ISSUES IN REPRODUCTIVE HEALTH
Highlights from New Concepts in Obstetrics and Gynecology, presented by the University of Miami Miller School of
Medicine, Department of Obstetrics and Gynecology
Educational Objectives
| The goal of this program is to improve management of patients with endometrial cancer and infertility. After
hearing and assimilating this program, the clinician will be better able to:
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 | Identify women at risk for endometrial cancer
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| Make the diagnosis of endometrial cancer using the appropriate diagnostic modality
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| Discuss the management of endometrial cancer
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| Implement a basic work-up for infertility and manage patients experiencing infertility
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| Determine which patients need to be referred to a reproductive endocrinologist.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a
proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.
Acknowledgments
Drs. Lucci and Shapiro were recorded at New Concepts in Obstetrics and Gynecology, sponsored by the University of
Miami Miller School of Medicine, Department of Obstetrics and Gynecology, andheld on February 21-23, 2008, in
Miami, FL. The Audio-Digest Foundation thanks the speakers and the University of Miami Miller School of Medicine
for their cooperation in the production of this program.
| ENDOMETRIAL CANCER: DIAGNOSIS AND MANAGEMENT—Joseph A. Lucci III, MD, Professor and Director,
Division of Gynecologic Oncology, University of Miami Miller School of Medicine, Miami, FL
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| General considerations: incidence and death rates remain stable; significant disparity in black women; 75% of patients
present with stage I or II disease; 25% present with stage III or IV; survival rates similar to those for ovarian
cancer
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| Risk factors: obesity (rate of endometrial cancer increasing as obesity increases); unopposed estrogen; complex
atypical hyperplasia; late menopause; nulliparity; diabetes mellitus (likely linked to variety of mechanisms, ie, estrogen
and fat metabolism); hypertension; tamoxifen (7-fold increased risk); decreased risk with oral contraceptives
and smoking; stimulation of endometrium due to unopposed estrogen—increased endogenous synthesis (eg,
granulosa cell tumors, obesity); decreased estrogen metabolism (ie, impaired hepatic function); inappropriate or incomplete
hormone replacement therapy
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| Diagnostic considerations: consider diagnosis in postmenopausal woman having bleeding or spotting; thin endometrial
strip seen on transvaginal ultrasonography (US) and endometrial cells on Papanicolaou (Pap) test warrant
further evaluation; lighter and less frequent menstrual periods not universal in perimenopausal women; gradual
anovulation can lead to complex endometrial hyperplasia and cancer; 25% of patients diagnosed before menopause
; ≥5% (and increasing) diagnosed at <40 yr of age; always consider endometrial sampling for patient not responding
to appropriate hormone therapy for abnormal bleeding; symptoms—unexplained vaginal spotting or
bleeding; persistent vaginal discharge; uterine enlargement; glandular cells or endometrial cells on Pap test (especially
in postmenopausal woman); majority of patients symptomatic at time of presentation, but 10% asymptomatic
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| Diagnostic evaluation: controversy surrounding impact of diagnostic methods and spread of disease
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| Endometrial biopsy: generally well tolerated; can be performed in office; may need to perform in operating room if patient
has severely stenotic cervix or vagina; endometrial sampling—insert Pipelle to apex; pull out plunger; rotate
device 360° to ensure adequate sampling; slowly withdraw device from uterine cavity; inadequate sampling if
Pipelle fills before withdrawn from cervical os or suction lost; may require 3 or 4 passes for adequate sampling; subsequent
passes better tolerated; 10% false-negative rate associated with improper use of Pipelle; adequate sampling
obtained only with proper use of device, regardless of type; transvaginal US—do not use as sole diagnostic method
of ruling out endometrial cancer; although risk for cancer low with endometrial stripe <4 mm, it is not zero; with
changes in endometrial thickness or fluid in endometrial cavity, consider additional diagnostic modality; hysteroscopy
and dilation and curettage (D and C)—associated with increased risk for malignant cells in peritoneal cytologic
specimen; continuous debate about value of cytology in endometrial cancer; peritoneal biopsy and omental
biopsy more prognostic for metastasis than simple cytology; speaker performs hys-teroscopy and D and C when unable
to obtain adequate sampling in office; etiology of postmenopausal bleeding varied (endometrial cancer third
most common cause); study evaluating atypical endometrial hyperplasia—community diagnosis of atypical endometrial
hyperplasia; endometrial biopsies sent for expert pathology review; poor correlation with diagnosis among
pathologists, even among experts; all patients underwent hysterectomy within 6 wk; 43% had endometrial cancer in
specimen at time of hysterectomy; reliance on quoted risks for cancer discouraged; important to know whether evidence
of atypical endometrial hyperplasia present; consider diagnosis of endometrial cancer until proven otherwise
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| Preserving fertility: endometrial biopsy and D and C subject to same types of interpretation errors, whether endometrium
benign or malignant; easy to lose orientation relative to myometrium; evidence of invasion not visible;
magnetic resonance imaging (MRI) and cancer antigen (CA-125) helpful in identifying myometrial invasion; both
tests recommended before initiating conservative management; CA-125—80% of patients with elevated CA-125
have metastatic disease; results of CA-125 vary significantly with menstrual cycle; hormone therapy—various therapies
reported; data show mean time to response 3 or 4 mo; pregnancy recommended as soon as clearance of disease
confirmed; relapse can occur in ≈ 40 mo; source of abnormality likely to be persistent; histologic types—
endometrioid adenocarcinoma accounts for majority of endometrial cancer cases; papillary serous carcinoma; clear
cell and undifferentiated carcinoma require aggressive treatment (not necessarily associated with estrogen metabolism)
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| Surgical management: preferred method of treatment when fertility not issue; data show 12% to 25% of patients
have higher stage disease on restaging; tumor grade sensitive indicator of tumor spread; 50% of patients with grade
3 lesions have deep myometrial invasion; bilateral pelvic and para-aortic lymph nodes required for adequate lymphadenectomy;
50% of nodes microscopically positive; surgical impression of involved nodes invalid, even in most
experienced hands; surgical technique—midline vertical or transverse incision; majority of speaker’s patients undergo
laparoscopic-assisted vaginal hysterectomy (LAVH) and lymphadenectomy with omental biopsy; less blood
loss, shorter recovery time, and shortened hospitalization; omentectomy—speaker does not perform full omentectomy;
large piece of omentum excised and divided into 5 specimens for pathology review; ≈8% of patients have
metastatic disease in omentum; speaker performs appendectomy in majority of patients (provides additional biopsy
site, prevents risk for appendicitis in irradiation field)
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| Uterine papillary serous carcinoma and clear cell carcinoma: highly aggressive with poor prognosis; require
surgical debulking; patient considered high-risk; treatment similar to that for ovarian cancer; CA-125 good
marker
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| Obese and medically compromised patient: transvaginal approach or LAVH appropriate for patients with
uterine fundal diameter <8 cm; not recommended if larger because of morcellation risk; data show survival of patients
undergoing appropriate adjuvant therapy close to that for patients who undergo full surgical staging (treatment
can be compromised when surgical management not adequate because of patient’s condition)
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| Hormone therapy: consider for patients at high risk for recurrence (ie, advanced-stage disease); vaginal brachytherapy
and chemotherapy; standard therapy—combination of doxorubicin (formerly known as adriamycin) with
cisplatin; speaker uses carboplatin (Paraplatin) and paclitaxel (eg, Taxol) or docetaxel (Taxotere)
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| Risk factors for recurrence: grades 2 or 3 histology; lymphovascular space invasion; greater than one-third myometrial
invasion; age of patient; high-intermediate risk—patient >70 yr of age with ≥1 risk factors, any patient
>50 yr of age with 2 risk factors, or any patient with 3 risk factors; vaginal brachytherapy and chemotherapy treatment
options; pelvic external beam irradiation treatment option for patients not having lymphadenectomy; patients
with estrogen-related tumors—response rate with progestational therapy may be similar to that of certain chemotherapy
agents; may require addition of aromatase inhibitors
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| INFERTILITY: MANAGEMENT FOR THE OB/GYN PRACTITIONER—Arthur Shapiro, MD, Professor of Clinical
Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Miami Miller School of Medicine
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| General considerations: definition—inability of couples of reproductive age to establish pregnancy in ≤1 yr of
unprotected sexual intercourse; prevalence—1 in 4 women experience infertility during reproductive years; female
cause accounts for ≈50%, male cause 35%, and combination ≈25%; ≈6 million infertile couples; 50% of couples
never receive treatment; with appropriate treatment, 2 of 3 couples succeed; decreasing follicle number with
age—number of follicles fixed early in life; primordial germ cells arrive in gonadal ridge by seventh week of gestation;
total germ cell number peaks at 20-wk gestation (6-7 million); declines to ≈1 million at birth; <500,000 by
puberty; gradual decline in follicle number by process of atresia; follicles become resistant to stimulation in perimenopause;
1 in 3 women miscarry in 40- to 44-yr age group; increased risk for chromosomal abnormalities with
increasing age (may account for miscarriage)
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| Indications for early fertility evaluation: women >35 yr of age; abnormal cycles (ie, short or long cycles); suspected
or documented pelvic inflammatory disease (PID); endometriosis; male factor; stress—evidence supports
effect of stress on fertility; can interfere with in vitro fertilization (IVF); providing patient with information and
ovulation- prediction home testing may improve and reduce stress
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| First examination: patient history and physical examination; basic fertility evaluation similar to prenatal evaluation;
HIV test recommended; counsel about factors influencing fertility (eg, body mass index [BMI], smoking, excessive
use of alcohol and caffeine-containing products, herbal medications, recreational drugs); discourage use of
vaginal lubricants (acidic in already acidic environment); folate supplementation recommended (data support reduction
in congenital abnormalities and prematurity)
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| Ovulatory status: establish ovulatory status; luteinizing hormone (LH) surge test; midluteal serum progesterone; US
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| Evaluation of hormone levels: baseline gonadotropins (ie, follicle-stimulating hormone [FSH], prolactins); not necessary;
fasting and 2-hr glucose with high BMI and family history of diabetes; androgens (ie, testosterone)
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| Ovarian reserve: day 3 levels of FSH and estradiol; clomiphene challenge test; progesterone challenge test obsolete;
anti-Mullerian hormone (low result serves as guide for referral to infertility specialist)
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| Uterine factors: US including sonohysterography; hystero-salpingography (HSG) widely used for uterine and tubal
evaluation; hysteroscopy gold standard for intrauterine evaluation
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| Tubal factors: same evaluation as uterus; Novy catheters require reproductive endocrinology infertility specialist;
PID and sexually transmitted diseases can be asymptomatic; serologic Chlamydia IgG serology may provide
clue; speaker recommends doxycycline 100 mg bid for 4 to 6 doses as prophylaxis before HSG; hydrosalpinx—
poor results with neosalpingostomy (pregnancy rate 10%); high rate of ectopic pregnancy; removal of fallopian
tube often recommended
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| Semen analysis: 1 to 3 days of abstinence recommended before testing; concentration and volume easily measured;
motility should be ≈50% or more; no evidence of obstruction on fructose measurement; fructose level run only with
suspicion of azoospermia; morphology 30% considered normal using World Health Organization (WHO) criteria,
>13% if using “strict” criteria; IVF success rates 4% to 13%; sperm DNA fragmentation and decondensation
analysis— DNA of sperm decondenses when fertilization occurs; <80% considered abnormal; defragmentation
tests for level of DNA damage; >15% considered abnormal; helpful in identifying whether patient candidate for intrauterine
insemination (IUI), IVF, or intracytoplasmic sperm injection (ICSI); Y chromosome partial deletions—
generally done if patient oligospermic or azoospermic; semen analysis should be repeated at least once (sperm cycle
plus or minus 72 days, wait at least that interval to repeat test); referral to urologist—varicocele; antibiotic
therapy initiated with presence of white blood cells in semen (both partners treated); endocrine work-up; testicular
biopsy; sperm extracted from testicle for ICSI if male azoospermic; frequency of coitus—optimum number of motile
sperm obtained with 3 to 4 ejaculations per week; coital frequency of twice per week adequate for conception
in normal couples; abstinence >10 days decreases sperm motility and fertility
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| Tests with uncertain diagnoses: endometrial biopsy—may be appropriate for those with recurrent miscarriage;
rate of luteal phase deficiency shown to be same in fertile and infertile populations; postcoital test—no published
standards; poor predictive value; female antisperm antibodies—no predictive value of serum antibody titers
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| Myomas: submucosal fibroids—lower probability of pregnancy and increase risk for miscarriage; remove fibroid if
invading uterine cavity by >50%; subserosal fibroids—no need to remove; intramural fibroids—remove if 6 cm;
surgery—myomectomy (especially for intramural fibroids) associated with postoperative adhesions; desire for pregnancy
no longer contraindication to MRI-guided focused US surgery; uterine artery embolization not recommended
for women who wish to preserve fertility; consider trial of IVF for woman with small fibroids
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| Endometriosis: ovarian endometrioma—remove if 4 cm; IVF pregnancy rates lower with stage III and IV; refer
for IVF before considering other therapies; some evidence of improved fertility after laparoscopy and medications
in women with stage I or II endometriosis; uterine septum—high spontaneous abortion rate; miscarriage rate reduced
to normal after hysteroscopic resection
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| Ovulation induction: reserved for anovulatory patients; no tubal obstruction or male factor present; success rates
15% to 20% per cycle; lack of estrogen demonstrated if patient who is not having regular cycles does not have
withdrawal bleeding after progesterone therapy; clomiphene not option; consider consultation with reproductive
endocrinologist or use of recombinant FSH
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| Therapy options: gonadotropin (recombinant FSH); natural intercourse; intrauterine insemination (IUI); clomiphene
therapy—day 3 to 5; give for 5 to 7 days; start ovulation prediction testing on day 13 (most patients with
polycystic ovary syndrome [PCOS] do not ovulate on own, but some may); transvaginal pelvic US on day 14 or
15 should reveal 14- or 15-mm follicle (20 to 28 mm at maturity); IUI usually performed 36 hr after human
chorionic gonadotropin (or next day with positive predictive test); luteal progesterone 1 wk after ovulation
should measure ≈15 ng/mL; increase clomiphene only if response poor
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| Aromatase inhibitors: not approved by Food and Drug Administration (FDA); letrozole given for 5 days causes rise
in gonadotropins; substitute for clomiphene yet to be shown
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| Failure to conceive: rethink situation; consider laparoscopy before initiating treatment with gonadotropin or refer
for IVF
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| Unexplained infertility: refer for IVF; 20% success rate in all age groups; pregnancy rate 45% if patients <35 yr of
age; gonadotropins and IUI second option
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Suggested Reading
American College of Obstetricians and Gynecologists. ACOG practice bulletin. Management of infertility
caused by ovulatory dysfunction. Number 34, February 2002. American College of Obstetricians and Gynecologists.
Int J Gynaecol Obstet 77(2):177, 2002; Baekelandt MM et al: Endometrial carcinoma: ESMO clinical
recommendations for diagnosis, treatment and follow-up. Ann Oncol Suppl 2ii19, 2008; DeHondt A et al: Endometriosis
and subfertility treatment: a review. Minerva Ginecol 57(3):257, 2005; Practice Committee of the
American Society for Reproductive Medicine: Aging and infertility in women. Fertil Steril 86(5 Suppl):S248,
2006; Practice Committee of the American Society for Reproductive Medicine: Effectiveness and treatment
for unexplained infertility. Fertil Steril 82 Suppl 1:S160, 2004; Practice Committee of the American Society
for Reproductive Medicine: 82 Suppl 1:S90, 2004; Shutter J et al: Prevalence of underlying
adenocarcinoma in women with atypical endometrial hyperplasia. Int J Gynecol Pathol 24(4):313, 2005.
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