Human Reproduction Update, Vol.12, No.4 pp. 351–361, 2006
Advance Access publication May 2, 2006
doi:10.1093/humupd/dml017
The origins and sequelae of abnormal neuroendocrine
function in polycystic ovary syndrome
S.K.Blank1,3, C.R.McCartney1,2 and J.C.Marshall1,2
1
The Center for Research in Reproduction and 2Division of Endocrinology, Department of Internal Medicine, University of Virginia
Health System, Charlottesville, VA, USA
3
To whom correspondence should be addressed at: Center for Research in Reproduction, Box 800391, University of Virginia Health
System, Charlottesville, VA 22908, USA. E-mail: [email protected]
Polycystic ovary syndrome (PCOS) is a common clinical disorder characterized by ovulatory dysfunction and hyperandrogenaemia. A neuroendocrine hallmark of PCOS is persistently rapid LH (GnRH) pulsatility, which favours
pituitary synthesis of LH over that of FSH and contributes to the increased LH concentrations and LH : FSH ratios
typical of PCOS. Inadequate FSH levels contribute to impaired follicular development, whereas elevated LH levels
augment ovarian androgen production. Whereas luteal phase elevations in progesterone normally slow GnRH pulse
frequency, women with PCOS do not experience normal progesterone-mediated slowing, due in part to impaired
hypothalamic progesterone sensitivity. This reduction in hypothalamic progesterone sensitivity appears to be mediated by elevated androgens because sensitivity can be restored with the androgen receptor blocker flutamide. The
ovulatory and hormonal abnormalities associated with PCOS generally present during puberty, typically associated
with hyperandrogenaemia. Along with elevated LH concentration and pulsatility, some girls with hyperandrogenaemia have impaired hypothalamic progesterone sensitivity similar to that seen in adult women with PCOS. We propose that peripubertal hyperandrogenaemia may lead to persistently rapid GnRH pulse frequency via impaired
hypothalamic feedback inhibition. The subsequent abnormalities in gonadotropin secretion, androgen production
and ovulatory function may support progression towards the adult PCOS phenotype.
Key words: androgens/endocrinology/gonadotrophin/polycystic ovaries/progesterone
Introduction
In 1935, Stein and Leventhal first described the association of
amenorrhoea, hirsutism, obesity and polycystic ovaries in a group
of reproductive aged women (Stein and Leventhal, 1935). Polycystic ovary syndrome (PCOS), as it is now known, is a common
disorder, affecting approximately 6–8% of women during their
childbearing years (Diamanti-Kandarakis et al., 1999; Asuncion
et al., 2000; Azziz et al., 2004). Although it is a heterogeneous
disorder with variable clinical presentations, it is defined clinically
by ovulatory dysfunction and hyperandrogenism—with or without
polycystic ovarian morphology—in the absence of other explanatory endocrinopathies (Zawadski and Dunaif, 1992). Ovulatory
dysfunction generally manifests as oligomenorrhoea or amenorrhoea with consequent subfertility, and hyperandrogenism may be
biochemical or clinical, with the latter including hirsutism, acne
and androgenic alopoecia. PCOS is also commonly associated
with obesity, insulin resistance and hyperinsulinaemia (Dunaif
et al., 1989; Carmina et al., 1992; Legro et al., 1998b; DeUgarte
et al., 2005), and women with PCOS are at increased risk of various metabolic disorders such as diabetes mellitus (Ehrmann et al.,
1999; Legro et al., 1999) and the metabolic syndrome (Glueck
et al., 2003; Apridonidze et al., 2005; Sam et al., 2005).
Despite decades of research, the aetiology of PCOS remains
unclear. Altered ovarian steroidogenesis, hyperinsulinaemia and
neuroendocrine abnormalities have all been proposed as primary
aetiological factors (Yen et al., 1970; Dunaif and Graf, 1989;
Poretsky and Piper, 1994; Ehrmann et al., 1995; Franks, 1995;
Utiger, 1996; Gilling-Smith et al., 1997). A role for intrinsic
abnormalities in ovarian steroidogenesis is supported by in vitro
studies demonstrating that ovarian theca cells from women with
PCOS produce excessive androgens (Gilling-Smith et al., 1994;
Nelson et al., 1999). In addition, women with PCOS demonstrate
abnormal ovarian steroid responses to gonadotropin stimulation
(Ehrmann et al., 1995; Ibanez et al., 1996; Gilling-Smith et al.,
1997; McCartney et al., 2004). Data also suggest an important role
for insulin in the pathogenesis of PCOS (Dunaif, 1997; Poretsky
et al., 1999). Insulin acts synergistically with LH to stimulate
ovarian androgen production (Barbieri et al., 1986; Nestler et al.,
1998a), and insulin suppresses hepatic production of sex-hormonebinding globulin, resulting in higher levels of free or bioavailable testosterone. Not only is there a high prevalence of insulin
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S.K.Blank, C.R.McCartney and J.C.Marshall
resistance and hyperinsulinaemia in women with PCOS (DeUgarte
et al., 2005), but both hyperandrogenaemia and ovulatory function
improve with treatments that decrease plasma insulin and/or
improve insulin signalling (Dunaif, 1997; Poretsky et al., 1999;
Azziz et al., 2001; Baillargeon et al., 2004). Neuroendocrine
abnormalities also occur in PCOS and are clearly involved in the
pathophysiology of this disorder. PCOS is marked by excessive
LH pulsatility and relative FSH deficiency (Rebar et al., 1976;
Waldstreicher et al., 1988; Taylor et al., 1997). In women with
PCOS, treatment with GnRH antagonists results in an acute, dosedependent reduction in both LH and testosterone levels (Hayes
et al., 1998), and treatment with long-term GnRH agonists leads to
suppression of ovarian androgen production to post-menopausal
levels (Chang et al., 1983; Steingold et al., 1987). Thus, LH is the
proximate physiological stimulus for androgen synthesis by
ovarian theca cells and plays an important role in maintaining
hyperandrogenaemia.
The initial manifestations of PCOS are frequently peripubertal
in onset. Many women with PCOS develop clinical hyperandrogenism shortly after puberty, and the majority never establish
regular menstrual periods. This suggests that PCOS has pre- or
peripubertal origins. Many of the aforementioned abnormalities
associated with PCOS, including aberrant neuroendocrine function, are also observed in adolescents with hyperandrogenaemia,
which is felt to represent a forerunner of adult PCOS. The origin
of elevated androgens in adult PCOS and adolescent hyperandrogenaemia is probably multifactorial, with entities such as abnormal ovarian steroidogenesis, hyperinsulinaemia and increased LH
drive probably being complementary and synergistic, and with the
relative contributions of each varying from individual to individual. Whether primary or secondary, neuroendocrine abnormalities
make an important contribution to the pathogenesis and development of PCOS and will be the focus of this review.
Gonadotropin regulation during the ovulatory
menstrual cycle
The ovulatory menstrual cycle is dependent on a series of highly
complex and integrated interactions between the central nervous
system (CNS), hypothalamus, pituitary gland and ovaries (in addition to hormone-responsive elements such as the endometrium).
However, the hypothalamo-pituitary unit is the primary driver of
reproductive function. A group of functionally integrated hypothalamic neurons—known collectively as the GnRH pulse generator—
secrete GnRH in a pulsatile fashion into the hypophyseal portal
system. GnRH pulses stimulate synthesis and secretion of LH and
FSH from pituitary gonadotropes. Interestingly, LH and FSH are
produced by the same gonadotrope cell, yet plasma LH and FSH
concentrations vary discordantly throughout the menstrual cycle.
For instance, FSH exceeds LH in the early follicular phase, whereas
LH predominates in the late follicular phase (Marshall and Kelch,
1986).
The frequency of GnRH pulses in part determines which gonadotropin hormone is preferentially synthesized and secreted, with
rapid GnRH pulses favouring LH, whereas slower GnRH pulses
favour FSH (Gross et al., 1987; Spratt et al., 1987). For example,
in vivo primate studies demonstrate that a GnRH pulse frequency
of one pulse per hour favours secretion of LH relative to FSH;
however, when pulse frequency is reduced to one pulse every 3 h,
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FSH concentration doubles whereas that of LH falls (Wildt et al.,
1981). Rodent studies suggest a mechanism for this phenomenon.
In rats, rapid GnRH pulses favour pituitary gonadotrope expression of the LH-β gene, whereas slower pulses favour expression of
the FSH-β gene (Dalkin et al., 1989). This is in part explained by
increased expression of pituitary follistatin induced by rapid
GnRH pulses (Kirk et al., 1994); follistatin binds to the intragonadotrope activin, thereby inhibiting its stimulatory effect on FSH-β
expression and shifting the balance towards LH production.
Ovarian hormones influence GnRH pulse frequency. Importantly, elevations in progesterone levels result in slowing of LH
and, by inference, GnRH pulse frequency. This slowing is seen
during the luteal phase as well as after exogenous administration
of physiologic doses of progesterone during the follicular phase
(Soules et al., 1984). Estradiol (E2) plays a permissive role in progesterone suppression of GnRH pulsatility (Goodman et al., 1981;
Nippoldt et al., 1989), probably through up-regulation of hypothalamic progesterone receptors (MacLusky and McEwen, 1978;
Romano et al., 1989). This modulatory effect of ovarian hormones
seems to be a primary regulator of GnRH pulse frequency,
because the GnRH pulse generator appears to have an intrinsic firing frequency of approximately one pulse per hour after puberty.
For example, in vitro studies reveal that the isolated adult human
mediobasal hypothalamus releases pulses of GnRH with a periodicity of 60–100 min (Rasmussen et al., 1989). A similar pulse
frequency is seen in women after natural and surgical menopause
as well as in women with premature ovarian failure, all of whom
lack ovarian steroid feedback (Rossmanith et al., 1990; Gill et al.,
2002). Additionally, this rate is not exceeded at any point during
the ovulatory menstrual cycle (Filicori et al., 1986; Rossmanith
et al., 1990; Adams et al., 1994). Given this intrinsic pulse frequency, alterations in GnRH pulsatility in normally cycling
women appear to be mediated through the imposition and
removal of negative feedback, with progesterone being primary
in this role.
The changes in GnRH pulse frequency and levels of gonadotropins, ovarian sex steroids and inhibins during the course of a normal ovulatory menstrual cycle are depicted in Figure 1, and the
differential control of gonadotropin secretion may be understood in
the context of the aforementioned data. GnRH pulsatility gradually
Figure 1. Schematic representation of hormonal changes during an ovulatory
menstrual cycle (Marshall JC and Eagleson CA, 1999; with permission from
Elsevier).
Neuroendocrine function in PCOS
increases during the follicular phase, apparently as a result of
gradual loss of the restraining influence of progesterone (McCartney et al., 2002), achieving a peak frequency of approximately one
pulse per hour in the late follicular phase (Filicori et al., 1986).
This leads to an increase in LH and a decrease in FSH during the
latter half of the follicular phase. In the late follicular phase, E2
production by the dominant follicle becomes sufficient to elicit
marked increases in pituitary LH release in response to the rapid
GnRH pulses resulting in positive feedback; this results in the
mid-cycle LH surge, which in turn provokes ovulation (Karsch
et al., 1973; Adams et al., 1994). Following ovulation, the corpus
luteum produces E2 and progesterone, which again slow GnRH
pulse frequency to one pulse every 3–4 h (Filicori et al., 1986),
resulting in preferential synthesis and release of FSH and initiation
of the next wave of follicular development.
Given the intricate and interdependent series of interactions that
must take place for ovulatory cyclicity to occur, perturbations at
any level of the hypothalamic–pituitary–ovarian axis can result in
ovulatory dysfunction.
Gonadotropin secretion in PCOS
Women with PCOS have consistent abnormalities in gonadotropin
secretion. In a study that carefully excluded post-ovulatory subjects, 75% of women with PCOS had elevated LH levels and 94%
had elevated LH : FSH ratios (Taylor et al., 1997). PCOS is characterized by increased LH pulse amplitude and exaggerated LH
responses to exogenous GnRH, whereas plasma FSH levels are
relatively low (Rebar et al., 1976; Taylor, 1998; Marshall and
Eagleson, 1999). Waldstreicher and colleagues demonstrated that
women with PCOS have persistently rapid LH (GnRH) pulse frequency, in the order of one pulse per hour, without the normal
cyclic variation seen in ovulatory women (Figure 2) (Waldstreicher
et al., 1988). Such persistently rapid GnRH pulsation favours synthesis and secretion of LH over FSH, helping to explain the elevated LH levels and LH : FSH ratios characteristic of PCOS
(Taylor et al., 1997). Because a frequency of approximately one
pulse per hour appears to be inherent to the post-pubertal GnRH
pulse generator, the persistently rapid LH pulsatility characteristic
of PCOS probably signifies a failure of the systems necessary to
suppress GnRH pulsatility, rather than representing an acceleration of the GnRH pulse generator. This failure of intermittent suppression may be the result of primary hypothalamic defects, an
abnormal hormonal milieu or a combination of the two.
Aetiology of abnormal gonadotropin secretion in PCOS
Hypothalamic neurotransmitters
In animals, dopamine and opioid pathways are inhibitory to GnRH
neurons, whereas noradrenergic pathways are stimulatory. Data
regarding the effects of γ-aminobutyric acid (GABA) have been
mixed (DeFazio et al., 2002; Han et al., 2002, 2004). Information
regarding CNS pathways in humans is by necessity indirect and
generally derived through the use of medications that stimulate or
inhibit these pathways. Decreased dopaminergic tone was hypothesized to play a role in PCOS, given that approximately 17% of
women with PCOS have coincident moderate hyperprolactinaemia (Luciano et al., 1984). However, the dopamine agonist bromocriptine does not improve clinical or biochemical parameters in
women with PCOS (Buvat et al., 1986; Murdoch et al., 1987).
Decreased opioid tone was hypothesized to contribute to PCOS, as
central opioidergic regulation mediates the normal luteal phase
slowing of LH (GnRH) pulsatility (Quigley and Yen, 1980; Wardlaw
et al., 1982; Soules et al., 1984), which is absent in PCOS. However, administration of exogenous progesterone to women with
PCOS slows GnRH pulse frequency through an opiate-dependent
process (Berga and Yen, 1989). Therefore, any apparent reduction
of opioid activity in PCOS is probably secondary to the absence of
progesterone effects (e.g. secondary to anovulation), rather than
primary defects in opioid tone. Potential roles for noradrenergic
and GABAergic pathways in PCOS have been explored via
administration of the α1-adrenoceptor antagonist thymoxamine
(Paradisi et al., 1987) and valproate, which increases GABA concentrations (Popovic and Spremovic, 1995). Neither study documented changes in mean LH concentrations or LH pulse
frequency (Paradisi et al., 1987; Popovic and Spremovic, 1995).
Thus, to date, no primary hypothalamic defects have been clearly
identified to explain the neuroendocrine abnormalities in PCOS.
This raises the possibility that the neuroendocrine abnormalities
are instead secondary to an abnormal hormonal environment.
Estrogens
Figure 2. Representative example of LH (circles) and FSH (squares) secretion in polycystic ovary syndrome (PCOS). The subject is a 23-year-old
woman with a history of oligomenorrhoea since menarche, whose last menstruation was 6 months before sampling. During the admission, mean estradiol
(E2) was 68 pg/ml, mean progesterone 0.3 ng/ml and mean testosterone 71 ng/dl.
The asterisks indicate LH pulses as identified using the computer algorithm
Cluster 7.
An earlier theory, known as the ‘estrone hypothesis’, suggested
that excess androstenedione was peripherally aromatized to
estrone, which in turn caused increased LH secretion (Yen et al.,
1976). This theory was based on the elevated estrone levels seen
in PCOS and the stimulatory effects of estrogens on LH secretion
during the mid-cycle LH surge. However, administration of exogenous estrone does not increase basal or GnRH-stimulated LH
concentrations in controls or in women with PCOS (Chang et al.,
1982). In addition, use of the peripheral aromatase inhibitor
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S.K.Blank, C.R.McCartney and J.C.Marshall
testolactone to block conversion of androstenedione to estrone
does not reduce LH pulse frequency (Dunaif et al., 1985). Therefore, available evidence does not support a role for estrone in the
pathogenesis of PCOS.
Insulin
Insulin resistance is a common metabolic abnormality seen in
obese and, to a lesser degree, lean women with PCOS, with studies estimating a prevalence between 53 and 76% (Dunaif et al.,
1989; Carmina et al., 1992; Legro et al., 1998b; DeUgarte et al.,
2005). Although the majority of women are able to compensate for
the insulin resistance with increased insulin secretion, 7–10% of
reproductive age women with PCOS meet the criteria for type 2
diabetes mellitus (Ehrmann et al., 1999; Legro et al., 1999). Similarly, women with type 2 diabetes are over six times as likely as
non-diabetic, age- and weight-matched controls to have PCOS
(Tok et al., 2004). Insulin acts synergistically with LH to stimulate
ovarian androgen production (Barbieri et al., 1986; Nestler et al.,
1998a), and insulin suppresses hepatic production of sex-hormone-binding globulin (Dunkel et al., 1985), resulting in higher
levels of free or bioavailable testosterone. Treatment of women
with PCOS with either metformin or thiazoladinediones not only
ameliorates insulin resistance but also results in improvements in
hyperandrogenaemia and ovulatory function (Dunaif et al., 1996;
Nestler and Jakubowicz, 1996; Ehrmann et al., 1997; Nestler
et al., 1998b; Moghetti et al., 2000; Fleming et al., 2002; Ghazeeri
et al., 2003; Lord et al., 2003). Although most of the androgen
reduction related to metformin and thiazoladinedione treatment is
thought to reflect decreases in circulating insulin levels, there is
also in vitro evidence for direct effects on ovarian steroidogenesis
(Attia et al., 2001; Mitwally et al., 2002; Mansfield et al., 2003).
Although hyperinsulinaemia appears to be an important contributor in the pathogenesis of PCOS, its role in neuroendocrine dysfunction is unclear. Insulin increases basal and GnRH-stimulated
LH and FSH secretion from cultured rat pituitary cells in vitro
(Adashi et al., 1981; Soldani et al., 1994). However, in analogous
in vivo studies, insulin does not augment gonodotrope responses to
GnRH (Poretsky et al., 1988). In women with PCOS, infusions of
exogenous insulin do not alter LH secretion (Dunaif and Graf,
1989; Patel et al., 2003; Mehta et al., 2005), and reduction of insulin in PCOS has inconsistent effects on LH levels (Poretsky et al.,
1999). Short-term treatment with metformin does not slow LH
pulse frequency, despite significant improvements in insulin levels
(Eagleson et al., 2003). Likewise, treatment with the thiazoladinedione pioglitazone does not alter LH pulse patterns, despite
improvement in insulin sensitivity (Mehta et al., 2005). Moreover,
LH appears to be negatively correlated with obesity (Morales et al.,
1996; Taylor et al., 1997), despite a positive correlation between
adiposity and insulin concentrations. Together, these findings suggest that the hyperinsulinaemia associated with PCOS does not
directly result in neuroendocrine abnormalities. However, hyperinsulinaemia may bring about important changes in hypothalamic
function indirectly by increasing androgen levels (discussed
below).
Progesterone
Cyclic (luteal) increases in progesterone result in regular, periodic
slowing of LH (GnRH) pulsatility in ovulatory women. However,
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a defining feature of PCOS is chronic oligoovulation or anovulation. Therefore, women with PCOS do not regularly experience
the post-ovulatory rise in progesterone seen in normally cycling
women. Undoubtedly, the lower progesterone levels associated
with anovulation play a role in the persistently rapid GnRH pulse
frequency characteristic of PCOS in adult women. However, this
alone does not appear to be a sufficient explanation for the neuroendocrine abnormalities of PCOS. Normally cycling women
have occasional anovulatory cycles, and many women with PCOS
ovulate intermittently, albeit infrequently. The modest rise in E2
and progesterone levels seen in anovulatory cycles in normal
women results in the slowing of LH pulsatility that may be equivalent to that seen during an ovulatory cycle (Clayton et al.,
1987). Conversely, intermittent ovulation does not correct the
rapid LH pulse frequency in PCOS, and LH levels are again elevated some 10–14 days after progesterone levels fall (Taylor et al.,
1997). Also, adolescent girls with hyperandrogenaemia—which is
felt to represent a forerunner of PCOS—have more rapid LH
(GnRH) pulse frequency than normal controls, even before
menarche when ovulatory cycles have not yet been established
(Apter et al., 1994).
Another possible contributor to decreased progesterone effects
in PCOS is reduced sensitivity of the GnRH pulse generator to the
negative feedback effects of sex steroids. To determine whether
the increased GnRH pulsatility in PCOS is explained simply by
abnormal sex steroid levels in the setting of chronic anovulation,
Daniels and Berga, in their study, used oral contraceptives to simulate luteal phase E2 and progesterone concentrations in women
with PCOS (Daniels and Berga, 1997). Oral contraceptives slowed
LH pulse frequency in hyperandrogenaemic anovulatory women
to some extent, but not to the same degree seen in normal controls.
Subsequent studies using 7 days of E2 and progesterone confirmed
that women with PCOS have reduced hypothalamic sensitivity to
progesterone-mediated suppression of LH (GnRH) pulse frequency compared with normal women (Pastor et al., 1998). Thus,
women with PCOS require higher levels of progesterone to
achieve the same degree of GnRH suppression as ovulatory controls. Interestingly, similar findings are observed in some adolescents with hyperandrogenaemia (Chhabra et al., 2005), which may
help explain the emergence of neuroendocrine abnormalities during puberty. Progesterone sensitivity is restored in adult PCOS
with the use of the androgen receptor blocker flutamide, indicating
that reduced progesterone sensitivity is secondary to hyperandrogenaemia, rather than a primary hypothalamic defect (Figure 3)
(Eagleson et al., 2000).
Androgens
Hyperandrogenism, like chronic anovulation, is a hallmark of
PCOS, and its origin appears to be multifactorial, with increased
LH and insulin stimulation of ovaries that appear to hypersecrete
androgens (Chang et al., 1983; Barbieri et al., 1986; Steingold
et al., 1987; Gilling-Smith et al., 1994; Nestler et al., 1998a;
Nelson et al., 1999). Regardless of the aetiology, elevated androgen levels appear to have important neuroendocrine consequences.
Early in vitro studies found that androgens increase GnRH
pulse frequency in isolated rat GnRH neurons (Melrose and
Gross, 1987). Initial studies in women with PCOS found that
neither androgen infusions (Dunaif, 1986) nor short-term (less
Neuroendocrine function in PCOS
Figure 3. Absolute change in LH pulses/12 hours following 7 days of estradiol (E2) and progesterone (P) in normal controls (left) and women with polycystic ovary syndrome (PCOS) (right). Data are plotted as a function of mean
plasma progesterone on day 7. The shaded areas show the range of responses
after administration of E2 and progesterone alone for 7 days. The closed circles represent findings when flutamide was administered for 28 days before
and during E2 and progesterone treatment (Eagleson CA et al., 2000; Copyright 2000, The Endocrine Society, with permission).
than 1 month) treatments with the androgen receptor blocker
flutamide (Sir-Petermann et al., 1993; Eagleson et al., 2000)
change basal LH concentrations or pulsatility. However, as discussed above, short-term treatment with flutamide restores
hypothalamic sensitivity to progesterone-mediated slowing of
LH pulsatility in women with PCOS (Eagleson et al., 2000), and
long-term (6 months) administration of flutamide may ameliorate many of the reproductive manifestations of PCOS (De Leo
et al., 1998).
Prenatal androgen exposure has been used as an animal model
of PCOS, with some interesting and informative findings. Prenatally androgenized female monkeys, sheep and rats exhibit abnormal neuroendocrine function, such as increased LH concentrations
and LH (GnRH) pulse frequency during subsequent pubertal maturation (Dumesic et al., 1997; Robinson et al., 1999; Abbott et al.,
2005; Foecking et al., 2005). Similar to women with PCOS, prenatally androgenized sheep demonstrate decreased sensitivity to
progesterone suppression of LH (GnRH) pulse frequency (Robinson
et al., 1999). Foecking and co-workers recently demonstrated that
prenatally androgenized rats have decreased basal and E2-induced
progesterone receptors in the hypothalamus, suggesting a possible
mechanism for androgen-mediated hypothalamic progesterone
insensitivity (Foecking et al., 2005). Prenatal androgenization also
increases GABAergic drive to GnRH neurons in mice, an abnormality which can be reversed with flutamide treatment as in adults
(Sullivan and Moenter, 2004).
In addition to providing a useful model for mechanistic studies
that are difficult to carry out in humans, there is some evidence that
prenatal androgenization may play a role in human disease.
Women with congenital adrenal hyperplasia have persistent evidence of ovarian hyperandrogenism even when well controlled on
glucocorticoid treatment, whereas their counterparts with late-onset
21-hydroxylase deficiency do not (Barnes et al., 1994). Women
with PCOS may maintain elevated androgen levels during pregnancy (Sir-Petermann et al., 2002), thus potentially exposing their
unborn daughters to elevated androgen levels in utero. PCOS clusters in families (Legro et al., 1998a; Kahsar-Miller et al., 2001),
and the search for specific genetic causes has proven elusive. In
theory, prenatal exposure to maternal hyperandrogenaemia may
in part explain the hereditary nature of the syndrome. However,
placental aromatase is highly effective in converting androgens to
estrogens, typically protecting the fetus from excess androgen
exposure in utero. In addition, the doses of androgens given in animal models create androgen levels that far exceed those seen in
pregnant women with PCOS. Therefore, it is unclear if the more
subtle elevations in androgens, typical of PCOS, reach the fetus or
have any effect on development.
As described above, elevated androgens have significant neuroendocrine effects, including impairment of hypothalamic progesterone sensitivity. This relative inability to slow GnRH pulse
frequency in part explains the persistently rapid GnRH pulse frequency in PCOS. This defect promotes excessive LH feedforward
drive with subsequent excessive ovarian androgen production as
well as relative FSH deficiency that contributes to ovulatory dysfunction. As discussed above, similar neuroendocrine abnormalities are observed in adolescent hyperandrogenaemia, yet it is
unclear how these abnormalities are established during puberty.
We have proposed one hypothetical paradigm that may explain
the genesis of neuroendocrine abnormalities in adolescents with
hyperandrogenaemia. Below, we discuss the reproductive neuroendocrinology of normal puberty together with neuroendocrine
findings in adolescents with hyperandrogenaemia.
Gonadotropin secretion in normal female puberty
and in adolescents girls with hyperandrogenaemia
The GnRH pulse generator is active during fetal development and
the early neonatal period, but the GnRH secretory system becomes
relatively quiescent during the 6–9 months after birth and remains
so during childhood. This juvenile period is characterized by low
levels of LH and FSH with a high FSH : LH ratio. GnRH pulse
frequency is slow (i.e. one pulse every 4–6 h in prepubertal girls),
and LH pulse amplitude is very low (Cemeroglu et al., 1996;
Clark et al., 1997). The onset of puberty is heralded by nocturnal,
sleep-entrained increases in LH pulse amplitude and frequency.
This results in a diurnal pattern of LH pulsatility that precedes
physical manifestations of pubertal maturation by approximately 2
years (Boyar et al., 1972; Wu et al., 1989; Wennink et al., 1990).
Nocturnal increases in LH secretion are followed by early morning rises in sex steroids such as E2 and testosterone (Norjavaara
et al., 1996; Ankarberg and Norjavaara, 1999; Mitamura et al.,
2000). As puberty progresses, daytime LH pulsatility increases,
rendering the diurnal changes less prominent; by late puberty,
sleep-associated increases in LH pulsatility are lost (Boyar et al.,
1972; Wennink et al., 1990).
The cause of diurnal changes in LH pulsatility during puberty is
unclear. It could primarily reflect diurnal feedforward drive from
higher CNS inputs. Indeed, a role for higher CNS inputs is suggested by the observation that increases in LH pulsatility closely
follow the onset of sleep (Boyar et al., 1972). However, diurnal
changes in sex steroids may also influence diurnal changes in LH
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pulsatility via intermittent negative feedback or by facilitating
changes in higher CNS functions. This possibility is suggested by
several observations. The early morning peaks of sex steroid concentrations precede the time when LH pulsatility wanes. Also, in
contrast to the normal patterns of diurnal LH and E2 secretion in
early pubertal girls, age-matched girls with gonadal dysgenesis
appear to demonstrate elevated LH pulse frequencies at all time
periods (Cemeroglu et al., 1996), suggesting that an ovarian factor
(e.g. E2) may be involved in the day–night differences of pubertal
LH pulse frequency. E2 infusion in peripubertal girls (Cemeroglu
et al., 1998) diminishes nocturnal increases in LH pulsatility.
While data in girls are lacking, infusions of testosterone in boys
also suppress nocturnal LH (GnRH) pulsatility (Kletter et al.,
1994), suggesting that the nocturnal rise in testosterone may also
play a role in girls. In addition, a role for sex steroids in the diurnal
pattern of GnRH secretion is in keeping with the notion (described
above) that changes in GnRH pulse frequency are determined by
the application and removal of negative feedback.
The mechanisms by which the hypothalamic–pituitary–gonadal
axis is quiescent during childhood and reactivates during puberty
also remain unclear. In girls, LH pulse frequency and amplitude
increases four- and nine-fold across pubertal maturation (Apter
et al., 1993). The relative dormancy of this axis during childhood
may reflect inhibition by higher CNS pathways. However, the
hypothalamus also appears to be exquisitely sensitive to sex steroid feedback during childhood, and as puberty advances, there is
decreasing sensitivity to E2 inhibition of LH secretion (Kelch
et al., 1973; Rapisarda et al., 1983). Thus, the gradual loss of sensitivity to feedback inhibition contributes to the increase in LH
pulsatility during puberty. The cause of decreasing sensitivity to
feedback inhibition is unknown, but given that hyperandrogenaemia appears to account for the abnormal reduction of feedback
sensitivity in adults with PCOS, one possibility is that the gradual
increase in androgen concentrations characteristic of normal
female puberty (Ankarberg and Norjavaara, 1999; Mitamura et al.,
2000) may mediate the reduction in feedback sensitivity associated with pubertal progression.
Hyperandrogenism during adolescence is thought to represent a
forerunner of PCOS. A study of girls with menstrual irregularities
showed that although some subjects normalize endocrine function
as they mature, the majority maintain hyperandrogenaemia, elevated LH levels and polycystic ovaries, characteristic of PCOS
(Venturoli et al., 1987). Additionally, adolescent hyperandrogenaemia is associated with higher androgen levels and lower fertility rates in adulthood (Apter and Vihko, 1990).
Relatively little is known about changes in gonadotropin secretion in adolescents with hyperandrogenism. Many such adolescents
demonstrate elevated mean LH, LH pulse frequency and LH pulse
amplitude (Venturoli et al., 1992). Compared with age-matched
controls, girls with hyperandrogenism exhibit higher daytime and
nighttime LH pulse frequency and higher mean 24 h LH : FSH
ratios (Apter et al., 1994). The transition from primarily sleeprelated LH secretion to predominance of daytime LH secretion is
advanced by some 2 years in hyperandrogenaemic girls (Apter
et al., 1994). Another study revealed that four of five adolescents
with hyperandrogenaemia demonstrated abnormal LH pulsatility
with increased LH pulsatility during the day, which contrasts with
sleep-associated increases, characteristic of normal adolescent
controls (Zumoff et al., 1983). Also, some hyperandrogenaemic
356
adolescents exhibit relative GnRH pulse generator resistance to the
feedback actions of progesterone and E2 (Chhabra et al., 2005).
Overall, these data suggest that neuroendocrine (LH) abnormalities
are present during puberty in adolescents who will go on to develop
adult PCOS.
A hypothesis regarding the genesis of neuroendocrine
dysfunction in adolescents with hyperandrogenaemia
The cause(s) of neuroendocrine abnormalities in adolescents with
hyperandrogenism is (are) unknown, but hyperandrogenaemia
itself may play a prominent role. Girls with precocious adrenarche
are at increased risk of developing PCOS (Ibanez et al., 2000).
Women with congenital adrenal hyperplasia demonstrate elevated
LH (Barnes et al., 1994), as do prenatally androgenized animals
(Dumesic et al., 1997; Robinson et al., 1999). The mechanism
accounting for this association is unclear, but, by analogy, to what
is observed in adults with PCOS, we have proposed that neuroendocrine abnormalities are partly related to androgen-dependent
decreases in GnRH pulse generator sensitivity to the negative
feedback actions of ovarian steroids. Thus, it remains possible that
any cause of hyperandrogenaemia—e.g. hyperandrogenaemia during fetal life or associated with premature adrenarche (Ibanez
et al., 2000), obesity (Wabitsch et al., 1995; Reinehr et al., 2005),
hyperinsulinaemia (Dunaif, 1997; Poretsky et al., 1999), polycystic ovarian morphology (Adams et al., 2004) or inherent abnormalities of ovarian steroidogenesis (Ehrmann et al., 1995)—may
produce abnormalities in feedback control of pulsatile GnRH
secretion, leading to persistently fast GnRH pulses. Of course, the
resulting abnormalities in gonadotropin secretion (increased LH
and relative decreases in FSH) would further contribute to ovarian
hyperandrogenaemia and ovulatory dysfunction, establishing a
vicious circle that promotes the progression towards the adult
PCOS phenotype.
Although the importance of diurnal GnRH pulsatility during
normal puberty is not established, we suggest that diurnal (daytime) slowing of GnRH pulse frequency is important to support
pituitary FSH secretion during puberty. We hypothesize that early
morning increases in gonadal steroids normally reduce GnRH and
LH pulsatility during the following day. Inasmuch as the diurnal
increases in sex steroids are important in mediating diurnal
changes in GnRH pulsatility, interference with negative feedback
of the GnRH pulse generator would be expected to diminish diurnal changes in pulse frequency. If hyperandrogenaemia results in
relative GnRH pulse generator resistance to negative feedback
suppression in peripubertal girls (as it does in adults), then any
cause of hyperandrogenaemia during puberty may produce elevated GnRH pulse frequency throughout the day and night,
increasing LH and decreasing FSH synthesis and secretion,
thereby contributing to both hyperandrogenaemia and ovulatory
dysfunction. Again, initial hyperandrogenaemia could occur via a
number of mechanisms including obesity, hyperinsulinaemia,
abnormal steroidogenesis, etc. However, the concomitant disruption of neuroendocrine function would serve to further exacerbate
hyperandrogenaemia, supporting the progression towards the adult
PCOS phenotype.
Additionally, if testosterone modulation of hypothalamic E2 and
progesterone sensitivity indeed play a role in mediating gradual
decreases of sensitivity feedback during normal puberty, then it is
Neuroendocrine function in PCOS
not all hyperandrogenaemic girls experience adverse neuroendocrine effects (Chhabra et al., 2005). Further study is needed
to determine what modulating factors determine which girls are
negatively affected by pubertal hyperandrogenaemia. Elucidation of inciting factors will eventually lead to effective early
intervention in susceptible populations. If the above concepts
are correct, interruption of the cycle with anti-androgens or
cyclic progesterone may possibly prevent the development of
PCOS.
Summary
Figure 4. (A) Schematic representation of hypothesized changes in hypothalamic sensitivity to feedback inhibition by sex steroids in normal and hyperandrogenaemic girls during puberty. (B) Schematic representation of the
evolution in 24 h patterns of GnRH (solid line) and sex steroids (dashed line)
during puberty in normal (top) and hyperandrogenaemic (bottom) girls.
Shaded areas represent periods of sleep.
logical that girls with hyperandrogenaemia would progress to an
adult pattern at an earlier age, and thereafter to exaggerated LH
pulsatility (Figures 4 and 5). This could in part explain why obesity is associated with early sexual maturation (Wang, 2002):
peripubertal obesity is associated with hyperandrogenaemia
(Reinehr et al., 2005), which may result in an early decrease in
hypothalamic sensitivity to negative feedback, permitting
advanced development of LH pulsatility and subsequent puberty.
Clearly, this theoretical paradigm requires further study, but it is
consistent with available data, and it offers a coherent explanation
for what has been observed in adult and adolescent PCOS. Further
investigations are needed to explore the origins and implications
of adolescent hyperandrogenaemia. The link between obesity and
elevated androgen levels is especially relevant in the light of the
rising incidence of childhood obesity in the developed world
(Ogden et al., 2002; Hedley et al., 2004). The International Obesity
Task Force estimates that there are 30–45 million obese schoolage children worldwide (Lobstein et al., 2004). Given that obesity
is associated with hyperandrogenaemia, and adolescent hyperandrogenaemia often progresses to adult PCOS, the epidemic of
childhood obesity may be followed by a rise in the incidence of
PCOS. However, not all obese girls are hyperandrogenaemic, and
PCOS remains an enigmatic disorder with variable clinical presentations and uncertain aetiology. Neuroendocrine abnormalities, including rapid LH (GnRH) pulse frequency, elevated
plasma LH and elevated LH : FSH ratios, are prominent in both
adult PCOS and adolescent hyperandrogenaemia. Elevated
androgens impair hypothalamic sensitivity to progesterone suppression of GnRH pulse frequency in women with PCOS. This
hypothalamic progesterone insensitivity contributes to abnormal
GnRH and gonadotropin secretion, impaired follicular development and increased ovarian androgen production. A subset of
hyperandrogenaemic adolescent girls demonstrates similarly
impaired hypothalamic progesterone sensitivity. Therefore, it is
possible that peripubertal hyperandrogenaemia—whether it
results from obesity, hyperinsulinaemia or abnormal adrenal or
ovarian steroidogenesis—initiates a vicious cycle in which
hyperandrogenaemia leads to neuroendocrine abnormalities
which in turn perpetuate hyperandrogenaemia. Further studies
are needed to explore these hypotheses and the origins of adolescent hyperandrogenaemia.
Acknowledgements
We are grateful to S. Chhabra, MD, C.A. Eagleson, MD, C.L.
Pastor, MD and K.A. Prendergast, MD for their previous contributions as clinical research fellows; A. Bellows, PhD, C. Chopra and
Q.J.L. Okonkwo, MD for research coordination; the GCRC staff and
nurses; and the Ligand Core Lab of the Center for Research in
Reproduction. This work was supported by National Institutes of
Health Grants RO1-HD-34179 and RO1-HD-33039 (J.C.M.), T32HD-07382 (S.K.B.) and 1-K23-HD-044742 (C.R.M.); National
Institute of Child Health and Human Development, National
Institutes of Health, Specialized Cooperative Centers Program in
Reproduction Research Grant U54-HD-28934 (J.C.M.); and GCRC
Grant 5-MO1-RR-00847.
Figure 5. Schema for the proposed action of excess androgens in modifying GnRH secretion during pubertal maturation in susceptible adolescent girls.
357
S.K.Blank, C.R.McCartney and J.C.Marshall
References
Abbott DH, Barnett DK, Bruns CM and Dumesic DA (2005) Androgen excess
fetal programming of female reproduction: a developmental aetiology for
polycystic ovary syndrome? Hum Reprod Update 11,357–374.
Adams JM, Taylor AE, Schoenfeld DA, Crowley WF Jr and Hall JE (1994)
The midcycle gonadotropin surge in normal women occurs in the face of
an unchanging gonadotropin-releasing hormone pulse frequency. J Clin
Endocrinol Metab 79,858–864.
Adams JM, Taylor AE, Crowley WF Jr and Hall JE (2004) Polycystic ovarian
morphology with regular ovulatory cycles: insights into the pathophysiology
of polycystic ovarian syndrome. J Clin Endocrinol Metab 89,4343–4350.
Adashi EY, Hsueh AJ and Yen SS (1981) Insulin enhancement of luteinizing
hormone and follicle-stimulating hormone release by cultured pituitary
cells. Endocrinology 108,1441–1449.
Ankarberg C and Norjavaara E (1999) Diurnal rhythm of testosterone secretion before and throughout puberty in healthy girls: correlation with
17beta-estradiol and dehydroepiandrosterone sulfate. J Clin Endocrinol
Metab 84,975–984.
Apridonidze T, Essah PA, Iuorno MJ and Nestler JE (2005) Prevalence and
characteristics of the metabolic syndrome in women with polycystic ovary
syndrome. J Clin Endocrinol Metab 90,1929–1935.
Apter D and Vihko R (1990) Endocrine determinants of fertility: serum androgen concentrations during follow-up of adolescents into the third decade
of life. J Clin Endocrinol Metab 71,970–974.
Apter D, Butzow TL, Laughlin GA and Yen SS (1993) Gonadotropin-releasing hormone pulse generator activity during pubertal transition in girls:
pulsatile and diurnal patterns of circulating gonadotropins. J Clin Endocrinol Metab 76,940–949.
Apter D, Butzow T, Laughlin GA and Yen SS (1994) Accelerated 24-hour
luteinizing hormone pulsatile activity in adolescent girls with ovarian
hyperandrogenism: relevance to the developmental phase of polycystic
ovarian syndrome. J Clin Endocrinol Metab 79,119–125.
Asuncion M, Calvo RM, San Millan JL, Sancho J, Avila S and Escobar-Morreale HF (2000) A prospective study of the prevalence of the polycystic
ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 85,2434–2438.
Attia GR, Rainey WE and Carr BR (2001) Metformin directly inhibits androgen production in human thecal cells. Fertil Steril 76,517–524.
Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Fereshetian AG,
O’Keefe M and Ghazzi MN (2001) Troglitazone improves ovulation and
hirsutism in the polycystic ovary syndrome: a multicenter, double blind,
placebo-controlled trial. J Clin Endocrinol Metab 86,1626–1632.
Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES and Yildiz BO
(2004) The prevalence and features of the polycystic ovary syndrome in
an unselected population. J Clin Endocrinol Metab 89,2745–2749.
Baillargeon JP, Jakubowicz DJ, Iuorno MJ, Jakubowicz S and Nestler JE
(2004) Effects of metformin and rosiglitazone, alone and in combination,
in nonobese women with polycystic ovary syndrome and normal indices
of insulin sensitivity. Fertil Steril 82,893–902.
Barbieri RL, Makris A, Randall RW, Daniels G, Kistner RW and Ryan KJ
(1986) Insulin stimulates androgen accumulation in incubations of ovarian
stroma obtained from women with hyperandrogenism. J Clin Endocrinol
Metab 62,904–910.
Barnes RB, Rosenfield RL, Ehrmann DA, Cara JF, Cuttler L, Levitsky LL and
Rosenthal IM (1994) Ovarian hyperandrogynism as a result of congenital
adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women. J Clin Endocrinol Metab 79,1328–1333.
Berga SL and Yen SS (1989) Opioidergic regulation of LH pulsatility in women
with polycystic ovary syndrome. Clin Endocrinol (Oxf) 30,177–184.
Boyar R, Finkelstein J, Roffwarg H, Kapen S, Weitzman E and Hellman L
(1972) Synchronization of augmented luteinizing hormone secretion with
sleep during puberty. N Engl J Med 287,582–586.
Buvat J, Buvat-Herbaut M, Marcolin G, Racadot A, Fourlinnie JC, Beuscart R
and Fossati P (1986) A double blind controlled study of the hormonal and
clinical effects of bromocriptine in the polycystic ovary syndrome. J Clin
Endocrinol Metab 63,119–124.
Carmina E, Koyama T, Chang L, Stanczyk FZ and Lobo RA (1992) Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin
resistance in polycystic ovary syndrome? Am J Obstet Gynecol
167,1807–1812.
Cemeroglu AP, Foster CM, Warner R, Kletter GB, Marshall JC and Kelch RP
(1996) Comparison of the neuroendocrine control of pubertal maturation
in girls and boys with spontaneous puberty and in hypogonadal girls. J
Clin Endocrinol Metab 81,4352–4357.
358
Cemeroglu AP, Kletter GB, Guo W, Brown MB, Kelch RP, Marshall JC,
Padmanabhan V and Foster CM (1998) In pubertal girls, naloxone fails to
reverse the suppression of luteinizing hormone secretion by estradiol. J
Clin Endocrinol Metab 83,3501–3506.
Chang RJ, Mandel FP, Lu JK and Judd HL (1982) Enhanced disparity of gonadotropin secretion by estrone in women with polycystic ovarian disease. J
Clin Endocrinol Metab 54,490–494.
Chang RJ, Laufer LR, Meldrum DR, DeFazio J, Lu JK, Vale WW, Rivier JE
and Judd HL (1983) Steroid secretion in polycystic ovarian disease after
ovarian suppression by a long-acting gonadotropin-releasing hormone
agonist. J Clin Endocrinol Metab 56,897–903.
Chhabra S, McCartney CR, Yoo RY, Eagleson CA, Chang RJ and Marshall JC
(2005) Progesterone inhibition of the hypothalamic gonadotropin-releasing hormone pulse generator: evidence for varied effects in hyperandrogenemic adolescent girls. J Clin Endocrinol Metab 90,2810–2815.
Clark PA, Iranmanesh A, Veldhuis JD and Rogol AD (1997) Comparison of
pulsatile luteinizing hormone secretion between prepubertal children and
young adults: evidence for a mass/amplitude-dependent difference without gender or day/night contrasts. J Clin Endocrinol Metab 82,2950–2955.
Clayton RN, Royston JP, Chapman J, Wilson M, Obhrai M, Sawers RS and
Lynch SS (1987) Is changing hypothalamic activity important for control
of ovulation? Br Med J (Clin Res Ed) 295,7–12.
Dalkin AC, Haisenleder DJ, Ortolano GA, Ellis TR and Marshall JC (1989)
The frequency of gonadotropin-releasing-hormone stimulation differentially regulates gonadotropin subunit messenger ribonucleic acid expression. Endocrinology 125,917–924.
Daniels TL and Berga SL (1997) Resistance of gonadotropin releasing hormone drive to sex steroid-induced suppression in hyperandrogenic anovulation. J Clin Endocrinol Metab 82,4179–4183.
De Leo V, Lanzetta D, D’Antona D, la Marca A and Morgante G (1998)
Hormonal effects of flutamide in young women with polycystic ovary
syndrome. J Clin Endocrinol Metab 83,99–102.
DeFazio RA, Heger S, Ojeda SR and Moenter SM (2002) Activation of A-type
gamma-aminobutyric acid receptors excites gonadotropin-releasing hormone neurons. Mol Endocrinol 16,2872–2891.
DeUgarte CM, Bartolucci AA and Azziz R (2005) Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model
assessment. Fertil Steril 83,1454–1460.
Diamanti-Kandarakis E, Kouli CR, Bergiele AT, Filandra FA, Tsianateli TC,
Spina GG, Zapanti ED and Bartzis MI (1999) A survey of the polycystic
ovary syndrome in the Greek island of Lesbos: hormonal and metabolic
profile. J Clin Endocrinol Metab 84,4006–4011.
Dumesic DA, Abbott DH, Eisner JR and Goy RW (1997) Prenatal exposure of
female rhesus monkeys to testosterone propionate increases serum luteinizing hormone levels in adulthood. Fertil Steril 67,155–163.
Dunaif A (1986) Do androgens directly regulate gonadotropin secretion in the
polycystic ovary syndrome? J Clin Endocrinol Metab 63,215–221.
Dunaif A (1997) Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 18,774–800.
Dunaif A and Graf M (1989) Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant
women with the polycystic ovary syndrome. J Clin Invest 83,23–29.
Dunaif A, Longcope C, Canick J, Badger T and Crowley WF Jr (1985) The
effects of the aromatase inhibitor delta 1-testolactone on gonadotropin
release and steroid metabolism in polycystic ovarian disease. J Clin Endocrinol Metab 60,773–780.
Dunaif A, Segal KR, Futterweit W and Dobrjansky A (1989) Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38,1165–1174.
Dunaif A, Scott D, Finegood D, Quintana B and Whitcomb R (1996) The insulin-sensitizing agent troglitazone improves metabolic and reproductive
abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab
81,3299–3306.
Dunkel L, Sorva R and Voutilainen R (1985) Low levels of sex hormone-binding globulin in obese children. J Pediatr 107,95–97.
Eagleson CA, Gingrich MB, Pastor CL, Arora TK, Burt CM, Evans WS and
Marshall JC (2000) Polycystic ovarian syndrome: evidence that flutamide
restores sensitivity of the gonadotropin-releasing hormone pulse generator
to inhibition by estradiol and progesterone. J Clin Endocrinol Metab
85,4047–4052.
Eagleson CA, Bellows AB, Hu K, Gingrich MB and Marshall JC (2003)
Obese patients with polycystic ovary syndrome: evidence that metformin
does not restore sensitivity of the gonadotropin-releasing hormone pulse
generator to inhibition by ovarian steroids. J Clin Endocrinol Metab
88,5158–5162.
Neuroendocrine function in PCOS
Ehrmann DA, Barnes RB and Rosenfield RL (1995) Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr Rev 16,322–353.
Ehrmann DA, Schneider DJ, Sobel BE, Cavaghan MK, Imperial J, Rosenfield
RL and Polonsky KS (1997) Troglitazone improves defects in insulin
action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in
women with polycystic ovary syndrome. J Clin Endocrinol Metab
82,2108–2116.
Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK and Imperial J
(1999) Prevalence of impaired glucose tolerance and diabetes in women
with polycystic ovary syndrome. Diabetes Care 22,141–146.
Filicori M, Santoro N, Merriam GR and Crowley WF Jr (1986) Characterization of the physiological pattern of episodic gonadotropin secretion
throughout the human menstrual cycle. J Clin Endocrinol Metab 62,
1136–1144.
Fleming R, Hopkinson ZE, Wallace AM, Greer IA and Sattar N (2002) Ovarian function and metabolic factors in women with oligomenorrhea treated
with metformin in a randomized double blind placebo-controlled trial. J
Clin Endocrinol Metab 87,569–574.
Foecking EM, Szabo M, Schwartz NB and Levine JE (2005) Neuroendocrine
consequences of prenatal androgen exposure in the female rat: absence of
luteinizing hormone surges, suppression of progesterone receptor gene
expression, and acceleration of the gonadotropin-releasing hormone pulse
generator. Biol Reprod 72,1475–1483.
Franks S (1995) Polycystic ovary syndrome. N Engl J Med 333,853–861.
Ghazeeri G, Kutteh WH, Bryer-Ash M, Haas D and Ke RW (2003) Effect of
rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in
women with polycystic ovary syndrome. Fertil Steril 79,562–566.
Gill S, Lavoie HB, Bo-Abbas Y and Hall JE (2002) Negative feedback effects
of gonadal steroids are preserved with aging in postmenopausal women. J
Clin Endocrinol Metab 87,2297–2302.
Gilling-Smith C, Willis DS, Beard RW and Franks S (1994) Hypersecretion of
androstenedione by isolated thecal cells from polycystic ovaries. J Clin
Endocrinol Metab 79,1158–1165.
Gilling-Smith C, Story H, Rogers V and Franks S (1997) Evidence for a primary abnormality of thecal cell steroidogenesis in the polycystic ovary syndrome. Clin Endocrinol (Oxf) 47,93–99.
Glueck CJ, Papanna R, Wang P, Goldenberg N and Sieve-Smith L (2003) Incidence and treatment of metabolic syndrome in newly referred women with
confirmed polycystic ovarian syndrome. Metabolism 52,908–915.
Goodman RL, Bittman EL, Foster DL and Karsch FJ (1981) The endocrine
basis of the synergistic suppression of luteinizing hormone by estradiol
and progesterone. Endocrinology 109,1414–1417.
Gross KM, Matsumoto AM and Bremner WJ (1987) Differential control of
luteinizing hormone and follicle-stimulating hormone secretion by luteinizing hormone-releasing hormone pulse frequency in man. J Clin Endocrinol Metab 64,675–680.
Han SK, Abraham IM and Herbison AE (2002) Effect of GABA on GnRH
neurons switches from depolarization to hyperpolarization at puberty in
the female mouse. Endocrinology 143,1459–1466.
Han SK, Todman MG and Herbison AE (2004) Endogenous GABA release
inhibits the firing of adult gonadotropin-releasing hormone neurons.
Endocrinology 145,495–499.
Hayes FJ, Taylor AE, Martin KA and Hall JE (1998) Use of a gonadotropinreleasing hormone antagonist as a physiologic probe in polycystic ovary
syndrome: assessment of neuroendocrine and androgen dynamics. J Clin
Endocrinol Metab 83,2343–2349.
Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR and Flegal KM
(2004) Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. JAMA 291,2847–2850.
Ibanez L, Hall JE, Potau N, Carrascosa A, Prat N and Taylor AE (1996) Ovarian 17-hydroxyprogesterone hyperresponsiveness to gonadotropin-releasing hormone (GnRH) agonist challenge in women with polycystic ovary
syndrome is not mediated by luteinizing hormone hypersecretion: evidence from GnRH agonist and human chorionic gonadotropin stimulation
testing. J Clin Endocrinol Metab 81,4103–4107.
Ibanez L, Dimartino-Nardi J, Potau N and Saenger P (2000) Premature adrenarche – normal variant or forerunner of adult disease? Endocr Rev
21,671–696.
Kahsar-Miller MD, Nixon C, Boots LR, Go RC and Azziz R (2001) Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of
patients with PCOS. Fertil Steril 75,53–58.
Karsch FJ, Dierschke DK, Weick RF, Yamaji T, Hotchkiss J and Knobil E
(1973) Positive and negative feedback control by estrogen of luteinizing
hormone secretion in the rhesus monkey. Endocrinology 92,799–804.
Kelch RP, Kaplan SL and Ghumbach MM (1973) Suppression of urinary and
plasma follicle-stimulating hormone by exogenous estrogens in prepubertal and pubertal children. J Clin Invest 52,1122–1128.
Kirk SE, Dalkin AC, Yasin M, Haisenleder DJ and Marshall JC (1994) Gonadotropin-releasing hormone pulse frequency regulates expression of pituitary follistatin messenger ribonucleic acid: a mechanism for differential
gonadotrope function. Endocrinology 135,876–880.
Kletter GB, Foster CM, Brown MB, Beitins IZ, Marshall JC and Kelch RP
(1994) Nocturnal naloxone fails to reverse the suppressive effects of testosterone infusion on luteinizing hormone secretion in pubertal boys. J Clin
Endocrinol Metab 79,1147–1151.
Legro RS, Driscoll D, Strauss JF 3rd, Fox J and Dunaif A (1998a) Evidence for
a genetic basis for hyperandrogenemia in polycystic ovary syndrome.
Proc Natl Acad Sci USA 95,14956–14960.
Legro RS, Finegood D and Dunaif A (1998b) A fasting glucose to insulin ratio
is a useful measure of insulin sensitivity in women with polycystic ovary
syndrome. J Clin Endocrinol Metab 83,2694–2698.
Legro RS, Kunselman AR, Dodson WC and Dunaif A (1999) Prevalence and
predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254
affected women. J Clin Endocrinol Metab 84,165–169.
Lobstein T, Baur L and Uauy R (2004) Obesity in children and young people: a
crisis in public health. Obes Rev 5 (Suppl. 1),4–104.
Lord JM, Flight IH and Norman RJ (2003) Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for
polycystic ovary syndrome. Cochrane Database Syst Rev, CD003053.
Luciano AA, Chapler FK and Sherman BM (1984) Hyperprolactinemia in
polycystic ovary syndrome. Fertil Steril 41,719–725.
MacLusky NJ and McEwen BS (1978) Oestrogen modulates progestin receptor concentrations in some rat brain regions but not in others. Nature
274,276–278.
Mansfield R, Galea R, Brincat M, Hole D and Mason H (2003) Metformin has
direct effects on human ovarian steroidogenesis. Fertil Steril 79,956–962.
Marshall JC and Kelch RP (1986) Gonadotropin-releasing hormone: role of
pulsatile secretion in the regulation of reproduction. N Engl J Med
315,1459–1468.
Marshall JC and Eagleson CA (1999) Neuroendocrine aspects of polycystic
ovary syndrome. Endocrinol Metab Clin North Am 28,295–324.
McCartney CR, Gingrich MB, Hu Y, Evans WS and Marshall JC (2002)
Hypothalamic regulation of cyclic ovulation: evidence that the increase in
gonadotropin-releasing hormone pulse frequency during the follicular
phase reflects the gradual loss of the restraining effects of progesterone. J
Clin Endocrinol Metab 87,2194–2200.
McCartney CR, Bellows AB, Gingrich MB, Hu Y, Evans WS, Marshall JC and
Veldhuis JD (2004) Exaggerated 17-hydroxyprogesterone response to
intravenous infusions of recombinant human LH in women with polycystic ovary syndrome. Am J Physiol Endocrinol Metab 286,E902–908.
Mehta RV, Patel KS, Coffler MS, Dahan MH, Yoo RY, Archer JS, Malcom PJ
and Chang RJ (2005) Luteinizing hormone secretion is not influenced by
insulin infusion in women with polycystic ovary syndrome despite
improved insulin sensitivity during pioglitazone treatment. J Clin Endocrinol Metab 90,2136–2141.
Melrose P and Gross L (1987) Steroid effects on the secretory modalities of
gonadotropin-releasing hormone release. Endocrinology 121,190–199.
Mitamura R, Yano K, Suzuki N, Ito Y, Makita Y and Okuno A (2000) Diurnal
rhythms of luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol secretion before the onset of female puberty in short
children. J Clin Endocrinol Metab 85,1074–1080.
Mitwally MF, Witchel SF and Casper RF (2002) Troglitazone: a possible modulator of ovarian steroidogenesis. J Soc Gynecol Investig 9,163–167.
Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, Zanolin E and
Muggeo M (2000) Metformin effects on clinical features, endocrine and
metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a
randomized, double-blind, placebo-controlled 6-month trial, followed by
open, long-term clinical evaluation. J Clin Endocrinol Metab 85,139–146.
Morales AJ, Laughlin GA, Butzow T, Maheshwari H, Baumann G and Yen SS
(1996) Insulin, somatotropic, and luteinizing hormone axes in lean and
obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab 81,2854–2864.
Murdoch AP, McClean KG, Watson MJ, Dunlop W and Kendall Taylor P
(1987) Treatment of hirsutism in polycystic ovary syndrome with bromocriptine. Br J Obstet Gynaecol 94,358–365.
Nelson VL, Legro RS, Strauss JF 3rd and McAllister JM (1999) Augmented
androgen production is a stable steroidogenic phenotype of propagated
theca cells from polycystic ovaries. Mol Endocrinol 13,946–957.
359
S.K.Blank, C.R.McCartney and J.C.Marshall
Nestler JE and Jakubowicz DJ (1996) Decreases in ovarian cytochrome
P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 335,617–623.
Nestler JE, Jakubowicz DJ, de Vargas AF, Brik C, Quintero N and Medina F
(1998a) Insulin stimulates testosterone biosynthesis by human thecal cells
from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J
Clin Endocrinol Metab 83,2001–2005.
Nestler JE, Jakubowicz DJ, Evans WS and Pasquali R (1998b) Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 338,1876–1880.
Nippoldt TB, Reame NE, Kelch RP and Marshall JC (1989) The roles of
estradiol and progesterone in decreasing luteinizing hormone pulse frequency in the luteal phase of the menstrual cycle. J Clin Endocrinol
Metab 69,67–76.
Norjavaara E, Ankarberg C and Albertsson-Wikland K (1996) Diurnal rhythm
of 17 beta-estradiol secretion throughout pubertal development in healthy
girls: evaluation by a sensitive radioimmunoassay. J Clin Endocrinol
Metab 81,4095–4102.
Ogden CL, Flegal KM, Carroll MD and Johnson CL (2002) Prevalence and
trends in overweight among US children and adolescents, 1999–2000.
JAMA 288,1728–1732.
Paradisi R, Venturoli S, Capelli M, Spada M, Giambiasi ME, Magrini O, Porcu
E, Fabbri R and Flamigni C (1987) Effects of alpha 1-adrenergic blockade
on pulsatile luteinizing hormone, follicle-stimulating hormone, and prolactin secretion in polycystic ovary syndrome. J Clin Endocrinol Metab
65,841–846.
Pastor CL, Griffin-Korf ML, Aloi JA, Evans WS and Marshall JC (1998) Polycystic ovary syndrome: evidence for reduced sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and
progesterone. J Clin Endocrinol Metab 83,582–590.
Patel K, Coffler MS, Dahan MH, Yoo RY, Lawson MA, Malcom PJ and
Chang RJ (2003) Increased luteinizing hormone secretion in women with
polycystic ovary syndrome is unaltered by prolonged insulin infusion. J
Clin Endocrinol Metab 88,5456–5461.
Popovic V and Spremovic S (1995) The effect of sodium valproate on luteinizing hormone secretion in women with polycystic ovary disease. J Endocrinol Invest 18,104–108.
Poretsky L and Piper B (1994) Insulin resistance, hypersecretion of LH, and a
dual-defect hypothesis for the pathogenesis of polycystic ovary syndrome.
Obstet Gynecol 84,613–621.
Poretsky L, Glover B, Laumas V, Kalin M and Dunaif A (1988) The effects of
experimental hyperinsulinemia on steroid secretion, ovarian [125I]insulin
binding, and ovarian [125I]insulin-like growth-factor I binding in the rat.
Endocrinology 122,581–585.
Poretsky L, Cataldo NA, Rosenwaks Z and Giudice LC (1999) The insulinrelated ovarian regulatory system in health and disease. Endocr Rev
20,535–582.
Quigley ME and Yen SS (1980) The role of endogenous opiates in LH secretion during the menstrual cycle. J Clin Endocrinol Metab 51,179–181.
Rapisarda JJ, Bergman KS, Steiner RA and Foster DL (1983) Response to
estradiol inhibition of tonic luteinizing hormone secretion decreases during the final stage of puberty in the rhesus monkey. Endocrinology
112,1172–1179.
Rasmussen DD, Gambacciani M, Swartz W, Tueros VS and Yen SS (1989)
Pulsatile gonadotropin-releasing hormone release from the human mediobasal hypothalamus in vitro: opiate receptor-mediated suppression. Neuroendocrinology 49,150–156.
Rebar R, Judd HL, Yen SS, Rakoff J, Vandenberg G and Naftolin F (1976)
Characterization of the inappropriate gonadotropin secretion in polycystic
ovary syndrome. J Clin Invest 57,1320–1329.
Reinehr T, de Sousa G, Roth CL and Andler W (2005) Androgens before
and after weight loss in obese children. J Clin Endocrinol Metab
90,5588–5595.
Robinson JE, Forsdike RA and Taylor JA (1999) In utero exposure of female
lambs to testosterone reduces the sensitivity of the gonadotropin-releasing
hormone neuronal network to inhibition by progesterone. Endocrinology
140,5797–5805.
Romano GJ, Krust A and Pfaff DW (1989) Expression and estrogen regulation
of progesterone receptor mRNA in neurons of the mediobasal hypothalamus: an in situ hybridization study. Mol Endocrinol 3,1295–1300.
Rossmanith WG, Liu CH, Laughlin GA, Mortola JF, Suh BY and Yen SS
(1990) Relative changes in LH pulsatility during the menstrual cycle:
using data from hypogonadal women as a reference point. Clin Endocrinol
(Oxf) 32,647–660.
360
Sam S, Legro RS, Bentley-Lewis R and Dunaif A (2005) Dyslipidemia and
metabolic syndrome in the sisters of women with polycystic ovary syndrome. J Clin Endocrinol Metab 90,4797–4802.
Sir-Petermann T, Rabenbauer B and Wildt L (1993) The effect of flutamide on
pulsatile gonadotrophin secretion in hyperandrogenaemic women. Hum
Reprod 8,1807–1812.
Sir-Petermann T, Maliqueo M, Angel B, Lara HE, Perez-Bravo F and
Recabarren SE (2002) Maternal serum androgens in pregnant women with
polycystic ovarian syndrome: possible implications in prenatal androgenization. Hum Reprod 17,2573–2579.
Soldani R, Cagnacci A and Yen SS (1994) Insulin, insulin-like growth factor I
(IGF-I) and IGF-II enhance basal and gonadotrophin-releasing hormonestimulated luteinizing hormone release from rat anterior pituitary cells in
vitro. Eur J Endocrinol 131,641–645.
Soules MR, Steiner RA, Clifton DK, Cohen NL, Aksel S and Bremner WJ
(1984) Progesterone modulation of pulsatile luteinizing hormone secretion in normal women. J Clin Endocrinol Metab 58,378–383.
Spratt DI, Finkelstein JS, Butler JP, Badger TM and Crowley WF Jr (1987)
Effects of increasing the frequency of low doses of gonadotropin-releasing hormone (GnRH) on gonadotropin secretion in GnRH-deficient men.
J Clin Endocrinol Metab 64,1179–1186.
Stein I and Leventhal M (1935) Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 29,181–191.
Steingold K, De Ziegler D, Cedars M, Meldrum DR, Lu JK, Judd HL and
Chang RJ (1987) Clinical and hormonal effects of chronic gonadotropinreleasing hormone agonist treatment in polycystic ovarian disease. J Clin
Endocrinol Metab 65,773–778.
Sullivan SD and Moenter SM (2004) Prenatal androgens alter GABAergic
drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder. Proc Natl Acad Sci USA 101,7129–7134.
Taylor AE (1998) Polycystic ovary syndrome. Endocrinol Metab Clin North
Am 27,877–902, ix.
Taylor AE, McCourt B, Martin KA, Anderson EJ, Adams JM, Schoenfeld D
and Hall JE (1997) Determinants of abnormal gonadotropin secretion in
clinically defined women with polycystic ovary syndrome. J Clin Endocrinol Metab 82,2248–2256.
Tok EC, Ertunc D, Evruke C and Dilek S (2004) The androgenic profile of
women with non-insulin-dependent diabetes mellitus. J Reprod Med
49,746–752.
Utiger RD (1996) Insulin and the polycystic ovary syndrome. N Engl J Med
335,657–658.
Venturoli S, Porcu E, Fabbri R, Magrini O, Paradisi R, Pallotti G, Gammi L
and Flamigni C (1987) Postmenarchal evolution of endocrine pattern and
ovarian aspects in adolescents with menstrual irregularities. Fertil Steril
48,78–85.
Venturoli S, Porcu E, Fabbri R, Magrini O, Gammi L, Paradisi R and Flamigni
C (1992) Longitudinal evaluation of the different gonadotropin pulsatile
patterns in anovulatory cycles of young girls. J Clin Endocrinol Metab
74,836–841.
Wabitsch M, Hauner H, Heinze E, Bockmann A, Benz R, Mayer H and Teller
W (1995) Body fat distribution and steroid hormone concentrations in
obese adolescent girls before and after weight reduction. J Clin Endocrinol Metab 80,3469–3475.
Waldstreicher J, Santoro NF, Hall JE, Filicori M and Crowley WF Jr (1988)
Hyperfunction of the hypothalamic–pituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotroph desensitization. J Clin Endocrinol Metab 66,165–172.
Wang Y (2002) Is obesity associated with early sexual maturation? A comparison
of the association in American boys versus girls. Pediatrics 110,903–910.
Wardlaw SL, Wehrenberg WB, Ferin M, Antunes JL and Frantz AG (1982)
Effect of sex steroids on beta-endorphin in hypophyseal portal blood. J
Clin Endocrinol Metab 55,877–881.
Wennink JM, Delemarre-van de Waal HA, Schoemaker R, Schoemaker H
and Schoemaker J (1990) Luteinizing hormone and follicle stimulating
hormone secretion patterns in girls throughout puberty measured using
highly sensitive immunoradiometric assays. Clin Endocrinol (Oxf)
33,333–344.
Wildt L, Hausler A, Marshall G, Hutchison JS, Plant TM, Belchetz PE and
Knobil E (1981) Frequency and amplitude of gonadotropin-releasing hormone stimulation and gonadotropin secretion in the rhesus monkey. Endocrinology 109,376–385.
Wu FC, Borrow SM, Nicol K, Elton R and Hunter WM (1989) Ontogeny of
pulsatile gonadotrophin secretion and pituitary responsiveness in male
puberty in man: a mixed longitudinal and cross-sectional study. J Endocrinol 123,347–359.
Neuroendocrine function in PCOS
Yen SS, Vela P and Rankin J (1970) Inappropriate secretion of follicle-stimulating hormone and luteinizing hormone in polycystic ovarian disease. J
Clin Endocrinol Metab 30,435–442.
Yen S, Chaney C and Judd H (1976) Functional aberrations of the hypothalamic-pituitary system in PCOS – a consideration for pathogenesis. In
The Endocrine Function of the Human Ovary. Academic Press, New
York, p. 273.
Zawadski J and Dunaif A (1992) Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In Dunaif A, Givens J, Haseltine F
and Merriam G (eds) Polycystic Ovary Syndrome. Blackwell Scientific,
Oxford, England, pp. 377–384.
Zumoff B, Freeman R, Coupey S, Saenger P, Markowitz M and Kream J
(1983) A chronobiologic abnormality in luteinizing hormone secretion in
teenage girls with the polycystic–ovary syndrome. N Engl J Med
309,1206–1209.
Submitted on December 13, 2005; resubmitted on March 10, 2006; accepted on
March 27, 2006
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