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1. What is the definition of an abortion?
An abortion (miscarriage) is defined as a termination or loss of pregnancy before 20 weeks of gestation
(as calculated from the date of the last menstrual period) or delivery of a fetus weighing less than 500 g.
2. What are the different types of abortions?
• Spontaneous (complete or incomplete)
• Induced
• Threatened
• Inevitable
• Missed
• Tubal (can occur with an ectopic pregnancy)
3. What is the incidence of spontaneous abortions?
Spontaneous abortion is the most common complication of early pregnancy. Approximately 8% to
20% of all clinically recognized pregnancies and as many as 13% to 26% of unrecognized pregnan-
cies end in miscarriage.
4. When do most clinically recognized spontaneous abortions occur?
Eighty percent of recognized spontaneous abortions occur in the first trimester, and the incidence
decreases with increasing gestational age.
5. What is the most common presentation of spontaneous abortion?
Vaginal bleeding with or without pelvic cramping in the first trimester.
6. What is the differential diagnosis of vaginal bleeding in the first trimester?
Vaginal bleeding is common in the first trimester, occurring in 20% to 40% of pregnant women;
even heavy, prolonged bleeding can be associated with a normal outcome. The differential diagnosis
includes the following:
• Threatened abortion
• Ectopic pregnancy
• Vaginal lesions
• Increased friability of the cervix
• Infections (cervicitis, vaginitis, cystitis)
7. What is the risk of spontaneous abortion in patients who experience first-
trimester bleeding?
This outcome affects 25% of women with first trimester bleeding.
8. What is the most common cause of spontaneous abortion?
Fetal genetic abnormalities are believed to account for as many as 75% of all spontaneous abortions.
They are present in 70% of first trimester losses and in 30% of losses in the second trimester.
9. What are the most common types of chromosomal anomalies found in
spontaneously aborted fetuses?
• As a group, autosomal trisomies are the most common (49%). Within this category, trisomy 16 is
the most frequent.
• Monosomy X (17%) is the most common single chromosomal abnormality. It is also known as
Turner syndrome.
• Polyploidies (19%)
• Structural abnormalities (translocations, inversions) (10%)
CHAPTER 25
SPONTANEOUS ABORTION AND
RECURRENT PREGNANCY LOSS
Paul Buzad, MD, and Travis W. McCoy, MD
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REPRODUCTIVE ENDOCRINOLOGY
10. What are other causes of spontaneous abortions?
Box 25-1 provides a list of possible causes.
11. What are the “most common” risk factors associated with spontaneous
abortions?
• Advanced maternal age
• Previous spontaneous abortion
• Maternal smoking of more than 10 cigarettes per day
12. What are the different types of abortions, and how is each type generally
managed?
Table 25-1 is an overview of treatment recommendations for each type of abortion.
13. How do I clinically differentiate among the different types of abortions when a
woman presents with vaginal bleeding?
A diagnostic flowchart is a helpful tool (Fig. 25-1).
Genetic Causes (Chromosomal Abnormalities)
• Numeric (aneuploidy): trisomy, monosomy, polyploidy
• Structural: translocations, inversions
Uterine Conditions
• Congenital uterine anomalies
• Leiomyomas
• Intrauterine adhesions (synechiae)
Endocrine Disorders
• Hypothyroidism (uncontrolled)
• Diabetes mellitus (uncontrolled)
• Hyperprolactinemia
Autoimmune Disorders
• Antiphospholipid syndrome
• Lupus
Infections
• Toxoplasma gondii
• Listeria monocytogenes
• Chlamydia trachomatis
• Ureaplasma urealyticum
• Mycoplasma hominis
• Herpes simplex virus
• Treponema pallidum
• Borrelia burgdorferi
• Neisseria gonorrhoeae
• Streptococcus agalactiae
Medications and Substances
• Alcohol (>2 days/week)
• Heavy caffeine (>300 mg/day)
• Tobacco use
• Cocaine
• Anesthetic gases
• High doses of radiation
• Isotretinoin
• Methotrexate
Box 25-1. Causes of Spontaneous Abortion
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14. What is needed to evaluate a woman who presents with bleeding in early pregnancy?
• History
• Last menstrual period?
• How much bleeding and for how long?
• Cramping?
• Passage of fetal tissue?
• Fever, chills, abdominal tenderness?
• Physical examination
• Temperature and vital signs?
• Abdominal tenderness?
• Rebound or guarding?
Table 25-1. Management of Spontaneous Abortions
TYPE DEFINITION MANAGEMENT
Complete abortion Spontaneous expulsion of all fetal
and placental tissue from uterus;
cervix closed on examination
Ultrasound scan to confirm an empty
uterus; no further intervention
necessary
Incomplete abortion Passage of some but not all fetal
or placental tissue from uterus;
cervix dilated on examination
IV hydration, CBC, type and screen and
crossmatch if necessary; if unstable,
immediate suction curettage; if
stable, medical management or
suction curettage
Threatened abortion Uterine bleeding <20 weeks of
gestation without cervical
dilation or effacement
Ultrasound scan to document fetal
viability, close follow-up
Inevitable abortion Uterine bleeding accompanied
by cervical dilation, but no
expulsion of fetal or placental
tissue through cervical os
Expectant management; termination of
the pregnancy can be considered,
but normal ongoing pregnancy still
possible
Missed abortion Fetal death <20 weeks of gestation
without expulsion of any fetal or
placental tissue
Suction curettage or medical
termination of pregnancy
Septic abortion Any of the foregoing abortions,
accompanied by fever and
uterine infection
IV antibiotics followed by immediate
suction curettage; considered an
emergency
CBC, Complete blood count; I V, intravenous.
History
and exam
Cervix
closed*
Cervix
open
Threatened (with fetal cardiac motion on US)
Complete (with empty uterus on US)
Missed (uterine sac, no cardiac motion on US)
Inevitable (fetal cardiac motion on US)
Incomplete (conception products in uterus on US)
*Don’t forget that ectopic pregnancy must be ruled out!
Figure 25-1. Diagnostic flowchart for spontaneous abortion. US, Ultrasound.
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REPRODUCTIVE ENDOCRINOLOGY
• Speculum examination
• Open cervix?
• Active bleeding?
• Passage of tissue?
• Purulent discharge?
• Bimanual examination
• Cervix: closed or dilated?
• Positive or negative cervical motion tenderness?
• Uterus: size, tenderness?
• Adnexa: masses?
• Tenderness?
• Laboratory tests
• Complete blood count, platelets
• Type and screen: Rh status; blood crossmatched if transfusion necessary
• β-Human chorionic gonadotropin (β-hCG): serial levels needed to follow the trend of titers that
can help make the diagnosis before detection of cardiac activity on ultrasound imaging
• Imaging: Transvaginal ultrasound (TVUS) is the most reliable and safe imaging modality to detect
the earliest evidence of a gestation (see question 16).
15. What is the utility of quantitative hCG measurement in a patient with a threatened
abortion?
In a normal early pregnancy, the hCG level should rise by approximately 66% every 48 hours and by
approximately 53% at a minimum (99th centile). In patients with an abnormal pregnancy, the hCG
level may still rise normally, rise slowly, plateau, or even fall.
16. What is the discriminatory zone?
Traditionally, a quantitative hCG level of 1500 mIU/mL has been called the discriminatory
zone because this is the level at which one expects to visualize an intrauterine pregnancy if the
pregnancy is normal. However, more recent data support a higher threshold, with 99% of gesta-
tional sacs visible with TVUS when the hCG level reaches 3500 mIU/mL. Absence of an intrauter-
ine pregnancy on TVUS with an hCG level higher than the discriminatory zone is highly suggestive
of an abnormal pregnancy (either an ectopic pregnancy or a nonviable intrauterine gestation).
17. Do Rh-negative women need Rho[D] immunoglobin for threatened, incomplete,
and complete spontaneous abortions?
Yes. All Rh-negative women who experience pregnancy-related vaginal bleeding (including ectopic
pregnancies) should receive Rho[D] immunoglobulin to prevent Rh isoimmunization. If the pregnancy
is earlier than 12 weeks of gestation, minidose (50 μg) Rho[D] immunoglobin can be given if available.
After 12 weeks of gestation, full dosing 300 μg is required.
18. How should women be followed after a complete abortion?
Their hCG levels should be followed on a weekly basis until hCG is no longer detectable. If the level
plateaus, this should raise concern for a heterotopic pregnancy, retained placental tissue, or a
gestational trophoblastic neoplasm. Heterotopic pregnancies occur when an intrauterine pregnancy
and an ectopic pregnancy coexist. They are very rare, but women undergoing assisted reproductive
technology (ART) are at higher risk compared with the general population.
19. What is the definition of recurrent pregnancy loss (RPL)?
RPL is defined as two or more failed pregnancies.
20. How often is an identifiable cause for RPL found?
An identifiable cause is found in approximately 50% of cases.
21. What does the initial workup for RPL include?
• Karyotype of both parents or products of conception (rule out genetic factors)
• Thyroid-stimulating hormone, glycosylated hemoglobin (HgbA1c), and prolactin (rule out endocrine
factors)
• Ultrasound scan or saline-infusion sonogram (SIS) (rule out uterine abnormalities)
• Testing for antiphospholipid syndrome (APS; anticardiolipin antibodies, anti-β
2
-glycoprotein anti-
bodies, and lupus anticoagulant)
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22. What is the chance of a live birth after one, two, and three miscarriages?
• After one miscarriage, the chance of live birth is approximately 82%.
• After two consecutive miscarriages, the chance of a live birth is approximately 73%.
• After three consecutive losses, the chance of a live birth is 68%.
23. What are the proposed mechanisms of antiphospholipid antibodies and lupus
anticoagulant in RPL?
These antibodies block prostacyclin formation and result in thromboxane excess. (Prostacyclin is a vasodi-
lator and inhibitor of platelet aggregation.) Thromboxane is a potent vasoconstrictor that promotes platelet
aggregation, and its excess can increase the risk of thrombosis. Antiphospholipid antibodies and lupus
anticoagulant may also bind to trophoblast cells and reduce proliferation, invasion, and the release of hCG.
24. How are patients with APS treated?
Generally, patients with APS are placed on low-dose aspirin (50 to 100 mg) when conception is
attempted. Subcutaneous unfractionated heparin or low-molecular-weight heparin (LMWH) is added
on confirmation of intrauterine pregnancy.
25. What is the role of empiric treatments for RPL?
In patients without a defined cause of RPL, the following empiric treatments have no significant
benefit and are not recommended:
• Aspirin
• Anticoagulation (heparin)
• Progesterone supplementation
• Intravenous immunoglobulins
BiBliography
1. Barnhart KT, Sammel MD, Rinaudo PF, Zhou L, Hummel AC, Guo W. Symptomatic patients with an early viable intrauter-
ine pregnancy: hCG curves redefined. Obstet Gynecol. 2004;104:50–55.
2. Doubilet PM, Benson CB, Bourne T, et al. Diagnostic criteria for nonviable pregnancy early in the first trimester. N Engl J
Med. 2013;369:1443–1451.
3. Ku CW, Allen Jr JC, Malhotra R, et al. How can we better predict the risk of spontaneous miscarriage among women
experiencing threatened miscarriage? Gynecol Endocrinol. 2015;31:647–651.
4. Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy
loss. Fertil Steril. 2008;89:1603.
5. Tulandi T, Al-Fozan H. Definition and etiology of recurrent pregnancy loss. UpToDate; 2014. Available by subscription at
www.uptodate.com. Accessed October 27, 2015.
6. Tulandi T, Al-Fozan H. Spontaneous abortion: risk factors, etiology, clinical manifestations, and diagnostic evaluation
UpToDate; 2014. Available by subscription at www.uptodate.com. Accessed October 27, 2015.
7. Vitzthum VJ, Spielvogel H, Thornburg J, West B. Prospective study of early pregnancy loss in humans. Fertil Steril.
2006;86:373–379.
8. Wang X, Chen C, Wang L, Chen D, Guang W, French J. Conception, early pregnancy loss, and time to clinical pregnancy:
a population-based prospective study. Fertil Steril. 2003;79:577–584.
9. Yakut S, Toru HS, Cetin Z, et al. Chromosome abnormalities identified in 457 spontaneous abortions and their histo-
pathological findings. Turk Patoloji Derg. 2015;31:111–118.
KEY POINTS: SPONTANEOUS ABORTIONS AND RECURRENT
PREGNANCY LOSS
1. An abortion is defined as a termination or loss of pregnancy before 20 weeks of gestation (as calcu-
lated from the date of the last menstrual period) or delivery of a fetus weighing less than 500 g. Eighty
percent of clinically recognized spontaneous abortions occur during the first trimester.
2. When differentiating the types of spontaneous abortions, it is important to consider whether the
cervix is open or closed and whether any or all of the tissue has passed.
3. Fetal genetic abnormalities are the most common causes of spontaneous abortions, and they account
for as many as 75% of spontaneous abortions in the first trimester. Autosomal trisomies are most
common type of abnormality, but the single most common is monosomy X (Turner syndrome).
4. All Rh-negative pregnant women who experience uterine bleeding require Rho[D] immunoglobulin
to prevent Rh isoimmunization.
5. RPL is defined as two or more failed pregnancies. Causes include genetic factors, uterine abnor-
malities, endocrine disorders, and APS.
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1. What is the definition of hirsutism, and what is virilization?
Hirsutism is excessive terminal hair growth in a male-pattern anatomic distribution generally attrib-
uted to hyperandrogenemia. It affects 5% to 10% of reproductive age women. Virilization describes
the more severe signs and symptoms of excess androgens, characterized by clitoromegaly, temporal
balding, voice deepening, and breast atrophy. This is different from hypertrichosis, which is an uncom-
mon general increase in vellus body hair.
2. What are the three types of body hair?
1. Lanugo hair: thin and faintly pigmented hair often found on neonates
2. Vellus hair: fine, soft, nonpigmented hair found in most adult body regions
3. Terminal hair: long, coarse, pigmented hair found at the scalp, axilla, pubic area of adults, and the
male beard and chest
3. What causes hirsutism?
• Increased exposure to androgens: secondary to exogenous androgen exposure, increased adrenal
androgen production, increased ovarian androgen production, or alterations in binding globulins
• Increased end-organ androgen sensitivity: secondary to increased 5α-reductase activity at the
follicle (converts testosterone to more potent dihydrotestosterone [DHT])
Androgens interact with the hair follicle, thus leading to a transformation from vellus to terminal hair.
4. Which androgens are produced by the body?
• Ovary: testosterone (25%), androstenedione (50%), dehydroepiandrosterone (DHEA) (20%)
• Adrenal gland: testosterone (25%), DHEA (50%), DHEA sulfate (DHEA-S) (100%)
• Peripheral tissue conversion (adipose/skin): testosterone from androstenedione (50%), DHEA from
DHEAS (30%), and DHT from testosterone
5. What are the modulators of androgen action?
• Sex hormone–binding globulin (SHBG) (80%) and albumin (20%): bind to circulating androgens,
thereby decreasing the amount of free androgens (only free androgens can act on target tissues)
• 5α-reductase: converts testosterone to DHT (more potent and active) at the level of the skin
6. What is the Ferriman-Gallwey scoring system?
A standardized grading system for scoring hirsutism. It is based on the distribution and degree of hair
growth. A score less than 8 is normal; a score greater than 15 is severe. Providers can also consider
patient-reported qualification of hirsutism (“patient-important hirsutism”).
7. What is the differential diagnosis for hirsutism?
• Idiopathic hyperandrogenemia: normal menses, increased androgens
• Idiopathic hirsutism: normal menses, normal androgen levels; likely caused by increased
5α-reductase activity in the skin
• Nonclassic congenital adrenal hyperplasia (NCCAH): adult-onset increase in adrenal androgens,
increased 17-hydroxyprogesterone (17-OH progesterone)
• Classic congenital adrenal hyperplasia (CAH): increased adrenal androgens, ambiguous genitalia
at birth, increased 17-OH progesterone
• Cushing syndrome: central obesity, moon facies, violaceous striae, hypertension, high 24-hour
urine free cortisol
• Hyperprolactinemia: galactorrhea, amenorrhea, increased prolactin
• Androgen-secreting tumor (ovarian or adrenal): sudden-onset hirsutism and virilization; very rare
CHAPTER 26
HIRSUTISM AND POLYCYSTIC
OVARIAN SYNDROME
Danny Younes, MD, and Travis W. McCoy, MD
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119
8. How should a patient with excessive hair growth initially be evaluated?
Workup is directed by the history and physical examination findings. Laboratory tests include total testoster-
one (>200 ng/dL suggests a tumor), DHEA-S (>700 μg/dL suggests an adrenal tumor), 17-OH progesterone
(drawn during follicular phase of cycle, normally elevated after ovulation to rule out CAH), and prolactin.
9. Which different medical treatments are available for hirsutism, and what are their
mechanisms of action and adverse effects?
Table 26-1 is an overview of treatment options. Initial treatment is usually with a combined oral con-
traceptive pill (OCP). OCPs lower free ovarian and adrenal androgens by increasing SHBG. To block the
effect of androgens, antiandrogens can be used in addition to OCPs. Spironolactone and finasteride
are the most commonly recommended antiandrogens. Flutamide carries a risk of hepatotoxicity.
Eflornithine is a topical cream. Because antiandrogens are teratogenic and can feminize male fetuses,
they should not be used without OCPs.
10. What adjuvant therapies are available?
• Short-term: shaving, epilation (plucking or waxing), chemical depilation (bleaching)
• Long-term: electrolysis (galvanic or thermal), laser epilation, photoepilation, weight loss
11. How soon is an effect on hirsutism seen once medical treatment has begun?
Treatment effect is usually not seen for 3 to 6 months, and it can often take longer. For this reason,
medical treatment is more effective, to prevent progression of hirsutism.
12. What is PCOS, and what causes it?
PCOS is a disorder characterized by chronic anovulation and increased androgen production, often
associated with other metabolic derangements such as insulin resistance, hyperlipidemia, and obesity.
It is considered a complex metabolic disorder, with numerous genetic and environmental factors
interacting and contributing to the pathophysiologic features.
13. What are the criteria for diagnosing PCOS?
PCOS is a diagnosis of exclusion; other underlying disorders must be ruled out first. Two sets of
criteria are accepted:
• Rotterdam Consensus criteria (2003): requires two or more of the following: anovulation or oligo-
ovulation, clinical or biochemical evidence of hyperandrogenism, polycystic ovaries on ultrasound
examination
• Androgen Excess and PCOS Society (2006): requires evidence of hyperandrogenism with ovarian
dysfunction
Table 26-1. Medical Treatments for Hirsutism
TREATMENT MECHANISM SIDE EFFECTS
Combined oral contraceptive
pill (OCP)
Increased SHBG
Decreased ovarian androgen production
Headache
GI upset
Spironolactone Competitive inhibitor of androgen-receptors Hyperkalemia
Teratogenicity
Finasteride 5α-reductase inhibitor, targeted to type 2
isoenzyme
Hepatotoxicity
Teratogenicity
Flutamide Androgen receptor antagonist Leukopenia
Hepatotoxicity
Photosensitivity
Teratogenicity
Eflornithine Topical; inhibitor of ornithine decarboxylase Acne
Erythema
Burning sensation
Glucocorticoids* Suppressors of adrenal androgen production Weight gain
Adrenal suppression
GI, Gastrointestinal; SHBG, sex hormone–binding globulin.
*Used only in cases of congenital adrenal hyperplasia.
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REPRODUCTIVE ENDOCRINOLOGY
14. What findings are commonly associated with PCOS?
• Irregular menses
• Perimenarchal onset of symptoms
• Insulin resistance (more pronounced in obese women)
• Mildly elevated DHEAS and testosterone
• Obesity (60% of patients)
• Polycystic ovaries on ultrasound scan (not diagnostic, can be seen in women without PCOS as well)
15. What are the major disorders that should be ruled out before making a diagnosis
of PCOS, and what tests can be used?
• Thyroid dysfunction: check thyroid-stimulating hormone
• Hyperprolactinemia: check prolactin
• Ovarian failure: check follicle-stimulating hormone
• Late-onset CAH (21-hydroxylase deficiency): check 17-OH progesterone during the follicular phase
• Cushing syndrome, ovarian and adrenal neoplasms: total serum testosterone is markedly elevated
16. What are two mechanisms that lead to excessive androgen production by ovarian
theca cells in PCOS?
Hyperinsulinemia and excessive amplitude or increase pulse frequency of luteinizing hormone from
the anterior pituitary.
17. How is PCOS related to obesity?
PCOS involves many positive feedback mechanisms. Insulin resistance worsens hyperandrogenism,
and both promote obesity. Obesity, in turn, worsens insulin resistance. Androgens and insulin resistance
lower SHBG production in the liver, thus causing even greater amounts of free circulating androgens.
Treatment should be directed at breaking these feedback loops by lowering androgens, increasing
SHBG, and reducing insulin resistance.
18. What are the long-term consequences of PCOS?
• Premature development of insulin-resistant diabetes
• Hyperlipidemia
• Hirsutism or acne
• Anovulatory infertility
• Increased risk of endometrial hyperplasia or endometrial cancer
Long-term management should address these problems through the regulation of menses and treat-
ment of any insulin-resistance, hyperlipidemia, and hirsutism.
B
iBliography
1. Azziz R, Sanchez LA, Knochenhauer ES, et al. Androgen excess in women: experience with over 1000 consecutive
patients. J Clin Endocrinol Metab. 2004;89:453–462.
2. Bode D, Seehusen D, Baird D. Hirsutism in women. Am Fam Physician. 2012;85:373–380.
3. Carmina E, Rosato F, Jannì A, Rizzo M, Longo RA. Extensive clinical experience: relative prevalence of different
androgen excess disorders in 950 women referred because of clinical hyperandrogenism. J Clin Endocrinol Metab.
2006;91:2–6.
4. Carr BR, Breslau NA, Givens C, Byrd W, et al. Oral contraceptive pills, gonadotropin-releasing hormone agonists, or
use in combination for treatment of hirsutism: a clinical research center study. J Clin Endocrinol Metab. 1995;80:
1169–1178.
5. Fauser BC, Diedrich K, Howles CM, et al. Contemporary genetic technologies and female reproduction. Hum Reprod
Update. 2012;18:231.
6. Martin KA, Chang RJ, Ehrmann DA, et al. Evaluation and treatment of hirsutism in premenopausal women: an Endocrine
Society clinical practice guideline. J Clin Endocrinol Metab. 2008;93:1105–1120.
KEY POINTS: HIRSUTISM AND POLYCYSTIC OVARIAN SYNDROME
1. Treatment of hirsutism should begin early to prevent progression. Medical treatments take months
to produce a visible response and are more effective in preventing worsening of the condition.
2. Antiandrogen therapies are largely teratogenic and can feminize male fetuses; they should be used
in conjunction with combined OCPs to increase efficacy and prevent pregnancy.
3. Treatment for PCOS should focus on reducing androgens and minimizing metabolic risks. Regulation
of menses is critical to prevent endometrial hyperplasia and carcinoma.
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7. 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. 2004;19:41–47.
8. Strauss JF. Some new thoughts on the pathophysiology and genetics of polycystic ovary syndrome. Ann N Y Acad Sci.
2003;997:42–48.
9. Teede H, Deeks A, Moran L. Polycystic ovary syndrome: a complex condition with psychological, reproductive and
metabolic manifestations that impacts on health across the lifespan. BMC Med. 2010;8:41.
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1. What is cervical dysplasia, and why is it clinically significant?
Cervical dysplasia is a precancerous lesion that, if left untreated, can progress to higher-grade
lesions or cervical cancer. The progression to cervical cancer is a slow process, taking years to occur.
Older terminology classified cervical dysplasia into cervical intraepithelial neoplasia (CIN) 1, 2, or 3;
recommendations made in 2012, however, classify it into either low-grade or high-grade squamous
intraepithelial lesions (LSIL and HSIL, respectively).
2. What are risk factors for cervical dysplasia?
Infection with the human papillomavirus (HPV) is a necessary precursor for the development of both
cervical dysplasia and most cases of cervical cancer (both squamous cell carcinoma and adenocarci-
noma). Therefore, early coitarche and increasing numbers of sexual partners raise the risk of duration
and frequency of HPV exposure, respectively, and increase the risk of cervical dysplasia. The most
important non–HPV-related risk factor is smoking.
3. How does infection with HPV result in cervical dysplasia?
HPV strains fall into two broad categories: low-risk strains and high-risk strains. Low-risk HPV strains
(6, 11, 40, 42, 43, 44, 53, 54, 61, 72, 73, and 81) are associated with anogenital warts and low-grade
cervical dysplasia (CIN 1/LSIL). High-risk HPV strains (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59,
and 68) are responsible for high-grade cervical dysplasia and cancer. The virus integrates into the
host cell’s genome and causes loss of transcriptional regulation and overexpression of oncoproteins
E6 and E7. HPV E6 protein binds to p53, and HPV E7 protein binds to retinoblastoma protein (Rb), thus
disabling these tumor suppressor genes and ultimately leading to uncontrolled promotion of cell cycle
progression. Most women infected with HPV, however, do not develop high-grade dysplasia or cervical
cancer.
4. How is HPV transmitted?
HPV is transmitted through sexual contact. It is the most common sexually transmitted infection, with
75% to 80% of persons infected by the age of 50 years. Barrier methods of contraception do not
completely protect against transmission.
5. What is the natural history of HPV infection?
HPV infection prevalence is highest in women 20 to 24 years old, and prevalence decreases with age.
HPV infections are thought to be transient and cleared by immune-competent hosts within 6 to 24 months.
Reactivation is possible, particularly in older persons. Infection with multiple strains of the virus is also
possible. During transient infections, HPV can lead to cellular abnormalities of the cervix that resolve with
clearance of the virus. Persistent infections increase the risk for high-grade dysplasia.
6. Are any effective primary prevention strategies available to reduce HPV infection?
Three HPV vaccines are currently approved by the Food and Drug Administration (FDA): a bivalent
vaccine against HPV types 16 and 18, a quadrivalent vaccine against types 16, 18, 6, and 11, and a
vaccine against nine HPV strains (6, 11, 16, 18, 31, 33, 45, 52, and 58). In clinical trials, the efficacy of
these vaccines in the prevention of high-grade dysplasia was 93% to 100% in HPV-naïve populations.
7. Who should be vaccinated against HPV?
The Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices
(ACIP) recommends that all children—boys and girls—11 to 12 years old should be routinely offered
HPV vaccination. Vaccination may begin as early as age 9 years and extend to age 26 years in women
and age 21 years in men. Although 2015 ACIP guidelines state that men may be vaccinated through
CHAPTER 27
PRECANCEROUS LESIONS OF
THE LOWER GENITAL TRACT
Lisa Garcia, MD
III GYNECOLOGIC ONCOLOGY
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