Steroids 78 (2013) 761766

Contents lists available at SciVerse ScienceDirect

Steroids
journal homepage: www.elsevier.com/locate/steroids

Changes in the PCOS phenotype with age

Ming-I. Hsu
Department of Obstetrics and Gynecology, Wan Fang Hospital, Taipei Medical University, No.111, Sec. 3, Xinglong Road, Taipei 11696, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-age women.
Received 21 March 2013 The diagnosis of PCOS is mainly based on the following three components: (1) hyperandrogenism, (2)
Received in revised form 23 March 2013 oligo-amenorrhea, and (3) the observation of polycystic ovaries on a sonogram. The comorbidities may
Accepted 23 March 2013
include insulin resistance, type II diabetes mellitus, hypertension and cardiovascular disease. Impor-
Available online 25 April 2013
tantly, the diagnostic criteria and complications related to PCOS are age-dependent. Androgen production
in women may decrease because of ovarian aging or decreased production by the adrenal glands over
Keywords:
time. The prevalence of hirsutism and acne decreases with age. Ovarian volume and follicle number also
Polycystic ovary syndrome
Phenotypes
decrease with age, with the age-related decrease in follicle number seemingly greater than that of ovar-
Age ian volume. Aging may also be associated with increased risk of insulin resistance and metabolic distur-
Obesity bances. Therefore, these age-related changes may affect the observed incidence and complications of
Insulin resistance PCOS. In adolescent patients, the criteria described above pose particular diagnostic problems because
Metabolic syndrome the characteristics of normal puberty often overlap with the signs and symptoms of PCOS. Hyperandrog-
enism and chronic anovulation are the primary disturbances in younger women with PCOS; whereas,
obesity, insulin resistance, and metabolic disturbances are predominant in older women with PCOS.
The deterioration of insulin resistance during the reproductive life of women with PCOS appears to be
mainly attributable to the increase in obesity. Therefore, if body weight could be controlled properly,
younger hyperandrogenic PCOS women might reduce their risk of insulin resistance and metabolic dis-
turbances later in life.
2013 Elsevier Inc. All rights reserved.

1. Introduction women are prone to signicant health problems related to hyper-

Polycystic ovarian syndrome (PCOS) is the most common endo-
crine disorder of reproductive-age women, affecting an estimated
68% [1] of such individuals depending on the diagnostic criteria
applied [2]. PCOS is a complex and heterogeneous disorder pre-
senting a challenge for clinical investigators. It is a multifaceted
reproductive, cosmetic, and metabolic problem, with an enigmatic
pathophysiological and molecular basis [3]. Although PCOS may
have a genetic component, the clinical features of this disorder
change with age, from adolescence to menopause and beyond
[4]. PCOS has potentially profound implications for women regard-
ing anovulatory infertility and other symptoms related to elevated
androgen levels in reproductive-aged women. In addition, older
Abbreviations: PCOS, polycystic ovarian syndrome; NIH, National Institutes of
Health; HPO, hypothalamicpituitaryovarian; AMH, anti-Mllerian hormone; PCO,
polycystic ovary morphology; AFC, antral follicle count; DHEAS, dehydroepian-
drosterone sulfate; SHBG, sex hormone-binding Globulin; mF-G score, modied
FerrimanGallwey score; LDL, low-density lipoprotein; HDL, high-density lipopro-
tein; OR, odd ratio.
Tel.: +886 2 29307930x2501; fax: +886 2 29300036.
E-mail address: hsumingi@yahoo.com.tw
insulinemia, with a high risk for diabetes and cardiovascular risk
factors [5]. The comorbidities of PCOS over the lifespan of an af-
fected woman may require individual therapeutic strategies, which
could prevent long-term chronic metabolic diseases [4].
2. Diagnostic criteria
Three diagnostic classication systems are currently in use for
PCOS: the National Institutes of Health (NIH) criteria, the Rotter-
dam criteria, and the Androgen Excess and PCOS Society criteria.
All of these criteria require the exclusion of other disorders, such
congenital adrenal hyperplasia and tumors. According to the NIH
criteria, PCOS is diagnosed by the combination of chronic oligo-
or anovulation and clinical or biochemical signs of hyperandroge-
nism [6]. According to the Rotterdam criteria, PCOS is diagnosed
in the presence of two of the following three symptoms: (1) oligo-
menorrhea, anovulation; (2) hyperandrogenism; and (3) the obser-
vation of polycystic ovaries by sonography [7]. Most recently, the
Androgen Excess Society published a task force report emphasizing
that androgen excess is a central feature of the disease and that
PCOS should be dened by the presence of hyperandrogenism in

0039-128X/$ - see front matter 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.steroids.2013.04.005
762 M.-I. Hsu / Steroids 78 (2013) 761766

combination with ovarian dysfunction (oligo-anovulation and/or cents [24]. The most important nding for clinical hyperandroge-
polycystic ovaries) [1]. Regardless of the set of criteria used, the nism in female adolescents is progressive hirsutism [23].
diagnosis of PCOS is determined by the three following compo- Adolescent hyperandrogenemia is associated with a reduction
nents: (1) hyperandrogenism (HA), (2) oligo-amenorrhea (OA), in peripheral tissue insulin sensitivity and compensatory hyperin-
and (3) the observation of polycystic ovaries (PCOs) on a sonogram. sulinemia, which implies an increase in the risk of type II diabetes
[25]. The increase in the prevalence of obesity, particularly among
younger age groups, is likely to have long-term implications for
3. PCOS diagnostic criteria change with age
cardiovascular disease (CVD) at relatively young ages. Applying
adult criteria for PCOS diagnosis to adolescent girls did not reliably
The clinical and biochemical presentations of PCOS change with
identify girls at risk for metabolic syndrome; indeed, an elevated
age [4]. The clinical presentation of chronic anovulation varies by
BMI was the strongest indicator of metabolic syndrome risk factors
age, with amenorrhea and oligomenorrhea being common among
[26]. Therefore, consideration should be given to the management
adolescents [8]. The menstrual cycles may become regular with
of girls and young women with polycystic ovaries and PCOS as this
age in women with PCOS [9,10]. The production of androgens in
group may have different needs and health risks than older women
women may decrease because of ovarian aging or decreased pro-
[27].
duction by the adrenal glands over time [11]. Hyperandrogenism
To diagnose PCOS in adolescents, guidelines have recently been
partially resolves before menopause in women with PCOS [12].
purposed [24]. Hyperandrogenism was diagnosed by elevated
Ovarian volume and follicle number decrease with age in women
blood androgens (hyperandrogenemia) or documented progressive
both with and without PCOS [13]. Furthermore, aging may also
hirsutism and discounting clinical nding such as acne and alope-
be associated with a defect in insulin action [14]. Therefore, the
cia [24]. A denitive diagnosis of PCOS in adolescents should re-
clinical features and metabolic consequences of PCOS may vary
quire all three Rotterdam elements (not just 2 out of 3) [24].
with age [15], and these age-related changes may affect the ob-
served incidence of PCOS [16]. To understand the age-related
changes in the diagnostic criteria of PCOS, it is crucial to determine 5. Anti-Mllerian hormone (AMH)
the complications of the related syndromes.
Anti-Mllerian hormone (AMH) is produced by the granulosa
cells of preantral and small antral follicles, and its levels can be as-
4. Adolescence
sessed in serum. As AMH is largely expressed during folliculogen-
esis, from the primary follicular stage to the small antral stage,
Common features of normal puberty, namely, menstrual irregu-
serum levels of AMH represent both the quantity and quality of
larities and insulin resistance, obscure the diagnosis of adolescent
the ovarian follicle pool and may be an useful marker of ovarian re-
PCOS [17]. Adolescents have a high prevalence of oligo-anovulation
serves [28,29]. The serum AMH level was strongly and positively
with prolonged menstrual intervals. Menstrual irregularity is com-
related to the number of antral follicles assessed by ultrasound
mon in the early years after menarche, and oligo-anovulation may
at baseline [30]; furthermore, AMH levels were also positively
be normal [18]. Menstrual disturbances in adolescents are often
associated with testosterone levels and ovarian volume [31]. We
explained by the immaturity of the hypothalamicpituitaryovar-
demonstrated that AMH is a good predictor of PCOS and that the
ian (HPO) axis. Disordered regulation of follicle-stimulating hor-
prevalence of PCOS increased with an increase in AMH concentra-
mone (FSH) and luteinizing hormone (LH) release has been
tion [32]. AMH is reported to be independent of menstrual cycle in
implicated in the pathogenesis of PCOS. The serum concentrations
most studies [33], which underlines its robustness as a biological
of sex hormones increase with age, from premenarchal to post-
marker of ovarian aging [33]. AMH levels decreased with an in-
menarchal [19]. In a study of postmenarchal women, approxi-
crease in age in both the PCOS cases and normo-ovulatory controls
mately 80% of the cycles were anovulatory in the rst year after
[33]. AMH measurement could be useful in the prediction of the
menarche, 50% in the third, and 10% in the sixth, and it is generally
menopausal transition [29,34]. Using AMH as a predicative marker,
accepted that it may take up to 5 years after menarche for the HPO
the reproductive lifespan of PCOS women is an average of 2 years
axis to reach maturation [19]. Furthermore, concomitant eating
longer than that of normo-ovulatory women [33]. Carmina
disorders are frequent, and secondary amenorrhea can be associ-
conducted a longitudinal study of 54 women with PCOS aged
ated with anorectic behavior in adolescents [20].
3539 years (mean 37 1 year) and 20 age- and weight-matched
Ovarian appearance in the early postmenarchal years may differ
control women. The results indicated that the AMH levels
from that in adulthood. In a sonographic study of healthy girls,
decreased by approximately 40% in PCOS (6.73.9 ng/mL, 40% de-
uterine growth continued several years after menarche; further-
crease) and control (1.71.0 ng/mL, 41% decrease) subjects during
more, the average ovarian volume increased from early childhood
5-year average intervals [35].
until the age of approximately 16 [21]. The difference between a
multifollicular appearance and polycystic ovarian morphology in
adolescents is poorly dened [21]. In adolescent patients, the crite- 6. Polycystic ovarian morphology
ria described above pose particular diagnostic problems because
the characteristics of normal puberty often overlap with the signs Polycystic ovarian morphology (PCO) is dened by ovarian vol-
and symptoms of PCOS [22]. ume (>10 cm3) and/or increased antral follicle count (AFC P 12 per
Mild hair growth and chronic anovulation are also regarded as ovary) by ultrasonographic examination. PCO is a common, age-
normal components of the late stages of puberty and early adoles- dependent nding among ovulatory women [36]. Ovarian volume
cence and may persist for several years; therefore, the diagnosis is and follicle number decrease with age in both healthy women
often not made until later in life, when endocrine and metabolic and women with PCOS [13]. In a study using data obtained from
dysfunctions have been rmly established [23]. Hyperandroge- 58,673 observations of ovarian volume, there is a statistically sig-
nism, dened as clinical and or biochemical hyperandrogenism, nicant decrease in ovarian volume with each decade of life from
might present differently for adolescents. Although most diagnos- age 30 to age 70 [37]. Pavliks study demonstrated a stable ovarian
tic criteria include hirsutism, acne, or androgenic alopecia as mark- volume up to age 35, a rapid decline between ages 35 and 55, and a
ers of clinical hyperandrogenism, acne and alopecia were not very minor decline after age 55 [37]. The ovarian volume in women
suggested as clinical markers for the diagnosis of PCOS in adoles- aged 2551 years was reported to reect the number of primordial
 M.-I. Hsu / Steroids 78 (2013) 761766
follicles remaining and ovarian volume measurement by transvag-
inal sonography may determine the ovarian reserve and reproduc-
tive age [38]. Menopause and ovarian failure occur as a
consequence of the continuous utilization of a xed store of pri-
mordial follicles, leading to almost total depletion at midlife.
The number of growing follicles at a given age is correlated with
those of the primordial stages [39]. The great majority of follicles
that disappear are lost by atresia, and the rate of loss accelerates
in the last decade of menstrual life [39]. After the numbers had fall-
en to the critical gure at 37.5 years of age, the loss rate increases,
corresponding to a faster rate of ovarian aging at approximately
51 years of age [40]. Alsamarai suggested that the decrease in ovar-
ian volume was less pronounced in women with PCOS than in con-
trol subjects [13]. In normal ovulatory women, ovarian volume was
signicantly lower in all age groups over 40 years compared with
the 35-to-39 age group, with measurable decreases across each
decade of reproductive life starting at age 40 [41]. We performed
a cross-sectional study in 781 cases between the ages of 20 and
40 (453 PCOS and 328 non-PCOS) and found that the ovarian vol-
ume was not signicantly correlated with age in either PCOS or
non-PCOS women [42].
In a community-based study of 262 ovulatory women ages 25
45, Johnstone reported that the prevalence of PCO was 32% and de-
creased with age but that the percentage of women with AFC P 12
decreased from 62% 2530 years old to 7% at 4145 years old [36].
The age-related decrease in follicle number seems more dominant
than the age-related decrease in ovarian volume [36].
7. Ovarian aging
Ovarian aging results in the diminution of the follicular cohort
in both normal and PCOS women, associated with decreased inhi-
bin B and AMH levels [43]. Similarly, the decreasing capacity of the
ovaries to release androgens in response to hCG stimulation was
observed in both healthy and PCOS women [44]. In a study on
the effect of age on the ovarian response to gonadotropin in wo-
men with PCOS, although there were no signicant age-related dif-
ferences in the ovulation rate, the pregnancy rate was signicantly
lower in the older PCOS patients than younger PCOS patients [45].
In terms of age-related decline in adrenal androgen production, the
adrenal capacity to secrete androgens (except for DHEA) remains
more stable during the menopausal transition in women with
PCOS than in the normal control women [46]. Advanced age in nor-
mogonadotrophic anovulatory infertile women is associated with
lower LH and androgen levels and with a decreased number of
ovarian follicles. Although the observed differences are relatively
small during reproductive years, these age-related changes may af-
fect the observed incidences of PCOS [16].
8. Oligo-amenorrhea
Oligo-amenorrhea is one of the key components for the diagno-
sis of PCOS. Several studies suggest that a gradual normalization of
menstrual cycle abnormalities occurs in PCOS with increasing age
[10,16]. AMH levels indicate the quantity of the ovarian follicle
pool and may be a useful marker of ovarian reserves [28]. We dem-
onstrated that serum AMH levels were strongly correlated to the
number of menstrual cycles per year [32], which could explain
the tendency of women with PCOS achieve cycle regularly as they
grow older [12]. In a study of oligo-amenorrheic infertile women,
advanced age in normogonadotrophic anovulatory infertile women
is associated with lower LH and a decreased number of ovarian fol-
licles [16]. Decreases in serum AMH levels with age could be ex-
plained by ovarian follicle loss with increasing age. In Carminas
study of 54 anovulatory hyperandrogenic women with PCOS, after
763
a 5-year follow-up, 10 anovulatory patients out of 54 (approxi-
mately 20%) became ovulatory at a mean age of 42 years [47]. Elt-
ing studied 205 women with PCOS using a telephone
questionnaire, revealing a highly signicant linear trend for a
shorter menstrual cycle length with increasing age; the proportion
of women with regular menstrual cycles increased from 41% for
women ages 3035 to 100% in the oldest group, ages 5155 [10].
Women with PCOS achieve regular menstrual cycles with age,
and the development of a new balance in the polycystic ovary,
caused solely by follicle loss through ovarian aging, can explain
the occurrence of regular cycles in older patients with PCOS [10].
In a study of aging women with PCOS comparing those who became
regular with those still menstruating irregularly, a lower follicle
count for women with PCOS was predictive of the achievement of
regular menstrual cycles with age [48], conrming that a decrease
in the size of the follicle cohort from ovarian aging is largely respon-
sible for the regular menstrual cycles in aging PCOS women [48].
Although the observed differences are relatively small during repro-
ductive years, these age-related changes in women with oligo-
amenorrhea may affect the observed incidence of PCOS [16].
9. Hyperandrogenism
Clinical and biochemical androgen excesses were the major char-
acteristics of women with PCOS; however, the elevated serum con-
centrations of androgens are the most consistent biochemical
abnormalities and may be considered the hallmark of the syndrome
[49]. An age-related decrease in androgen secretion, as in normal
women, also occurs in women with PCOS. Ovarian steroid secretion
capacity starts to decline as early as approximately 30 years of age
[44]; hyperandrogenism partly resolves before menopause in wo-
men with PCOS [12]. Acne and hirsutism were thought to be the ma-
jor clinical markers of clinical hyperandrogenism. We studied 781
women and found that the prevalence of acne and hirsutism were
both negatively correlated with age in women with and without
PCOS [42]. Bili studied 472 oligo-amenorrheic infertile patients
and found that age was inversely correlated with testosterone,
androstenedione and dehydroepiandrosterone [16]. Moran studied
145 hyperandrogenic women and reported a negative association
between DHEAS levels and age [50]. Winters studied 84 women with
PCOS and found that the levels of total testosterone and non-SHBG
bound testosterone were lower in older women with PCOS [12].
Although the decreasing ovarian capacity to release androgens
in response to hCG stimulation observed in healthy women also
occurs in women with PCOS, PCOS basal serum levels of androgens
and ovarian androgen secretion capacity are markedly increased
and remain high throughout the reproductive years [44]. In a lon-
gitudinal study of 193 women who were followed from a mean age
of 22 years to a mean age of 43 years, an approximately 25% de-
crease in testosterone levels and an approximately 30% decrease
in DHEAS were observed [35]. We demonstrated that all serum
androgen markers (total testosterone, androstenedione, and
DHEAS) were signicantly negatively correlated with age. Further-
more, the prevalence of acne and hirsutism decreased with
advanced age, modied FG score, and serum DHEAS levels, and
there was a signicant negative association with age in women
with and without PCOS [42]. Accordingly, the prevalence of both
clinical hyperandrogenism and biochemical hyperandrogenemia
should decrease in women of advanced age.
10. Metabolic syndrome and insulin resistance
Metabolic syndrome and insulin resistance were the major con-
cerns among the long-term complications in women with PCOS.
Metabolic syndrome is a cluster of adverse cardiovascular features,
764 M.-I. Hsu / Steroids 78 (2013) 761766

Table 1
PCOS phenotype changes with age in cross-sectional and longitudinal studies.

Authors Study Patients Results

Liang et al. (2011) [42]
Panidis et al. (2012) [61]
Carmina et al. (2012) [47]
Cross-sectional 453 PCOS and 328 non-PCOS
Cross-sectional 1212 PCOS and 254 healthy women
Longitudinal 193 women with PCOS, aged 20
25 years, and followed at 5-year
intervals for 20 years
Younger PCOS had signicantly higher androgens levels, but lower BMI
and lower insulin resistance than older PCOS.
A progressive decline in hyperandrogenic phenotype and increased
insulin resistance with advancing age.
After 20 years of follow-up in women with PCOS. After 10 years,
androgens decreased; at 15 years, waist circumference increased; at
20 years, there were more ovulatory cycles, suggesting a milder
disorder, whereas the persisting metabolic abnormalities increased.

including central obesity, atherogenic dyslipidemia, insulin resis-
tance, a prothrombotic state, elevated blood pressure, and in-
creased circulation proinammatory markers [26]. Age is also an
important risk factor for developing metabolic disorders and insu-
lin resistance. Aging may also be associated with a defect in insulin
action that is manifested by decreased whole-body tissue sensitiv-
ity to insulin without a change in tissue responsiveness [14]. The
glucose intolerance may reect part of the aging process. In elderly
subjects, the severity of carbohydrate intolerance is directly corre-
lated with the degree of peripheral insulin resistance [51].
We reported that advanced age was associated with increased
cholesterol, triglyceride, and low-density lipoprotein (LDL) levels;
furthermore, fasting glucose and 2-h glucose were both signicantly
correlated with age [42]. The National Cholesterol Education Pro-
gram Adult Treatment Panel (ATPIII; third report of the National
Cholesterol Education Program) guidelines dene metabolic
syndrome according to the following ve parameters: waist circum-
ference, fasting serum glucose, fasting serum triglycerides, serum
high-density lipoprotein (HDL) cholesterol and blood pressure. Most
of these parameters worsen with age. Therefore, it is logical that
metabolic syndrome and insulin resistance are also age-dependent.
11. Obesity
Obesity is a prominent feature of PCOS, occurring in 4050% of
patients [52,53]. Lipid abnormalities, including elevated LDL and
triglyceride levels and decreased HDL, are often found in women
with both PCOS and obesity [54]. Obesity appears to exert an addi-
tive, synergistic impact on the manifestations of PCOS, indepen-
dently and negatively affecting insulin sensitivity, diabetes risk
and cardiovascular prole [55,56]. Obesity unmasks or amplies
symptoms and endocrine and metabolic abnormalities. We studied
273 women and found that obesity (Odd Ratio (OR) = 14.0, 95% CI,
7.526.5) results in a higher risk for developing insulin resistance
than hyperandrogenemia (OR = 2.1, 1.33.6) or oligo-amenorrhea
(OR = 1.8, 1.03.3) [57]. Furthermore, body weight status was the
major factor determining the risk of impaired glucose tolerance
and metabolic syndrome in women with PCOS [58].
Obesity is not only a major determinant of long-term complica-
tions in PCOS but also an important factor in the diagnosis of PCOS
[59]. In one study, the prevalence of PCOS was greater in overweight
and obese women than in lean women [60]. Obesity worsens both
biochemical hyperandrogenemia and chronic anovulation, which
are the two most important diagnostic criteria of PCOS [60]. We
found that obese subjects with PCOS had a higher risk of developing
oligomenorrhea (OR = 2.2, 1.33.7) and biochemical hyperandro-
genemia (OR = 2.6, 1.64.2) than non-obese women with PCOS
[59]. Therefore, when assessing the diagnosis and complications,
obesity should be thoroughly taken into account.
12. Phenotypes change with age
The best way to study the aging process in women with PCOS is
to perform a longitudinal study with same subject; however, it is
difcult to include a large sample size with a long-time follow
up. Therefore, large-sample-size cross-sectional studies might also
provide some useful information (Table 1).
13. Case studies
As described above, the age of subjects could inuence the sta-
tus of diagnosed PCOS. Subjects with PCOS, as diagnosed by 2003
Rotterdam criteria, might have different phenotypes according to
age group. We reported a cross-sectional study that included 453
women with PCOS and found that for women who fullled diag-
nostic criteria for PCOS, younger women had a signicantly higher
percentage of acne and hirsutism, higher mF-G score, and lower
cholesterol and triglycerides than older women. In contrast, older
women had higher levels of obesity, lower levels of androgens,
and higher levels of insulin resistance and metabolic disturbances
than younger women [42]. Our results were conrmed by Panidis,
who studied 1,212 women with PCOS and found a progressive de-
cline in circulating androgens with advancing age [61]. Further-
more, patients 2130 years old had lower plasma glucose and
insulin levels, lower homeostasis model assessment of insulin
resistance index, and lower BMI than patients 3139 years old
[61]. From cross-sectional studies, among patients with diagnosed
PCOS, chronic anovulation and hyperandrogenism were the pre-
dominant characteristics in adolescents. Because the prevalence
of clinical and/or biochemical hyperandrogenism signicantly de-
creased with age and the severity of menstrual disturbance may
improve after the age of 20, ovarian volume and morphology seem
to be relatively stable with age for women younger than 35 [37,42].
Therefore, polycystic ovary morphology became the prevalent
inclusion criterion used by some investigators for the diagnosis
of PCOS in women over 20 years of age.
Both our study and that of Panidis found that the prevalence of
PCOS phenotypes changed with age, with younger women with
PCOS having more severe hyperandrogenism but lower insulin
resistance and BMI than older women with PCOS [61]. Interest-
ingly, serum testosterone levels were positively correlated with
BMI [42], and the prevalence of hyperandrogenism was twice as
high for obese women as for non-obese women [59]. To fulll
the diagnostic criteria, older women with PCOS had a higher prev-
alence of obesity than younger women [42,61]; therefore, the dete-
rioration of insulin resistance during the reproductive life of
women with PCOS appears to be mainly attributable to the in-
crease in obesity [61].
However, the question is whether younger hyperandrogenic
PCOS women will become older obese women with insulin resis-
tance? This question could not be answered by a cross-sectional
study. Recently, Carmina published a large longitudinal study that
included 193 women with PCOS, aged 2025 years, who were diag-
nosed according to Rotterdam criteria and followed at 5-year inter-
vals for 20 years [47]. After 10 years, androgens decreased; at
15 years, waist circumference increased; and at 20 years, ovarian
volume decreased. Serum luteinizing hormone and follicle-
stimulating hormone decreased non-signicantly, and fasting
 M.-I. Hsu / Steroids 78 (2013) 761766
insulin and quantitative insulin-sensitivity check index was un-
changed. Eighty-ve women (44%) were ovulatory at 20 years,
and 18 women (8%) could no longer be diagnosed as having PCOS
[47]. After 20 years of follow-up in women with PCOS, androgens
and ovarian volume decreased and there were more ovulatory cy-
cles, suggesting a milder disorder, whereas metabolic abnormali-
ties persisted and waist circumference increased [47].
14. Conclusion
Most available data suggest that the prevalence of cardiovascu-
lar diseases in women with polycystic ovary syndrome (PCOS) is
lower than expected based on risk calculations during fertile years.
Advanced age is associated with decreased hyperandrogenism and
increased metabolic disturbances in women with and without
PCOS. Hyperandrogenism and chronic anovulation may be the ma-
jor disturbances in younger women with PCOS, however, increases
in body weight might contribute to insulin resistance and meta-
bolic disturbances in later life. If body weight could be controlled
properly, young hyperandrogenic PCOS women might not neces-
sarily become older obese insulin-resistant PCOS women.
Acknowledgments
This work was supported by a grant from the National Science
Council Grant NSC 101-2629-B-038-001 and by Taipei Medical
University grants TMU98-AE1-B01.
References
[1] Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale. The
androgen excess and PCOS Society criteria for the polycystic ovary syndrome:
the complete task force report. Fertil Steril 2009;91:45688.
[2] March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The
prevalence of polycystic ovary syndrome in a community sample assessed
under contrasting diagnostic criteria. Hum Reprod 2010;25:54451.
[3] Diamanti-Kandarakis E, Piperi C. Genetics of polycystic ovary syndrome:
searching for the way out of the labyrinth. Hum Reprod Update
2005;11:63143.
[4] Pasquali R, Gambineri A. Polycystic ovary syndrome: a multifaceted disease
from adolescence to adult age. Ann NY Acad Sci 2006;1092:15874.
[5] Hart R, Norman R. Polycystic ovarian syndromeprognosis and outcomes. Best
Pract Res Clin Obstet Gynaecol 2006;20:75178.
[6] Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome:
towards a rational approach. In: Dunaif AGJ, Haseltine F, editors. Polycystic
ovary syndrome. Boston: Blackwell Scientic; 1992. p. 37784.
[7] Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group.
Revised 2003 consensus on diagnostic criteria and long-term health risks
related to polycystic ovary syndrome. Fertil Steril 2004;81:1925.
[8] Manseld MJ, Emans SJ. Adolescent menstrual irregularity. J Reprod Med
1984;29:399410.
[9] Birdsall MA, Farquhar CM. Polycystic ovaries in pre and post-menopausal
women. Clin Endocrinol (Oxf) 1996;44:26976.
[10] Elting MW, Korsen TJ, Rekers-Mombarg LT, Schoemaker J. Women with
polycystic ovary syndrome gain regular menstrual cycles when ageing. Hum
Reprod 2000;15:248.
[11] Brown ZA, Louwers YV, Fong SL, Valkenburg O, Birnie E, de Jong FH, Fauser BC,
Laven JS. The phenotype of polycystic ovary syndrome ameliorates with aging.
Fertil Steril 2011;96:125965.
[12] Winters SJ, Talbott E, Guzick DS, Zborowski J, McHugh KP. Serum testosterone
levels decrease in middle age in women with the polycystic ovary syndrome.
Fertil Steril 2000;73:7249.
[13] Alsamarai S, Adams JM, Murphy MK, Post MD, Hayden DL, Hall JE, Welt CK.
Criteria for polycystic ovarian morphology in polycystic ovary syndrome as a
function of age. J Clin Endocrinol Metab 2009;94:496170.
[14] Rowe JW, Minaker KL, Pallotta JA, Flier JS. Characterization of the insulin
resistance of aging. J Clin Invest 1983;71:15817.
[15] Rodrguez-Morn M, Guerrero-Romero F. Insulin resistance is independently
related to age in Mexican women. J Endocrinol Invest. 2003;26:428.
[16] Bili H, Laven J, Imani B, Eijkemans MJ, Fauser BC. Age-related differences in
features associated with polycystic ovary syndrome in normogonadotrophic
oligo-amenorrhoeic infertile women of reproductive years. Eur J Endocrinol
2001;145:155749.
[17] Diamanti-Kandarakis E. PCOS in adolescents. Best Pract Res Clin Obstet
Gynaecol 2010;24:17383.
[18] Apter D, Vihko R. Premenarcheal endocrine changes in relation to age at
menarche. Clin Endocrinol (Oxf) 1985;22:160753.
765
[19] Apter D. Serum steroids and pituitary hormones in female puberty: a partly
longitudinal study. Clin Endocrinol (Oxf) 1980;12:10720.
[20] Wiksten-Almstrmer M, Hirschberg AL, Hagenfeldt K. Prospective follow-up of
menstrual disorders in adolescence and prognostic factors. Acta Obstet
Gynecol Scand 2008;87:11628.
[21] Holm K, Laursen EM, Brocks V, Mller J. Pubertal maturation of the internal
genitalia: an ultrasound evaluation of 166 healthy girls. Ultrasound Obstet
Gynecol 1995;6:17581.
[22] Roe AH, Dokras A. The diagnosis of polycystic ovary syndrome in adolescents.
Rev Obstet Gynecol 2011;4:4551.
[23] Jeffrey Chang R, Cofer MS. Polycystic ovary syndrome: early detection in the
adolescent. Clin Obstet Gynecol. 2007;50:17887.
[24] Carmina E, Obereld SE, Lobo RA. The diagnosis of polycystic ovary syndrome
in adolescents. Am J Obstet Gynecol. 2010;203:201.e15.
[25] Lewy VD, Danadian K, Witchel SF, Arslanian S. Early metabolic abnormalities
in adolescent girls with polycystic ovarian syndrome. J Pediatr
2001;138:3844.
[26] Hart R, Doherty DA, Mori T, Huang RC, Norman RJ, Franks S, Sloboda D, Beilin L,
Hickey M. Extent of metabolic risk in adolescent girls with features of
polycystic ovary syndrome. Fertil Steril 2011;95:234753.
[27] Michelmore KF. Polycystic ovary syndrome in adolescence and early
adulthood. Hum Fertil (Camb) 2000;3:96100.
[28] Kwee J, Schats R, McDonnell J, Themmen A, de Jong F, Lambalk C. Evaluation of
anti-Mllerian hormone as a test for the prediction of ovarian reserve. Fertil
Steril 2008;90:73743.
[29] La Marca A, Volpe A. Anti-Mllerian hormone (AMH) in female reproduction:
is measurement of circulating AMH a useful tool? Clin Endocrinol (Oxf)
2006;64:60310.
[30] van Rooij IA, Broekmans FJ, te Velde ER, Fauser BC, Bancsi LF, de Jong FH,
Themmen AP. Serum anti-Mllerian hormone levels: a novel measure of
ovarian reserve. Hum Reprod 2002;17:306571.
[31] Carlsen SM, Vanky E, Fleming R. Anti-Mllerian hormone concentrations in
androgen-suppressed women with polycystic ovary syndrome. Hum Reprod
2009;24:17328.
[32] Lin YH, Chiu WC, Wu CH, Tzeng CR, Hsu CS, Hsu MI. Anti-Mllerian hormone
and polycystic ovary syndrome. Fertil Steril 2011;96:2305.
[33] Tehrani FR, Solaymani-Dodaran M, Hedayati M, Azizi F. Is polycystic ovary
syndrome an exception for reproductive aging? Hum Reprod
2010;25:177581.
[34] Lambalk CB, van Disseldorp J, de Koning CH, Broekmans FJ. Testing ovarian
reserve to predict age at menopause. Maturitas 2009;63:28091.
[35] Carmina E, Campagna AM, Mansuet P, Vitale G, Kort D, Lobo R. Does the level
of serum anti-Mllerian hormone predict ovulatory function in women with
polycystic ovary syndrome with aging? Fertil Steril 2012;98:10436.
[36] Johnstone EB, Rosen MP, Neril R, Trevithick D, Sternfeld B, Murphy R, Addauan-
Andersen C, McConnell D, Pera RR, Cedars MI. The polycystic ovary post-
rotterdam: a common, age-dependent nding in ovulatory women without
metabolic signicance. J Clin Endocrinol Metab 2010;95:496572.
[37] Pavlik EJ, DePriest PD, Gallion HH, Ueland FR, Reedy MB, Kryscio RJ, van Nagell
Jr. JR. Ovarian volume related to age. Gynecol Oncol 2000;77:4102.
[38] Wallace WH, Kelsey TW. Ovarian reserve and reproductive age may be
determined from measurement of ovarian volume by transvaginal
sonography. Hum Reprod 2004;19:16127.
[39] Gosden RG, Faddy MJ. Ovarian aging, follicular depletion, and steroidogenesis.
Exp Gerontol 1994;29:26574.
[40] Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated
disappearance of ovarian follicles in mid-life: implications for forecasting
menopause. Hum Reprod 1992;7:13426.
[41] Oppermann K, Fuchs SC, Spritzer PM. Ovarian volume in pre- and
perimenopausal women: a population-based study. Menopause
2003;10:20913.
[42] Liang SJ, Hsu CS, Tzeng CR, Chen CH, Hsu MI. Clinical and biochemical
presentation of polycystic ovary syndrome in women between the ages of 20
and 40. Hum Reprod 2011;26:34439.
[43] Vulpoi C, Lecomte C, Guilloteau D, Lecomte P. Ageing and reproduction: is
polycystic ovary syndrome an exception? Ann Endocrinol (Paris)
2007;68:4550.
[44] Piltonen T, Koivunen R, Perheentupa A, Morin-Papunen L, Ruokonen A,
Tapanainen JS. Ovarian age-related responsiveness to human chorionic
gonadotropin in women with polycystic ovary syndrome. J Clin Endocrinol
Metab 2004;89:376975.
[45] Guido M, Belosi C, Selvaggi L, Lattanzi F, Apa R, Fulghesu AM, Lanzone A. The
effect of age on the ovarian response to gonadotropin and on pregnancy rate in
polycystic ovary syndrome. Gynecol Endocrinol 2003;17:21521.
[46] Puurunen J, Piltonen T, Jaakkola P, Ruokonen A, Morin-Papunen L, Tapanainen
JS. Adrenal androgen production capacity remains high up to menopause in
women with polycystic ovary syndrome. J Clin Endocrinol Metab
2009;94:19738.
[47] Carmina E, Campagna AM, Lobo RA. A 20-year follow-up of young women with
polycystic ovary syndrome. Obstet Gynecol 2012;119:2639.
[48] Elting MW, Kwee J, Korsen TJ, Rekers-Mombarg LT, Schoemaker J. Aging
women with polycystic ovary syndrome who achieve regular menstrual cycles
have a smaller follicle cohort than those who continue to have irregular cycles.
Fertil Steril 2003;79:115460.
[49] Franks S. Polycystic ovary syndrome in adolescents. Int J Obes (Lond)
2008;32:103541.
766 M.-I. Hsu / Steroids 78 (2013) 761766
[50] Moran C, Knochenhauer E, Boots LR, Azziz R. Adrenal androgen excess in
hyperandrogenism: relation to age and body mass. Fertil Steril
1999;71:6714.
[51] Fink RI, Kolterman OG, Grifn J, Olefsky JM. Mechanisms of insulin resistance
in aging. J Clin Invest 1983;71:152335.
[52] Hsu MI, Liou TH, Chou SY, Chang CY, Hsu CS. Diagnostic criteria for polycystic
ovary syndrome in Taiwanese Chinese women: comparison between
Rotterdam 2003 and NIH 1990. Fertil Steril 2007;88:7279.
[53] Gambineri A, Pelusi C, Vicennati V, Pagotto U, Pasquali R. Obesity and the
polycystic ovary syndrome. Int J Obes Relat Metab Disord 2002;26:88396.
[54] Diamanti-Kandarakis E, Papavassiliou AG, Kandarakis SA, Chrousos GP.
Pathophysiology and types of dyslipidemia in PCOS. Trends Endocrinol
Metab 2007;18:2805.
[55] Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin
resistance, independent of obesity, in polycystic ovary syndrome. Diabetes
1989;38:116574.
[56] Hoeger K. Obesity and weight loss in polycystic ovary syndrome. Obstet
Gynecol Clin North Am 2001;28:8597.
[57] Chun-Sen H, Chien-Hua W, Wan-Chun C, Ching-Tzu L, Chun-Jen C, Hsu MI.
Obesity and insulin resistance in women with polycystic ovary syndrome.
Gynecol Endocrinol. 2011;273006.
[58] Liang SJ, Liou TH, Lin HW, Hsu CS, Tzeng CR, Hsu MI. Obesity is the
predominant predictor of impaired glucose tolerance and metabolic
disturbance in polycystic ovary syndrome. Acta Obstet Gynecol Scand
2012;91:116772.
[59] Liou TH, Yang JH, Hsieh CH, Lee CY, Hsu CS, Hsu MI. Clinical and biochemical
presentations of polycystic ovary syndrome among obese and non-obese
women. Fertil Steril 2009;92:19605.
[60] Martnez-Bermejo E, Luque-Ramrez M, Escobar-Morreale HF. Obesity and the
polycystic ovary syndrome. Minerva Endocrinol 2007;32:12940.
[61] Panidis D, Tziomalos K, Macut D, Delkos D, Betsas G, Misichronis G, Katsikis I.
Cross-sectional analysis of the effects of age on the hormonal, metabolic, and
ultrasonographic features and the prevalence of the different phenotypes of
polycystic ovary syndrome. Fertil Steril 2012;97:494500.