Human Reproduction Update, Vol.12, No.5 pp. 557–571, 2006
Advance Access publication May 3, 2006
doi:10.1093/humupd/dml020
Ovarian feedback, mechanism of action and possible
clinical implications
Ioannis E.Messinis
Department of Obstetrics and Gynaecology, University of Thessalia, Medical School, 22 Papakiriazi Street, 41222 Larissa, Greece
To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, University of Thessalia, Medical School,
22 Papakiriazi Street, 41222 Larissa, Greece. E-mail: [email protected]
The secretion of gonadotrophins from the pituitary in women is under ovarian control via negative and positive feedback mechanisms. Steroidal and non-steroidal substances mediate the ovarian effects on the hypothalamic-pituitary
system. During the follicular phase of the cycle, estradiol (E2) plays a key role, while circulating progesterone (at low
concentrations) and inhibin B contribute to the control of LH and FSH secretion respectively. During the luteal
phase, both E2 and progesterone regulate secretion of the two gonadotrophins, while inhibin A plays a role in FSH
secretion. The intercycle rise of FSH is related to changes in the levels of the steroidal and non-steroidal substances
during the luteal-follicular transition. In terms of the positive feedback mechanism, E2 is the main component sensitizing the pituitary to GnRH. Activity of a non-steroidal ovarian substance, named gonadotrophin surge-attenuating
factor (GnSAF), has been detected after ovarian stimulation. It is hypothesized that GnSAF, by antagonizing the sensitizing effect of E2 on the pituitary, regulates the amplitude of the endogenous LH surge at midcycle. Disturbances in
the feedback mechanisms can occur in various abnormal conditions or after treatment with pharmaceutical compounds that interfere with the production or the action of endogenous hormones.
Key words: FSH/LH/estrogen/ovarian feedback/progesterone
Introduction
Menstrual cyclicity in women is greatly dependent on negative
and positive ovarian feedback mechanisms. The activity and
strength of these mechanisms change markedly from birth to menopause. Before puberty, only the negative feedback mechanism is
in action, whereas after menopause, the two mechanisms are abolished. During the normal menstrual cycle, steroidal and nonsteroidal substances mediate the effects of the ovaries on the
hypothalamic-pituitary system. In this article, the contribution of
these substances to the control of gonadotrophin secretion in
women will be discussed based on established knowledge and
recent information.
Negative feedback mechanisms
Before puberty, the hypothalamus is extremely sensitive to the
suppressing effect of the very low levels of circulating estrogen
(Winter and Faiman, 1973), although an as-yet-unclarified central
inhibitory mechanism may also contribute to the repression of the
gonadostat (Roth et al., 1972; Plant and Shahab, 2002). As
puberty approaches, the hypothalamus becomes less sensitive to
the suppressing effect of estrogen, while the central mechanism is
inhibited (Foster and Ryan, 1979). This results in derepression of
the gonadostat and increasing secretion of gonadotrophins. During
the normal menstrual cycle, the pattern of changes in FSH and LH
levels can be easily explained by changes in circulating steroids
(Ross et al., 1970; Messinis and Templeton, 1988a; Roseff et al.,
1989). Although E2 in the follicular phase and progesterone in the
luteal phase predominate, recent evidence indicates that the whole
process is less simplified. First, during the follicular phase, progesterone is also present in the circulation, although at low levels,
and second, non-steroidal substances, such as inhibin, activin and
follistatin, are also produced by the ovaries.
Follicular phase
The role of ovarian steroids
There are several ways to investigate the action of ovarian steroids
on gonadotrophin secretion in women: by administrating exogenous steroids, by administrating selective estrogen receptor blockers or aromatase inhibitors, by eliminating endogenous hormones
through ovariectomy or by enhancing endogenous estrogen activity through ovarian stimulation. Several studies have demonstrated
the ability of exogenous estrogen to suppress FSH and LH levels
during the follicular phase of the cycle (Tsai and Yen, 1971; Monroe
et al., 1972a; Young and Jaffe, 1976; Messinis and Templeton,
1990). It has been suggested that the two gonadotrophins are
equally sensitive to the suppressing effect of E2 (Messinis and
Templeton, 1990). However, recent research has shown that the
© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For
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I.E.Messinis
secretion of FSH and LH is differentially controlled by the ovaries
(Dafopoulos et al., 2004a). In a series of experiments in which two
simulated follicular phases and one simulated luteal phase in between
were artificially induced in estrogen-deprived post-menopausal
women by exogenous administration of estrogen and progesterone, the elevated serum FSH and LH concentrations gradually
declined as E2 and progesterone values increased. Although by the
end of the simulated luteal phase, the levels of LH had been suppressed to the normal premenopausal range, those of FSH were
still higher than in the early follicular phase of the normal menstrual cycle (Dafopoulos et al., 2004a). This suggests that E2 plus
progesterone only partly affect FSH secretion and that other
already known ovarian substances may also be important as will
be discussed in the next section on non-steroidal hormones. In the
same study, however, during the second simulated follicular
phase, the already reduced levels of FSH remained stable, while
those of LH increased gradually despite the increasing concentrations of E2 (Dafopoulos et al., 2004a). It is suggested from these
data that E2 regulates differentially FSH and LH secretion in
women.
The inability of follicular phase E2 levels to maintain low LH
levels in the presence of non-functioning ovaries suggests that
during the normal follicular phase this steroid is not the only mediator of the ovarian negative feedback effect on LH secretion. It is
likely that endogenous progesterone also contributes, because in
the above experiments serum concentrations of this steroid were
lower in the post-menopausal women than in the normal follicular
phase (Dafopoulos et al., 2004a). Furthermore, treatment of normal women with the antiprogestagen, mifepristone, during the
early- and midfollicular phases of the cycle results in a significant
increase in basal LH levels (Kazem et al., 1996). So far, no other
studies have particularly investigated the ability of progesterone,
in concentrations normally found in the follicular phase of the
cycle, to control gonadotrophin secretion in women. In one study,
exogenous administration of this steroid to women with polycystic
ovary syndrome (PCOS) resulted in a significant reduction of the
already elevated serum LH concentrations, but only luteal phase
progesterone levels were achieved (Buckler et al., 1992).
Progesterone is normally produced by luteinizing granulosa and
by luteal cells. Although the source of its production during the
follicular phase has not been clarified, one study has suggested the
adrenal gland (Judd et al., 1992). However, it has been shown
more recently that following ovariectomy, performed in the midfollicular phase of the cycle, serum concentrations of progesterone
declined to almost unmeasurable concentrations (Alexandris et al.,
1997). This suggests that the ovaries produce progesterone even
during the follicular phase of the cycle. The fact that in the same
study (Alexandris et al., 1997) as well as in previous studies
(Wallach et al., 1970; Yen and Tsai, 1971a; Monroe et al., 1972b;
Daw, 1974; Chakravarti et al., 1977; Muttukrishna et al., 2002)
serum E2 levels also declined, while FSH and LH levels increased
gradually following ovariectomy, provides evidence that endogenous ovarian steroids are important for the control of gonadotrophin secretion.
Ovarain stimulation for IVF is an alternative way to study the role
of endogenous estrogens in gonadotrophin secretion. It has been
shown that during induction of multiple follicular development with
the use of FSH, a rapid decline in the concentrations of basal LH
occurs, while E2 concentrations rise to supraphysiological levels
558
(Messinis and Templeton, 1987a; Messinis et al., 1998). At least
two studies have suggested that it is the rising E2 that suppresses
LH levels on this occasion. In one of them (Messinis et al., 1994),
a single FSH dose of 450 IU, injected to normal women on cycle
day 2, resulted in a temporal but significant increase in serum E2
values and in a concomitant suppression of basal LH values.
In the second study (Messinis and Templeton, 1989), normally
cycling women were treated in one cycle with clomiphene citrate
and in another cycle with daily injections of FSH. In both cycles,
serum E2 concentrations increased to supraphysiological levels,
but LH levels were suppressed only in the FSH-treated cycles,
while in the clomiphene cycles they increased significantly. These
two studies provide evidence that the suppressing factor of LH
levels during treatment with FSH is endogenous E2, which in the
case of clomiphene was unable to act due to the occupation of
estrogen receptors. The site of action of estrogen is primarily the
pituitary; however, an effect on the hypothalamus cannot be
excluded (Nakai et al., 1978; Plant et al., 1978; Kelner and Peck,
1984; Richardson et al., 1992).
Although E2 plays a predominant role in the control of gonadotrophin secretion during the follicular phase, this has not been universally acknowledged. One of the reasons is possibly the fact that
despite elevated FSH in normally cycling women, towards the end
of their reproductive life, circulating E2 levels remain within the
normal range (Lee et al., 1988). In addition, a recent study showed
that while serum E2 values on cycle days 3–5 of normally menstruating women aged 40–50 years correlated negatively with
FSH, inhibin B was the only independent predictor of FSH values
(Burger et al., 2000).
The role of non-steroidal ovarian hormones
Along with the steroids, the ovaries produce non-steroidal substances, such as inhibins (Bicsak et al., 1986; Roberts et al., 1993).
These proteins by definition suppress only basal FSH secretion
from the pituitary. Although in vitro data have shown that under
specific circumstances LH secretion may be also affected (Farnworth
et al., 1988), this hormone is much less sensitive to inhibition than
FSH (Attardi et al., 1991). It has been suggested that during the follicle selection process, the follicle destined to become dominant
produces inhibin B (de Kretser et al., 2002), the levels of which are
high in the early- to midfollicular phases and very low in the late
follicular and luteal phases (Groome et al., 1996). In contrast, the
levels of inhibin A are low in the follicular phase and rise markedly
during the luteal phase, indicating that this form is produced mainly
by the corpus luteum (Groome et al., 1996).
In terms of the role of inhibin in the secretion of gonadotrophins, there is little evidence in humans, and only animal data
have convincingly indicated that this protein participates in the
control of FSH secretion in vivo. In particular, immunoneutralization of inhibin by the injection of antibodies to rats resulted in a
significant increase in FSH levels (Rivier et al., 1986). Also,
administration of inhibin antiserum to rats and hamsters increased
FSH-β mRNA without affecting LH-β (Attardi et al., 1992; Kishi
et al., 1996). In addition, administration of recombinant inhibin A
to rats or to castrated rams blocked the FSH surge and suppressed
plasma FSH levels respectively (Rivier et al., 1991; Tilbrook
et al., 1993). Finally, in rhesus monkeys, inhibin A given during
the early follicular phase rapidly decreased circulating FSH levels
(Stouffer et al., 1994; Molskness et al., 1996).
Ovarian feedback mechanisms
Data in humans only indirectly indicate that inhibin participates
in the control of FSH secretion. In one study, in which normally
cycling women were treated with clomiphene for 15 days during
the follicular phase, LH levels increased continuously throughout
the treatment, while those of FSH after an initial rise declined to
the pretreatment levels (Messinis and Templeton, 1988b). As clomiphene is an anti-estrogenic compound, it is suggested that for
the control of FSH secretion, non-estrogenic mechanisms are also
important, supporting the hypothesis of inhibin participation. In
post-menopausal women, elevated FSH declines during treatment
with estrogen but never returns to premenopausal levels suggesting that inhibin may be missing in these women (Lind et al., 1978;
Dafopoulos et al., 2004a).
Recent studies in normally cycling premenopausal women have
shown a significant decline in inhibin, E2 and progesterone
concentrations following ovariectomy (Alexandris et al., 1997;
Muttukrishna et al., 2002). When the operation was performed in
the follicular phase, the levels of both inhibin A and inhibin B
decreased significantly, but when it was performed in the luteal
phase only inhibin A declined (Muttukrishna et al., 2002). These
data confirm that inhibin B is mainly produced in the follicular
phase and inhibin A in the luteal phase but do not provide a clear
relationship between these hormones and FSH. Nevertheless,
when older perimenopausal but normally cycling women with
increased early follicular FSH levels were compared with younger
women with normal FSH levels, it was found that the older
women also had lower inhibin B but similar inhibin A concentrations (Klein et al., 1996; Burger et al., 1998; Klein et al., 2004).
Furthermore, in women with imminent premature ovarian failure,
but with ovulatory cycles, persistently elevated FSH was accompanied by reduced levels of inhibin B and inhibin A (Welt et al.,
2005a). It is likely from these data that inhibin plays a role in the
ovarian negative feedback control of FSH secretion in women.
However, inhibin B is particularly important during the follicular
phase of the cycle (Table I).
The role of other non-steroidal substances, such as activin
and follistatin, is less clear. Activin is a dimeric product of the
β-subunit of inhibin and exists in three forms, ‘A’, ‘B’ and ‘AB’
(Muttukrishna et al., 2004). Animal data have shown that activin
stimulates the secretion of FSH from pituitary cells in culture
(Ling et al., 1986; Vale et al., 1986) as well as in vivo (McLachlan
et al., 1989; Rivier and Vale, 1991; Stouffer et al., 1993), and
therefore, this protein does not have a place in the negative feedback mechanism. In women, due to methodological difficulties,
only activin A has been measured in blood during the normal menstrual cycle, and the data have shown fluctuations with higher levels in the early follicular phase, at midcycle and in the late luteal
phase (Muttukrishna et al., 1996). The importance of these
changes is not clear, although activin A may contribute to the
increase in FSH levels at these particular periods.
Follistatin was initially thought to be an inhibin agonist (Robertson
et al., 1987; Ueno et al., 1987), but it was subsequently found to be
a binding protein for activin that may have no other specific biological roles (Nakamura et al., 1990). Most circulating follistatin
in cycling women is activin bound (McConnell et al., 1998). Data
in animals, however, have shown that follistatin may exert actions
on FSH secretion in vivo. In particular, administration of human
recombinant follistatin-288 to ovariectomized rams reduced the
secretion of FSH but not LH (Tilbrook et al., 1995). Also, in a
study in ewes, it was shown that the same recombinant product
was able to suppress FSH levels in the peripheral circulation without affecting basal GnRH secretion or the frequency and the
amplitude of GnRH pulses (Padmanabhan et al., 2002). The mechanism of this effect is unclear but is possibly related to the bioavailability of activin (Padmanabhan et al., 2002).
Data on the mechanism of action of inhibin are lacking in
women, and information is derived only from studies in animals. It
has been suggested that in the context of the negative feedback
mechanism, inhibin acts directly on the pituitary without affecting
GnRH secretion, although it may reduce the GnRH-induced FSH
secretion (de Kretser et al., 2002). However, the existence of
inhibin/activin and follistatin subunits in the pituitary cells of various species indicates that these proteins may also exert local
effects (Mather et al., 1992; Bilezikjian et al., 1993; Farnworth
et al., 1995). Especially, activin A has been shown to be secreted
by rat anterior pituitary cells in culture (Liu et al., 1996a), whereas
activin B is the major form in such cells (Bilezikjian et al., 1994).
It is possible, therefore, that the effect of these proteins on FSH
secretion is exerted via antocrine/paracrine pathways (Corrigan
et al., 1991). Follistatin is also secreted from rat pituitary cells
(Liu et al., 1996b), and therefore, its inhibitory effect on FSH
secretion may be via the neutralization of pituitary activin (Ling
et al., 1986; Vale et al., 1986; Muttukrishna and Knight, 1991).
The role of another non-steroidal substance named anti-Mullerian
hormone (AMH) is less clear. In women, AMH is expressed in the
granulosa cells of follicles from the primordial to the antral stage
until the size of 4–6 mm (Weenen et al., 2004). Although it appears
that serum levels of AMH on cycle day 3 of normally cycling
women decline with increasing age (de Vet et al. 2002) and show a
negative correlation with FSH (van Rooij et al., 2002), its role in the
ovarian negative feedback system has not been clearly established.
Luteal phase
During the luteal phase, the increased values of progesterone and
E2 play an important role in the maintenance of the low FSH and
Table I. Ovarian hormones that mediate the negative feedback effect on FSH and LH secretion in women
Follicular phase
FSH
Inhibin B
Luteal phase
Luteal-follicular transition (intercycle rise of FSH)
LH
FSH
LH
Onset
Termination
Estradiol
Estradiol
Progesterone
Inhibin A
Estradiol
Removal of negative action of:
Estradiol
Inhibin A
Positive action of:
Activin A
Estradiol
Progesterone
Progesterone
Inhibin B
559
I.E.Messinis
LH levels (Table I). This is derived from experiments in women
that have shown that after ovariectomy, performed in the midluteal
phase, both E2 and progesterone concentrations decreased significantly within the first 24 h, while those of FSH and LH increased
gradually (Alexandris et al., 1997). Although these data underlie
the importance of these two steroids in the control of gonadotrophin secretion in the luteal phase, they do not specify the role of
each of them. The latter has been further investigated in a recent
study (Messinis et al., 2002) demonstrating that maintenance of
midluteal levels of E2 with the administration of exogenous estrogen immediately after ovariectomy postponed the expected
increase in FSH and LH concentrations by on average 3 days.
When, however, the midluteal concentrations of progesterone
were also maintained with the exogenous administration of this
steroid, the increase in FSH and LH values was prevented
(Messinis et al., 2002). This suggests that it is the combined action
of E2 and progesterone that mediates the negative feedback effect
of the ovaries on gonadotrophin secretion during the luteal phase
of the cycle. Whether progesterone alone could express a similar
action has not been investigated, although under experimental
conditions the negative feedback effect of progesterone is apparent in the presence of estrogen (Soules et al., 1984).
During the luteal phase, the frequency of GnRH pulses
decreases, while the amplitude increases (Filicori et al., 1986).
Although this could be due to the high progesterone concentrations (Soules et al., 1984), it seems that both E2 and progesterone
are required to maintain this pattern (Nippoldt et al., 1989). The
suppressing effect of these two steroids on gonadotrophin secretion is possibly mediated via an increase in β-endorphin activity in
the hypothalamus (Wehrenberg et al., 1982).
Apart from the steroids, no other ovarian substances have been
detected to specifically suppress basal LH secretion in women. For
FSH, however, inhibin may participate in the negative feedback
mechanism during the luteal phase but does not affect LH secretion. This is derived from data in both animals and women. Infusion of inhibin A into rhesus macaques starting at midluteal phase
resulted in a progressive decline in FSH levels (Stouffer et al.,
1994). A recent study in women has shown a significant decline in
inhibin A values within the first 12 h from ovariectomy performed
in the luteal phase that was followed by a gradual but significant
increase in serum FSH concentrations (Muttukrishna et al., 2002).
Although in that study E2 and progesterone levels also declined, a
negative correlation between the values of inhibin A and FSH was
found. In the same study, inhibin B levels did not change significantly after ovariectomy, suggesting that this protein is not a regular component of the negative feedback mechanism during the
luteal phase of the cycle (Muttukrishna et al., 2002). Nevertheless,
previous data have demonstrated that normally cycling premenopausal women with raised FSH values in the early follicular phase
had during the luteal phase inhibin A, and during the follicular
phase inhibin B, concentrations significantly lower than in women
with normal FSH levels (Danforth et al., 1998; Santoro et al.,
1999; Welt et al., 1999; Muttukrishna et al., 2000). These data
provide evidence that both forms of inhibin participate in the control of FSH secretion in women with inhibin A being important
during the luteal phase and inhibin B during the follicular phase of
the cycle.
The role of activin and follistatin in the control of human gonadotrophin secretion during the luteal phase is, as in the follicular
560
phase, not clear. Measurement of follistatin in the circulation of
women has not shown any significant alterations throughout the
whole menstrual cycle (Khoury et al., 1995; Kettel et al., 1996;
Evans et al., 1998).
Luteal-follicular transition
During the passage from the luteal to the next follicular phase, an
increase, or ‘intercycle rise’, in serum FSH concentrations occurs.
FSH starts to increase 2–3 days before the onset of the menstrual
period, although recent data have shown that the initial rise occurs
4 days before menses (Miro and Aspinall, 2005). FSH remains
elevated during the early follicular phase and returns to the basal
value in midfollicular phase (Mais et al., 1987; Messinis et al.,
1993c). During the period of FSH increase, also named the ‘FSH
window’, the selection of the dominant follicle takes place. The
described changes in FSH levels were measured by immunoassays, but when a specific in vitro bioassay was used,
increased signal was detected earlier, i.e. in midluteal to late luteal
phase (Christin-Maitre et al., 1996).
The intercycle rise of FSH appears to be controlled by ovarian
substances (Figure 1). Before the onset of the FSH rise, a gradual but
significant decline in the levels of inhibin A, E2 and progesterone
takes place (Roseff et al., 1989; Groome et al., 1996). It is assumed,
therefore, that the intercycle rise of FSH starts in late luteal phase as
a result of the reduced activity of the negative feedback mechanism
that suppressed FSH secretion during the early- and midluteal
FSH
Inhibin B
Inhibin A
E2
P4
Figure 1. Hormonal dynamics during the luteal-follicular transition. The FSH
intercycle rise is the result of the reduced activity of the negative feedback
mechanism due to the decrease in estradiol (E2), inhibin A and progesterone
(P4) concentrations in late luteal phase. The FSH increase is terminated by the
rising E2 and inhibin B levels produced by the dominant follicle. The diagram,
regarding the pattern of hormonal changes, is based on data presented in two
references (Messinis et al., 1993c; Groome et al., 1996).
Ovarian feedback mechanisms
phases. Inhibin B does not participate in this mechanism. However, from the time FSH levels reach a peak at the onset of menstruation, inhibin B levels increase gradually and significantly
(Groome et al., 1996). It is possible that the increasing concentrations of inhibin B under the influence of FSH during the early
follicular phase (Welt et al., 1997) suppress FSH secretion, narrowing thus the FSH window.
Based on these data, it is assumed that both forms of inhibin
are important for the control of FSH secretion during the intercycle period in women with inhibin A playing a role in the process
that ‘opens’ and inhibin B in the mechanism that ‘closes’ the FSH
window (Table I). Although this makes sense, a study in women
has shown that maintenance of midluteal concentrations of E2
during the intercycle period postponed the intercycle rise of FSH
despite a decline in inhibin concentrations (Le Nestour et al.,
1993). Furthermore, following the selection of the dominant follicle in the normal cycle, serum FSH declined as E2 levels
increased (van Santbrink et al., 1995). It is suggested from these
results that E2 is possibly more important than inhibin in regulating the FSH window. More recent data in women treated with the
anti-estrogenic compound, tamoxifene, have confirmed the
greater role of E2 over inhibin in the negative control of FSH
secretion during the luteal phase and the luteal-follicular transition with inhibin B being more important as the follicular phase
progresses (Welt et al., 2003).
The role of progesterone in the control of the intercycle rise of
FSH is less clear, although this hormone may participate via an
effect on GnRH secretion. Progesterone is believed to reduce the
frequency and increase the amplitude of LH pulses during the
luteal phase of the cycle (Soules et al., 1984; Nippoldt et al.,
1989). Therefore, the withdrawal of the progesterone effect in late
luteal phase increases the frequency of GnRH pulses (McCartney
et al., 2002), an event that stimulates predominantly the secretion
of FSH (Marshall and Kelch, 1986; Hall et al., 1992). This is possibly one of the reasons that the increase of LH during the intercycle period is less discernible. In any case, however, the frequency
of GnRH pulses contributes to but is not solely responsible for the
intercycle rise of FSH in women (Welt et al., 1997).
Another mechanism that might contribute to the intercycle rise
of FSH includes activin A. The concentrations of this protein,
despite limitations in the existing methodology, start to increase
from the midluteal phase, preceding through the intercycle rise of
FSH (Muttukrishna et al., 1996). Also, aged but normally cycling
women with raised FSH values in the early follicular phase
had increased concentrations of activin A in the luteal phase
(Muttukrishna et al., 2000). Similarly, a significant increase in
serum activin A levels over age has been reported in healthy postmenopausal women (Baccarelli et al., 2001). In terms of the role
of other forms of activin, such as activin B and activin AB, there
are no data in the literature regarding their concentrations in the
circulation of women.
Positive feedback mechanisms
It has been known for years that E2 is the main component of the
positive feedback effect of the ovaries on the hypothalamic-pituitary
system (Ferin et al., 1974). This steroid sensitizes the pituitary to
GnRH and enhances the self-priming action of GnRH on the pituitary gonadotrophs (Lasley et al., 1975). The interaction between
E2 and GnRH is important for the expression of the endogenous
gonadotrophin surge at midcycle (Hoff et al., 1977).
Pituitary sensitivity to GnRH
Experiments in women involving the i.v. infusion of GnRH or the
i.v. administration of consecutive GnRH pulses have differentiated two functional pools of gonadotrophin secretion in the gonadotrophs (Lasley et al., 1975; Wang et al., 1976; Yen and Lein,
1976; Hoff et al., 1977). The first, also named ‘releasable’ pool,
releases gonadotrophins immediately after stimulation by GnRH,
whereas the second or ‘reserve’ pool, which represents the synthesis of new hormones, requires a longer stimulation by GnRH.
Under these circumstances, the reserve is converted to the acutely
releasable pool before gonadotrophins are secreted.
During the i.v. administration of two submaximal doses of
GnRH, 10 μg each, to normal women 2 h apart, the response to the
first pulse is maximum at 30 min and represents the pituitary ‘sensitivity’, while the whole area under the curve lasting 240 min represents the pituitary reserve (Lasley et al., 1975). The response to
the second GnRH pulse is greater than the response to the first
pulse, a pattern that is particularly evident in the presence of estrogen and is called ‘the self-priming effect’ of GnRH on the pituitary (Lasley et al., 1975; Wang et al., 1976; Hoff et al., 1979).
Although this reflects increased number of GnRH receptors in the
gonadotrophs (Laws et al., 1990), it may be also related to
increased availability of GnRH in the pituitary as E2 inhibits
GnRH metabolism by monkeys and rat pituitary cells (Danforth
et al., 1990). In addition, data in rats have shown that GnRH controls LH biosynthesis by increasing glycosylation and polypeptide
synthesis of LH, while E2 facilitates LH secretion by lowering the
concentrations of GnRH needed to stimulate these two processes
(Ramey et al., 1987). The biphasic pattern of LH response to
GnRH has been also shown in vitro using rat pituitary cells in a
perifusion system (Evans et al., 1983; Loughlin et al., 1984).
When GnRH experiments were performed during the human
menstrual cycle, it was found that the pituitary sensitivity and
reserve as well as the self-priming effect were augmented in the
late follicular phase as compared to the early follicular phase
(Wang et al., 1976; Hoff et al., 1977). This augmentation of LH
secretion as a response to repeated injections of GnRH in an estrogenic environment is related to the rate with which LH molecules
are discharged from the pituitary (Sollenberger et al., 1990),
although the duration of the LH secretory events and consequently
the LH mass are also augmented (Quyyumi et al., 1993). It has
been found that the pituitary sensitivity to GnRH, estimated as the
30-min response to a single i.v. GnRH dose of 10 μg, does not
change significantly in women during the early- and midfollicular
phases of the cycle, despite the significant rise in E2 concentrations, but increases markedly during the late follicular phase
(Messinis et al., 1994, Messinis et al., 1998). This suggests that
the sensitizing effect of E2 on the pituitary is inhibited during the
early- and midfollicular phases and is facilitated in the late follicular phase of the normal menstrual cycle. Alternatively, the ovaries
during the early- and midfollicular phases produce a substance
that is able to antagonize the sensitizing effect of E2 on the pituitary gonadotrophs.
Experiments that were performed in healthy estrogen-deprived
post-menopausal women support this assumption (Dafopoulos
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I.E.Messinis
et al., 2004a). In particular, two simulated follicular phases with a
luteal phase in between were created in these women with the
exogenous administration of E2 and progesterone. The experiments lasted for 43 days, and the pituitary sensitivity, expressed as
the 30 min response to 10 μg GnRH i.v., was investigated on a
daily basis. Immediately after the end of the simulated luteal
phase, the response of LH to GnRH was similar to that in the early
follicular phase of the normal menstrual cycle. However, from that
point onwards, i.e. in the following simulated follicular phase a
continuous increase in the pituitary sensitivity to GnRH was seen,
which was different from that described in the normal follicular
phase (Figure 2). These data are compatible with the hypothesis of
a missing ovarian substance in the case of post-menopausal
women because their ovaries are not functioning.
Such a substance could be gonadotrophin surge-attenuating factor (GnSAF) that in superovulated women reduces the pituitary
response to GnRH and attenuates the endogenous LH surge
(Messinis et al., 1985; Messinis and Templeton, 1989). Another
candidate could be progesterone, but this is not likely because
when normal women were treated with the antiprogestagen, mifepristone, both the pituitary sensitivity and reserve were significantly attenuated as compared to control cycles of the same
women (Kazem et al., 1996). It is clear from these data that when
the progesterone activity is neutralized, the pituitary sensitivity
is decreased, and therefore, the lack of progesterone in the postmenopausal women would be expected to result in a decrease and
Figure 2. LH response to GnRH (ΔLH) in women. Comparison between (䊉)
a simulated follicular phase (Group 1) and (䉱) a control normal follicular
phase (Group 2). In Group 1, estrogen-deprived post-menopausal women were
treated with exogenous estradiol valerate and progesterone to induce concentrations of these two steroids similar to those in the follicular phase and the
luteal phase of the normal menstrual cycle. Two simulated follicular phases
and one luteal phase in between were induced. Days 32–42 correspond to the
second simulated follicular phase immediately after the simulated luteal phase.
The changes in LH represent the pituitary sensitivity to GnRH (30 min
response to an i.v. injection of 10 μg). The different pattern of LH changes is
interpreted as indicating that the ovaries (Group 2) produce a substance (gonadotrophin surge-attenuating factor) that in the early follicular and midfollicular
phases prevent the increase in pituitary sensitivity to GnRH. This substance
was not produced in Group 1 as the ovaries were not functioning.*P < 0.05.
Adapted from Dafopoulos et al., 2004a.
562
not in an increase in the pituitary responsiveness to GnRH during
the administration of E2. In other words, progesterone in the follicular phase of the normal cycle, although in low concentrations,
probably sensitizes the pituitary to GnRH and in that way facilitates the E2 positive effect. In agreement with this notion are data
in rats in which the sensitizing effect of progesterone on the GnRH
self-priming in pituitary monolayers was abolished by coincubation with mifepristone (Byrne et al., 1996). Even, in the absence of
progesterone, according to data in rats, GnRH self-potentiation
requires a cross-talk with the progesterone receptor (Waring and
Turgeon, 1992).
LH surge onset
As has been shown in several studies, E2 is the predominant factor
that triggers the onset of the endogenous LH surge during the normal menstrual cycle provided a threshold level is exceeded for a
certain period of time (Karsch et al., 1973; Keye and Jaffe, 1975;
Young and Jaffe, 1976; March et al., 1979; Liu and Yen, 1983;
Karande et al., 1990). It has been demonstrated that this level is
around 200 pg/ml, and the period of pituitary exposure to it at least
48 h (Young and Jaffe, 1976; Simon et al., 1987; Karande et al.,
1990). Even supraphysiological levels of E2 induced by the exogenous administration of estrogen are able to stimulate an LH surge
(Messinis et al., 1992). The interaction of E2 with GnRH is
important for the LH surge onset via an increased expression of
the GnRH self-priming on the pituitary (Hoff et al., 1977).
The extent to which other ovarian hormones, such as progesterone, participate in the positive feedback mechanism at midcycle is
less clear. Experiments in women have shown that progesterone
can induce a positive feedback effect only after pretreatment with
estrogen, even when the appropriate threshold for E2 has not been
reached (Chang and Jaffe, 1978; March et al., 1979). At midcycle,
the shift in steroidogenesis represents the ability of the preovulatory follicle to produce more progesterone than E2 (McNatty et al.,
1979a,b). There has been debate, however, in the literature as to
whether the progesterone secretion and, therefore, its concentrations in the circulation increase a little while before the onset of the
midcycle LH surge (Johansson and Wide, 1969; Thorneycroft et al.,
1974; Laborde et al., 1976; Landgren et al., 1977; Djahanbakhch
et al., 1984). In one study, in which blood samples were taken from
normal women every 2 h for 5 days during the periovulatory
period, a clear increase in progesterone concentrations was demonstrated before the real onset of the surge (Hoff et al., 1983).
It is possible, therefore, that at midcycle the role of progesterone is permissive. In experiments performed in women, the
administration of progesterone advanced the onset of an E2induced LH surge (Chang and Jaffe, 1978; Liu and Yen, 1983;
Messinis and Templeton, 1990). Also, in rats progesterone
enhanced E2-induced GnRH secretion from the medial basal
hypothalamus (Miyake et al., 1982), while the antiprogestagen,
mifepristone, blocked the midcycle gonadotrophin surge in
women when given after the emergence of the dominant follicle
(Batista et al., 1992). Although the role of circulating progesterone
in the positive feedback mechanism in women requires clarification, data in ovariectomized estrogen-treated progesterone receptor knockout mice have shown that activation of these receptors is
necessary for the expression of the GnRH self-priming effect and
the generation of the E2-induced gonadotrophin surge (Chappell
Ovarian feedback mechanisms
et al., 1999). Additional information in ovariectomized and adrenalectomized rats indicates that neuroprogesterone synthesized in the
hypothalamus under the influence of E2 is an obligatory mediator
of the positive feedback mechanism that is induced by this steroid
(Micevych et al., 2003). Furthermore, data in rats have shown that
estrogens induce de novo synthesis of progesterone from cholesterole in the hypothalamus, which plays a role in the onset of the LH
surge (Soma et al., 2005). It is possible, therefore, that progestestogenic mechanisms involving the progesterone receptor participate in the E2 positive feedback mechanism, regulating thus the LH
surge onset.
The site of action of E2 for the positive feedback effect is both
the hypothalamus and the pituitary (Xia et al., 1992). A preovulatory surge of GnRH has been detected in the ewe (Moenter et al.,
1991). However, a LH surge has been induced by estrogens in
monkeys with no GnRH production (Ferin et al., 1979). In
women, while data are lacking, one study has shown an increase in
plasma immunoreactive GnRH, as a result of estrogen administration, that precedes the increase of LH and FSH (Miyake et al.,
1983). It is likely, therefore, that the primary site of the positive
feedback effect is the pituitary and that GnRH plays a permissive
role (Knobil, 1988). A recent study has shown that in rats a direct
action of E2 on the anterior pituitary is obligatory for the positive
feedback effect on LH secretion (Yin et al., 2002). Progesterone
seems also to exert the positive feedback effect via the hypothalamus (Terasawa et al., 1982).
The mechanism of the E2 positive effect on gonadotrophin
secretion is via the estrogen receptors (ER). Whether this involves
ERα or ERβ or both is not clear. Both types exist in the gonadotrophs (Mitchner et al., 1998), while data in rats have shown that
estrogens may regulate their own receptors as well as the pituitary
responsiveness to them (Schreihofer et al., 2000). The effect of E2
is also mediated by changes in the activity of neurotransmitters in
the hypothalamus, such as β-endorphin, whose plasma levels start
to increase 2 days before the LH peak (Laatikainen et al., 1985).
clones were obtained that in the in vitro bioassay system of rat
pituitary cells were able to reduce the GnRH-induced LH secretion demonstrating, therefore, GnSAF bioactivity (Tavoulari et al.,
2004). More recently, with the use of RT-PCR and the appropriate
primers, the expression of HSA mRNA was found in human granulosa cells obtained from women undergoing IVF treatment
(Karligiotou et al., 2006). All fragments of HSA were expressed in
the nucleus of the granulosa cells, and only the promoter and the
C-terminal fragment were expressed in the cytoplasm (Karligiotou
et al., 2006). Evidence has been provided that GnSAF is different
from inhibin, first because it reduces LH rather than FSH secretion
(Pappa et al., 1999), second because during the process of purification from human follicular fluid inhibin was removed from the
system (Pappa et al., 1999; Fowler et al., 2002) and third because
when antibodies against inhibin were used in vitro the bioactivity
of GnSAF was preserved (Balen et al., 1995a; Byrne et al., 1995).
Several studies have shown in vivo bioactivity of GnSAF during
ovarian stimulation in women with FSH (Messinis et al., 1991,
1993a,b, 1994, 1996). It has been suggested that FSH stimulates
the production of GnSAF from growing follicles but not from the
corpus luteum (Messinis et al., 1996).
Physiological role of GnSAF: LH surge amplitude
Although GnSAF bioactivity is particularly evident during ovarian
stimulation, it is possible that this factor plays a physiological role
during the normal menstrual cycle affecting gonadotrophin secretion. Studies in women during the natural cycle have suggested that
GnSAF is produced during the luteal-follicular transition under the
influence of the intercycle rise of FSH (Messinis et al., 1991,
1993c, 2002) (Figure 3). A hypothesis has been developed that the
activity of GnSAF in the circulation is high during the early- and
midfollicular phases, and this maintains the pituitary in a state of
low responsiveness to GnRH (Messinis and Templeton, 1991;
Fowler et al., 2003; Messinis, 2003). However, in the late follicular
phase, there is a decline in GnSAF bioactivity that facilitates the
Characterization of GnSAF
It has been suggested that GnSAF attenuates the endogenous LH
surge and reduces the pituitary response to GnRH in superovulated
women (Messinis et al., 1985, 1986; Messinis and Templeton,
1986, 1989) Whether GnSAF is similar to a gonadotrophin surge
inhibiting factor (GnSIF) in monkeys (Sopelak and Hodgen, 1984)
and rats (Geiger et al., 1980; Koppenaal et al., 1992) is not known.
It may be that GnSAF and GnSIF share some structural similarities, although species differences may be important (Fowler and
Templeton, 1996).
Attempts to purify GnSAF/GnSIF from various sources have
shown molecular masses ranging from 12.5 to 69 kDa with different aminoacid sequences (Tio et al., 1994; Danforth and Cheng,
1995; Pappa et al., 1999; Fowler et al., 2002). A study using
human follicular fluid as a source (Pappa et al., 1999) has shown a
molecular weight of 12.5 kDa and identity to the C-terminal fragment of human serum albumin (HSA).
That GnSAF may be related to HSA was further supported by
two recent studies. In one of them (Tavoulari et al., 2004), the production of recombinant polypeptides of HSA corresponding to
subdomain IIIB residues of 490–585 was feasible by using the
expression-secretion system of Pichia Pastoris GS115. Different
LH surge
LUTEAL
PHASE
FOLLICULAR
PHASE
LUTEAL
PHASE
FOLLICULAR
PHASE
FSH
GnSAF
Inhibin B
E2
FSH
GnSAF
Inhibin A
P4
Figure 3. Activity of gonadotrophin surge-attenuating factor (GnSAF) during
the normal menstrual cycle in relation to inhibin A, inhibin B, estradiol (E2)
and progesterone (P4) patterns. It is postulated that GnSAF is produced during
the luteal-follicular transition under the influence of the intercycle rise of FSH.
563
I.E.Messinis
HYPOTHALAMUS
HYPOTHALAMUS
GnRH
GnRH
(+)
(-)
(+)
HYPOTHALAMUS
GnRH
storage
(-)
storage
(+)
(-)
storage
release
E2
release
GnSAF
FSH LH
P4
Inhibin B
E2
release
GnSAF
FSH LH
P4
Inhibin B
OVARY
OVARY
Early
follicular
Mid
follicular
E2
GnSAF
FSH LH
P4
OVARY
Late
follicular
Figure 4. A hypothesis on the physiological role of gonadotrophin surge-attenuating factor (GnSAF) during the normal menstrual cycle. GnSAF interacts with
estradiol (E2) on the pituitary to decrease the GnRH-induced LH secretion. This factor is produced mainly by small growing follicles, and therefore, its activity is
high in the early- to mid-follicular phase. The activity of GnSAF is reduced in the late follicular phase and at midcycle, facilitating thus the sensitizing effect of E2
on the pituitary and the full expression of the endogenous LH surge. Progesterone (P4) may sensitize the pituitary to GnRH throughout the follicular phase, while
inhibin B may decrease the GnRH-induced FSH secretion in the early- and midfollicular phase of the cycle.
sensitizing effect of E2 on the pituitary and the full expression of
the midcycle LH surge (Messinis et al., 1994) (Figure 4).
That GnSAF activity is higher in the early- and midfollicular
phases than in the late follicular phase is also supported by in vitro
studies demonstrating GnSAF activity in human follicular fluid particularly of small- and medium-sized follicles rather than of large
follicles (Fowler et al., 1990, 2001). According to this hypothesis,
the role of GnSAF in humans is to control the amplitude and not the
onset of the LH surge. In fact, an endogenous LH surge occurs
invariably as a response to the positive feedback effect of E2 either
in the early- or in midfollicular phases of the normal menstrual
cycle, but this surge is attenuated as compared to midcycle (Taylor
et al., 1995; Messinis et al., 2001). Therefore, E2 and GnSAF seem
to interact at the pituitary gonadotrophs with the former expressing
a sensitizing effect and the latter an antagonistic effect.
Of the other ovarian hormones, progesterone seems also to play
a role in the control of the amplitude of the LH surge. Under
experimental conditions in normally cycling or in post-menopausal
women, exogenous progesterone amplified the LH surge that was
induced by the administration of exogenous estrogen (Liu and
Yen, 1983; Messinis and Templeton, 1990). Data in rats have
shown that this action of progesterone is mediated via an enhanced
activation of GnRH neurons (Lee et al., 1990).
Termination of the LH surge
The midcycle LH surge normally has a duration of 48–72 h (Hoff
et al., 1983; Messinis and Templeton, 1988a; Shoham et al., 1995).
564
The factors, however, that control the termination of the endogenous LH surge during the normal menstrual cycle have not been
clarified. After the onset of the LH surge, E2 concentrations
decline. It is rather unlikely that the withdrawal of the E2 effect
terminates gonadotrophin secretion, because termination also
occurred in experiments in which high estrogen concentrations
were maintained during the LH surge (Liu and Yen, 1983). In
addition, animal studies have shown that E2 is important for triggering the LH surge but is not required after its onset (Evans et al.,
1997). Nevertheless, data in rats have shown that estrogen can
reduce ERα and ERβ protein and increase a truncated ER product-1
that suppresses the activity of both types of receptors in vivo and
in cell lines, suggesting that this may be a mechanism via which
these steroids limit the positive feedback effect (Schreihofer et al.,
2000, 2002). More recent data, however, have demonstrated that
the loss of the LH surges in ovariectomized rats during chronic
treatment with E2 was achieved without any changes in the proportion of GnRH cells expressing ERα or ERβ (Legan and Tsai,
2003).
Serum progesterone levels in women increase gradually from
the onset to the end of the LH surge and continuously, thereafter,
during the luteal phase of the cycle (Hoff et al., 1983). It is possible that the rising progesterone levels contribute to the termination of the LH surge via a negative feedback effect. Experimental
data in women have shown that when an LH surge was induced
with the exogenous administration of E2, LH values declined following the peak but went down to the presurge level only after the
administration of progesterone (Messinis and Templeton, 1990).
Ovarian feedback mechanisms
A recent study has provided more information regarding the
mechanism that is responsible for the termination of the endogenous LH surge in women (Dafopoulos et al., 2006). In particular,
the positive feedback effect of exogenous E2 was investigated in
two cycles of normally cycling women who underwent ovariectomy on day 3 of the second cycle. An endogenous LH surge was
induced by exogenous E2 given from cycle days 3–5 that was
comparable in the two cycles up to the point of the LH peak. A
descending limb, however, was evident only in the first cycle with
the intact ovaries. In contrast, in the second cycle in which the
ovaries were removed, LH and FSH levels did not decline but
fluctuated around the peak value of the surge for the rest of the
experimental period (Dafopoulos et al., 2006). These data suggest
that the termination of the E2-induced LH surge is not related to an
exhaustion of the pituitary reserves but is controlled by ovarian
factors. As progesterone values decreased after ovariectomy and
were lower than during the corresponding days in the first cycle
with the intact ovaries, this steroid is a possible candidate for the
surge termination. A decrease in GnRH pulse frequency in the late
as compared to the early- and mid-portions of the midcycle LH
surge (Adams et al., 1994) can be part of the mechanism of progesterone action on gonadotrophin secretion.
Menopause
Following menopause, changes in the relationships between the
ovaries and the hypothalamic-pituitary system take place. Ovarian
failure leading to menopause is a gradual process that usually
starts several years before menopause (Burger et al., 2002). It has
been shown that basal FSH concentrations are raised, whereas
those of inhibin B are reduced in the early follicular phase of the
cycle during the perimenopausal period, although cyclicity is
maintained (Klein et al., 1996; Soules et al., 1998). At the same
time, LH values remain normal suggesting that the negative feedback effect of the ovaries is partly attenuated long before menopause. After menopause, however, the negative feedback
mechanism is abolished, since following ovariectomy in healthy
post-menopausal women FSH, LH, and E2 values do not change
and only testosterone levels decline substantially (Dafopoulos
et al., 2004b). Therefore, the post-menopausal ovaries do not produce estrogens but only testosterone (Sluijmer et al., 1995; Laughlin
et al., 2000) which, however, does not contribute to the negative
feedback system (Dafopoulos et al., 2004b). The latter can be reestablished in post-menopausal women after the exogenous
administration of estrogens and progesterone (Yen and Tsai,
1971b; Lind et al., 1978; Lutjen et al., 1986). Despite the absence
of ovarian feedback, age-related changes occur in the hypothalamic component that are characterized by a decrease in GnRH
pulse frequency with age (Lambalk et al., 1997; Santoro et al.,
1998; Hall et al., 2000).
Due to the very low circulating E2 concentrations in the postmenopausal women, the positive feedback mechanism is also not
active. However, the secretion of LH and FSH and, therefore,
GnRH is still pulsatile (Hall et al., 2000). Furthermore, in a recent
study, the pituitary sensitivity to GnRH, assessed as the 30 min
response to 10 μg GnRH i.v., remained unchanged during the
week following ovariectomy as compared to the pre-operative pattern (Dafopoulos et al., 2004b). When, however, exogenous estrogens were given to post-menopausal women in order to achieve
concentrations similar to those during the follicular phase of the
normal menstrual cycle, the sensitivity of the pituitary to GnRH
increased gradually (Dafopoulos et al., 2004a). Also, a LH surge
can be induced in post-menopausal women after the exogenous
administration of estrogens (Tsai and Yen, 1971; Lachelin and
Yen, 1978; Liu and Yen, 1983; Lutjen et al., 1986). It is clear,
therefore, that after menopause the absence of the feedback mechanisms is due to ovarian insufficiency, whereas the hypothalamicpituitary system remains intact with increased GnRH secretion
and able to respond to the negative and positive feedback effects
of exogenous steroids (Gill et al., 2002). Nevertheless, because the
magnitude of the response in post-menopausal women has not
been quantified in a comparative way with that in premenopausal
women, an altered sensitivity to the ovarian steroids cannot be
excluded, based on recent data in perimenopausal women suggesting hypothalamic-pituitary insensitivity to estrogens (Weiss et al.,
2004).
Clinical implications
Abnormal conditions
During the reproductive years, disturbances in the feedback mechanisms may occur, characterized by menstrual irregularities, such
as dysfunctional uterine bleeding, menorrhagia or amenorrhea. In
terms of the negative feedback mechanism, a possible abnormality
is a reduced suppression of gonadotrophin secretion. This happens
when the production of ovarian steroids is inadequate as in primary ovarian failure or after ovariectomy. Women with premature
ovarian failure and ovulatory cycles have higher FSH and lower
inhibin B and inhibin A levels (Welt et al., 2005a). Although premature ovarian failure is a permanent condition, in some cases the
ovaries become only temporarily inactive. When, however, gonadotrophin levels decrease either spontaneously or after treatment
with E2, normal cyclicity is re-established and even a pregnancy
can occur (Taylor et al., 1996).
The opposite situation, i.e. an augmented negative feedback
mechanism has not been described in humans. It is known that in
women with PCOS serum FSH is normal, while LH is either normal or elevated (Balen et al., 1995b). The inability of follicles to
mature to the preovulatory stage in these patients is due at least in
part to the lack of an intercycle rise of FSH, as when FSH concentrations are slightly elevated by the exogenous administration of
this hormone, follicle selection can take place (van der Meer et al.,
1994). Although the pathophysiology of this syndrome is in several aspects unclear, the lack of an intercycle rise of FSH may be
partly related to an augmentation of the negative feedback effect
mediated by elevated inhibin. It has been shown, however, that
inhibin levels are not higher in patients with PCOS as compared to
controls (Pigny et al., 2000). On the contrary, the concentrations
of both inhibin A and inhibin B in the follicular fluid of PCOS follicles have been found to be significantly lower than in sizematched follicles from normal women (Welt et al., 2005b).
Normally cycling women express a positive feedback effect at
midcycle and ovulate invariably. In cases of follicle arrest including hyperandrogenic conditions, PCOS, hyperprolactinaemia,
hypogonadotrophic-hypogonadism and premature ovarian failure,
there is no regular expression of a positive effect of endogenous
E2. With the exception of hypogonadotrophic-hypogonadism, in
565
I.E.Messinis
the majority of these cases, a positive feedback effect can be demonstrated during an estrogen provocation test (Shaw, 1976).
Therefore, when ovulation is induced in hypogonadotrophichypogonadic women, hCG should be given to induce final follicle
maturation (Messinis, 2005). It has been suggested that the elevated LH that is seen in the serum of about 40% of patients with
PCOS is related to a continuous positive action of E2 on the pituitary (Lobo et al., 1981; Waldstreicher et al., 1988). Although this
has to be confirmed, such an action does not fulfil the criteria of a
positive feedback effect. However, a continuous sensitizing action
of E2 on the pituitary that enhances the pituitary response to GnRH
in PCOS patients cannot be excluded, although data in monkeys
do not support such a hypothesis (Richardson et al., 1992).
Administration of pharmaceutical compounds
Changes in the integrity of the feedback system can occur in normal women under the treatment with various pharmaceutical compounds. Oral contraceptives, containing ethinylestradiol and a
progestagen, maintain the pituitary in a state of low secretion of
gonadotrophins. During the week free of treatment, a FSH rise is
usually below the threshold for follicle selection, and due to follicle arrest, an endogenous LH surge does not occur (Kuhl et al.,
1985). Administration of E2 to normal women during the second
half of the luteal phase reduces FSH intercycle levels and the size
of antral follicles (Fanchin et al., 2003a). This results in a better
synchronization of follicle growth during the ensuing follicular
phase under the stimulation by exogenous FSH (Fanchin et al.,
2003b).
Selective blockage of the positive feedback mechanism can be
achieved in women with the injection of a GnRH antagonist.
When such a compound is given in mid follicular or late follicular
phases of the cycle, the endogenous LH surge is blocked or
becomes abortive (Leroy et al., 1994). The use, however, of
GnRH antagonists as contraceptive means is not feasible due to
variability in the time of LH surge onset, as well as the high cost
and the inconvenience caused to patients. The GnRH agonists act
in a different way than the antagonists and block both the negative
and the positive feedback mechanisms (Fraser, 1988). Other drugs
that can directly affect the feedback system are the anti-estrogenic
compounds, such as clomiphene citrate and tamoxifene. These
drugs bind the estrogen receptors and block the negative feedback
effect, resulting in increased gonadotrophin secretion (Shaw,
1976). Clomiphene also blocks the positive feedback effect during
its administration and for some days after the end of the treatment,
while follicle maturation is progressing (Messinis and Templeton,
1988b). An attenuation of the negative feedback effect in women
can be also achieved with the use of aromatase inhibitors (Mitwally
and Casper, 2001).
Changes in the feedback mechanisms in women can also occur
as a result of increased ovarian activity that takes place during
ovarian stimulation for IVF. In these cases, the negative feedback
is augmented and the positive feedback action is markedly attenuated. During ovarian stimulation, the concentrations of E2 in the
circulation become supraphysiological (Messinis et al., 1985),
while inhibin concentrations also increase excessively (Tsonis
et al., 1988). These result in a significant suppression of LH and
FSH secretion (Messinis and Templeton, 1987a, Messinis et al.,
1998). Gonadotrophin secretion is also markedly reduced during
566
the endogenous LH surge despite the very high E2 concentrations
(Messinis et al., 1985). This has been related to the increased production of GnSAF by the stimulated ovaries, which antagonizes
the stimulating effect of E2 on the pituitary (Messinis and Templeton,
1989).
Nevertheless, during multiple follicular development, the
endogenous LH surge is blocked on several occasions (Messinis
and Templeton, 1987a). When a LH surge occurs, it is either
premature or on time in relation to the size of the preovulatory
follicle (Messinis and Templeton, 1986; Templeton et al., 1986).
In clinical terms, a premature LH surge may result in premature
luteinization and therefore in a low success rate during IVF treatment. The LH surge in these cases can be prevented by the administration of GnRH analogues, although with the antagonists
premature LH peaks >10 IU/l have been reported in a rate from
3 to 35% of the cycles (Albano et al., 2000; Borm and Mannaerts,
2000; Felberbaum et al., 2000; European and Middle East
Orgalutran Study Group, 2001; Engel et al., 2002; Messinis et al.,
2005). Luteinization, however, occurs in a small percentage of the
cases with raised LH.
The importance of LH suppression during ovarian stimulation
induction has not been clarified because data in the literature are
conflicting (Westergaard et al., 2000; Humaidan et al., 2002;
Kolibianakis et al., 2004; Huirne et al., 2005). LH secretion is also
suppressed during the luteal phase of stimulated cycles (Messinis
and Templeton, 1987b; Tavaniotou et al., 2001). It seems that the
suppression of gonadotrophin secretion during ovarian stimulation
is a continuous process starting in the follicular phase and ending
up in a disrupted luteal phase. The latter is inadequate not only
after an attenuated LH surge (Messinis and Templeton, 1987b) but
also after hCG, recombinant LH or a GnRH agonist administration
for final follicle maturation (Beckers et al., 2003).
Conclusions
The two feedback mechanisms are important determinants of the
relationships between the ovaries and the hypothalamic-pituitary
system. The ovarian steroids, E2 and progesterone, are the principal mediators of the suppressing effect on gonadotrophin secretion during the normal menstrual cycle. Evidence has been
provided that for FSH secretion non-steroidal substances, such as
inhibin A and B, also play an important role. E2 is the main component of the positive feedback mechanism that induces the midcycle endogenous LH surge. Further research is required to clarify
the specific role of each of the steroidal and non-steroidal substances in the context of the feedback mechanisms.
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Submitted on February 9, 2006; resubmitted on March 24, 2006; accepted on
March 31, 2006
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