvodynia: constant, unremitting vulvar burning (patient may describe rawness, fiery, itching/burning
sensation); few or no physical findings; older patient may have concurrent vulvovaginal atrophy; description of
pain similar to other neuralgias (eg, posttraumatic neuralgia); suggests problem with cutaneous perception, centrally
or at nerve root
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| Etiology: pain likely neuropathic because of burning quality and ineffectiveness of narcotics; patients with local
vulvar vestibulitis experience tactile allodynia in which central nervous system (CNS) amplification of sensory effects
of light touch occurs on vulva; increase in blood flow to area may result in erythema; other possible
etiologies—contact irritation, topical medications (recommended all medications and ointments be discontinued at
first visit and new treatment plan developed), allergy (speaker has not found allergy patch testing of value), trauma,
laser or surgery; infection with yeast not considered cause, but can produce “flares”; condition not caused by virus
[(eg, herpes simplex virus (HSV)]
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| Clinical evaluation: coexisting conditions—endometriosis, interstitial cystitis, functional bowel disorders, fibromyalgia,
psychiatric disorders, past or current abuse; physical examination—observe patient when taking history
to understand level of distress; perform careful and gentle vulvar inspection, looking for lesions, ulcers, and
erythema; use moistened cotton swab to assess vestibular tenderness (use gentle touching over Bartholin glands, on
posterior fourchette and along each side of urethra; have patient rate pain on scale of 0 to 10; patients with true vestibulitis
have exquisite touch tenderness; gently palpate vagina to assess levator muscle tightness and for vaginismus;
perform speculum examination; culture for presence of yeast and obtain wet prep if evidence of vaginal
discharge present; empiric treatment not recommended (can worsen condition); perform abdominal and bimanual
examination, assessing for pelvic or suprapubic pain
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| Introital pain: can begin with inflammation or irritation (with or without infection) or just pain in vulva; psychosomatic
issues (eg, increased anxiety, dissatisfaction with sexual partner) can cause pelvic muscle-spasm pain response;
contraction of levator muscles leads to anatomic constriction of vaginal introitus; vicious cycle begins,
resulting in solid vaginal opening that makes intercourse difficult; physical therapy with concurrent treatment required
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| Differential diagnosis of visible vulvar pain conditions: infection (eg, candidiasis, HSV), inflammation (eg,
lichen planus), vaginal atrophy, trauma, neoplasia, or neurologic disorder (eg, herpes neuralgia, cord compression);
biopsy and treat lesions; biopsy not recommended if area appears normal
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| Treatment: general—local skin care; avoidance of vulvar irritants (ie, soaps, perfumes); discontinuance of medications,
creams, and ointments; low oxalate diet; calcium citrate; topical estrogen (if evidence of vaginal atrophy);
topical lidocaine (for use before sexual intercourse or at bedtime); low-dose medical therapy; sex therapy and psychotherapy
(if evidence of psychologic issues); medical therapy—amitriptyline (Elavil) 25 to 75 mg at bedtime or
gabapentin (Neurontin) 300 to 2700 mg daily; consider antidepressant; nonsteroidal anti-inflammatory drugs
(NSAIDs) for general pain; 30% to 80% improvement in pain scores in most patients using Elavil or Neurontin;
secondary treatment of localized vulvodynia—high-dose medical therapy or combination of Elavil and Neurontin;
physical therapy with biofeedback (especially if vaginismus suspected); psychosexual evaluation; surgery (partial
vestibulectomy with vaginal flap advancement, ≈70% cure rate); secondary treatment of generalized vulvodynia—
high-dose medical therapy, psychosexual evaluation, anesthesia pain assessment or spinal cord neuromodulation
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Suggested Reading
ACOG Committee on Gynecologic Practice. ACOG Committee Opinion: Number 345, October 2006: vulvodynia.
Obstet Gynecol 108:1049, 2006. D’Hooghe TM et al: Future directions in endometriosis research. Ann NY Acad Sci
1034:316, 2004; Giudice LC et al: Endometriosis. Lancet 364:1789, 2004; Littman E et al: Role of laparoscopic
treatment of endometriosis in patients with failed in vitro fertilization cycles. Fertil Steril 84:1574, 2005; Marcoux S
et al: Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on
Endometriosis. N Engl J Med 337:217, 1997; Nezhat C et al: The dilemma of endometriosis: is consensus possible
with an enigma? Fertil Steril 84:1587, 2005; Reed BD et al: Treatment of vulvodynia with tricyclic antidepressants:
efficacy and associated factors. J Low Genit Tract Dis 10:245, 2006; Sinaii N et al: High rates of autoimmune and
endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a
survey analysis. Hum Reprod 17:2715, 2002.
Mentioned on this Program
Endometriosis Association: www.endometriosisassn.org
Endometriosis Research Foundation (WERF): www.endofoundation.org
Educational Objectives
| The goal of this program is to educate the listener about the diagnosis and treatment of infertility, pain, and health risks
associated with endometriosis, and about the management of patients with vulvodynia. After hearing and assimilating
this program, the clinician will be better able to:
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| 1. Identify the signs, symptoms, and clinical appearance of endometriosis.
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| 2. Discuss etiologies and therapies for endometriosis-associated infertility and chronic pelvic pain.
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| 3. Summarize the health risks associated with endometriosis.
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| 4. Define vulvodynia and distinguish localized vulvodynia from generalized vulvodynia.
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| 5. Describe the care of the patient with vulvodynia.
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Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following
has been disclosed: Dr. Walters is a consultant for American Medical and is on the Speakers’ Bureau of Boston Scientific.
Acknowledgements
Dr. Giudice was recorded at Controversies in Women’s Health, sponsored by the University of California, San Francisco,
School of Medicine, and held December 7-8, 2006, in San Francisco. Dr. Walters was recorded at the 2006 Update
in Female Urology and Urogynecology, sponsored by the Cleveland Clinic Foundation, and held October 27-28,
2006, in Cleveland, OH. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in
the production of this program.
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