THE ABNORMAL PAP AND PCOS
From the 32nd Annual Family Medicine Review Update 2006, presented last May, by the University of Minnesota
Medical School
| THE ABNORMAL PAP—Patricia Adam, MD, MSPH, Assistant Professor, Department of Family Medicine and Community
Health, University of Minnesota Medical School, and Associate Program Director, Smiley’s Family Medicine
Residency Program, University of Minnesota Medical Center, Minneapolis
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| Cytology and histology: 30% of women with atypical squamous cells of undetermined significance (ASC-US)
have mild dysplasia, 10% have severe dysplasia; high-grade squamous intraepithelial lesion (HSIL); atypical squamous
cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H); low-grade squamous intraepithelial
lesion (LSIL); atypical glandular cells of undetermined significance (AGUS); cervical intraepithelial neoplasia
(CIN)—eg, carcinoma in situ (CIS) or CIN 3 (severe dysplasia); dysplasia and CIN used interchangeably;
correlations—LSIL on Papanicolaou (Pap) testing correlates with CIN 1 (mild dysplasia); HSIL on Pap correlates
with CIN 2 and 3 (moderate and severe dysplasia)
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| Likelihood of CIN 2 or 3 on abnormal Pap: ASC-US—9% to 15% chance; multiple management options;
ASC-H—≤90%; colposcopy only option; LSIL—15% to 30%; colposcopy primary management; other options
available for adolescents and postmenopausal women; HSIL—most cases high-grade disease; colposcopy only option;
CIN progression—CIN 1 benign (60%-70% regress; observe at first); CIN 2 or 3 may progress (treatment required)
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| Human papillomavirus (HPV): low-risk—causes genital warts; unlikely to cause CIN; high-risk—necessary
for development of cervical cancer; prevalence—most prevalent in adolescents and women ≈20 yr of age (prevalence
similar to that of LSIL); HSIL more prevalent at later age; 80% of women at some point positive for HPV;
80% of women clear HPV in 6 to 18 mo
|
| HPV testing: hybrid capture II testing approved by Food and Drug Administration (FDA); polymerase chain reaction
(PCR) testing more sensitive for HPV and allows for typing (“but we don’t really know what to do with typing”);
pitfalls—HPV prevalent in young girls; positive results do not indicate illness; because HPV sexually
transmitted, cannot “perform testing lightly”; low-grade HPV should not be tested for
|
| HPV regression: factors that may delay regression—tobacco smoking; low folate levels; immunocompromise;
high folate levels—inverse correlation with folate levels and HPV and abnormal Pap results; women with higher
folate levels tend to clear sooner; trial saw speedier regression of CIN with 10 mg of folate daily; condoms—
controversial; small study saw increased regression in women in partnerships with men using condoms; reasonable to
suggest
|
| Case presentation: woman 22 yr of age with ASC-US on Pap testing; asymptomatic; tobacco smoker; management
options—1) repeat cytology; if negative, repeat (if negative again, perform routine screening); if positive,
perform colposcopy; 2) HPV testing; study saw 50% decrease in colposcopy referrals with HPV testing; if positive,
perform colposcopy (if colposcopy normal, perform cytology at 6 and 12 mo or HPV testing at 12 mo); 2 negative
Pap tests equal 1 negative HPV test; HPV testing sensitive and specific (if negative, colposcopy not required); if
HPV testing at 12 mo positive, perform colposcopy; woman has mild dysplasia; management options include 1)
treatment, 2) observation and follow-up in 1 yr with Pap testing and colposcopy, or 3) observation and follow-up in
1 yr with HPV testing; 2-yr observation reasonable
|
| Case presentation: sexually active woman 18 yr of age; LSIL on Pap testing; options include 1) colposcopy or 2)
HPV testing in 1 yr (if positive, perform colposcopy) or Pap testing at 6 and 12 mo; begin Pap testing in women
who have been sexually active for 3 yr and women ≥21 yr of age; regression high in adolescents
|
| Case presentation: woman 65 yr of age with new LSIL on Pap testing; woman’s Pap history normal; options for
low-risk women include 1) colposcopy, 2) HPV testing in 1 yr (if positive, perform colposcopy) or Pap testing at 6
and 12 mo; because of atrophy, intravaginal estrogen (eg, Premarin Vaginal Cream) recommended (apply 1 to 2 wk
qhs and wait 1 wk before performing repeat Pap testing or colposcopy)
|
| Case presentation: woman 35 yr of age with history of normal Pap testing; monogamous for 10 yr; screening options
include annual Pap testing, conventional Pap testing every 2 to 3 yr, liquid-based Pap testing every 2 to 3 yr,
or Pap and HPV testing every 3 yr
|
| New screening recommendations: American Cancer Society (2002)—annual Pap testing for high-risk groups;
liquid-based Pap testing every 2 yr; for women ≥30 yr of age, do not perform liquid-based Pap testing and HPV
testing more frequently than every 3 yr; American College of Obstetricians and Gynecologists (ACOG)—annual
testing with conventional or liquid-based Pap testing for women 21 to 29 yr of age; United States Preventive Services
Task Force (2003)—insufficient evidence about using HPV and liquid-based cytology; in women with normal
Pap testing, conventional or liquid-based Pap testing every 2 to 3 yr recommended; interim guidance—if HPV
testing and Pap testing negative, repeat in 3 yr; if Pap abnormal, perform colposcopy; if HPV test positive and Pap
test negative, risk for CIN 2 or 3 10%; repeat in 6 to 12 mo (if HPV test positive or Pap abnormal, perform colposcopy;
if both negative, repeat in 3 yr); advantages—tests for necessary risk for cervical cancer; cost-effective when
done every 3 yr; disadvantages—complicated; more patient education needed; more sophisticated tracking needed;
“inappropriate” trigger for seeing patient every year removed
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| HPV vaccine: quadrivalent; targets cervical cancer and genital warts; should be given at 0, 1, and 6 mo; to be given
to preteenagers; effect on cancer uncertain for 10 yr
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| Summary: referring abnormal Pap for colposcopy acceptable; discuss guidelines with colposcopist; educate patients
about HPV; HPV testing decreases number of colposcopies for ASC-US; useful for following patients with
CIN; immediate colposcopy can be avoided in adolescents and low-risk postmenopausal women with LSIL
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| POLYCYSTIC OVARY SYNDROME —Johanna Archer, MD, MS, Assistant Professor, Department of Obstetrics,
Gynecology, and Women’s Health, Reproductive Medicine Center, University of Minnesota Medical School, Minneapolis
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| Diagnosis of polycystic ovary syndrome (PCOS): in 1990, criteria unclear; wide discrepancy in population
studies; Rotterdam Consensus (2003)—2 of 3 criteria needed for diagnosis; polycystic ovaries; oligo- or anovulation;
clinical or biochemical evidence of high testosterone; exclusion of other etiologies; criteria may be problematic
because women with polycystic ovaries with high levels of testosterone who ovulate regularly with no
problems becoming pregnant and women with polycystic ovaries with ovulatory dysfunction (common in women
with eating disorders or hypothalamic amenorrhea and in adolescents) may be inappropriately diagnosed with
PCOS
|
| Polycystic ovaries: “string of pearls” (ie, thick cortex with pearls of follicles seen on ultrasonography) description
no longer appropriate for diagnosis of PCOS; >12 follicles (2-9 mm) in ovary and/or increased ovarian volume (0.5
x length x width x thickness); not applicable to women on hormonal medication (eg, oral contraceptives [OCs]) or
women with one follicle >10 mm; ultrasonography on cycle day 3 to 5 recommended; one affected ovary sufficient
to meet criterion; 20% of women have appearance of polycystic ovaries, but only 5% to 10% have PCOS
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| Oligo- or anovulation: use menstrual cycle history; 70% of women with PCOS have regular cycle history, 50%
have cycles >35 days, with <9 menses per year; 20% of women with PCOS have amenorrhea (ie, no menses for 6
mo or 3 normal-length cycles); 30% of PCOS women report regular menstrual cycles, but 10% oligo- or anovulatory;
risk increases with obesity
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| Clinical or biochemical evidence of high testosterone: hirsutism—terminal hair in male pattern; often treated
by patient with, eg, electrolysis or waxing; Ferriman-Gallwey score ≥6 raises suspicion, score of 8 diagnoses hirsutism;
hair follicle concentration varies with ethnicity; acne on neck, chest, or back; androgenic alopecia (loss of
hair along hairline and across front of scalp); laboratory methods and accuracy of measuring testosterone levels
variable; normal ranges not well established and differ between older and younger women (androgen production
decreases by 50% at age 40 yr); normal testosterone levels after 2 yr of stopping OC use; check total testosterone,
not free testosterone
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| Exclusion of other causes: hyperprolactinemia (measure fasting prolactin and 2 hr after awakening); thyroid dysfunction;
nonclassical adrenal hyperplasia (check fasting 17-hydroxyprogesterone during follicular phase of cycle);
women with hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN) syndrome obese and hirsute;
testing not diagnostic for PCOS—fasting glucose, insulin ratio, quantitative insulin sensitivity check index
(QUICKI), and homeostasis model of assessment (HOMA) not indicative of PCOS; ratio of leuteinizing hormone
(LH) to follicle-stimulating hormone (FSH) level cannot be used to diagnose PCOS
|
| Pathophysiology: not completely understood; abnormalities at hypothalamus, pituitary, and ovary; β-cell dysfunction;
defect in insulin signaling pathway in fat cells and skeletal muscle cells; hypothesis—genetic component and
environmental factors influence phenotype; no single gene found to consistently cause PCOS phenotype; multiple
genetic abnormalities; heterogeneous disorder (ie, variance between ethnic groups and geographic backgrounds)
|
| Prevalence: PCOS in 3.5% to 11.0% of reproductive-aged women; >75% of women with anovulation; 80% to 90%
of women with hirsutism; 32% of sisters of PCOS women, 24% of mothers of PCOS women
|
| Consequences: infertility; recurrent pregnancy loss in 30% to 40%; obesity; increased risk for endometrial cancer;
impaired glucose tolerance; type 2 diabetes; dyslipidemia; coronary atherosclerosis; metabolic syndrome
|
| Metformin: used to treat high levels of insulin and anovulation in PCOS women; does not cause hypoglycemia;
side effects include nausea, vomiting, and diarrhea (side-effect profile of Glucophage XR comparable to placebo);
start with 500 mg at night and increase by 500 mg weekly (up to 1500 mg; decrease to 1000 mg if patients do not
tolerate 1500 mg); perform baseline liver function tests and check creatinine before starting (recheck every 3 mo
and yearly if patient still on medication); restores menstruation in obese PCOS women 62% of time; restores ovulation
in 56% of PCOS women, compared to 35% on placebo; chance of ovulation increases with longer use; 17%
of women on metformin conceived, compared to 5% on placebo; increased risk for multiple gestation; metformin
vs clomiphene (Clomid)—higher oligomenorrhea or amenorrhea in Clomid group; cumulative pregnancy rate
higher in metformin group; live-birth rate higher in metformin group (not statistically significant); recurrent pregnancy
loss—controversial; rule out other etiologies (eg, antiphospholipid antibody syndrome); defined by ≥2 pregnancy
losses; women with PCOS believed to have decreased serum glycodelin and insulin-like growth factor
binding protein (needed for implantation); study found higher miscarriage rate in women on Clomid, compared to
metformin; pregnancy category B drug (ie, safety based on animal studies; toxicity seen with excessive doses); inform
patients of small risk for abnormalities
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| Obesity and metabolic syndrome: weight loss can restore ovulation and improve hirsutism and acne; impaired
glucose tolerance increases risk for diabetes; women with PCOS become diabetic 20 to 30 yr earlier than normal
women; metabolic syndrome—leads to coronary artery disease; ratio of triglyceride to high-density lipoprotein
(HDL; ratio >3.0 or 3.2) may help determine likelihood of insulin resistance and metabolic syndrome; increased
risk for cardiovascular disease; endothelial dysfunction in younger women (30-40 yr of age) with PCOS and normal
weight
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| ACOG recommendations: all women with PCOS should have 75-g oral glucose tolerance test (OGTT); measure
2-hr glucose and insulin (repeat every 2 yr); obtain triglyceride to HDL ratio; improve insulin sensitivity with
weight loss, exercise, metformin, or glitazones; patient selection criteria for metformin use uncertain; metformin in
adolescents with PCOS improved insulin sensitivity, decreased androgens, decreased lipids, and regulated menstrual
cycle; treatment—OCs; consider metformin or glitazones for women who want to become pregnant; glitazones
(pregnancy category C) not used as commonly due to weight gain; in women 20 to 24 yr of age, OCs and
simvastatin shown to decrease testosterone, compared to OCs alone
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Educational Objectives
| The goal of this program is to educate the listener about abnormal findings on Papanicolaou (Pap) testing and about
polycystic ovary syndrome (PCOS). After hearing and assimilating this program, the participant will be better able to:
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 | 1. Predict risk for severe dysplasia based on Pap test results.
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| 2. Choose appropriate screening methods for human papillomavirus (HPV) based on clinical findings.
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| 3. Counsel patients about risks and regression of HPV.
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| 4. Use the Rotterdam Consensus to identify women with PCOS.
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| 5. Describe the risks and benefits of using metformin in women with PCOS.
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Discussed on This Program
Clomiphene citrate [Clomid, Milophene, Serophene]
Estrogen, vaginal [Estrace Vaginal Cream, Estring, Femring, Ogen Vaginal Cream, Premarin Vaginal Cream]
Folic acid (folacin; pteroylglutamic acid; folate) [Folvite]
Human papillomavirus vaccine [Gardasil]
Metformin HCl [Fortamet, Glucophage, Glucophage XR, Riomet]
Simvastatin [Zocor]
Suggested Reading
Archer JS et al: Hirsutism and acne in polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 18:737,
2004; Azziz R: Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome the Rotterdam criteria
are premature. J Clin Endocrinol Metab 91:781, 2006; Bhanot UK: Atypical squamous cells ASCUS is out!
Now, ASC-US and ASC-H for reporting of cervical cytology. Asian Pac J Cancer Prev 7:161, 2006; Boardman
LA et al: Atypical squamous cells of undetermined significance, human papillomavirus, and cervical intraepithelial
neoplasia 2 or 3 in adolescents ASC-US, age, and high-grade cervical neoplasia. J Low Genit Tract Dis 10:140, 2006;
Bruner KS et al: ASC-US and HPV testing in women aged 40 years and over. Diagn Cytopathol 31:358, 2004;
Cattrall FR et al: Long-term metabolic, cardiovascular and neoplastic risks with polycystic ovary syndrome. Best
Pract Res Clin Obstet Gynaecol 18:803, 2004; Dokras A et al: Screening women with polycystic ovary syndrome
for metabolic syndrome. Obstet Gynecol 106:131, 2005; Ehrmann DA: Polycystic ovary syndrome. N Engl J Med
352:1223, 2005; Hart R et al: Definitions, prevalence and symptoms of polycystic ovaries and polycystic ovary
syndrome. Best Pract Res Clin Obstet Gynaecol 18:671, 2004; Irwin K et al: Cervical cancer screening, abnormal
cytology management, and counseling practices in the United States. Obstet Gynecol 108:397, 2006; Jakubowicz
DJ et al: Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab
87:524, 2002; Kiatpongsan S et al: Role of human papillomavirus DNA testing in management of women with
atypical squamous cells of undetermined significance. Int J Gynecol Cancer 16:262, 2006; Knochenhauer ES et
al: Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United
States: a prospective study. J Clin Endocrinol Metab 83:3078, 1998; La Marca A et al: Metformin treatment of
PCOS during adolescence and the reproductive period. Eur J Obstet Gynecol Reprod Biol 121:3, 2005; Lee SJ et
al: Analyses of atypical squamous cells refined by the 2001 Bethesda System: the distribution and clinical significance
of follow-up management. Int J Gynecol Cancer 16:664, 2006; Monsonego J et al: Human papillomavirus
testing improves the accuracy of colposcopy in detection of cervical intraepithelial neoplasia. Int J Gynecol Cancer
16:591, 2006; Palomba S et al: Prospective parallel randomized, double-blind, double-dummy controlled clinical
trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory
women with polycystic ovary syndrome. J Clin Endocrinol Metab 90:4068, 2005; The Rotterdam ESHRE/ASRM-Sponsored
PCOS consensus workshop group: Revised 2003 consensus on diagnostic criteria
and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 19:41, 2004; Walker JL et
al: Predicting absolute risk of CIN3 during post-colposcopic follow-up: results from the ASCUS-LSIL Triage Study
(ALTS). Am J Obstet Gynecol 195:341, 2006.
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. For this issue,
the faculty reported nothing to disclose.
Drs. Adam and Archer were recorded in Minneapolis, MN, at the 32nd Annual Family Medicine Review Update
2006, presented May 1-5, 2006, by the University of Minnesota Medical School. The Audio-Digest Foundation
thanks the speakers and the University of Minnesota Medical School for their cooperation in the production of this
program.
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