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Molecular Endocrinology 18(4):769–775
Copyright © 2004 by The Endocrine Society
doi: 10.1210/me.2003-0317
MINIREVIEW
Steroids and Oocyte Maturation—A New Look at an
Old Story
STEPHEN R. HAMMES
Department of Internal Medicine, Division of Endocrinology and Metabolism, Department of
Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8857
Female fertility requires precise regulation of oocyte meiosis. Oocytes are arrested early in the
meiotic cycle until just before ovulation, when
ovarian factors trigger meiosis, or maturation, to
continue. Although much has been learned about
the late signaling events that accompany meiosis,
until recently less was known about the early actions that initiate maturation. Studies using the
well-characterized model of transcription-independent steroid-induced oocyte maturation in Xenopus laevis now show that steroid metabolism,
classical steroid receptors, G protein-mediated
signaling, and novel G protein-coupled receptors,
all may play important roles in regulating meiosis.
Furthermore, steroids appear to promote similar
events in mammalian oocytes, implying a conserved mechanism of maturation in vertebrates.
Interestingly, testosterone is a potent promoter of
mammalian oocyte maturation, suggesting that
androgen actions in the oocyte might be partially
responsible for the polycystic ovarian phenotype
and accompanying infertility associated with high
androgen states such as polycystic ovarian syndrome or congenital adrenal hyperplasia. A detailed appreciation of the steroid-activated signaling pathways in frog and mammalian oocytes may
therefore prove useful in understanding both normal and abnormal ovarian development in humans.
(Molecular Endocrinology 18: 769–775, 2004)
HISTORY LESSON: PROGESTERONE PROMOTES
XENOPUS OOCYTE MATURATION IN VITRO
that ovulation could be induced by treating female
frogs with ovarian tissue that had been pretreated with
pituitary extracts (7–9), suggesting that some component of the ovarian tissue, and not a pituitary factor,
induced ovulation. In 1968, Dennis Smith reported that
follicular cells from frog ovarian tissue produced a
factor(s) that could induce ovulation (10). He proposed
that progesterone was the ovulation-inducing factor
produced by the follicular cells, as submicromolar
concentrations of progesterone promoted maturation
in vitro.
F
EMALES FROM NEARLY every species of animal
are born with their full complement of oocytes;
however, these immature oocytes are arrested in
prophase I of meiosis. Just before ovulation, gonadotropins stimulate ovarian follicular development, which
in turn promotes oocytes to reenter the meiotic cycle,
or mature, until they arrest again in metaphase II of
meiosis. These mature oocytes are then competent for
ovulation and subsequent fertilization (1–3). To date,
much is still unknown about the ovarian signals that
both inhibit and promote oocyte maturation, especially
in mammals.
The phenomenon of steroid-induced maturation of
Xenopus laevis oocytes is one of the best-studied
models of meiosis (4, 5). More than 60 yr ago, Rugh (6)
induced ovulation in amphibians by treating females
with pituitary extracts. Shortly afterward, others found
THE ROLE OF ANDROGENS IN XENOPUS
OOCYTE MATURATION
Although progesterone had been the assumed in vivo
mediator of Xenopus oocyte maturation for many decades, its physiological importance had not been verified. In fact, many steroids other than progesterone
were equally potent promoters of oocyte maturation in
vitro (5). This point was particularly important given
that progesterone promoted oocyte maturation in
other lower vertebrates such as fish, yet progesterone
metabolites were actually the primary mediators of
maturation in vivo (11, 12).
The physiological role of progesterone in Xenopus
ooctye maturation was examined by injecting frogs
Abbreviations: AR, Androgen receptor; CDK1, cyclindependent kinase 1; DHEA, dehydroepiandrosterone; hCG,
human chorionic gonadotropin; mPR, membrane PR; PR,
progesterone receptor.
Molecular Endocrinology is published monthly by The
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community.
769
770 Mol Endocrinol, April 2004, 18(4):769–775
with human chorionic gonadotropin (hCG) followed by
measurement of serum and ovarian steroid levels (13).
Surprisingly, progesterone was nearly undetectable,
regardless of the dose of hCG or the time after injection that the frogs were examined. Instead, the androgens androstenedione and testosterone, which were
equally or more potent promoters of oocyte maturation relative to progesterone, respectively, were abundant. These data suggested that androgens, rather
than progesterone, were in fact the dominant mediators of Xenopus oocyte maturation in vivo.
THE OOCYTE IS REQUIRED FOR ANDROGEN
PRODUCTION IN XENOPUS LAEVIS
The high androgen and low progesterone production
by Xenopus ovaries suggested that either very little
progesterone was produced or that progesterone was
rapidly metabolized after synthesis. Characterization
of the steroid biosynthetic pathway in Xenopus ovaries
supported the former alternative, as ovarian androgen
production bypassed progesterone and proceeded almost entirely through the ⌬5 pathway (14) (Fig. 1). Frog
ovaries also rapidly metabolized exogenously added
progesterone to testosterone, demonstrating that, although not significantly used in vivo, steroid metabolism via the ⌬4 pathway was also possible. Surprisingly, CYP17, the enzyme that converts pregnenolone
to dehydroepiandrosterone (DHEA) and progesterone
to androstenedione, was expressed exclusively in oocytes, whereas all other steroidogenic enzymes were
found in the surrounding follicular cells (14). This sug-
Hammes • Minireview
gests that Xenopus oocytes play a critical role in the
production of the steroid used to promote their own
maturation (Fig. 1). The concept of oocytes regulating
their own maturation mirrors studies in mammalian
ovaries, where oocytes secrete factors such as growth
differentiation factor 9 (GDF9) to promote granulosa
cell proliferation and differentiation, which are in turn
necessary for normal follicle growth and maturation
(15, 16). Depending on the animal, oocytes might
therefore utilize different mechanisms to orchestrate
proper follicular development and subsequent ovulation.
One final critical concept derived from these metabolism studies is that, because oocytes contain high
levels of CYP17 activity, they rapidly metabolize progesterone to androstenedione. As androstenedione
and progesterone are equally potent promoters of oocyte maturation, both steroids are likely mediating
maturation upon addition of progesterone.
STEROID RECEPTORS IN THE OOCYTE
Identification of receptor(s) involved in steroid-mediated oocyte maturation has been an ongoing challenge for many years. Early evidence indicated that
these receptor(s) were near the cell surface, because
1) steroids covalently attached to polymers or BSA,
thus unable to enter oocytes, still induced maturation
(4, 17); 2) high-affinity steroid binding sites [equilibrium
constant (Kd) values in the 10–100 nM range] were
detected in oocyte membrane preparations (12, 18–
20); and 3) steroid-induced maturation was shown to
occur independently of transcription, as it was unaf-
Fig. 1. Steroidogenesis in the X. laevis Ovary
Steroid production in the Xenopus ovary requires both follicular cells and oocytes. Pregnenolone (PREG) is produced in
follicular cells but is a poor substrate for 3␤-hydroxysteroid dehydrogenase (3␤HSD); thus, virtually no progesterone (PROG) is
produced. Instead, pregnenolone is rapidly converted to 17-hydroxypregnenolone (17OHPREG) and then DHEA by CYP17
expressed exclusively in the oocyte (the ⌬5 pathway). DHEA, which cannot promote oocyte maturation but is an excellent
substrate for 3␤HSD, must then reenter surrounding follicular cells for conversion to androstenedione (AD) and testosterone
(Test). These two androgens subsequently act back on the oocyte to promote maturation. Because testosterone is more potent
and abundant than androstenedione, it is most likely the primary androgen that regulates maturation in vivo. Bold green print and
lines represent the dominant physiological pathway for androgen production, although the ⌬4 pathway (red) can be used if
progesterone is added exogenously.
Hammes • Minireview
fected by the transcriptional inhibitor actinomycin D
(21, 22). Progress toward identifying these membranelocalized steroid receptors was recently accelerated
by the discovery that classical nuclear/cytoplasmic
steroid receptors associated with plasma membranes
mediate nongenomic steroid-induced signaling in
other systems. Examples include estrogen-induced
activation of MAPK and endothelial nitric oxide synthase in breast and endothelial cells, respectively
(23–25), estrogen and androgen-mediated protection
from apoptosis in bone cells (26, 27), and
testosterone-mediated activation of MAPK and the
transcription factor cAMP response element-binding
protein (CREB) in Sertoli cells (Walker, W., personal
communication).
With these examples in mind, the role of classical
steroid receptors in progesterone- and androgeninduced maturation of Xenopus oocytes was explored.
Approximately 3 yr ago, two laboratories independently cloned different isoforms of the classical nuclear/cytoplasmic progesterone receptor (PR) from
Xenopus oocytes and demonstrated through overexpression and antisense experiments that modulation
of intracellular PR levels resulted in small changes in
progesterone sensitivity (28, 29). Additionally, a small
percentage of PRs (5–10%) were shown to be associated with the oocyte plasma membrane, and coimmunoprecipitation indicated that they might interact
with the membrane-signaling molecules MAPK and
phosphatidylinositol 3-kinase (30). Together, these
studies suggested that the classical PRs might be
playing at least a partial role in progesterone-mediated
maturation.
In contrast to the studies examining PR, experiments using androgens to promote maturation,
thereby eliminating concern over steroid metabolism,
have more clearly implicated the classical androgen
receptor (AR) as a mediator of androgen-induced
events (13, 22). Biochemical and immunohistochemical studies showed that the AR is associated with the
plasma membrane of Xenopus oocytes. Further, the
AR antagonist flutamide specifically attenuated androgen-mediated signaling and maturation in isolated oocytes, as well as hCG-stimulated maturation of oocytes in intact ovarian follicles. Finally, elimination of
endogenous AR by RNA interference specifically reduced androstenedione-mediated maturation in vitro.
Surprisingly, although the AR appears to be an important mediator of testosterone-induced signaling
and maturation, some known agonists of AR-mediated
transcription are poor promoters of oocyte maturation.
For example, R1881, one of the most potent activators
of AR-mediated transcription, was unable to promote
nongenomic signaling and maturation in oocytes. In
fact, R1881 inhibited testosterone-mediated events in
oocytes, suggesting that it binds to the AR and acts as
a competitive inhibitor of nongenomic testosteroneinduced signaling (22). Conversely, androstenediol
was a poor promoter of AR-mediated transcription,
Mol Endocrinol, April 2004, 18(4):769–775
771
but a strong mediator of maturation and nongenomic
signaling in oocytes (31).
Although classical steroid receptors appear to play
some role in steroid-induced maturation of Xenopus
oocytes, a new family of potential membrane-associated steroid receptors has been described that may
also be important in some animals. The first of these
receptors was cloned from oocytes of the spotted
seatrout (32, 33). Seatrout oocytes mature in response
to progesterone, although the physiological maturation-promoting steroid is the progesterone metabolite
21-trihydroxy-4-pregnen-3-one (20␤-S). This novel
membrane PR (mPR), is part of a family of proteins that
bear structural, but little sequence, homology to the G
protein-coupled receptor family. Binding studies using
bacterially expressed mPR revealed specific, high affinity binding to progesterone and progesterone metabolites. In addition, mPR expressed in breast cells
mediated a pertussis toxin-sensitive decrease in intracellular cAMP in response to progestins, which is consistent with progestin-mediated reductions in fish oocyte cAMP levels, and suggests that mPR may couple
to G␣i. Finally, injection of mPR antisense oligonucleotides into zebrafish oocytes attenuated progestininduced oocyte maturation, indicating that endogenous mPR may be necessary for oocyte maturation in
fish. To date, the role of mPR in mediating oocyte
maturation in other animals has yet to be determined.
INTRACELLULAR SIGNALING AND OOCYTE
MATURATION—A RELEASE OF
INHIBITION MODEL
Oocyte maturation is associated with a myriad of intracellular signals, most of which are conserved across
species, suggesting a common mechanism of maturation in vertebrates. Many of these signals accompany maturation regardless of the initiating factor;
thus, they may be activated by the maturation process
itself rather than directly by steroids.
One critical molecule activated during oocyte maturation in most species is the MOS protein. Mos
mRNA is present in oocytes during meiotic arrest;
however, little is translated into protein. During maturation, several factors, including Eg2 and cytoplasmic
polyadenylation element binding protein (CPEB), alter
the polyadenylation of Mos mRNA to allow its translation (34, 35). MOS is a potent activator of MAPK
cascade and cyclin-dependent kinase 1, or CDK1
(also called CDC2). Induction of any of these three
components promotes activation of the other two,
resulting in a powerful positive feedback loop that
triggers maturation (36). The necessity of these signals
for maturation is controversial, however, as oocytes in
which the MAPK cascade has been blocked or MOS
expression eliminated still mature under some conditions (37–42). Regardless of their requirement for maturation, the strongly positive effects of all three signals
772
Mol Endocrinol, April 2004, 18(4):769–775
on each other and on maturation suggest that they
play significant, but perhaps not exclusive, roles in
promoting oocyte maturation.
Of note, MOS, CDK1, and MAPK activation are not
detectable until hours after initiation of meiosis. In
contrast, cAMP appears to be important earlier in the
regulation of maturation. Elevation of intracellular
cAMP levels by addition of cAMP analogs or phosphodiesterase inhibitors blocks oocyte maturation in
most species, suggesting that cAMP is an important
inhibitor of meiosis. Consistent with these findings,
some studies have shown that intracellular cAMP levels drop rapidly after initiation of maturation by steroid
(43–46), although whether this decrease in intracellular
cAMP is either necessary or sufficient to promote oocyte maturation remains controversial (47, 48).
Together, these studies suggest a release-of-inhibition mechanism of oocyte maturation whereby intracellular signals such as cAMP maintain meiotic arrest
(Fig. 2). Meiosis may in part be inhibited by G proteins,
as constitutive G␤␥ and G␣s signaling appears to hold
isolated Xenopus oocytes in meiotic arrest, and both
are capable of stimulating adenylyl cyclase to elevate
intracellular cAMP (20, 49, 50). This constitutive G
protein signaling might be mediated by free endogenous G protein subunits or by an endogenously activated G protein-coupled receptor (possibly a member
of the mPR family) (51, 52). Steroids may then trigger
Hammes • Minireview
maturation by overcoming or blocking these inhibitory
signals, thus lowering intracellular cAMP levels and
allowing meiosis to progress.
STEROIDS AND MAMMALIAN OOCYTES
Interestingly, regulation of mammalian oocyte maturation is quite similar to that in Xenopus laevis. Meiotic
arrest of mouse oocytes also appears to be regulated
by constitutive signals that elevate intracellular cAMP,
and the same signaling pathways are activated when
mouse oocytes mature (45, 53, 54). In contrast to
Xenopus, however, mouse oocytes spontaneously
mature when removed from the ovary, suggesting that
the primary signal maintaining meiotic arrest of mouse
oocytes comes from the ovary rather than being endogenous to the oocyte itself, as with frog oocytes.
Because isolated mouse oocytes spontaneously reenter meiosis in vitro, studies aimed toward identifying
factors that promote maturation have been difficult. A
meiosis-activating C29 sterol, FF-MAS, which may
play a role in enhancing oocyte maturation in vitro, has
been described (55). In addition, some studies have
shown that micromolar concentrations of testosterone
partially inhibit spontaneous maturation under certain
conditions (21, 56–58). These studies are all difficult to
Fig. 2. Release of Inhibition Model for Oocyte Maturation
A, Meiotic arrest is maintained by constitutive signals that elevate cAMP and prevent maturation. In Xenopus, these signals are
endogenous to the oocyte, and include G␣s and G␤␥, which may be signaling independent of or in response to a G proteincoupled receptor (GPCR) (perhaps a member of the mPR family). In mice, these signals may be regulated by an unknown ovarian
inhibitor (I) activating a GPCR or some other receptor. Steroids overcome this inhibition, allowing meiosis to progress (B). Two
of many possible mechanisms are 1) liganded classical steroid receptor (SR) interrupts GPCR- (left) or free G protein-mediated
(right) signaling; 2) competitive binding of steroid directly to the GPCR either decreases G␣s/G␤␥ signaling or, in fish, perhaps
activates G␣i via mPR. Once the inhibitory signals, which include cAMP, are removed or overcome, secondary signals such as
Mos, MAPK, and cdc2 are activated. These signals then promote each other in a powerful positive-feedback loop, resulting in
germinal vesicle breakdown (GVBD) and maturation.
Hammes • Minireview
interpret, however, as they 1) looked primarily at
changes in oocytes that were already spontaneously
maturating; 2) used oocytes that had been preexposed to high levels of sex steroids (e.g. mice were
pretreated with gonadotropins or were postpubertal);
and 3) only saw effects with high (micromolar) concentrations of sterol.
To avoid the problems of steroid priming and spontaneous maturation, recent studies were performed
using oocytes from prepubertal female mice that were
not pretreated with gonadotropins (59). In addition,
these oocytes were treated with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine to maintain
meiotic arrest. Interestingly, both testosterone and estradiol were able to overcome this inhibitory signal and
promote germinal vesicle breakdown, as well as activation of CDK1 and MAPK, in a dose-dependent fashion (EC50 values in the 100–200 nM range). As in
Xenopus, these responses appeared to occur independently of transcription. Further, testosterone and
estradiol responses were inhibited by flutamide and
ICI 182,780, respectively, indicating that classical steroid receptors might be involved. Finally, as with frog
oocytes, the AR transcriptional agonist R1881 did not
promote activation of MAPK or maturation in mouse
oocytes and, in fact, partially inhibited testosteronemediated maturation.
Further in vivo studies will be necessary to confirm
the physiological importance of steroid-mediated maturation in mice; however, these studies support the
“release of inhibition” model oocyte maturation presented in Fig. 2. One could speculate that unknown
inhibitory signals (I) within the mouse ovary hold meiosis in prophase I, perhaps by elevating intracellular
cAMP through interactions with G protein-coupled receptors. In vitro removal of oocytes from the ovary
would eliminate these inhibitory signals, thus resulting
in spontaneous maturation. Alternatively, in vivo stimulation by gonadotropins before ovulation would lead
to follicle growth and production of sex steroids. Only
a few dominant follicles might be expected to produce
enough steroid to overcome the inhibitory signals and
allow meiosis and subsequent ovulation to progress.
The ability of androgens to signal in mammalian
oocytes suggests an intriguing mechanism that might
partially explain the polycystic phenotype seen in the
ovaries of women with androgen excess from polycystic ovarian syndrome (60), congenital adrenal hyperplasia (61), CYP19 (aromatase) deficiency (62), or
exogenous androgen usage (63). Given the importance of cross-talk between oocytes and surrounding
cells for normal follicle growth (15, 16), one could
speculate that excess or altered nongenomic androgen signaling in oocytes might modify this relationship
and contribute to the unregulated follicular growth and
lack of dominant follicle production in women with
androgen excess. This dysregulation might in turn lead
to anovulation and infertility. Whether the ovaries of
these patients contain excess mature oocytes is not
known; however, the AR antagonist flutamide im-
Mol Endocrinol, April 2004, 18(4):769–775
773
proves fertility in some women with polycystic ovarian
syndrome (60, 64), consistent with androgen signaling through the AR playing a role in their infertility.
Further, female mice lacking the AR have reduced
fertility (65), suggesting that androgen actions via
the AR are important, but not necessary, for normal
ovarian physiology.
In summary, steady progress over many decades
has revealed a complex set of factors regulating oocyte maturation and ovarian development. By combining lessons learned from the traditional experimental
systems in frogs and fish with those more recently
from mouse models, it is now possible to begin addressing the role of steroids in human oocyte development. Thus, what began nearly 70 yr ago as an
injection of pituitary extracts into frogs has progressed
to the potential development of novel modulators of
nongenomic steroid-mediated signaling that might
precisely regulate oocyte maturation in women with
fertility defects.
Acknowledgments
We thank the many researchers who have contributed to
the field of oocyte maturation and apologize to those whom
we could not reference due to space limitations. We also
thank Will Walker for his advice in the preparation of this
manuscript.
Received August 20, 2003. Accepted November 11, 2003.
Address all correspondence and requests for reprints to:
Stephen R. Hammes, Department of Internal Medicine, Division of Endocrinology and Metabolism, Department of Pharmacology, University of Texas Southwestern Medical Center
at Dallas, Dallas, Texas 75390-8857. E-mail: stephen.hammes@
utsouthwestern.edu.
S.R.H. is a W. W. Caruth, Jr. Scholar in Biomedical Research and is supported by NIH Grant DK59913 and Grant
I-1506 from the Welch Foundation.
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