Current Perspectives in Polycystic
MARILYN R. RICHARDSON, M.D., University of Kansas Medical Center, Kansas City, Kansas
Polycystic ovary syndrome has been viewed primarily as a gynecologic disorder requiring
medical intervention to control irregular bleeding, relieve chronic anovulation, and facil-
itate pregnancy. A large body of evidence has demonstrated an association between
insulin resistance and polycystic ovary syndrome. The former condition has an estab-
lished link with long-term macrovascular diseases such as type 2 diabetes mellitus, hyper-
tension, and atherosclerotic heart disease, consequences that also are observed in
women with polycystic ovary syndrome. In addition, chronic anovulation predisposes
women to endometrial hyperplasia and carcinoma. The purpose of this review is to
examine the clinical course of this syndrome, which spans adolescence through
menopause, and suggest a simple and cost-effective diagnostic evaluation to screen the
large numbers of women who may be affected. Therapy, which should be individualized,
should incorporate steroid hormones, antiandrogens, and insulin-sensitizing agents.
Weight loss by way of reduced carbohydrate intake and gentle exercise is the most
important intervention; this step alone can restore menstrual cyclicity and fertility, and
provide long-term prevention against diabetes and heart disease. Treatment alternatives
should be directed initially toward the most compelling symptom. Longitudinal care is of
paramount importance to provide protection from long-term sequelae. (Am Fam Physi-
cian 2003;68:697-704. Copyright 2003 American Academy of Family Physicians.)
are well placed to make early diagnoses ofPCOS and to help patients avoid the long-term consequences.
is the most common endocri-nopathy among women of repro-ductive age and is estimated to
Young women of reproductive age most fre-
quently seek attention initially because of irreg-
described masculinized women with amenor-
ular menses, hirsutism, or infertility, but PCOS
rhea, sterility, and enlarged ovaries containing
has a long prodrome with detectable abnor-
multiple cysts. The syndrome was placed in
malities throughout the life cycle of affected
the gynecologic realm for control of chronic
women. The earliest manifestations of PCOS
anovulation, abnormal menstrual bleeding,
are discernible in the peripubertal years.
resistance develop with increased frequency in
impaired glucose tolerance.3,4 The connection
arche.11,12 In the early reproductive period,
to an insulin post-receptor defect was isolated
chronic anovulation results in reduced rates of
in women with PCOS in the early 1990s.5 As a
conception. When pregnancy is achieved, it
result of these recent associations, attention is
frequently terminates in spontaneous, first-
now focused on treating the central deficits
trimester loss or is associated with gestational
diabetes.6 Approximately 25 to 30 percent of
these women show impaired glucose tolerance
lipid levels, and obesity that have broader
by the age of 30, and 8 percent of women with
health implications (Table 1)
.3,6-10 This new
PCOS develop frank type 2 diabetes mellitus
information profoundly alters our view of the
gravity of this condition. Family physicians
tension, and coronary artery disease compared with con-
trol patients. PCOS appears to follow a familial distribu-
Intermediate and Long-Term Consequences
tion; 40 percent of the sisters and 20 percent of the moth-
Associated with PCOS
ers of affected women also have the syndrome to varyingdegrees.15
In many women the symptoms are easily recognizable,
but ethnicity influences the extent of symptoms, especially
with regard to hirsutism and obesity. Therefore, taking a
diligent history with regard to menstrual patterns is cru-
cial to help establish the diagnosis. The National Institute
of Child Health and Development16 held a consensusmeeting to develop the following diagnostic criteria for
NOTE: These abnormalities may be identified in women with PCOS
PCOS: (1) clinical or biochemical evidence of hyperan-
at various life stages. Listed in order from most common to leastcommon.
drogenism; (2) oligo-ovulation; and (3) exclusion of otherknown disorders, such as congenital adrenal hyperplasia
PCOS = polycystic ovary syndrome; LDL = low-density lipoprotein;HDL = high-density lipoprotein.
Information from references 3, and 6 through 10.
The wide spectrum of manifestations ranges from mild
acne and increased terminal (coarse) hair growth in midline
cerebrovascular disease are prevalent. Women with poly-
structures (face, neck, abdomen), to android changes in
cystic ovaries are seen to have more extensive coronary
body habitus, with waist-to-hip ratios of more than 1. Vari-
artery disease by angiography.8 In two case-control stud-
ations are influenced by ethnicity,17 as well as coexisting con-
ies,9,10 women in their 40s had greater intima-medial thick-
ditions (such as hyperthyroidism) that alter androgen
ness of the carotid vessels, and more atherogenic lipid pro-
biosynthesis. For example, Asian women with PCOS are
files: increased total and low-density lipoprotein (LDL)
rarely hirsute, but hirsutism is a frequent finding in black
cholesterol and triglyceride levels, and decreased high-den-
women with PCOS. Yet the actual incidences of hyperan-
sity lipoprotein (HDL) cholesterol levels.9,10
drogenemia and insulin resistance do not show a racial
These metabolic abnormalities are compounded by the
prevalence of obesity, which occurs in more than 65 per-
In addition, nonhirsute women with oligo-ovulation
cent of women with PCOS.3 Abnormal androgen produc-
may have laboratory evidence of hyperandrogenism.
tion declines as menopause approaches (as it does in
Frank or rapid “virilization” involving clitoromegaly, vocal
women without PCOS), and menstrual patterns somewhat
chord thickening, or male-pattern baldness is rare in
normalize. However, in retrospective cohort studies,13,14
patients with PCOS and, when present, suggests another
perimenopausal and postmenopausal women with a his-
cause of hyperandrogenism, such as adrenal disorders or
tory of PCOS had increased rates of type 2 diabetes, hyper-
androgen-producing tumors (Table 2)
Oligo-ovulation manifests as menstrual irregularity and
Diagnostic criteria for polycystic ovary syndrome
occurs in 70 percent of women with PCOS. Among
include (1) clinical or biochemical evidence of
women with more regular menses, many have variable
hyperandrogenism, (2) oligo-ovulation, and (3)
degrees of ovulatory dysfunction. Often the menstrual for-
exclusion of other known disorders, such as
mula (i.e., three to five days of menstrual flow every 28 to
adrenal hyperplasia or hyperprolactinemia.
35 days) occurs for the first one to two years after menar-che (which occurs at the normal age), but menses then
become less frequent, occurring every 45 to 365 days.
Because the estrogen from ovarian and adipose tissues
Bleeding can be unpredictable, heavy, and pro-
stimulates proliferation of endometrium that is not stabi-
longed, and chronic endometrial proliferation can
lized by post-ovulatory progesterone, bleeding can be
unpredictable, heavy, and prolonged. Chronic endometrialproliferation can result in carcinoma.
SYMPTOMS WITH VARIABLE FREQUENCY
More than 65 percent of women with PCOS
Although there is no consensus as to which laboratory
have a body mass index exceeding 27. The fat distribution
tests should be used to diagnose PCOS, most physicians
often is abdominal/visceral, similar to that frequently asso-
agree that the evaluation should screen for hyperandro-
ciated with metabolic abnormalities (e.g., hypertension,
genemia as well as for abnormalities that have serious
dyslipidemia, insulin resistance, glucose intolerance). Most
health consequences. Often, the clinical picture is readily
women deny childhood obesity and describe normal
apparent from the history and physical findings. Thus, test-
weight until after menarche. Significant weight gain
ing for parameters known to be abnormal in women with
appears in the mid-teens and accelerates in the later teens
PCOS, such as luteinizing hormone (LH) and follicle-
stimulating hormone (FSH) ratios, is unnecessary, redun-
The presence of obesity also is influenced by ethnicity. It
is most common in Hispanic, black, and white women, less
In the author’s opinion, the evaluation should follow
striking in women of Mediterranean descent, and rare in
these principles: exclude other etiologies of amenorrhea,
Asian women.17 Obesity is likely to facilitate the metabolic
such as prolactin or thyroid abnormalities; exclude other
abnormalities of PCOS, as evidenced by the reduction in
causes of hyperandrogenism; exclude glucose intolerance;
insulin resistance and restoration of cyclic menses follow-
and detect insulin resistance and lipid abnormalities.
ing weight loss.19 A 1982 study,20 which has been con-firmed by later research, showed that a 10 to 15 percent
weight reduction resulted in spontaneous conception in
Normal testosterone determinations in the hirsute patient
more than 75 percent of obese patients with PCOS.
can be misleading, partially because of inherent variation in
These velvety, raised skin deposits
in intertriginous areas are associated with insulin resis-tance and result from insulin stimulation of the basal lay-
ers of the epidermis. When found in conjunction with
Differential Diagnosis of Hyperandrogenism
hyperandrogenism, the condition is termed HAIR-ANsyndrome (hyperandrogenic-insulin resistant–acanthosis
nigricans); it occurs in 2 to 5 percent of hirsute women.21
The majority of women with PCOS (70 percent) are
insulin resistant, but hyperinsulinemia is far more severe inwomen with HAIR-AN syndrome.
Ovaries with multiple, small (less than
10 mm) follicular cysts surrounding the ovarian stroma are
found in 16 to 25 percent of normal women and in female
patients with ammenorrhea caused by other etiologies.22Nearly 80 percent of women with hyperandrogenism have
PCOS = polycystic ovary syndrome; HAIR-AN = hyperandrogenic-
polycystic ovaries,23 but these may not be present at the time
insulin resistant—acanthosis nigricans.
of evaluation in women who have used oral contraceptive
Adapted with permission from Azziz R. Hirsutism. In: Droege-
pills (OCPs), insulin-sensitizing agents, or other forms of
mueller W, Sicarra JJ, eds. Gynecology and obstetrics.Vol 5.
ovarian suppression. Therefore, the presence of polycystic
Philadelphia: Lippincott, 1994:1-22.
ovaries on ultrasonography is not a diagnostic essential.
TABLE 3Laboratory Investigation of PCOS
0.5 to 4.5 µU per mL (0.5 to 4.5 mU per L)
600 to 3,400 ng per mL (1.6 to 9.2 µmol per L)
0.4 to 2.7 ng per mL (1.4 to 9.4 nmol per L)
Follicular phase < 2 µg per L (6.1 nmol per L)
65 to 119 mg per dL (3.6 to 6.6 mmol per L)
Exclude type 2 diabetes or glucose intolerance
35 to 85 mg per dL (0.9 to 2.2 mmol per L)
80 to 130 mg per dL (2.1 to 3.4 mmol per L)
NOTE: Diagnosis of PCOS established by exclusion of other causes of oligomenorrhea or hyperandrogenism. Other tests may be of benefitin monitoring therapy.
PCOS = polycystic ovary syndrome;
␤-hCG = beta subunit human chorionic gonadotropin; TSH = thyroid-stimulating hormone; DHEAS =dehydroepiandrosterone sulfate; NCAH = nonclassic adrenal hyperplasia; HDL = high-density lipoprotein; LDL = low-density lipoprotein.
commercial testing methods.24 However, bioavailable (free)
Both free testosterone and sex hormone-binding globu-
testosterone levels may support the diagnosis, especially in a
lin may be useful in monitoring the efficacy of androgen
nonhirsute woman with other signs and symptoms of
suppression therapy. Total testosterone levels greater than
PCOS. Hyperandrogenemia also might be established by
20 ng per dL (0.7 nmol per L) or DHEAS levels greater
elevated serum levels of dehydroepiandrosterone sulfate
than 700 ng per mL (1.9 µmol per L) are suggestive of
androgen-secreting tumors; these patients should bereferred for gynecologic investigation.25
Morning 17␣-hydroxyprogesterone (17-OHP) determi-
nation is important to exclude nonclassic adrenal hyperpla-
sia secondary to 21-hydroxylase deficiency, which is present
MARILYN R. RICHARDSON, M.D., is clinical assistant professor of
in 1 to 8 percent of hirsute women.26 When elevated 17-
obstetrics and gynecology in the Division of Reproductive Endocrinol-
OHP is discovered, the next step should be a short adreno-
ogy and Infertility at the University of Kansas Medical Center, KansasCity, Kan. She received her medical degree from the University of
corticotropic hormone stimulation test to further delineate
Kansas School of Medicine, Kansas City, and completed a residency in
the enzymatic defect. The ratio of LH to FSH is greater than
obstetrics and gynecology at the University of Missouri–Kansas City
3:1 in about 30 percent of women with PCOS and may be
School of Medicine, Truman Medical Center, Kansas City, and a fellow-ship in reproductive endocrinology and infertility at the University of
diagnostically helpful in nonhirsute women with mild ovu-
Texas Health Science Center at Dallas.
latory dysfunction, but this determination is not routinely
Address correspondence to Marilyn R. Richardson, M.D., University of
necessary if the clinical picture is otherwise clear.
Kansas Medical Center, Department of Obstetrics and Gynecology, Divi-
Because nearly 30 percent of women with PCOS have
sion of Reproductive Endocrinology and Infertility, 3901 Rainbow Blvd.,
impaired glucose tolerance, determinations of glucose tol-
Kansas City, KS 66160 (e-mail: firstname.lastname@example.org). Reprints arenot available from the author.
erance and insulin resistance are of paramount impor-
TABLE 4Medical Treatment Options in PCOS
PCOS = polycystic ovary syndrome; FSH = follicle-stimulating hormone; LH = luteinizing hormone.
*—1 = Suppression of hyperandrogenism; 2 = restore menstrual cyclicity; 3 = prevent endometrial hyperplasia; 4 = induce/facilitate ovu-lation; 5 = facilitate weight loss; 6 = reduce hyperinsulinemia.
†—Estimated cost to the pharmacist for one month of therapy based on average wholesale prices in Red book. Montvale, N.J.: MedicalEconomics Data, 2002. Cost to the patient will be higher, depending on prescription filling fee.
tance. One approach is to perform standard oral glucose
choices should be based on the woman’s most pressing
tolerance testing with insulin levels. Peak levels of insulin
concern and her stage of reproductive life (Figure 1).
that exceed 100 µU per mL (718 pmol per L) are suggestive
the current awareness of the long-term consequences asso-
of insulin resistance. This test may be unnecessarily cum-
ciated with PCOS, the physician carries the responsibility
bersome and expensive for general screening, however, and
of tailoring therapy to add preventive benefits. In addition,
the author’s practice is to reserve this test for use in women
cosmetic alterations can result in depression and with-
with a family history of glucose intolerance, morbid obe-
drawal from social and career pursuits. Thus, the physician
sity, or other symptoms suggestive of diabetes.
should be armed with information about removal of
A more efficient assessment may be to use the ratio of
unwanted hair. Shaving and depilation are the most effi-
fasting levels of glucose to insulin. When less than 4.5, this
cient short-term means for terminal hair removal while
ratio has a significant correlation with insulin resistance and
initiating androgen suppression using some of the modal-
has been studied for use as a screening test in obese patients
with PCOS. It combines sensitivity (95 percent) and speci-ficity (84 percent) for insulin resistance, with positive and
negative predictive values of 87 percent and 97 percent in
OCPs are the most efficient means of androgen sup-
obese patients with PCOS.27 This predictive capacity may
pression (ovarian as well as adrenal), and nearly any com-
not hold true in nonobese women with PCOS.
bination OCP is effective in treating PCOS. This therapy
The author includes assessments of total, HDL, and LDL
results in lower and static LH levels without surges. The
cholesterol levels as well as triglyceride levels to help in
estrogen component stimulates hepatic production of sex
planning and follow-up of recommended dietary modifi-
hormone-binding globulin that reduces bioavailable
cations to reduce obesity and cardiovascular risk. Finally,
androgen and can reduce hirsutism and acne. The prog-
endometrial biopsy is helpful to rule out endometrial
estin component provides competitive antagonism to
hyperplasia in patients with prolonged amenorrhea (morethan five months). A list of laboratory tests that may helpto identify patients with PCOS is provided in Table 3.
A ratio of less than 4.5 of fasting glucose to
insulin levels correlates significantly with insulin
The primary goal of all forms of therapy is to suppress
resistance and has been studied for use as a
insulin-facilitated, LH-driven androgen production.
screening test in obese patients with polycystic
Although numerous medications (Table 4)
are effective in reducing insulin and androgen levels, the
Management of Polycystic Ovary Syndrome
FIGURE 1. Management of polycystic ovary syndrome. After the primary concern is identified, the patient can decide ifcontraception or fertility is preferred. Lifestyle modification is a central measure in either case.
androgen at its receptors, reducing the action of testos-terone at the target organ.
Newer formulations contain progestins of lower andro-
Therapy with spironolactone (Aldactone) has a direct
genicity, such as norgestimate, desogestrel, and gestodene.
suppressive effect on enzymes in the androgen biosynthetic
OCPs can be used alone or in conjunction with antiandro-
pathway. Because of its structural similarity to testosterone,
gens, gonadotropin-releasing hormone agonists, or
it can competitively inhibit androgen receptor binding and
insulin-sensitizing agents. Restoration of the menstrual
is useful in the treatment of hirsutism. Three of six open
cycle and prevention of endometrial hyperplasia are addi-
clinical trials showed improvement in hirsutism, but results
of double-blind placebo-controlled trials were not as posi-
Hirsute women should be counseled that regression of
tive.28 One study29 has shown that spironolactone can
terminal hair growth during OCP therapy is a slow
reduce the caliber and growth rate of terminal hair. Dosages
process, requiring up to eight months for noticeable bene-
as high as 200 mg per day are tolerated, and menses some-
fits. It is appropriate to institute permanent methods of
times resume. This agent is most effective when combined
hair removal by way of electrolysis or laser ablation after
with OCPs; some form of contraception is advisable when
suppression of hyperandrogenism has been achieved.
it is used alone. A newly released formulation of OCP con-
Because these women are highly estrogenized (as a result
tains an analog of spironolactone, drospirenone. Drospire-
of peripheral conversion of androgenic precursors),
none combined with ethinyl estradiol (Yasmin) is indicated
menses can be induced by administration of progesta-
tional agents for approximately 10 days. Women should beadvised that their cycles are not re-established by this treat-
ment, and that if it is not repeated at two- or three-month
Clomiphene citrate (Serophene) or gonadotropins can
intervals, unchecked endometrial growth can result in
be used to establish menses but should be reserved for use
endometrial hyperplasia. If menstrual bleeding does not
in patients who wish to become pregnant. Because the
occur within 14 days of completion of progesterone
woman with PCOS is uniquely sensitive to these agents and
administration, another etiology for amenorrhea rather
risks higher rates of ovarian hyperstimulation and multiple
than PCOS should be sought. Progesterone administration
gestation,30 specialty referral for this therapy is recom-
does not provide relief from any other symptoms or pre-
mended. Clomiphene administration will result in ovula-
vent any of the long-term conditions. It is useful on a
tion in 50 to 60 percent of cases, in pregnancy in 30 percent,
scheduled basis only for menstrual regulation.
and in multiple gestation (twins or greater) in 3 percent.
Although the body of data is limited, it is suggested that
excessive or prolonged exposure to clomiphene citrate
Lifestyle modifications with weight loss have
(more than 12 months) could increase the risk of ovarian
achieved pregnancy rates as high as 60 percent
cancer.31 When clomiphene fails, gonadotropin administra-
tion frequently is successful in helping women to achievepregnancy (70 percent), but it requires self-injection, iscostly, and carries an even higher rate of hyperstimulationand multifetal pregnancy (as high as 30 percent).32
it brings about the greatest global improvement in car-diovascular risks, insulin sensitivity, and menstrual pat-
terns; it is most difficult because of the compliance issue.
Metformin (Glucophage), a biguanide and insulin-sen-
Weight loss should not be rapid or drastic but should be
sitizing agent, has been used to restore menstrual cyclic-
achieved through consistent lifestyle modification that
ity and induce ovulation in PCOS without the use of
includes gentle exercise, intake of dietary carbohydrates
additional fertility drugs. Use of this agent is associated
with a low glycemic index, and a reduced intake of fats
with reductions in serum levels of bioavailable androgen,
and simple sugars. Severe dietary deprivation is uni-
LH, and atherogenic lipids. Levels of plasminogen activa-
tor inhibitor I and Lp(a) lipoprotein also were reduced.33
No single food plan is recommended, but frequent feed-
There are no data to show a benefit in women who are
ings (four to six times per day) are important to avoid
not insulin resistant, but a few physicians support its
hypoglycemia and hunger. Hypoglycemia leads to cravings
and poor food choices that, in turn, result in simple sugar
Metformin is presently classified as a category “B” risk in
intake and reactive hyperinsulinemia. In the experience of
pregnancy, which indicates that there are no apparent fetal
the author, most women respond well to the admonition
defects associated with its use in the late trimester of preg-
to eat more food more frequently to lose weight.
nancy, based on animal studies. Because the human effects
In addition to the metabolic improvements, successful
of first-trimester use are unknown, discontinuation of
weight loss has the benefit of improving body image,
therapy at the onset of pregnancy confirmation has been
reducing depression, and restoring a sense of control. Pro-
standard. However, a recent prospective study of women
grams that have targeted this issue alone have achieved
with PCOS who continued metformin therapy through
pregnancy rates as high as 60 percent without medical
the first trimester of pregnancy showed no evidence of
intervention.35 There are no data to support the use of
fetal harm, calling into question this recommendation.34
lipid-lowering drugs in women younger than 40 years, but
The rate of early spontaneous abortion was reduced
dietary regulation should be encouraged. Family physi-
from 73 percent without metformin to 10 percent. In our
cians should monitor blood pressure elevations and smok-
clinical setting, the initial dosage of 500 mg is given at bed-
ing cessation for further cardiovascular protection.
time each night for one week to reduce the occurrence of
Knowledge gained over the past 60 years has carried
gastrointestinal side effects and is increased by 500 mg per
PCOS beyond the realm of gynecology and infertility, and
week to a total dosage of 1,500 mg per day in divided doses.
warrants heightened attention from physicians who will
Insulin, glucose, and androgen levels are retested after eight
focus on the functional abnormalities that have serious
weeks. If improvement is not shown, the dosage is
long-term consequences. It is important to recognize that
increased to 2,550 mg. Menses often will occur within this
PCOS is an entity with a long lifespan, requiring “control”
treatment time. If fertility is desired, ovulation induction
rather than “cure,” and that therapies will change with the
agents can be added. Metformin therapy is associated with
stage of life (Figure 1).
A considerable armamentarium of
a slight risk of lactic acidosis and is not used in patients
therapies exists for the family physician, using specialty
with impaired liver or renal function.
referral for patients with intractable vaginal bleeding,infertility, or dermatologic problems.
The most successful but difficult therapy to “adminis-
The author indicates that she does not have any conflicts of inter-
ter” is weight loss. Weight loss is most successful because
est. Sources of funding: none reported.
nicity influence the prevalence of adrenal hyperandrogenism andinsulin resistance in polycystic ovary syndrome? Am J Obstet
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VOR Cavalier Geel 4 jarige paarden plaats naam afstamming Prijzen-geld B.W.P.- Thunder van de Zuuthoeve x Eclinta van den Bosrand (Clinton)Zangersheide- Namelus R x Jolien (Ahorn Z)Zangersheide- Carosso VDL x Fonka-A (Electro)Zangersheide- Der Senaat 111 x Goa van de Nachtegaele (Quickfeuer)B.W.P.- DR. Doolittle x Air Dream (Aircraft)B.W.P.- Echo van het Neerenbosch x Celsa vd
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