ISSUES IN REPRODUCTIVE ENDOCRINOLOGY
| UNDERSTANDING AND TREATING POLYCYSTIC OVARIAN SYNDROME —John A. Schnorr, MD, Assistant
Professor of Obstetrics and Gynecology, and Director, Division of Reproductive Endocrinology, The Medical
University of South Carolina, Charleston
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| General considerations: 2003 Rotterdam PCOS consensus workshop—polycystic ovary syndrome (PCOS) diagnosis
requires 2 of these 3 criteria, hyperandrogenism (clinical or serum), chronic anovulation (severe oligomenorrhea),
or evidence of polycystic-looking ovaries on ultrasonography (US; controversial component; in United States,
most clinicians believe only first 2 necessary); work-up should rule out congenital adrenal hyperplasia (CAH), thyroid
abnormalities, and hyperprolactinemia; speaker does not believe ovarian abnormalities important component
(≈20% of reproductive-aged women [particularly younger women] have ovarian abnormalities), but believes combination
of irregular menstrual cycles and hyperandrogenism important components
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| Presenting problems: oligomenorrhea or amenorrhea; evidence of hyperandrogenism (hirsutism, acne, male-pattern
balding), infertility, obesity, and weight gain; diagnosis often missed in thin women; diabetes common; study data
on insulin resistance —looked at elevated insulin levels in patients with PCOS, compared to age- and weight-
matched controls; significant insulin resistance in nonobese patients; obese patients likely to have mild defect in insulin
receptor, exacerbated by weight; defective insulin receptor in thin woman more virulent (no association with
weight); elevated insulin levels—insulin directly stimulates androgen production from stroma of polycystic ovaries
and stroma of normal ovaries if given in excess; insulin augments luteinizing hormone (LH)–stimulated androgen
secretion from ovary; unlikely insulin resistance result of hyperandrogenism, but rather, hyperandrogenism result
of insulin resistance
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| Long-term consequences: type 2 diabetes (17%-45% increased risk); dyslipidemia; endometrial cancer; hypertension
(≈40%); myocardial infarction (7-fold increased risk); gestational diabetes; pregnancy-induced hypertension
(14% increased risk); ovarian cancer (≈2-fold increased risk)
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| Pathogenesis of PCOS: insulin-receptor gene mutation; increased phosphorylation in serine receptor; results in impaired
uptake of glucose; more insulin secreted, causing decreased insulin-like growth factor-I (IGF-I) production
in liver (regulates enzymes in adrenal gland and ovary to make more androgen); ovulation rate changed through
hypothalamus; results in hirsutism
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| Methods to reduce insulin levels: weight loss—most studies show decreased androgen levels and improved ovulation
rate with 10% weight reduction; abnormality in insulin receptor fundamental problem (excess weight may exacerbate);
issue of patient’s weight should be addressed, but refrain from blaming entire condition on weight
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 | Insulin sensitizers: troglitazone—insulin-lowering drug; removed from market because of hepatic toxicity; thiazolidinediones
most effective at changing insulin resistance; mechanism of action involves binding to nuclear receptors
(peroxisome proliferator-activated receptors [PPARs]) that regulate transcription of insulin-response
genes critical for control of glucose and lipid metabolism; study of 410 patients with PCOS randomized to troglitazone
150 mg, 300 mg, or 600 mg daily, or placebo; results showed patients taking insulin-sensitizing agents
had lower insulin levels, lower insulin resistance, lower testosterone levels, and lower hirsutism scores, as well
as improvement in ovulatory dysfunction; similar mechanism of action with rosiglitazone and pioglitazone (not
associated with hepatic toxicity); metformin—decreases hepatic glucose production (decreases intestinal absorption
of glucose); small effect by changing insulin resistance; does not produce hypoglycemia; ≈10% of patients
cannot tolerate due to gastrointestinal side effects; study results (Nestler et al)—showed decreased insulin and
testosterone levels and increased sex hormone–binding globulin (SHBG); ovulation rates in study groups included
placebo group, 3%; patients receiving metformin, 40%; patients receiving clomiphene citrate (Clomid),
8%; and patients receiving Clomid and metformin, 90%
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| Evaluation and treatment: establish diagnosis—review menstrual history; obtain serum total and free testosterone
levels (if no clinical signs of hirsutism); transvaginal US; prolactin, thyroid-stimulating hormone (TSH) and beta
human chorionic gonadotropin ( β-hCG); CAH—genetic defect; production of androgen and cortisol blocked; diagnosis
based on elevated serum level of 17α-hydroxyprogesterone; treat with dexamethasone or glucocorticoid,
rather than insulin-sensitizing agent; screen all patients with PCOS for diabetes (with 2-hr glucose tolerance test,
baseline insulin levels not necessary); patient desiring fertility—metformin (start at 500 mg daily and increase
weekly to goal dose of 500 mg tid); multiple-pregnancy rates low; decreased rates of spontaneous abortion; data
show 71% of patients with regular menstrual cycles pregnant in 6 mo; follow up in 3 mo; use combination of
rosiglitazone and metformin (Avandia) or pioglitazone and metformin (Actos) if patient still not having cyclic
menses; Clomid increases chance for multiples; refer to infertility specialist; in patient not desiring fertility, oral
contraceptives (OCs; 35 µg)—increase SHBG; decrease free testosterone; decrease hirsutism; promote regular
menstrual cycles; when OCs contraindicated—give cyclic progesterone to protect uterus; encourage additional
form of contraception; controversial whether metformin should be used (no long-term data showing improvement
in cardiovascular health parameters); still unknown—which insulin-sensitizers best? are there markers to predict
who will respond to insulin-sensitizers? should insulin-sensitizers be used for long-term management?
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| APPROACH TO THE PATIENT WITH AMENORRHEA —Shirley Uy, MD, Associate Professor of Family Medicine,
the David Geffen School of Medicine at the University of California, Los Angeles
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| General considerations: incidence—primary amenorrhea, 0.1% to 2.5%; secondary, 0.7% to 3%; associated with infertility,
osteoporosis, genital atrophy, endometrial hyperplasia leading to cancer, and social and psychosexual dysfunction;
average age for menstruation 13 yr, with age range of 9 to 16 yr; primary amenorrhea—no menses by 16
yr of age with sexual development, or no menses by 14 yr of age without sexual development; secondary
amenorrhea—no menses for 3 cycles or total of 6 mo; physiologic causes of secondary amenorrhea—pregnancy,
lactation, and menopause; pathologic causes—PCOS, hypothalamic dysfunction, hyperprolactinemia, and ovarian
failure
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| Menstrual axis: hypothalamus secretes gonadotropin-releasing hormone (GnRH); anterior pituitary secretes follicle-
stimulating hormone (FSH) and LH, causing ovaries to secrete estrogen and progesterone; positive and negative
feedback mechanisms play role in regulating system, as well as internal and external factors
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| Uterine and outflow tract problems: Asherman’s syndrome—occurs after dilation and curettage (D and C) or after
severe endometritis, leading to adhesions and synechiae; symptoms include molimina without cyclic pain; diagnostic
modalities—hysterosalpingography, saline US, or hysteroscopy; most patients have withdrawal bleeding after
superphysiologic doses of estrogen and progesterone; cervical stenosis—can occur after procedure to cervix (eg,
abortion, cryotherapy, conization, or loop electrosurgical excision procedure [LEEP]); pinpoint os seen on physical
examination; symptoms include molimina with cyclic pain
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| Ovarian failure: elevated FSH; considered menopause if woman >40 yr of age; premature ovarian failure if <40 yr of
age; incidence ≈1% in women <40 yr of age; can be transient before permanent failure occurs; ≈50% of women
have progestin withdrawal bleeding; Savage syndrome—gonadotropin-resistant ovary syndrome; ovarian follicle
in primordial stage; seen in ≈30% of women; biopsy not recommended; autoimmune oophoritis—40% of women;
rule out autoimmune disease (eg, Hashimoto’s disease, hypoparathyroidism, Addison’s disease, or diabetes) if patient
<35 yr of age; other causes of premature ovarian failure—radiation, chemotherapy, infections (eg, tuboovarian
abscess, oophoritis parotidea), surgery; check for genetic abnormality if patient <25 yr of age; galactosemia rare
cause (metabolites have direct toxic effect on ovary)
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| Pituitary causes: hyperprolactinemia—prolactinoma and primary hypothyroidism; nonprolactin-secreting tumors—
adrenocorticotropic hormone (ACTH) causing Cushing’s syndrome, growth hormone causing acromegaly, and
TSH causing hyperthyroidism; destruction of pituitary—Sheehan’s syndrome and Simmonds’ disease
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| Hypothalamic causes: strenuous exercise—most common cause; increase in catechol estrogens and β-endorphins
inhibits GnRH secretion and LH/FSH release; low estrogen increases risk for osteoporosis; stress—eg, going away
to school, divorce, death in family; in extreme stress (eg, in concentration camps, death row) almost 100% amenorrhea;
weight loss/anorexia—when weight falls below 85% of ideal, GnRH secretion inhibited; lesions—
craniopharyngioma, tuberculosis, sarcoid infiltration, status post-encephalitis; GnRH inhibited, leading to lower
levels of FSH and low estrogen; no withdrawal bleeding after progestin challenge; medications—especially psychotropics;
after OC suppression—can last 6 mo; chronic debilitating disease—uncontrolled diabetes, end-stage renal
disease, malabsorption syndromes, and hyperthyroidism; functional causes—no organic findings; abnormal
pattern of GnRH leading to LH pulsatility; dysfunction can occur with normal estradiol levels (>40 pg/mL); complete
failure with estradiol levels <40 pg/mL
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| Hyperandrogenic anovulation: PCOS (most common cause); adult onset CAH; Cushing’s syndrome; androgen-secreting
tumor; PCOS—elevated GnRH and LH secretion; increased levels of circulating androgens peripherally
converted to estrogen (generally unopposed); presentation usually oligomenorrhea or amenorrhea; ≈75% of patients
obese; hyperandrogenism manifests with hirsutism, acne, acanthosis nigricans, and androgenic alopecia; patient
may not have progestin-induced withdrawal bleeding; associated with insulin resistance, diabetes, and
endometrial hyperplasia (increasing risk for cancer)
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| Evaluation: history—last menstrual period; rule out pregnancy; symptoms of molimina (without, problem likely
anovulatory; with symptoms, outflow tract problem likely); stress, dieting, weight loss, and heavy exercise suggest
hyperthalamic problem; fatigue and weight gain suggest hypothyroidism; hot flushes and vaginal dryness suggest
ovarian failure; headache or visual changes suggest tumor; galactorrhea suggests hyperprolactinemia; acne and hair
growth suggest PCOS or hyperandrogenic state; consider chronic illness as cause of hypothalamic amenorrhea; recent
curettage or procedure to cervix; medications—OCs or psychotropic drugs; family history—age at menarche
of other women in family; body habitus—consider possibility of Turner’s syndrome if patient very short, anorexia
if extremely underweight, or PCOS if obese; skin—hirsutism, acne, acanthosis nigricans suggests PCOS or other
hyperandrogenic condition; neck—thyromegaly or webbed neck suggests Turner’s syndrome; eyes—with proptosis,
consider Graves’ disease; pituitary or central tumor with visual field loss; breasts—level of development indicative
of estrogen; galactorrhea suggests prolactin level; abdominal—check for mass (pregnancy); external
genitalia—evidence of too much or too little pubic hair; testicular feminization (clitoromegaly); adrenal or ovarian
tumor; internal genitalia—cervical stenosis; imperforate hymen; enlarged uterus; ovarian mass
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| Evaluation: first visit—obtain history (eg, recent D and C or other procedure to cervix); with evidence of cervical
stenosis, dilate cervix; with evidence of Asherman’s syndrome and intrauterine adhesions, sound uterus or perform
hysterosalpingography, saline US, or hysteroscopy; with evidence of galactorrhea, magnetic resonance imaging
(MRI); check testosterone and dehydroepiandrosterone (DHEA) levels with virilization; tests—pregnancy test,
LH and FSH levels, and estrogen; second visit—if prolactin elevated, initiate hyperprolactinemia work-up; consider
hypo- or hyperthyroidism with elevated TSH; with elevated testosterone, rule out ovarian tumor; rule out adrenal
tumor (by computed tomography [CT]) with elevated DHEA
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| Diagnosis: hypothalamic-pituitary failure—estrogen low and FSH normal or slightly low; without history of excessive
stress, weight loss, or exercise, rule out central nervous system tumor; check adrenal function; treat patient
with estrogen and progesterone; refer patient desiring pregnancy to fertility specialist; premature ovarian failure—
estrogen low and FSH elevated; if patient <40 yr of age (menopause if >40 yr of age); if patient <25 yr of age,
karyotype; if <35 yr of age, rule out other autoimmune causes; treat with estrogen and progesterone; refer for artificial
reproductive technology (ART) if pregnancy desired; estrogen levels >40 pg/mL —pelvic US to distinguish between
PCOS (unless evidence of hirsutism or LH/FSH ratio >2 or 3) and hypothalamic dysfunction; counsel
patient with hypothalamic dysfunction to gain weight and decrease level of exercise; patient with PCOS should be
screened for diabetes and FSH level obtained; prescribe 10 days of progesterone (Provera) approximately every 2
mo to prevent hyperplasia; OCs or levonorgestrel intrauterine device (IUD) for contraception; induce ovulation
with Clomid if patient desires pregnancy
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| Causes of primary amenorrhea: ovarian failure from Turner’s syndrome, autoimmune problems; congenital absence
of uterus and vagina (Mayer-Rokitansky-Küster-Hauser syndrome); GnRH deficiency (Kallman syndrome); constitutional
delay
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Suggested Reading
Burghen GA et al: Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol
Metab 50:113, 1980; Genazzani AD et al: Diagnostic and therapeutic approach to hypothalamic amenorrhea.
Ann N Y Acad Sci 1092:103, 2006; Legros RS et al: Clomiphene, metformin, or both for infertility in the
polycystic ovary syndrome. N Engl J Med 356:551, 2007; Master-Hunter T et al: Amenorrhea: evaluation and treatment.
Am Fam Physician 73:1374, 2006; Setji TL et al: Polycystic ovary syndrome: diagnosis and treatment. Am J
Med 120:128, 2007; 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; Trivax B et al: Diagnosis of Polycystic Ovary Syndrome. Clin Obstet Gynecol 50:168, 2007.
Educational Objectives
| The goal of this program is to increase diagnosis and improve management of polycystic ovarian syndrome (PCOS),
and update clinicians on the diagnostic work-up for amenorrhea. After hearing and assimilating this program, the clinician
will be better able to:
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| 1. State the diagnostic criteria for PCOS as defined by the Rotterdam consensus.
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| 2. Identify patients (clinically) who may have PCOS and appraise the long-term health consequences associated
with PCOS.
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| 3. Discuss the role of insulin resistance in causing PCOS, and recognize the utility of insulin sensitizers in treating
PCOS.
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| 4. Identify the etiology of amenorrhea.
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| 5. Implement a work-up for patients with secondary amenorrhea.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members 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 reported nothing to disclose.
Acknowledgements
Dr. Schnorr was recorded at the Fall Symposium on Issues in Women’s Health: How to Treat a Lady, sponsored by the
Medical University of South Carolina, and held October 20-22, 2006, in Charleston, SC. Dr. Uy was recorded at Office
Gynecology/Women’s Health for Primary Care, sponsored by the David Geffen School of Medicine at the University
of California, Los Angeles, and held July 27-30, 2006, in Anaheim, CA. The Audio-Digest Foundation thanks the
speakers and the sponsors for their cooperation in the production of this program.
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