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PCO Diferential Diagnosis
PCO Diferential Diagnosis
CME REVIEWARTICLE
CHIEF EDITORS NOTE: This article is part of a series of continuing education activities in this Journal through which a total
of 36 AMA/PRA category 1 credit hours can be earned in 2006. Instructions for how CME credits can be earned appear on
the last page of the Table of Contents.
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TABLE 1
Historical factors in self-selected women with polycystic ovary syndrome (PCOS) and control women. Adapted from Legro et al. (48)
Characteristic
Irregular menstrual cycles
Nulliparous
Use of fertility medications
in attempt to achieve
pregnancy
Hyperandrogenemia I
(T #58 ng/dL)
Hyperandrogenemia II
(T #58 ng/dL and/or uT
#16 ng/dL)
PCOS Women,
% (n)
Control Women,
% (n)
Odds Ratio
95% Confidence
Interval for Odds Ratio
P Value
96 (44)
84 (44)
59 (39)
0 (37)
43 (79)
6 (36)
Undefined
7
24
(0, 2, !)
(3, 21)
(5, 228)
"0.001
"0.001
"0.001
66 (35)
11 (80)
15
(6, 40)
"0.001
74 (35)
13 (80)
20
(7, 63)
"0.001
By Fisher exact test, all P for individual characteristic comparisons of the 2 groups were "0.001.
TABLE 2
Revised diagnostic criteria of polycystic ovary syndrome
Revised 2003 criteria (patients should have 2 of criteria 13)
1 Oligo- or anovulation
2 Clinical and/or biochemical signs of hyperandrogenism
3 Polycystic ovaries
4 Exclusion of other etiologies (congenital adrenal hyperplasia,
androgen-secreting tumors, Cushing syndrome)
Modified from The Rotterdam ESHRE/ASRM-Sponsored PCOS
Consensus Workshop Group (Group 2004) (2).
PCOS deserve further evaluation. Patients who are either obese or who have a family history of noninsulindependent diabetes mellitus should be evaluated for
insulin resistance. Because nonobese women with
PCOS also may have insulin resistance, some investigators advise assessing insulin resistance in all women
with PCOS. There is controversy about the best manner
of assessing insulin sensitivity, but the most practical
evaluation involves a 2-hour glucose tolerance test with
insulin levels measured after a 75-g glucose load. The
test should be performed after an 8- to 12-hour fast and
serum levels of insulin and glucose should be collected
every 30 minutes from zero to 120 minutes.
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Fig. 2. Adaptation of Ferriman and Gallwey visual method of scoring hair growth in women. Points are assigned based on the amount
of hair visualized in each area of the body. A summary score of greater than 8 is considered indicative of hirsutism. Adapted from Hatch
et al. (49).
ovulation and fertility treatment for reproductive purposes (8). However, they will only induce ovulation
in the cycle(s) in which they are administered. In
addition to hormonal treatment, appropriate psychologic support and follow up must be added to hormonal treatment.
Hyperprolactinemia
Elevations in prolactin affect the breast, the gonads, and occasionally mood. Additionally, at least
one study suggests an association of hyperprolactinemia with insulin resistance in the patient with PCOS
(9). Prolactin directly stimulates breast secretions,
and as a result, approximately 90% of women with
hyperprolactinemia develop galactorrhea. The impact of elevated prolactin on the gonads is hypothesized to be the result of the disruption of normal
pulsatility of gonadotropin-releasing hormone (GnRH)
and consequent alterations in the secretion of FSH
and LH. Clinically, the end result is anovulation
with either amenorrhea or oligomenorrhea in most
women.
Hyperprolactinemia can be divided into pituitary
and nonpituitary causes. Pituitary causes include
prolactin-secreting microadenomas, nonsecreting pituitary tumors, craniopharyngiomas, Rathke cleft
cysts, altered forms of prolactin, and idiopathic hyperprolactinemia. Any disruption of the pituitary
stalk or macroadenomas can lead to failure of the
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Hypothyroidism
In reproductive-age women, hypothyroidism results
in changes in cycle length and amount of bleeding.
Therefore, menstrual disorders can include oligomenorrhea and amenorrhea, polymenorrhea, and menorrhagia (12). The excessive bleeding disorders may result
from estrogen breakthrough bleeding secondary to
anovulation. Additionally, defects in hemostasis such
as decreased levels of factors VII, VIII, IX, and XI
may be present in hypothyroidism and contribute to
the polymenorrhea and menorrhagia seen in these
patients (13).
Hypothyroidism should be excluded in all cases of
menstrual irregularity. On physical examination, the
clinician may see a delay in the onset of puberty with
respect to chronologic age or paradoxically precocious puberty and galactorrhea in juvenile hypothyroidism (14). Although overt hypothyroidism is
easily detected by measuring the level of serum thyroid stimulating hormone (TSH), subclinical disease
may require performance of a prolactin stimulation
test with metoclopramide. This becomes particularly
important as reproductive age is reached because
subclinical hypothyroidism is of greater clinical importance in infertile women with menstrual disorders
(15).
Adequate thyroid supplementation should resolve
the reproductive symptoms associated with hypothyroidism, including oligo- or amenorrhea, and allow
progression of delayed puberty. Additionally, in
cases of severe hypothyroidism with associated hyperprolactinemia, prolactin levels should return to
normal as the hypothalamic thyrotropin-releasing
hormone (TRH) level, which stimulates prolactin as
well as TSH, normalizes (14).
Hyperadrenalism
Cushing syndrome refers to chronic glucocorticoid
excess irrespective of the cause. It should be in the
differential diagnosis of PCOS, obesity, diabetes,
hirsutism, and menstrual disorders. The most common time for presentation is during the reproductive
years (ages 2040), and the disease occurs in women
more often than men in a ratio of 10:1. Furthermore,
of adults with Cushing syndrome, 70% have Cushing
disease.
Cushing disease refers to the presence of an
ACTH-hypersecreting pituitary adenoma that demonstrates partial resistance to the normal suppressive
effect of glucocorticoids. As a result of systemic
hypercortisolism, peripheral tissues manifest the
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Androgen-Producing Tumors
These tumors can be either ovarian or adrenal in
origin. In the presence of ovarian androgen-secreting
tumors, autonomous androgen production may result in
chronic anovulation and virilization. The tumor types
include hilus cell tumors, arrhenoblastomas (SertoliLeydig cell tumors), benign cystic teratomas, luteinized
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bolic abnormalities represent the most serious longterm risk factors for patients with PCOS. Legro and
colleagues (41) have demonstrated that by their
fourth decade of life, as many as 40% of patients with
PCOS have impaired glucose tolerance and up to 10%
go on to develop type II diabetes mellitus. Given these
risks, the attenuation of hyperinsulinemia may have a
beneficial effect on the long-term sequelae thought to
develop in patients with PCOS. Currently, the use of
metformin, an insulin-sensitizing agent, provides the
opportunity to treat hyperinsulinemic patients with
PCOS with the goals of improving insulin resistance
and lowering insulin levels, thereby improving associated metabolic sequelae, including dyslipidemia,
glucose intolerance, and hyperandrogenism.
A study by Palmert and colleagues (42) concluded
that adolescents with PCOS are at increased risk for
both impaired glucose tolerance and diabetes mellitus. Additionally, they found that a 2-hour glucose
tolerance test after a 75-g oral load was the most
sensitive test to screen for insulin resistance in this
population.
Metformin (dimethylbiguanide) is an oral agent
used in the treatment of noninsulin-dependent diabetes mellitus (NIDDM). It maintains glucose homeostasis through suppression of hepatic glucose
output. Additionally, it improves insulin sensitivity
and decreases insulin levels. Overall, the use of metformin leads to a decrease in serum insulin and
androgen levels, as well as an improvement in ovulatory function (43). Metformin should be given to
reach maximum combined doses of 1500 to 2000 mg
per day divided over 2 to 3 daily doses. The goal of
treatment should be to improve insulin resistance and
hyperinsulinemia while encouraging the use of diet
and exercise for long-term therapy. Assessment of
insulin sensitivity should occur at no less than yearly
intervals. Treatment with metformin requires that
renal and liver function be assessed on an annual
basis.
In addition to metformin, thiazolidinediones continue to be under investigation for use in the management of PCOS-related metabolic abnormalities.
Early work with troglitazone before its withdrawal
from the market indicated that daily treatment with
400 mg for 12 weeks resulted in a decrease in insulin
and androgen levels in patients with PCOS (44). As
a family of compounds, thiazolidinediones are selective ligands for PPAR$, a nuclear receptor that regulates the transcription of multiple insulin-responsive
genes crucial to the control of glucose and lipid
metabolism and plays a central role in the regulation
of adipocyte gene expression and regulation (4547).
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