CLINICAL ISSUES IN WOMEN’S REPRODUCTIVE HEALTH
| POLYCYSTIC OVARY SYNDROME —John F. Randolph, Jr, MD, Associate Professor, Department of Obstetrics and
Gynecology, University of Michigan Medical School, Ann Arbor
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| Defining polycystic ovary syndrome (PCOS): change in thinking on PCOS in last 5 to 10 yr; many women seeing
specialist for reasons other than trying to get pregnant; defining PCOS challenge since 1930s; 1990 landmark National
Institutes of Health (NIH) consensus conference convened to formulate definition of PCOS; 2 criteria for PCOS, 1) menstrual
dysfunction (oligomenorrhea or amenorrhea), hyperandrogenism (clinical or biochemical, eg, hirsutism, acne,
body composition, or biochemical evidence), 2) exclusion of other potential causes, eg, Cushing’s disease
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| Rotterdam criteria: 2003 definition set by European Society for Human Reproduction and Embryology (ESHRE) and
American Society for Reproductive Medicine (ASRM) at Rotterdam; need 2 of 3 criteria, 1) disordered ovulation, 2) hyperandrogenism,
and 3) polycystic ovaries by ultrasonography (multiple subcortical early antral follicles of 8 to 12 mm) and increased
stromal-to-follicular ratio (stroma produces androgens); do not confuse with superovulation (induced for infertility)
or with multicystic ovaries seen in early adolescent girls before maturity
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| Prevalence of PCOS: Rotterdam criteria resulted in doubling of prevalence of PCOS in United States to 15% to 20% of
population; because of relationship to body composition and size (obesity), expect PCOS to constitute larger percentage
of practice as more subclinical cases become clinical; of oligomenorrheic women, majority have PCOS; of amenorrheic
women, large minority have PCOS
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| Genetic disorder: most forms of PCOS probably autosomal dominant; half of patients’ first-degree relatives have
PCOS; under new criteria, one fourth of patients’ sisters have clinical PCOS and another quarter have PCOS-appearing
ovaries; tell patients about genetic cause because most struggling with weight their entire adult lives and need to know
PCOS metabolic condition that can be managed
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| Associated diseases: type 2 diabetes; dyslipidemias; endometrial cancer; type 2 diabetes—in studies, up to one third
of women with PCOS had impaired glucose tolerance, and significant percentage had type 2 diabetes
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| Skin conditions related to PCOS: acne—mostly related to androgens; occurs early and changes rapidly;
hirsutism—tends to occur in early-to-mid ’20s and takes longer to evolve and improve; patient’s perception key; acanthosis
nigricans—indicates severe insulin resistance and high risk for type 2 diabetes; if present, take aggressive approach
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| Hirsutism: Ferriman and Gallwey (1961)—devised scoring system now commonly used; time-consuming clinically but
good research tool; found women who considered themselves normal never reported hair on upper back or upper abdomen;
≈3% reported terminal hair on sternum (midchest, not nipples); ≈10% reported hair on chin; hair above lip much more common;
McKnight study (1969)—400 normal women, 36 hirsute women, 239 normal men; one quarter of normal women
reported hair on upper lip, making this poor discriminator for hirsutism (likely due to ethnic or genetic variability); one third
reported hair below umbilicus and linea alba; limb hair not related to androgens; hirsutism refers to central hair, which may
be modifiable; hirsute women looked just like men (had same hair distribution as men, although density possibly different)
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| Androgens: in normal women, half made in adrenals and half in ovaries; women with PCOS get more androgens from
ovaries, typically androstenedione and testosterone; in target tissues, testosterone converted by 5α-reductase to dihydrotestosterone
(DHT; 10 times more potent and stimulates terminal hair growth); majority of androgens circulate bound
to protein, eg, only ≈2% of testosterone free; small decrease in bound fraction can double free fraction
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| Causes of hirsutism: PCOS—androgen excess coming from ovaries due to increased production or increased availability
caused by decrease in binding protein; testosterone decreases binding protein; familial hirsutism— increased 5α-
reductase activity (genetic trait); increases conversion of testosterone to DHT; these women have excess DHT and hirsutism
but no other characteristics of PCOS
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| Body composition: ovarian hyperandrogenism can increase muscle mass; hyperandrogenism associated with central
obesity; adipose tissue most insulin-resistant; ≈80% of women with PCOS have increased fat mass and, therefore, increased
insulin resistance; Diabetes Prevention Program Research Group study (2002)—>3000 men and women
with impaired glucose tolerance at major risk for type 2 diabetes went on rigorous weight-loss and moderate-intensity exercise
program coupled with individualized education and reinforcement; 2.8 yr later, follow-up showed reduction in incidence
of diabetes of 58%; progression to diabetes 4.8 people per 100 person-years in experimental group vs 11 per 100
person-years in control groups (average weight loss 10-15 lb)
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| Metabolic problem: PCOS should be seen as genetic metabolic problem; traditional gynecology viewed PCOS as
bleeding and infertility problem; PCOS major contributor to metabolic syndrome in women
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| Insulin resistance: prospective study of 254 women with PCOS showed 31% had impaired glucose tolerance and 7.5%
had type 2 diabetes; fasting glucose to insulin ratio <4.5 used as indicator of insulin resistance (good sensitivity in obese
white women with PCOS, but does not detect insulin resistance in many other groups); as yet, no gold standard for measuring
insulin resistance
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| Cardiovascular disease (CVD): PCOS diagnosed when women young, so not yet able to link with CVD in later life;
mortality—data not mature enough to demonstrate link between PCOS and CVD mortality, but risk factors present and clinicians
believe increased risk for CVD mortality exists in PCOS
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| Endometrial cancer: relationship of PCOS to endometrial cancer demonstrated long ago; PCOS independent risk factor
(3-fold increased risk) for endometrial cancer; lack of ovulation increases unopposed estrogen, which promotes endometrial
growth; hyperinsulinemia contributes to risk (insulin also endometrial growth factor); Cancer and Steroid Hormone Study
(CASH)—demonstrated odds ratio of 2.4 for increased incidence of ovarian cancer in women with PCOS where other studies
could not; oral contraceptives (OCs) protective (used to treat PCOS)
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| Breast cancer: no documented relationship with PCOS; since women with PCOS do not ovulate and do not make
progesterone, speaker speculates that PCOS may be protective
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Management of PCOS
| Goals: increase insulin sensitivity; decrease hyperandrogenism by decreasing bioavailable androgens; prevent endometrial
hyperplasia, neoplasia, and abnormal uterine bleeding
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| Patient education: explain that PCOS is genetic metabolic disease with many environmental influences, life-long consequences,
and risks; emphasize healthy lifestyle, stressing diet (diabetic diet balanced and controls calories) and exercise
(150 min/wk); medication as adjunct to lifestyle changes; even reduction in weight of 7% decreases testosterone and results
in resumption of menses; so relatively modest weight loss can have significant metabolic impact
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| Traditional therapies: traditional OCs highly effective; prevent endometrial hyperplasia, improve hirsutism and acne,
decrease free androgens and ovarian androgen production; however, they decrease insulin sensitivity, and some increase
triglycerides; OCs help reach some treatment goals but not all
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| Other medications: insulin sensitizer (metformin) and thiazolidinediones (troglitazone [Rezulin], rosiglitazone [Avandia],
and pioglitazone [Actos]) not well studied for PCOS
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 | Metformin: 850 mg bid taken as part of tri-arm study (gastrointestinal [GI] side effects reduced dose to once daily for
≈16% of subjects); results—reduction in incidence of diabetes one third, compared to placebo; average weight loss
one third that of subjects who made intense lifestyle changes; medications work but not as well as lifestyle changes;
metformin inhibits production of glucose and improves tissue sensitivity to insulin; no direct effect on steroidogenesis;
side effects—include lactic acidosis and renal complications, although PCOS patient population mostly has good kidney
function; metformin not approved for PCOS treatment; GI side effects mainly diarrhea, so start slowly; absolute
dose for PCOS not determined (500 to 850 mg tid); speaker does less monitoring (only baseline renal function, unless patient
complains of symptoms); response—initially mixed response to metformin studies because unclear whether result
due to weight loss or to drug; hirsutism not yet well studied with metformin; used by speaker as frontline treatment because
it works and addresses metabolic problem not addressed in past with OCs
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| Diagnosis: history and physical examination; rule out diabetes and impaired glucose tolerance using fasting glucose test;
whether fasting insulin measured depends on goal, but speaker does not use to determine whether to treat with metformin;
if patient has regular cycles or clear skin, obtain pelvic ultrasonography; if significant skin problems present, obtain
serum free testosterone to rule out testosterone-producing ovarian tumor (rare)
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| Treatment: determine goal; always start with lifestyle changes; for general health, speaker prescribes metformin; combination
gives benefits of feeling better, weight loss, and, sometimes, regular cycles; OCs indicated for bleeding problems;
consider metformin for patient with high insulin level and suspected metabolic issues; for skin problems, OCs (consider
metformin or spironolactone [Aldactone]); study of diet with or without metformin—metformin adds to lifestyle
changes, mostly by decreasing testosterone and abdominal fat
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| Antiandrogen treatments: androgen receptor blockers and adrenal suppression only for increased adrenal androgens
(refer to endocrinologist); finasteride (Propecia) works well for hirsutism but expensive and contraindicated in pregnancy;
need at least 100 mg bid of receptor blockers for effect
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| Infertility: metformin speaker’s frontline therapy; enables avoidance of clomiphene and gonadotropins and possible resultant
ovarian hyperstimulation syndrome and multiple pregnancies; increases response to all other treatments; study of
clomiphene vs metformin—nonobese patients with PCOS; ovulation rate two thirds with metformin (about same as clomiphene
but increased over time, while rate decreased over time in clomiphene group); pregnancy rate twice as high in
metformin group and improved over time; cumulative pregnancy rate with metformin double rate with clomiphene; more
trials needed; long-term benefits of metformin not known; current trend to use in pregnancy through first trimester; use for
gestational diabetes controversial, especially after first trimester
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| Take home messages: keep mindset that PCOS familial metabolic disorder modifiable by lifestyle (“the original metabolic
therapy”); consider medication adjunct or third leg to diet and exercise
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| REPRODUCTIVE HEALTH IN WOMEN WITH RHEUMATIC DISEASE —Alan N. Brown, MD, Assistant Professor
of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston
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| Systemic lupus erythematosus (SLE): systemic autoimmune disease; antinuclear antibodies (ANA); patient presents
with widespread nonspecific symptoms that confound physician; can involve every organ; disease of young women;
blacks and Hispanics tend to have SLE more frequently and more severely than white patients; genetics play clear role
(concordance seen in twins); prevalence 1 in 1000 in United States
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| SLE criteria: serositis, oral ulcers, usually on hard palate where it meets soft palate, or nasal ulcers (usually painless); extreme
photosensitivity, ie, rash on exposure to minimal sunlight; malar erythema (flat or raised) with sparing of nasolabial
folds and area under chin; discoid rash (anywhere on body) with PASTE changes, ie, follicular plugging, central atrophy,
scarring or scaling, telangiectasia, and erythema; SLE arthritis not destructive of joints but can be disabling; positive
ANA—needed for diagnosis but does not equal SLE (healthy individuals can be ANA-positive); levels do not correlate with
disease activity
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| SLE and cardiovascular risk: risk for CAD increased as much as 50-fold in premenopausal patients 35 to 44 yr of
age; risk factors include prednisone use, hyperhomocysteinemia, antiphospholipid antibodies, and abnormal endothelium
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| SLE and fertility: area of debate; SLE does not affect fertility, but previous treatment of SLE with cyclophosphamide
(used to treat most severe manifestations of SLE) strongly associated with infertility, especially in women >30 yr of age
(1-yr course certain to cause premature ovarian failure); risk ≈50% in women 20 to 30 yr of age, less but still present in
teenagers; can overcome with gonadotropin-releasing hormone (GnRH) agonists (offer to women of childbearing age
treated with cyclophosphamide); SLE in pregnancy—high rate of preeclampsia, spontaneous abortion, intrauterine fetal
demise, and premature birth; small risk (≈3%) placenta and fetus may become targets of maternal autoantibodies; risk for
neonatal lupus 15% to 20% (caused by maternal antibodies; resolves with waning of maternal antibodies)
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| SLE and oral contraceptives: data conflicting; suggested that estrogen-containing OCs cause lupus to flare and that
women with SLE have higher incidence of OC-related thrombosis; Estrogens in Lupus Erythematosus: National Assessment
(SELENA) study halted due to controversy about hormone replacement therapy; speaker asks lupus patients with
renal disease not to use estrogen-containing OCs; patients with antiphospholipid antibodies should not use OCs due to
risk for thrombosis and flare of renal disease; progestin-only OCs may be safer, but evidence insufficient
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| Sexual dysfunction: in 50 female scleroderma patients, speaker surprised to find significant differences from men in
problems with arousal, lubrication, orgasm, pain on intercourse, and satisfaction; over three quarters reported trouble
with sexual function, and over half very dissatisfied with their sexual health
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Educational Objectives
| The goal of this program is to educate the listener on polycystic ovary syndrome (PCOS) and systemic lupus erythematosus
(SLE) and their effects on women’s reproductive health. After hearing and assimilating this program, the clincian will be
better able to:
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| 1. Explain the current view of PCOS as a genetic metabolic condition.
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| 2. Discuss PCOS management with lifestyle and medication.
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| 3. Describe the role of metformin in management of PCOS and related conditions.
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| 4. Identify signs and symptoms of SLE.
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| 5. Address fertility issues in women with SLE.
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Discussed On this Program
Clomiphene citrate [Clomid, Milophene, Serophene]
Cyclophosphamide [Cytoxan, Cytoxan Lyophilized, Neosar]
Finasteride [Propecia, Proscar]
Hydroxychloroquine sulfate [Plaquenil, Plaquenil Sulfate]
Metformin HCl [Fortamet, Glucophage, Glucophage XR, Riomet]
Methotrexate (amethopterin; MTX) [Methotrexate LPF, Rheumatrex Dose Pack, Trexall]
Pioglitazone HCl [Actos]
Rosiglitazone maleate [Avandia]
Spironolactone [Aldactone]
Troglitazone [Rezulin] (withdrawn)
Suggested Reading
Boudreaux MY et al: Risk of T2DM and impaired fasting glucose among PCOS subjects: results of an 8-year follow-
up. Curr Diab Rep 6:77, 2006; Brown AN: Diagnosis and management of early rheumatoid arthritis. J S C Med Assoc
99:296, 2003; Carmina E et al: Metabolic syndrome in polycystic ovary syndrome (PCOS): lower prevalence in southern
Italy than in the USA and the influence of criteria for the diagnosis of PCOS. Eur J Endocrinol 154:141, 2006; Coffey
S et al: Health-related quality of life in women with polycystic ovary syndrome: a comparison with the general population
using the Polycystic Ovary Syndrome Questionnaire (PCOSQ) and the Short Form-36 (SF-36). Gynecol Endocrinol 22:80,
2006; Elkind-Hirsch KE: Thiazolidinediones for the Therapeutic Management of Polycystic Ovary Syndrome: Impact
on Metabolic and Reproductive Abnormalities. Treat Endocrinol 5:171, 2006; Emery P et al: The efficacy and safety
of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIB randomized,
double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 54:1390, 2006; Essah PA et al: The metabolic
syndrome in polycystic ovary syndrome. J Endocrinol Invest 29:270, 2006; Homburg R: Should patients with polycystic
ovarian syndrome be treated with metformin? A note of cautious optimism. Hum Reprod 17:853, 2002; Issa SN et al:
Damage control in rheumatoid arthritis. Hard-hitting, early treatment is crucial to curbing joint destruction. Postgrad Med
116:14, 2004; Koren G et al: Metformin use during the first trimester of pregnancy. Is it safe? Can Fam Physician
52:171, 2006; Lord JM et al: Obesity, polycystic ovary syndrome, infertility treatment: lifestyle modification is paramount.
BMJ 332:609, 2006; McDonagh JE et al: A young woman with SLE: diagnostic and therapeutic challenges.
Lupus 6:633, 1997; Norman RJ et al: The role of lifestyle modification in polycystic ovary syndrome. Trends Endocrinol
Metab 13:251, 2002; Pasquali R: Obesity and androgens: facts and perspectives. Fertil Steril 85:1319, 2006;
Pincus T et al: How aggressive should initial therapy for rheumatoid arthritis be? Rheumatology (Oxford) 44:133,
2005; Somers EC et al: Use of a gonadotropin-releasing hormone analog for protection against premature ovarian failure
during cyclophosphamide therapy in women with severe lupus. Arthritis Rheum 52:2761, 2005; Watts J: Understanding
the causes and management of hirsutism. Nurs Times 102:26, 2006; Zafar S: Role of metformin in correcting
hyperinsulinemia, menstrual irregularity and anovulation in polycystic ovary syndrome. J Ayub Med Coll Abbottabad
17:54, 2005; Zulian E et al: Spironolactone in the treatment of polycystic ovary syndrome: effects on clinical features,
insulin sensitivity and lipid profile. J Endocrinol Invest 28:49, 2005.
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. Brown is on the Speakers’ Bureau for Abbott Laboratories.
Dr. Randolph addressed the Annual Clinical Update in Obstetrics and Gynecology, sponsored by the University of
Michigan Medical School, Department of Obstetrics and Gynecology and held March 9-10, 2006, in Ann Arbor, MI.
Dr. Brown was recorded at 5th Annual Fall Symposium Issues in Women’s Health, presented October 28-30, 2005, in
Charleston, SC, by the Medical University of South Carolina, Department of Obstetrics and Gynecology, Office of
Continuing Medical Education, College of Medicine and by the Office of Continuing Education, College of Nursing.
The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
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