ISSUES IN REPRODUCTIVE MEDICINE
| POLYCYSTIC OVARY SYNDROME: PATHOPHYSIOLOGY AND CLINICAL MANAGEMENT —John L.
Frattarelli, MD, Associate Professor of Obstetrics, Gynecology and Reproductive Sciences, Division of Reproductive
Endocrinology and Infertility, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical
School, New Brunswick, NJ
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| General considerations: polycystic ovary syndrome (PCOS) originally described in 1935; wedge resection described
in 1965 (still used occasionally today for treatment); most common endocrine disorder in reproductive women
(occurs in ≈4%); basic pathophysiologic defect remains unknown
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| Diagnosis: 1990 National Institutes of Health criteria—chronic anovulation, clinical and/or biochemical hyperandrogenism,
and exclusion of other etiologies; 2003 Rotterdam consensus—oligomenorrhea or anovulation, clinical
and/ or biochemical hyperandrogenism, polycystic ovary (PCO)-appearing ovaries; different phenotypes—PCO-
appearing ovaries and anovulation; PCO-appearing ovaries and hyperandrogenism; anovulation, hyperandrogenism,
and normal-appearing ovaries; patient can have combination of all 3, with different levels of severity; diagnosing
PCO-appearing ovaries on ultrasonography (US)—early follicular phase; may occur in one or both ovaries;
>12 antral follicles (follicles <10 mm in diameter); rescan in 1 mo if follicle >10 mm in diameter; ovarian volume
>10 mL (volume defined as 0.5 x length x width x thickness) provides diagnosis of PCOS; PCO commonly seen in
young reproductive-aged women
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| Pathogenesis: likely neuroendocrine dysfunction associated with ovarian dysfunction, insulin receptor dysfunction,
and adrenocortical dysfunction acting in concert; PCOS associated with increased risk for medical problems in reproductive
years and later in life; ≈50% of patients with PCOS clinically obese; obesity associated with increased
androgen levels, decreased sex hormone–binding globulin (SHBG) levels, increased endogenous or free androgen
levels, decreased circulating estrogen levels, and increased insulin and leptin levels; PCOS and obesity—waist-to-
hip ratio >0.80 consistent with android obesity (puts patient at increased risk for cardiovascular disease [CVD]);
obesity worsens underlying defects associated with PCOS; as little as 5% reduction in weight can induce menstrual
cyclicity and decrease hirsutism and biochemical hyperandrogenism; lean PCOS patient can have severe hirsutism
and hyperandrogenism; lean PCOS patient also at risk for diabetes and CVD
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| Insulin resistance: elevated glucose level (patient cannot utilize glucose in muscle tissue); increased androgen levels;
androgen levels feed back onto insulin pathway, increasing insulin level (Chang 1982 first to show significantly
higher insulin levels in patients with PCOS); 1999 study showed impaired glucose tolerance in 45% of obese
women with PCOS, and type 2 diabetes in 10%
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| Treatment: determine treatment goal (eg, pregnancy, prophylactic therapy, control of hyperandrogenism); exercise
and weight loss cornerstones of treatment; however, weight loss difficult in women with PCOS; patient may require
adjunctive therapy; hirsutism treatment— mechanical methods; ovarian suppression; antiandrogens; insulin
sensitizers; cell cycle regulators (eg, eflornithine [Vaniqa cream]); established hair follicles remain; long-term treatment
necessary (6 mo before reevaluation recommended); menstrual dysfunction—onset usually prepubertal; patient
may or may not be ovulatory; deficient progesterone secretion; constant estrogen stimulation of endometrium
places patient at increased risk for endometrial hyperplasia and dysfunctional uterine bleeding; endometrial biopsy
recommended, especially if patient anovulatory for prolonged time; treatment options include lifestyle changes,
oral contraceptives (OCs), medroxyprogesterone acetate, and metformin
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| Insulin-sensitizing agents: treatment end point reduction in androgens or resumption of ovulation; metformin—
inhibits hepatic gluconeogenesis; increases peripheral glucose utilization and sensitivity; other unknown mechanisms;
maximum clinical response achieved within 2 mo; severe lactic acidosis may occur if patient becomes dehydrated;
uses include treatment of oligomenorrhea, ovulation induction, treatment of hyperandrogenism, weight
loss, diabetes prevention, pregnancy loss prevention, and gestational diabetes prevention; decreases waist-to-hip
ratio; decreases all androgens and decreases insulin levels; improves hirsutism; may have additive effects if combined
with OCs
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| Fertility treatment in women with PCOS: Nestler et al (1998) showed 90% of women receiving metformin began
to ovulate, compared to 8% of women receiving placebo; Cochrane database review showed ovulation and
pregnancy rate increased among women receiving metformin and clomiphene (eg, Clomid) vs clomiphene alone;
Palumba et al found metformin superior to clomiphene; Moll et al found no benefit in adding metformin to clomiphene;
2007 study showed clomiphene superior and no benefit in adding metformin to clomiphene; Pregnancy in
Polycystic Ovary Syndrome (PPCOS) Trial —3 treatment arms clomiphene plus placebo, metformin plus placebo,
and clomiphene plus metformin; results showed fairly low pregnancy rate in patients on metformin alone; higher
pregnancy rate among women on clomiphene or clomiphene plus metformin; live birth rate fairly low among
women on metformin, compared to clomiphene alone or clomiphene plus metformin (no statistical difference between
clomiphene alone and metformin plus clomiphene); no statistical difference in loss rate among women on
clomiphene or clomiphene plus metformin (slightly higher pregnancy loss rate among women on metformin);
women on metformin had lower rate of multiple gestations (multiple rate low throughout 3 arms); pregnancy and
live birth rates lower among women never taking medication for ovulation induction who used only metformin;
subsequent studies in women with body mass index (BMI) <30 or >35 showed lower pregnancy rates and live
births among women using metformin alone
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| Thiazolidinediones: troglitazone off market due to liver toxicity; rosiglitazone (Avandia) 4 to 8 mg daily; maximum
insulin drop achieved in 1 mo; true insulin sensitization occurs with decrease in insulin levels; long-term benefit
for CVD unknown; small studies comparing rosiglitazone plus clomiphene to metformin plus clomiphene show
similar ovulation and pregnancy rates
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| Laparoscopic ovarian drilling: decreases ovarian stroma, making ovary more sensitive to endogenous hormones;
randomized controlled trial comparing laparoscopic ovarian drilling to 3 cycles of gonadotropins—pregnancy
rates similar; oocyte quality lower in patients with PCOS (possibly because of increased androgen component or
different androgen milieu in women with PCOS); fragmented embryos seen in women with PCOS
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| Metformin as adjunct to PCOS in artifical reproductive technology (ART): pregnancy rate significantly
higher; no difference in loss rate; live birth rate significantly higher, and embryo quality on day 3 significantly
higher
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| Insulin-sensitizing agents for health maintenance: difficult for women with insulin resistance to lose weight,
even with calorie restriction and exercise; data show no significant difference in weight loss, menstrual cyclicity, or
insulin resistance with high protein/low carbohydrate diet or low protein/high carbohydrate diet; recommend patient
follow diet preference; mechanism for weight loss with metformin—decreases caloric intake by suppressing appetite;
independent of gastrointestinal effects; weight loss preferentially in adipose tissue; reduction in incidence of
type 2 diabetes with lifestyle intervention or metformin—data show incidence of newly diagnosed diabetes 11% with
placebo, 8% with metformin, and 5% with lifestyle changes; pregnancy loss—2 studies showed lower rate of pregnancy
loss among women on metformin, compared to controls; trial data did not show significant difference
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| Long-term management: OCs alone not adequate; significant health risks and consequences associated with
PCOS; universal annual lipid screening recommended for all women >35 yr of age; women with PCOS should undergo
lipid screening as soon as diagnosis made; statins—no long-term data available
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| Summary: prescribe OCs for irregular bleeding; treat hirsutism or hyperandrogenism with OCs plus antiandrogens
or insulin-sensitizing agents; ovulation induction and metformin for infertility; new diagnostic criteria include US;
literature supports metformin use for type 2 diabetes, and weight loss for patients with PCOS and hyperandrogenism
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| INFERTILITY: DIAGNOSIS AND TREATMENT —Elizabeth A. Stewart, MD, Professor of Obstetrics and Gynecology,
Mayo Clinic College of Medicine, Rochester, MN
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| Patient expectations: expectations about becoming pregnant much different from those of past generations; past
generations of women delighted when they did not become pregnant on wedding night and every year thereafter;
often, patient expects conception to occur almost immediately after stopping contraception; reassure patient that it
is normal to take 6 mo or even up to 2 yr to become pregnant (potential problems should still be addressed)
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| Causes: sexually transmitted diseases (STDs)—appropriate to talk to young women about practicing safe sex to protect
future fertility; smoking—underappreciated as cause; can cause infertility in men and women; weight—
overweight or underweight, anorexic or bulimic; advancing age—most common cause seen in clinical practice
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| Normal fertility: in couples without fertility problems, probability of conceiving 20% to 25% per cycle (highest probability
during first cycle); 85% to 90% of couples conceive in ≤1 yr; evaluate couples with no risk factors who have
failed to conceive after 1 yr; evaluate at 6 mo if woman >33 yr of age or risk factors in either partner (eg, surgery for endometriosis,
fibroids, chemotherapy); efficacy of fertility treatment declines for women >35 yr of age; data from Hutterites
(community that provides good information about natural fecundity)—overall, infertility 2.4%; 11% if woman
>34 yr of age; 33% if >40 yr of age; 87% if >45 yr of age
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| Basic infertility work-up: is woman ovulating? regular menses best indication; ovulation testing probably not
worthwhile (even women who do not have trouble conceiving have cycles in which they do not ovulate normally);
major sperm abnormality? fallopian tubes open and uterus normal? lifestyle factors—sexual dysfunction (underappreciated
issue); tobacco, excessive alcohol, recreational drugs, excessive caffeine, and calcium channel blockers
(for men); limited intercourse; lubricants (can have spermicidal effects, vegetable oil recommended); nonsteroidal
anti-inflammatory drugs (NSAIDs) used mid-cycle (inhibit breakdown of follicle wall); excessive hot tub use (can
affect sperm counts); excessive exercise (woman can develop hypothalamic pattern); stress; frequency of
intercourse—every other day recommended; however, added stress should not be placed on couple if they cannot
comply with schedule; current treatment strategy—focus on spending money on therapy rather than establishing diagnosis
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| Standard tests: semen analysis—conventional semen analysis recommended; semen collection condoms without
spermicides recommended for man who cannot collect specimen by masturbation; hysterosalpingography (HSG)—
provides best assessment of fallopian tubes; speaker believes in therapeutic value; pretreat patient with NSAIDs
and prophylactic doxycycline for 3 days (full course of antibiotics recommended with evidence of bilateral hydrosalpinges);
ovarian reserve testing—either day 3 follicle-stimulating hormone (FSH) and estradiol or US to assess
antral follicle count; infertility treatments limited if patient does not have adequate ovarian reserve
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| Ancillary tests: rubella screen; thyrotropin (TSH; affects ovulatory function as well as fetal brain development);
genetic screening (cystic fibrosis); diabetes screening; US for uterine evaluation (for women at risk for endometriosis,
fibroids, polyps, and uterine anomalies); tests seldom used—endometrial biopsy; postcoital test; antibody testing;
extensive hormonal testing; endometriosis surgery if no pain
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| Semen analysis: total motile sperm count—volume (in mL) times count (in millions per mL) times motility (%);
goal ≈20 million; morphology—according to World Health Organization (WHO), >15% normal; difference between
isolated morphology defect and all parameters being abnormal; strict criteria (eg, Kruger, Tygerberg) used to
evaluate fertilizing ability if patient undergoing in vitro fertilization (IVF)
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| Treatment: egg problem—ovulation induction using clomiphene or gonadotropins; sperm problem—increase
number or use same number more effectively; urologic evaluation useful for assessing varicoceles and hormonal
problems associated with sperm count (use of clomiphene to increase sperm count not shown successful); intrauterine
insemination (IUI) or IVF usually performed; tubal problem—surgery or IVF; unexplained infertility—goal to
select better egg and/or extra eggs and to select best sperm and get it to right place at right time; stimulating eggs—
options include clomiphene (produces 1.5 eggs per cycle on average [2 eggs produced approximately every other
cycle; risk for triplets or more <1%]) or minimal stimulation regimen (clomiphene plus single dose of gonadotropins);
gonadotropin injection less commonly used; IUI—selects best sperm and gets it to right place at right time;
efficacy of superovulation and IUI (1999 statistics)—baseline pregnancy rate ≈2% per cycle; ≈2.5% using intracervical
insemination; ≈5% for IUI and super ovulation plus intracervical insemination; ≈8% with superovulation induction
and IUI; IVF—ovarian stimulation, egg retrieval, fertilization, and embryo transfer; first step for tubal
infertility and male factor infertility; eggs directly exposed to sperm; last resort for all other problems; pronuclear
freezing—freezes most embryos shortly after fertilization; excellent cumulative pregnancy rates with frozen embryo
transfer; avoids high-risk multiple gestation; IVF at Mayo Clinic—≈50% of young women achieve pregnancy
in first cycle; percentage drops dramatically with age
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Suggested Reading
Guzick DS: Ovulation induction management of PCOS. Clin Obstet Gynecol 50:255, 2007; Guzick DS et al: Efficacy
of superovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive
Medicine Network. N Engl J Med 340:177, 1999; Legro RS et al: A fasting glucose to insulin ratio is a useful measure
of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 84:383, 1999; Legro
RS et al: The Pregnancy in Polycystic Ovary Syndrome study: baseline characteristics of the randomized cohort including
racial effects. Fetil Steril 86:914, 2006; Lord JM et al: Insulin-sensitizing drugs (metformin, troglitazone,
rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. Cochrane Database System Review
3:CD003053, 2003; Nestler JE et al: Effects of metformin on spontaneous and clomiphene-induced ovulation in the
polycystic ovary syndrome. N Engl J Med 338:1876, 1998; Sinawat S et al: Long versus short course treatment with
Metformin and Clomiphene Citrate for ovulation induction in women with PCOS. Cochrane Database Syst Rev
(1):CD006226, 2008; Van Voorhis BJ: Clinical practice. In vitro fertilization. N Engl J Med 356:379, 2007.
Educational Objectives
| The goal of this program is to improve the diagnosis and management of women with polycystic ovary
syndrome (PCOS) and infertility. After hearing and assimilating this program, the clinician will be better
able to:
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 | 1. Make the diagnosis of PCOS based on the current Rotterdam consensus.
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| 2. Identify underlying neuroendocrine dysfunctions associated with PCOS.
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| 3. Counsel patients with PCOS about long-term health consequences and provide treatment options.
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| 4. Identify lifestyle factors that contribute to infertility.
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| 5. Implement a basic work-up for infertility.
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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
Dr. Frattarelli was recorded at the 22nd Annual Issues and Controversies in Ob/Gyn, sponsored by the University of
Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, and held on November 8-10, 2007, in
Lake Buena Vista, FL. Dr. Stewart was recorded at OB/GYN Clinical Reviews, sponsored by Mayo Clinic, and held on
November 8-9, 2007, in Rochester, MN.
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