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142
Neuroendocrine Control of the Menstrual Cycle
Janet E. Hall
7
THE REPRODUCTIVE AXIS
Normal reproductive function in women involves repeti-
tive cycles of follicle development, ovulation, and prepara-
tion of the endometrium for implantation should conception
occur in that cycle. This pattern of regular ovulatory cycles is
achieved through precise functional and temporal integration
of stimulatory and inhibitory signals from the hypothalamus,
the pituitary, and the ovary (Fig. 7.1). The reproductive sys-
tem functions in a classic endocrine mode. The master hor-
mone, gonadotropin-
releasing hormone (GnRH), is secreted
in a pulsatile fashion from the hypothalamus into the pituitary
portal venous system. GnRH regulates the synthesis and sub-
sequent release of follicle-
stimulating hormone (FSH) and
luteinizing hormone (LH) from gonadotropes within the
anterior pituitary into the circulation. FSH and LH stimulate
the recruitment and development of ovarian follicles, ovula-
tion, corpus luteum formation, and the coordinated secretion
of estradiol, progesterone, inhibin A, and inhibin B. A key
component of this system is the modulatory effect of ovarian
steroids and inhibins on gonadotropin secretion. Ovarian ste-
roids impact the amplitude and/or frequency of GnRH secre-
tion through their effects on KNDy neurons, discussed below
(also see Chapter 1), that act upstream of GnRH neurons in
the hypothalamus.1–4 In addition, ovarian steroids and inhibins
act directly at the pituitary level. Negative feedback restraint
of FSH secretion is critical to the development of the single
mature oocyte that characterizes human reproductive cycles.
In addition to negative feedback controls, the menstrual cycle
is unique among endocrine systems in its dependence on
estrogen-
positive feedback to produce the preovulatory LH
surge that is essential for ovulation.
NEUROENDOCRINE COMPONENTS OF THE
REPRODUCTIVE AXIS
•
Genetic findings from patients with congenital deficiencies in gonad-
otropin secretion have significantly advanced our understanding of
the ontogeny and upstream regulation of GnRH.
•
Kisspeptin, neurokinin B, and dynorphin are important regulators
of GnRH synthesis and secretion and transduce gonadal steroid feed-
back to GnRH neurons.
•
The differential control of LH and FSH requires the integration of
GnRH pulse amplitude and frequency with direct pituitary feedback
from estradiol and inhibins.
•
Ovarian negative feedback on LH and FSH is primarily, but not
exclusively, mediated through kisspeptin control of GnRH secretion
with the additional pituitary effect of the inhibin/activin/follistatin
system on FSH.
•
Ovarian positive feedback in women and nonhuman primates
is mediated primarily at the pituitary level with the permissive
involvement of GnRH; in rodents increased kisspeptin-
mediated
GnRH stimulation is required in addition to direct pituitary effect.
GONADOTROPIN-RELEASING HORMONES
Luteinizing-
releasing hormone (LHRH) was isolated, char-
acterized, and synthesized in 1971.5 The central role of this
decapeptide in the propagation of the species makes it fit-
ting that Drs. Schally and Guillemin received the Nobel
Prize in Physiology and Medicine in 1977 for its isolation.
It was expected that separate releasing hormones for LH
and FSH would be discovered. However, subsequent stud-
ies provided evidence that both LH and FSH are secreted in
response to LHRH, resulting in the common use of the term
gonadotropin-
releasing hormone (GnRH) for the decapeptide
originally referred to as LHRH.
GnRH neurons differentiate in the olfactory placode, cross the
cribriform plate into the forebrain, and migrate to the medial basal
hypothalamus, where they establish connections with the pituitary
portal system in the median eminence as part of the hypotha-
lamic tuberoinfundibular system.6 The initial leg of this migratory
journey occurs along the scaffold of olfactory, vomeronasal, and
terminal nerves. The importance of this developmental pathway
is evidenced in patients with Bosma arhinia microphthalmia syn-
drome. In this syndrome, individuals are born without a nose, are
anosmic, and fail to go through puberty due to hypogonadotropic
hypogonadism.7 In humans there are approximately 7000 GnRH
expressing neurons in areas of the brain linked to gonadotropin
OUTLINE
THE REPRODUCTIVE AXIS
NEUROENDOCRINE COMPONENTS OF THE REPRODUCTIVE
AXIS
GONADOTROPIN-RELEASING HORMONES
Pulsatile Secretion of GnRH
Neuromodulators of GnRH Secretion
Sleep and Circadian Effects on GnRH Secretion in Women
GONADOTROPIN-
PRODUCING CELLS OF THE PITUITARY
Gonadotropn Isoforms
Effect of Obesity
Differential Control of LH and FSH Secretion
OVARIAN FEEDBACK ON THE HYPOTHALAMUS AND
PITUITARY
Negative Feedback
Positive Feedback
THE NORMAL MENSTRUAL CYCLE
Clinical Characteristics
Ovarian Feedback and the Dynamics of GnRH Secretion
and Pituitary Responsiveness
Follicular Phase
Midcycle Surge
Luteal Phase
Luteal-Follicular Transition
Racial Differences in Menstrual Cycle Dynamics and Fertility
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CHAPTER 7 Neuroendocrine Control of the Menstrual Cycle 143
7
regulation.8 Unlike neurons secreting other hypothalamic releas-
ing factors, GnRH neurons do not exist in a defined nucleus but
are scattered throughout the medial basal hypothalamus, with
additional scattered neurons in the preoptic area.9
Over the past three decades, genetic studies in patients with
idiopathic hypogonadotropic hypogonadism (IHH) with con-
comitant disruption of the olfactory system resulting in anosmia
(Kallmann Syndrome; KS) or without anosmia (normosmic idio-
pathic hypogonadotropic hypogonadism; nIHH), have resulted
in unprecedented growth in our understanding of the complex
neuroendocrine control of reproduction. Mutations in well over
50 genes have now been discovered in this rare patient popula-
tion.10 Validation of their function in animal and cell systems
indicates that these can be broadly classified into four groups. A
number of genes have been discovered that are involved in the
early migration and axonal guidance of GnRH neurons on the path
to their eventual home in the hypothalamus, some of which are
associated with other developmental defects. This group of genes
includes Kallmann 1 (KAL1) now known as anosmin 1 (ANOS1),11
chromodomain helicase DNA binding protein 7 (CHG7),12 sex-
determining region of Y-
box 10 (SOX10),13 semaphorin-3A
(SEMA3A),14,15 fasciculation and elongation protein zeta family
zinc finger 1 (FEZF1),16 fibronectin leucine-
rich transmembrane
protein 3 (FLRT3),17 IL-
17 receptor D (IL17RD),17 and structural
maintenance of chromosomes flexible hinge domain-
containing
protein 1 (SMCHD1),7 among others. Genes involved in the con-
trol of GnRH secretion include kisspeptin and its receptor (KISS1/
KISS1R),18–20 tachykinin 3 and its receptor (TAC3/TACR3),21
gonadotropin-
releasing hormone1 (GNRH1),22,23 and dosage-
sensitive sex reversal 1 (DAX1), also known as nuclear receptor
subfamily 0, group B, member 1 (NROB1).24 Genes that appear to
play a role in both GnRH ontogeny and function include fibroblast
growth factor 8 and its receptor fibroblast growth factor receptor
1 (FGF8/FGFR1),25–28 prokineticin 2 and its receptor (PROK2/
PROKR2),29,30 heparin sulfate 6-
O-
sulfotransferase 1 (HS6ST1),31
WD repeat domain 11 (WDR11),32 AXL receptor tyrosine kinase
(AXL),33 NMDA receptor synaptonuclear signaling and neuro-
nal migration factor (NSMF),34 dual specificity phosphatase 6
(DUSP6),17 sprouty homolog 4 (SPRY4),17 and fibroblast growth
factor 17 (FGF17).17 Finally, the genes involved in gonadotrope
stimulation that have been discovered to date in association with
IHH include only DAX1 and gonadotropin-
releasing hormone
receptor (GNRHR).35 As more patients are identified and studied,
this list will undoubtedly continue to grow.
Pulsatile Secretion of GnRH
A prominent feature of the reproductive system is the absolute
requirement for pulsatile secretion of GnRH into the pituitary
portal system for normal gonadotropin secretion. The now clas-
sic studies of Knobil and colleagues in hypothalamic-
lesioned
monkeys receiving GnRH first showed that intermittent stimula-
tion of the pituitary results in secretion of LH and FSH, while
constant GnRH stimulation is associated with suppression of
gonadotropin levels.36 Isolated GnRH neurons exhibit an intrin-
sic pulsatility,37 but there is also a significant body of research
indicating that external influences modify and coordinate the
secretion of GnRH, influencing both the amplitude and fre-
quency of pulsatile GnRH secretion.
Neuromodulators of GnRH Secretion
While a number of neurotransmitters are involved in the control
of GnRH secretion in animal species, only a few have been shown
to have an effect on humans.38 Although there is evidence for
a stimulatory role of the α-
adrenergic system in several animal
models, it is much less likely that it plays a role in the control
of the human menstrual cycle. The role of the dopaminergic
system remains controversial, but studies that have documented
an increase in LH pulse frequency in response to a dopamine
antagonist in women with hypothalamic amenorrhea suggest that
dopamine may inhibit GnRH secretion in women.39,40
Kisspeptin
Knock-
out models suggest that there is considerable redundancy in
the systems that ultimately control GnRH secretion; however, it is
now firmly established that the kisspeptin pathway is a key upstream
modifier of GnRH secretion. As with the genes that are now known
to control the developmental migration of GnRH neurons, a role
for kisspeptin in reproduction was initially discovered by the com-
bination of genetic studies in patients with IHH which identified
mutations in the gene encoding the kisspeptin receptor (KISS1R,
formerly known as G-
protein coupled receptor 54 [GPR54]) and
knock-
out mouse models.18,19 Kisspeptin is an extremely powerful
stimulator of LH, an action that is blocked by a GnRH antagonist,
Ovary
Uterus
GnRH
Estradiol
Estradiol
Inhibin A
Inhibin B
FSH
LH
Estradiol
Pituitary
KISS
NKB
DYN
NKB
Fig. 7.1 Neuroendocrine control of reproduction requires the pulsatile
secretion of gonadotropin-
releasing hormone (GnRH) released into
the pituitary portal system to stimulate the synthesis and secretion
of luteinizing hormone (LH) and follicle-
stimulating hormone (FSH)
from pituitary gonadotropes. The gonadotropins, in turn, stimulate
follicle development and secretion of gonadal steroids and peptides. As
shown on the right, negative feedback of estradiol and progesterone on
hypothalamic GnRH secretion is mediated through kisspeptin (KISS),
neurokinin B (NKB), and dynorphin (DYN) which are colocalized in the
KNDY neurons of the median eminence. Inhibin A, inhibin B, and estradiol
also exert negative feedback effects directly at the pituitary. As shown on
the left, rising levels of estradiol are responsible for the positive feedback at
the pituitary, which generates the preovulatory gonadotropin surge. (From
Hall JE, Cacciopa P, NIEHS, personal communication.)

PART I The Fundamentals of Reproduction
144
indicating that the effect of kisspeptin on LH is mediated through
control of GnRH secretion.41,42 The kisspeptin system is thought
to play a dominant role in the onset of puberty and mediates estro-
gen and progesterone negative feedback in the median eminence.2
Studies of kisspeptin administration in women, performed using
different isoforms and either subcutaneous, intravenous bolus, or
intravenous infusion modes of administration, have demonstrated
a marked difference in LH response depending on cycle phase
and hormonal status.43 The response to kisspeptin is consistently
robust in the late follicular, preovulatory, and luteal phases of the
menstrual cycle and in postmenopausal women, while there is some
inconsistency in the early follicular phase with a lower, and in some
cases absent, LH response to kisspeptin44 The LH response to
continuous kisspeptin was similarly low in postmenopausal women
but increased after two weeks of estrogen replacement in a dose-
dependent fashion, an effect that appears to be mediated at both the
pituitary and the hypothalamic level.45
In rodents and sheep, there is ample evidence that positive
feedback is manifest in the hypothalamus as well as the pituitary
with the generation of a marked increase in GnRH at the time
of the midcycle gonadotropin surge.46,47 Kisspeptin neurons in
the anteroventral periventricular nucleus (AVPV) have now been
implicated in this estrogen-
positive feedback on GnRH secretion
in rodents.1 The relationship of the AVPV to the suprachiasmatic
nucleus (SCN) in the rodent provides a potential mechanism for
the known circadian timing of the proestrus surge in the rodent.48
Despite compelling evidence in lower animal species, it is
likely that kisspeptin control of GnRH does not play a role in the
midcycle surge in women; studies in women demonstrate a pau-
city of kisspeptin neurons in an analogous hypothalamic region49
and evidence discussed below demonstrates that a GnRH surge
is not required for the generation of a midcycle LH surge in
GnRH-deficient women50 and further suggests that a GnRH
surge is not present in normal women.51
Neurokinin B
Neurokinin B (NKB), which is encoded by the tachykinin 3 gene
(TAC3) and its cognate receptor, NK3R, encoded by TACR3,
have also been implicated in the normal control of GnRH secre-
tion through genetic studies in patients with IHH.21 NKB stimu-
lates LH secretion, acting upstream of the GnRH neuron.52,53
TAC3 and KISS are colocalized in the human as well as in other
species,54 particularly in the arcuate/median eminence. There is
significant evidence that the effect of NKB on GnRH is exerted
primarily through kisspeptin. NKB agonists stimulate gonado-
tropin secretion55 while NKB3 antagonists inhibit LH secretion,
but do not appear to do so in the setting of high estrogen, as in
the preovulatory phase56 Interestingly, the NKB3/NK3R system
also plays a role in hot flashes in estrogen-
deficient states.56–58
Endogenous Opioids/Dynorphin
There is substantial evidence for the involvement of endorphins in
transducing the negative feedback effects of progesterone on pulsa-
tile GnRH secretion from studies using the opioid receptor blocker,
naloxone, in women.59,60 However, naloxone binds not only to
the mu receptor but also to the kappa and gamma receptors and
thus these early studies could not provide mechanistic specificity.
Dynorphin which binds to the kappa-
opioid receptor has now been
identified as the key mediator of progesterone negative feedback.61
KNDy Neurons
In a variety of animal species and humans it has been shown that kis-
speptin, NKB, and dynorphin are coexpressed in cells in the arcuate
nucleus/median eminence that are now referred to as KNDy neu-
rons. These neurons express estrogen, progesterone, and androgen
receptors and mediate gonadal steroid negative feedback on GnRH
secretion with increasing evidence that they are also involved in the
initiation and termination of GnRH secretion that results in its pul-
satile secretion.62 Gamma-
amino butyric acid (GABA) may also be
involved in mediating estrogen-
negative feedback on GnRH secre-
tion, particularly in the arcuate/median eminence.63,64
RFamide-Related Peptides
RFaimde-
related peptides (RFRP) are the mammalian orthologues
of gonadotropin inhibitory hormone (GnIH) which was first dis-
covered in the hypothalami of the quail.65 In humans, RFRP-
1 and
RFRP-
3 neurons send axonal projections to GnRH neurons.66,67
RFRPs are secreted into the pituitary portal system68 and their
receptor, G-
protein coupled receptor 147 (GPR147), is present
on gonadotropes as well as in the hypothalamus66 Taken together
with functional data from animal and cellular systems, these find-
ings suggest that RFRPs function at both the hypothalamus and
pituitary to regulate the secretion of LH and FSH. Interestingly,
there is also evidence that RFRPs increase food intake in sheep
without reducing energy expenditure.67 There is currently limited
data to address the role of these peptides in humans. A three-
hour
infusion of custom synthesized GnIH resulted in a modest sup-
pression of LH secretion in postmenopausal women but failed
to inhibit LH secretion in response to pulses of kisspeptin-
10 in
men.69 Additional studies will be required to ascertain its physiol-
ogy and potential therapeutic role in men and women.
Sleep and Circadian Effects on GnRH Secretion
in Women
Endocrine systems are profoundly influenced by both sleep and
endogenous circadian rhythms, which are intrinsic rhythms
that persist in the absence of sleep or other environmental cues.
Diurnal (day and night) rhythms of LH and gonadal steroids
have been well described in men and women. However, studies in
which sleep and other environmental cues were controlled have
failed to demonstrate an endogenous circadian rhythm of LH or
FSH in early follicular phase women (Fig. 7.2) and in postmeno-
pausal women, despite the presence of robust circadian rhythms
of temperature, cortisol, and TSH.70,71
In contrast, there is compelling evidence that sleep directly
affects the pulsatile secretion of LH and presumably that of
GnRH. Studies that have separated the effects of sleep from time
of day demonstrate that during puberty in boys and girls, pulsatile
LH secretion is increased during sleep.72,73 More recent studies
indicate that LH pulses are most commonly preceded by slow
wave sleep (SWS)74 and further studies have shown that even
with repeated sleep interruption, 20 min of accumulated sleep is
associated with LH pulse onset in this population.75 These stud-
ies suggest that factors associated with SWS stimulate GnRH
secretion or that there is an upstream regulator of both GnRH
secretion and deep sleep in puberty.
Paradoxically, with the maturation of the reproductive system
and the onset of ovulatory menstrual cycles, there is a notable
slowing of pulsatile LH secretion at night in the early follicu-
lar phase of the cycle.76,77 Sleep reversal studies in women have
demonstrated that the early follicular phase of nighttime slowing
is due to sleep rather than the time of day.78 Importantly, within
sleep, brief periods of wakefulness are associated with the onset
of LH pulses (Fig. 7.3), while SWS is inhibitory to LH pulses.78
Data relating luteal phase characteristics to early follicular
phase nighttime pulse frequency suggests that prior progesterone
exposure sensitizes the GnRH pulse generator to the inhibitory
effects of sleep in the early follicular phase.79 In this regard, it is of
interest that GnRH pulse frequency, as determined by the pulsa-
tile secretion of the gonadotropin-
free alpha subunit (FAS), is also
slower during sleep than wake in postmenopausal women whose
gonadal steroid levels are similar to those in early puberty, where
sleep is stimulatory.80 Although the effect of sleep is much less than

7
in normally cycling women, this finding suggests that the inhibi-
tory effect of sleep on LH pulse frequency is not only related to
prior progesterone exposure but that other factors relating to the
development of a mature reproductive axis are involved.
GONADOTROPIN-
PRODUCING CELLS OF THE
PITUITARY
LH and FSH are synthesized in gonadotropes, which comprise
between 7% and 15% of the cells in the pituitary. Immuno
histochemical studies in the rat indicate that approximately 70%
of gonadotropes stain for both LH and FSH, while the remainder
stains for LH or FSH in approximately equal numbers. As the
animals approach the day of the gonadotropin surge in proestrus,
monohormonal cells begin to express both βLH and βFSH, while
a population of cells that express growth hormone (GH) also
express the gonadotropin subunits.81
LH and FSH are glycoprotein hormones whose polypeptide
and polysaccharide components are essential for their activity.
Biosynthesis of intact gonadotropins involves (1) translation of
βLH, βFSH, and the common gonadotropin α-
subunit; (2) post-
translational modification and folding; (3) combination of the β-
and α-subunits; and (4) modification of the oligosaccharide residues
on LH and FSH as they traverse the Golgi.82 FSH is synthesized
under the dual control of GnRH and the activin/inhibin/follistatin
system and is secreted primarily in a constitutive manner with little
storage. In contrast, LH is packaged into granules and stored. LH
and the gonadotropin-
free α subunit (FAS) are then secreted in
response to GnRH stimulation of the gonadotrope.
Gonadotropn Isoforms
Multiple isoforms of LH and FSH, differing in their carbohydrate
structure and charge, coexist in both pituitary and serum. When
combined with a β-subunit, the α-
subunit has two glycosylation
sites. FSHβ also has two potential glycosylation sites, while LHβ
has a single potential site. This results in the secretion of FSHtri
and FSHquatro and LHdi and LHtri. Terminal sulfonated and/
or sialylated residues on these glycoforms add further isoform het-
erogeneity to secreted gonadotropins. More basic forms of both
LH and FSH yield a greater in vitro potency, but a shorter half-
life
in the circulation, while the opposite is true for less basic forms.83
The greater number of sialic acid residues on FSH prolongs its
half-life,84 whereas the greater number of sulfonated N-
acetyl-
galactosamine (GalNAc) asparagine-
linked oligosaccharides on
LH is associated with more rapid clearance due to binding to a
specific hepatic receptor.85 Sulfonation and sialylation of LH and
FSH vary across the menstrual cycle and in the absence of gonadal
steroids; postmenopausal women have a greater preponderance of
sialylated forms of both LH and FSH.86 The number of sulfonated
and sialylated residues on LH and FSH is tightly linked to hor-
mone clearance in women and, by inference, to bioactivity.84 Thus,
the disappearance of LH following GnRH receptor blockade with
a potent GnRH antagonist is significantly prolonged in post-
menopausal women compared to women in the follicular phase
and at the midcycle surge (MCS),87 while the disappearance of
FAS is unaffected by the absence of gonadal function (Table 7.1).
Changes in the isoform composition of FSH in the normal men-
strual cycle are likely to augment the effect of the rise in FSH on
follicle recruitment and development during the luteal-
follicular
transition through a decrease in clearance; in contrast isoform
changes that increase clearance would curtail the potential effect of
the increase in FSH on follicle recruitment at midcycle.
Effect of Obesity
There is also evidence that gonadotropin secretion is modulated
by a factor or factors related to obesity. Serum levels of LH are
inversely related to body mass index (BMI) in normal women and
in women with polycystic ovary syndrome (PCOS).88 Further
studies have indicated that the inhibitory effect of obesity on
LH secretion in PCOS is not mediated at the hypothalamus
but is associated with a decrease in both the pituitary response
to GnRH and the half-
life of endogenous, but not exogenous,
LH.89,90 The latter finding is consistent with the increase in sul-
fonated isoforms of LH and FSH as a function of increasing BMI
in women with PCOS.86 Recent studies have shown that in obese
men and obese women without PCOS, the combination of an
insulin and lipid/heparin infusion which results in increased free
fatty acids and triglycerides, suppresses LH and FSH.91 Although
the characteristics of pulsatile LH secretion were not measured
in this study, the studies described above would suggest that the
resultant decrease in LH and FSH is mediated at the pituitary.
Fig. 7.2 Mean + sem of temperature, FSH, LH, FAS, and TSH
levels in early follicular phase women (n = 11) during a constant
routine of light, position, wake, and nutritional intake over a 24-
hour
period. These studies indicate the constancy of gonadotropin levels
across the day and night in the absence of sleep with maintenance of
endogenous circadian rhythms of temperature and TSH. Individual studies
are aligned to the onset of habitual sleep onset for each subject beginning
8 hours from the onset of sampling, although subjects were awake for the
full 24 hours of the study. (Adapted from Klingman KM, Marsh EE, Klerman
EB, Anderson EJ, Hall JE. Absence of circadian rhythms of gonadotropin
secretion in women. J Clin Endocrinol Metab. 2011;96[5]:1456–1461.)

146
Differential Control of LH and FSH Secretion
Although secreted from a common cell type within the gonad-
otrope, LH and FSH have markedly different functions in the
control of ovarian physiology. These differences in function are
reflected in their different patterns of secretion during normal
reproductive cycles. The divergent control of LH and FSH is
achieved through a combination of differential control of the
synthesis and secretion of LH and FSH by the pattern of GnRH
stimulation, the preferential control of FSH synthesis by the
activin/follistatin system, and differential feedback by ovarian ste-
roids and the inhibins at the pituitary. Understanding the control
of LH and FSH secretion is critical to our understanding of the
dynamics of the menstrual cycle.
Gonadotropin-Releasing Hormone
FSH is secreted along with LH in response to acute stimulation
by GnRH, but the relative role of GnRH in the overall control of
FSH synthesis is much less than for LH. Blockade of the GnRH
receptor using a specific GnRH receptor antagonist results in
90% inhibition of LH secretion, but only 40% to 60% inhibi-
tion of FSH.92 Synthesis and secretion of LH and FSH are dif-
ferentially controlled by the amplitude and frequency of GnRH
stimulation.93,94 LH is highly responsive to increases in the dose
of GnRH, while FSH is relatively insensitive to the GnRH
dose. A physiological frequency of GnRH results in the synthe-
sis and secretion of FSHβ, LHβ, and free α subunit. However,
increases or decreases in the physiological frequency have differ-
ential effects on LH and FSH (Table 7.2). Slow frequencies of
GnRH stimulation favor synthesis and secretion of FSH in vitro
and are associated with an increase in FSH in human studies in
settings in which gonadal feedback is low.95 In GnRH-
deficient
men and women, an increase in the frequency of GnRH stimula-
tion increases mean levels of LH with no appreciable change in
FSH96,97 (Fig. 7.4), effects that have implications for the patho-
physiology of PCOS which is characterized by an increased fre-
quency of pulsatile GnRH stimulation of the pituitary.89 The
direct effect of GnRH pulse frequency on GnRH receptor num-
ber98 underlies the frequency modulation of LH and FSH secre-
tion, at least in part. In addition, increased GnRH pulse frequency
increases follistatin which would attenuate activin stimulation of
FSH synthesis, as discussed below.99
While an increase in GnRH pulse frequency increases the
synthesis and mean levels of LH, LH pulse amplitude is inversely
related to GnRH pulse frequency.100,101 Studies in GnRH-
deficient men and women have shown that slower GnRH pulse
frequencies are associated with a higher LH pulse amplitude in
Fig. 7.3 As indicated in the left panel,
sleep is specifically associated with
slowing of luteinizing hormone (LH)
pulses. The LH interpulse interval (IPI) is
longer and amplitude is higher in normal
women during sleep (blue bars) compared
with wake (purple bars), whether sleep
occurs at night or during the day. As
indicated in the right panel, wakefulness is
more likely in the 5 to 10 minutes before
the onset of an LH pulse (blue bars) than
in a similar period indexed to a random
LH point that is not associated with an
LH pulse (purple bars). (Adapted from
Hall JE, Sullivan JP, Richardson GS. Brief
wake episodes modulate sleep-
inhibited
luteinizing hormone secretion in the early
follicular phase. J Clin Endocrinol Metab.
2005;90[4]:2050–2055.)
–15
to –10
*
*** **
Min
of
wakefulness/5
minutes
3
2
1
0
–10
to –5
–5
to 0
–20
to –15
Minutes from onset
*
* **
**
**
Wake sleep
day
Mean
LH
(IU/L)
LH
amp
(IU/L)
LH
IPI
(minutes)
10
5
0
10
5
0
200
100
0
Wake sleep
night
TABLE 7.1 The Half-
Life of LH, But Not the Gonadotropin Free α Subunit (FAS), Is Influenced by the Gonadal Steroid Milieu
LH Gonadotropin Free α Subunit
Baseline (IU/L) Mean
± SEM
T1/2 (minutes)
Mean ± SEM
Baseline (pg/mL) Mean
± SEM
T1/2 (minutes)
Mean ± SEM
Postmenopausal 62 ± 3 139 ± 35 774 ± 45 51 ± 26
EFP, LFP, ELP 10 ± 1 57 ± 28 266 ± 44 41 ± 12
MCS 56 ± 11 78 ± 20 627 ± 122 41 ± 19
LH, luteinizing hormone; FSH, follicle-
stimulating hormone.
(From Sharpless JL, Supko JG, Martin KA, Hall JE. Disappearance of endogenous luteinizing hormone is prolonged in postmenopausal women. J Clin
Endocrinol Metab. 1999;84[2]:688–694.)
TABLE 7.2 Differential Effects of GnRH Pulse Frequency on LH and FSH
LH FSH
Increased frequency
“In vitro”
mRNA ↑ →
GnRH-deficient men/women
Mean ↑ →↓
Amplitude ↓
Decreased frequency
“In vitro”
mRNA ↓ ↑
GnRH-deficient men/women
Mean ↓ →↑
Amplitude ↑

7
response to GnRH, while faster frequencies are associated with
a decrease in the LH pulse amplitude response to GnRH. This
decrease in LH amplitude seen with pulse frequencies that are
faster than those encountered in physiological settings96,97 may
be the earliest sign of the pituitary desensitization that is well rec-
ognized in association with continuous infusions of GnRH or the
use of a GnRH agonist.
Autocrine/Paracrine Regulation of Gonadotropins: Activin,
Inhibin, and Follistatin
Activins, inhibins, and follistatins were first discovered as gonadal
factors with preferential actions on FSH secretion from pitu-
itary gonadotropes.102 The inhibins, named for their inhibitory
effect on FSH secretion in pituitary cell cultures, are heterodi-
mers that are composed of one of two β-subunits, βA or βB, and
a closely related α-
subunit to form inhibin A or inhibin B. In
contrast, the activins, which stimulate the synthesis and secretion
of FSH, are homodimers of two β-
subunits. Activin is secreted
by gonadotropes and other pituitary cell populations. Like other
members of the TGF-
β superfamily of growth and differentia-
tion factors, activins exert most of their effects by autocrine or
paracrine mechanisms. Activins sequentially interact with one
of the two known type-
II activin receptors, ActRII or ActRIIB,
and the type-
1 receptor, activin receptor-
like kinase 4 (ALK4).102
The expression of FSHβ is extremely sensitive to the stimulatory
action of activins, which work in concert with and are permissive
to the actions of GnRH through the promotion of transcription
of both FSHβ and the GnRH receptor.103
The inhibins act as specific antagonists of the FSH stimulatory
actions of activin by binding to betaglycan and sequestering the
type-
II activin receptors. While inhibin is made in the pituitary,
circulating inhibin derived from the ovary plays a far greater role
in the negative control of FSH. In addition, bone morphogenic
proteins, BMP-
6 and BMP-
7, are capable of modulating FSH
synthesis in gonadotropes suggesting that other systems may also
be involved in the control of FSH.102,104
Follistatin is a monomeric protein that is distinct from the
activin and inhibin family and acts as a virtually irreversible bind-
ing protein by complexing with activin and masking the binding
sites on activin for the type-
I and type-
II receptors.105 Synthesis
of follistatin in pituitary folliculostellate cells and gonadotropes is
controlled by activin and GnRH and may be additionally modu-
lated by gonadal steroids. The follistatin 288 isoform (FS288) has
a high affinity for cell-
surface proteoglycans and is presumed to
act within the pituitary.104 Activin levels do not appear to vary
during female reproductive cycles. However, changes in fol-
listatin have been noted during the rat estrus cycle, suggesting
that the effects of activin on FSH synthesis and secretion may be
modulated through changes in follistatin in addition to effects
of inhibin.104 As indicated above, follistatin is increased by fast
frequencies of GnRH stimulation and decreased with slower fre-
quencies99 compatible with the hypothesis that the activin and
follistatin system mediates the effect of GnRH pulse frequency
on FSH. Thus, while GnRH appears to be sufficient for control
of LH synthesis and secretion, the activin-
inhibin-
follistatin sys-
tem and perhaps BMPs play a significant role in conjunction with
GnRH in regulating the synthesis and secretion of FSH.
OVARIAN FEEDBACK ON THE HYPOTHALAMUS AND
PITUITARY
Negative Feedback
Estrogen
It is well known that low doses of estrogen inhibit gonadotropin
secretion. Increased gonadotropin levels in patients with aromatase
deficiency provide the most specific evidence of estrogen-
negative
feedback on the control of both LH and FSH in men and
women.106 This is supported by the marked increase in LH and
FSH levels in postmenopausal and ovariectomized women.107 The
loss of gonadal feedback in ovariectomized rats is associated with
increased expression of LHβ, FSHβ, and α subunit mRNA, an
increase in the number of cells expressing LHβ accompanied by
an increased in cell size and an increase in total expression per cell,
and an increase in LH and FSH secretion. Administration of low
doses of estradiol reverses these changes,108 as has also been shown
in ovariectomized sheep and monkeys.
There is considerable evidence that supports a primary
hypothalamic site of estrogen-
negative feedback on pituitary
gonadotropin secretion.38,109 Studies in which GnRH secretion
has been measured using a push-
pull hypothalamic perfusion
technique in rats—or cannulation of the pituitary portal circula-
tion in sheep and monkeys—indicate that GnRH rises follow-
ing ovariectomy and falls with estrogen replacement. Estradiol
administration is associated with a decrease in GnRH expres-
sion in rat hypothalamic tissue slices and in a GnRH neuronal
Fig. 7.4 The differential effect of increasing
gonadotropin-
releasing hormone (GnRH) pulse
frequency on luteinizing hormone (LH) and follicle-
stimulating hormone (FSH) as demonstrated in a
GnRH-
deficient woman receiving intravenous pulsatile
GnRH at intervals indicated by the dotted lines. The
study began after 7 days of pulsatile GnRH administration
at a dose of 75 ng/kg and a frequency of every 90 minutes.
Blood was sampled for 6 hours at dosing intervals of 90
minutes, 60 minutes, and 30 minutes. LH, but not FSH,
increased with the shortest dosing interval. The means of
LH and FSH, normalized for the overall amount of GnRH
administered (nLH and nFSH), suggest that faster GnRH
pulse frequencies are associated with early stages of
pituitary desensitization. (From Hall JE, Taylor AE, Hayes
FJ, Crowley WF Jr. Insights into hypothalamic-
pituitary
dysfunction in polycystic ovary syndrome. J Endocrinol
Invest. 1998;21[9]:602–611.)
LH mean
nLH mean
10.4
10.4
8.9
9.0
14.3
4.8
FSH mean
nFSH mean
20
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
LH
(IU/L)
FSH
(IU/L)
Time (hour)
GnRH dose (75 ng/kg)
10.4
10.4
9.6
6.4
10.7
3.6
15
10
5
0
35
30
25
20
15
10
5

148
cell line. Studies in estrogen receptor (ER) knock-
out animals
support an essential role for ERα in estrogen-
negative feedback,
although both forms of the receptor are present in the hypothal-
amus.109 The major hypothalamic estrogen-
negative feedback
effect is mediated through neurons upstream of GnRH itself,
most importantly the KNDY neurons of the arcuate/median
eminence.1,2 Estrogen-
receptive GABA neurons within the pre-
optic area may also play a role in mediating the negative feed-
back effects of estrogen on GnRH secretion. Although involved
in progesterone negative feedback at the hypothalamus, the
opioid system is unlikely to be involved in estrogen-
negative
feedback.38
In women, the mechanisms underlying estrogen-
negative
feedback have generally been investigated in postmenopausal
or ovariectomized women. The quantity of GnRH, estimated
in vivo using submaximal GnRH receptor blockade, is higher
in postmenopausal compared with premenopausal women,110
consistent with the increase in GnRH mRNA that has been
demonstrated in postmenopausal women studied at autopsy.111
With the administration of low levels of estradiol, the quan-
tity of GnRH returned to follicular phase levels in postmeno-
pausal women, suggesting that the increase in GnRH in the
absence of gonadal feedback can be attributed entirely to the
loss of estrogen.112 To further support a hypothalamic site of
estrogen-
negative feedback in women, neuroimaging studies
have now provided evidence of decreased metabolic activity in
the medial basal hypothalamus in association with brief expo-
sure to relatively low doses of estradiol in postmenopausal
women.113 Estradiol administration does not decrease GnRH
pulse frequency in the majority of studies in postmenopausal
women107 and thus, the negative feedback effect of estradiol on
the hypothalamus is likely to be mediated through changes in
GnRH pulse amplitude. These results in women are similar to
those in which GnRH was measured directly in pituitary por-
tal blood in ovariectomized sheep and monkeys and showed
a decrease in GnRH pulse amplitude, but not frequency in
response to estradiol administration.114,115 Autopsy studies
in women are consistent with a role for neurons expressing
kisspeptin, NKB, substance P, dynorphin, and ERα in medi-
ating the negative feedback of estrogen in the medial basal
hypothalamus.49,116,117
While the studies detailed above demonstrate a significant
hypothalamic effect of estrogen-
negative feedback, they do not
exclude a pituitary site of action. In cultured pituitary cells,
estradiol transiently reduces the LH response to GnRH,118 and
administration of estradiol to hypothalamic-
lesioned monkeys
receiving pulsatile GnRH decreased LH secretion.119 Both ERα
and ERβ are present on gonadotropes109,120 and characterization
of the gonadotrope-
specific ERα (ESR1) knock-
out mouse has
now provided definitive evidence of a direct inhibitory effect of
estradiol at the pituitary in the rodent.121 Studies in postmeno-
pausal women that isolated the pituitary from hypothalamic
input have extended these findings from lower animal species to
humans by demonstrating that physiological levels of estradiol
have a direct pituitary effect on gonadotropin secretion that is
greater for FSH than for LH.122
Progesterone
Progesterone has a profound effect on gonadotropin secretion
that manifests at the hypothalamic level through the slowing of
pulsatile GnRH secretion.123,124 This effect requires estrogen
priming,125 likely through upregulation of progesterone recep-
tors in the hypothalamus.126 In postmenopausal women receiving
low doses of estradiol, the addition of progesterone uniformly
suppresses GnRH pulse frequency using either LH or FAS as
markers of GnRH secretion,112 and administration of proges-
terone decreases the overall amount of GnRH secretion.110 It
is likely that progesterone exerts its effects on GnRH secretion
primarily through its receptors on KNDY neurons.38,127 As indi-
cated above, there is ample evidence that the β-endorphin sys-
tem plays a critical role in mediating the effects of progesterone
on GnRH pulse frequency and studies in sheep indicate that the
inhibitory effect of progesterone on GnRH secretion is mediated
by dynorphin, a critical component of KNDY neurons.61
Inhibin A and Inhibin B
Evidence for a nonsteroidal gonadal factor with feedback effects
on the pituitary dates to the early 1900s but it was not until the
mid-
1980s that inhibin was isolated and subsequently found to
be part of a family of peptides that includes inhibin A, inhibin B,
activin, and the functionally related protein, follistatin.104 Inhibin
B is present in the circulation in men while both inhibin A and
inhibin B are detected in serum and follicular fluid in women dur-
ing their reproductive years.128–131
Inhibin A is secreted in both the follicular and luteal phases
of the menstrual cycle. During folliculogenesis, peak levels of
inhibin A are attained in the preovulatory period and inhibin
A is correlated with the size of the dominant follicle in normal
cycles,129,130 as is estradiol. Follicular phase inhibin A is primar-
ily the product of granulosa cells; however, there is some evi-
dence for theca cell production in the mature follicle.132 Studies
of βA inhibin subunit expression132 and measurement of dimeric
inhibin A in follicular fluid133 are consistent in indicating maximal
follicular phase levels in the preovulatory follicle. However, it is
now appreciated that inhibin A is also synthesized and secreted at
earlier stages of follicular development, beginning in the mid to
late follicular phase.134 The peak in inhibin A in the luteal phase
and its decline with luteolysis are consistent with production by
the corpus luteum, as expected from the high levels of βA inhibin
subunit expression in the corpus luteum.132
IncontrasttoinhibinA,thepatternofinhibinBinserumsuggests
that it is primarily secreted from small antral follicles. A correlation
of inhibin B levels with the size of the dominant follicle is remark-
ably absent in women during spontaneous ovulatory cycles,130 sug-
gesting that inhibin B is consistent with studies showing that inhibin
B levels in follicular fluid do not change as a function of follicle size
or maturity.133 They are also consistent with earlier studies demon-
strating that expression of βB inhibin subunit mRNA is highest in
early antral follicles, with lower levels in the dominant follicle and
no evidence of βB-
subunit expression in the corpus luteum.132 The
latter studies have also shown that inhibin B synthesis is confined to
the granulosa cells and is absent in theca cells.
Regulation of Inhibin A and Inhibin B by Gonadotropins. A
significant body of data has demonstrated an increase in inhibin
B secretion in conjunction with early follicular development
stimulated by physiological levels of FSH. This was initially
suggested by the relationship of the rise in FSH during the
luteal-
follicular transition to the concomitant increase in inhibin
B. In GnRH-
deficient women, replacement of pulsatile GnRH
at the slower luteal phase frequency of every 4 hours compared
with the early follicular phase frequency of every 90 minutes
resulted not only in the failure of FSH to rise normally during
the luteal-
follicular transition but also in the absence of both
follicular growth and an increase in the secretion of inhibin B135
(Fig. 7.5). This study demonstrated the remarkable sensitivity
of serum inhibin B levels to changes in FSH stimulation within
the physiological range during the earliest stages of follicular
development.
In studies designed to examine the response to differential
gonadotropin stimulation at different stages of follicle develop-
ment, recombinant human LH (rhLH) or FSH (rhFSH) was
administered to women following downregulation of endogenous
GnRH secretion using a potent GnRH agonist.136 Consistent

7
with failure to observe LH receptors in small antral follicles,
rhLH alone had no effect on follicle growth or hormone secre-
tion when administered daily for up to 7 days. However, daily
subcutaneous administration of rhFSH resulted in normal early
follicular phase levels of FSH and an increase in inhibin B secre-
tion that preceded that of estradiol and inhibin A (Fig. 7.6).
Studies using preantral and small antral follicles obtained from
ovaries at the time of oophorectomy for nonovarian indications
indicated that inhibin B is constitutively secreted from preantral
follicles.134 Importantly, FSH does not stimulate the secretion
of inhibin B from granulosa cells. Taken together, these studies
demonstrate that the increase in inhibin B observed in vivo in
response to FSH results from an increased number of granulosa
cells rather than direct stimulation of secretion by FSH. At later
stages of follicular development, both LH and FSH stimulate
secretion of inhibin A and estradiol from the dominant follicle
but have no effect on inhibin B.134
Evidence for an Endocrine Negative Feedback Role for
Inhibin A or Inhibin B. Inhibin was initially discovered
based on its ability to inhibit FSH secretion in pituitary cell
cultures.102 Inhibin subunits are expressed in a variety of tissues
including the adrenal. However, the only significant source of
circulating dimeric inhibins is the gonads and there is compelling
evidence that the principal mechanism of action of inhibin in
suppressing pituitary FSH secretion is an endocrine action. In
addition, FSH levels decrease in response to the administration
of pharmacological doses of inhibin A administered in the
follicular and luteal phases in the rhesus monkey.137,138 The most
compelling line of evidence that inhibin regulates FSH secretion
under normal physiological circumstances in women is the failure
of physiological levels of gonadal steroids to restore FSH levels
to normal in postmenopausal women. The model of reproductive
aging has been used by a number of investigators to refine
this evidence. FSH levels increase with age, before increases
in LH or decreases in estradiol139,140 and a number of studies
have demonstrated an inverse relationship between increasing
FSH and decreasing inhibin B in association with reproductive
aging.139,141,142
Reproductive aging is associated with a decline in fertility
that begins in the third decade but accelerates rapidly after age
35 associated with a decrease in the pool of ovarian follicles.143
It is also at age 35 that an increase in follicular phase FSH is first
seen. In women 35 or older with regular ovulatory cycles and
follicular phase FSH levels still within the normal range, there
is a small but significant increase in FSH in the early follicular
phase only; decreased inhibin B levels across the entire follicu-
lar phase and estradiol levels do not differ from normal women
in the early follicular phase but increase in the midfollicular and
late follicular phases.130 In the luteal phase, inhibin B, inhibin A,
and progesterone are lower in older cycling women while estra-
diol levels are preserved. While ovulatory cycles are maintained
during the early stages of reproductive aging, inhibins B and A
progressively decrease and are associated with a similar progres-
sive increase in FSH and maintenance of estradiol.144 These data
support an endocrine role for the inhibins independent of estra-
diol in the negative feedback control of FSH as well as a key role
for FSH in maintaining estradiol levels in the face of a declining
pool of ovarian follicles. In young women with regular ovula-
tory cycles, it is more difficult to determine whether the inhibins
contribute to negative feedback on FSH independent of estra-
diol and particularly whether inhibin B and/or inhibin A play a
role in the midfollicular phase decline in FSH that is critical to
the monofollicular development that characterizes normal repro-
ductive cycles in women. While the tools to determine the role
of inhibin directly by either administration or blockade are not
available, it is possible to investigate the estrogen component of
FSH negative feedback and thereby infer the physiological role
of inhibin. Studies in which estradiol levels were maintained by
estradiol administration during the luteal-
follicular transition
have been interpreted to suggest that inhibin A is not involved
in the negative feedback control of FSH in the luteal-
follicular
Fig. 7.5 The increased frequency of pulsatile GnRH during
the luteal follicular transition facilitates the luteal-
follicular
rise in FSH as indicated in this study in GnRH-
deficient
women, each studied twice. The normal rise in FSH in
relation to menses is attenuated when the frequency of
intravenous GnRH (75 ng/kg) remains at the luteal phase
frequency of every 240 minutes (teal circles) compared to the
usual increase of every 90 minutes at the time of menses as
indicated by the dotted line (purple circles). The attenuated
rise in FSH with continuation of the slow luteal phase
frequency after menses resulted in absence of the normal
follicular phase rise in inhibin B (teal bars, 240 min GnRH
pulse interval; purple bars, 90 min GnRH pulse interval). (From
Welt CK, Martin KA, Taylor AE, et al. Frequency modulation
of follicle-
stimulating hormone (FSH) during the luteal-
follicular
transition: evidence for FSH control of inhibin B in normal
women. J Clin Endocrinol Metab. 1997;82[8]:2645–2652.)
15
20
FSH
(IU/L)
10
0
3 2 0 1 2 6
0
100
200
3 4 5
5
Inhibin
B
(pg/mL)
240 minutes
240 minutes
GnRH pulse
frequency
90 minutes
Days from onset of menses

150
transition.145,146 An alternative approach is to block the estrogen
receptor. Results of studies using the estrogen receptor blocker,
tamoxifen, indicate that the low levels of estradiol in the early fol-
licular phase contribute to negative feedback on FSH, mediated
at a hypothalamic level as shown in GnRH deficient women.147
However, FSH failed to approach menopausal levels indicating
that inhibin B is also critical for FSH regulation during the nor-
mal cycle. Thus, both estradiol and the inhibins are required for
FSH restraint during the follicular phase.147
Activin/Follistatin
The control of FSH is dependent not only on inhibin and estra-
diol but also on the activin/follistatin system. Activin acts as a
local growth and differentiation factor in the ovary as well as the
pituitary.104 During the normal menstrual cycle, total activin A
levels are highest at the midcycle and during the luteal follicular
transition.148 However, there is no change in activin A in follicu-
lar fluid as a function of follicle development,133 no change in free
activin across the menstrual cycle,149 and no difference in activin
B between the follicular and luteal phases.150 Furthermore, a
potential endocrine role of activin can only be considered in the
context of follistatin which is synthesized in many tissues as well
as the pituitary. While activin has been measured in serum, cir-
culating activin is irreversibly bound by the circulating isoform
of follistatin, FS315.151 No mechanisms have been identified
within tissues that would alter neutralization by follistatin, and
therefore it is almost certain that activin acts in an autocrine and
paracrine (but not endocrine) fashion in the pituitary to regulate
FSH secretion.
Gonadotropin Surge Attenuating Factor
Gonadotropin Surge Attenuating Factor (GnSAF), also known as
gonadotropin surge inhibiting factor (GnSIF), is an ovarian fac-
tor that reduces GnRH-
induced LH secretion.152,153 Despite
many years of investigation, the molecular structure of GnSAF has
not been completely characterized,152,154,155 which has hampered
efforts to fully understand its regulation and physiological role. Its
name derives from the initially hypothesized role of this compound
in preventing an early LH surge and premature luteinization of
the preovulatory follicle. However, there is now evidence in animal
models and in women that there is an inverse relationship between
GnSAF bioactivity and follicle size, with the highest concentra-
tions in small growing follicles,152 suggesting that its primary role
may be during earlier stages of follicle development.
Positive Feedback
Role of the Pituitary in Positive Feedback and Generation
of the Preovulatory Surge
In addition to inhibition of gonadotropin secretion, estrogen
exerts a stimulatory effect to generate the preovulatory LH
surge. This positive feedback effect is seen in multiple animal
species,109 and in women. There are two critical questions that
form the basis of a mechanistic understanding of gonadotropin
surge generation: the first is how estrogen can exert both inhibi-
tory and stimulatory effects on LH secretion, and the second is
whether the site of estrogen-
positive feedback is at the pituitary,
the hypothalamus, or both. The direction of estrogen feedback
Fig. 7.6 Hormone response to recombinant human
follicle-
stimulating hormone (FSH; 150 IU daily) for 6 days
in normal women after GnRH agonist downregulation
of endogenous gonadotropin secretion. (From Welt CK,
Schneyer AL. Differential regulation of inhibin B and inhibin a by
follicle-
stimulating hormone and local growth factors in human
granulosa cells from small antral follicles. J Clin Endocrinol
Metab. 2001;86[1]:330–336.)
FSH (IU/L)
200
400
600
800
500
1000
1500
0
200
400
0
0
1000
2000
3000
0
0 1 2 3
0
150
300
450
1
2
3
4
0
50
100
0
5
10
15
4 5 6
%
Change
Hormone
level
Time (days)
Inhibin B (pg/mL)
Estradiol (pg/mL)
Inhibin A (IU/mL)

7
is dependent on both the degree of estrogen exposure and its
duration with low levels of estradiol administration resulting in
decreased LH secretion within 12 to 24 hours, while positive
feedback requires exposure to higher concentrations over a more
prolonged duration.156–158
Pituitary effect of high levels of estrogen. There is ample
evidence that high levels of estrogen augment the pituitary response
to GnRH across species. Studies in animal models demonstrate
an increase in the number of cells expressing the gonadotropin
subunits, an increase in GnRH receptor number, an impact on the
function of ion channels in the plasma membrane, and regulation
of both gene expression and second messenger systems within
gonadotropes.98,159,160 Studies in LβT2 pituitary cells indicate that
activin may act in concert with estrogen to increase GnRH receptors
on pituitary gonadotropes103 while NPY secretion from the median
eminence may contribute to pituitary sensitization through changes
in the affinity of the GnRH receptor for its ligand.161
Pituitary effect of progesterone. In GnRH-
deficient women
receiving pulsatile GnRH with or without progesterone indicate
that low levels of progesterone as seen in the periovulatory period,
increase LH pulse amplitude through a direct pituitary action.162
This effect is independent of the indirect effects of progesterone
on the amplitude of LH pulses associated with slowing of GnRH
stimulation of the pituitary.100,101
Inhibin A augments the effect of high estrogen levels at the
pituitary. Inhibin A is elevated in women before ovulation,130,163
and there are several lines of evidence suggesting that it may play
a role in positive feedback at the pituitary level. Inhibin A increases
GnRH receptors by three-to sixfold in pituitary cell cultures,164 and
this is also true in vivo in the sheep.165 The effects of estradiol and
inhibin A on GnRH receptors are additive.166 The effect of inhibin
A on the percentage of LH positive cells and the percent of LH
positive cells that bind GnRH is greater than the effect of estradiol;
however, inhibin A has a less pronounced effect than estradiol on
positive feedback effects downstream of the LH receptor.167
Pituitary effects of kisspeptin. An emerging body of data
suggests that there may be a pituitary role for kisspeptin in
addition to its well-
studied hypothalamic role.168 Kisspeptin has
been found in the pituitary portal system in rodents and sheep169;
however, it does not change dynamically, suggesting that
kisspeptin may not be directly involved in pituitary regulation.
However, Kiss1 and Kiss1r are expressed on gonadotropes and
other pituitary cell types in rodents, and expression of Kiss1 is
upregulated at the level of the gonadotrope by a direct action of
estrogen acting through the ERα receptor.170 Kisspeptin induces
transcription of LHβ and FSHβ gene expression in LβT2 cells171
and increases GnRHR expression in this same cell type.172 Kissr1
in the pituitary is enhanced in female mice during the estradiol-
induced LH surge,171 possibly through the effect of the increased
secretion of GnRH at midcycle in rodents (see below) and its
stimulatory effect on kissr1.172 While kisspeptin positive cells
were demonstrated in the anterior pituitary in the monkey,
they were not shown to be colocalized to the gonadotrope,173
pointing to potential species differences. KISS1R is present in the
human pituitary174; however, further information is not available
to determine whether alterations may contribute to pituitary
sensitization to GnRH in the setting of high estradiol levels at
the time of the midcycle surge.
In summary, high levels of estrogen have a profound effect on
the pituitary to increase LH secretion through increases in GnRHR
as well as its downstream effects. This pituitary effect of high levels
of estrogen is likely augmented by elevated inhibin A, the direct
pituitary effects of low levels of progesterone, and possibly through
a pituitary effect of elevated kisspeptin on LH secretion.
Species Differences in Hypothalamic Input to the
Preovulatory Surge
In the rat and sheep, estrogen-
positive feedback on gonadotropin
secretion requires an increase in GnRH secretion in addition to
pituitary augmentation of the GnRH signal. In rodents, this increase
in GnRH secretion is dependent on specific circadian signals.175 In
rodents, estrogen-
negative feedback occurs in the arcuate nucleus of
the medial basal hypothalamus, and kisspeptin neurons in the region
coexpress NKB and dynorphin. In contrast, positive feedback occurs
in the anteroventral periventricular nucleus (AVPV), where kiss-
peptin neurons do not express NKB and dynorphin.1,3
Generation of the preovulatory surge in nonhuman primates
appears to be fundamentally different from that in the rodent—
while there may be some alteration in GnRH input, this is not
controlled in the preoptic area (the site of the AVPV), it is not
tied to circadian signals, and the gonadotropin surge does not
require an increase in GnRH.47
As in nonhuman primates, an increase in GnRH secretion is
not required for the generation of a normal gonadotropin surge in
women176,177; moreover, there is no evidence for augmentation of
GnRH secretion or even an altered pattern of GnRH stimulation
associated with generation of the surge in women.51,178,179 Taken
together, these data suggest that the gonadotropin surge in normal
women requires ongoing pulsatile GnRH stimulation but is other-
wise mediated through the marked increase in pituitary sensitivity
to GnRH. Thus, while an increase in GnRH is required for gen-
eration of the gonadotropin surge in rodents and sheep, GnRH
appears to play a permissive role in generation of the preovulatory
LH surge in normal women as it does in nonhuman primates.46,47
THE NORMAL MENSTRUAL CYCLE
•
Normal reproductive function in women involves repetitive cycles of
follicle development, ovulation, and preparation of the endometrium
for implantation should conception occur during that cycle.
•
Increased FSH stimulation during the luteal-
follicular transition
leads to the recruitment of a cohort of follicles as well as the emer-
gence and growth of a dominant follicle.
•
Secretion of estradiol and inhibin from the ovary is required to limit
ongoing FSH stimulation while rising levels of estradiol in combination
with other potential factors are essential to the gonadotropin surge.
•
The corpus luteum secretes progesterone and estradiol to prime the
uterus for implantation and its demise allows FSH to rise with the
beginning of a new cycle.
Clinical Characteristics
By convention, the first day of menses is designated “Day 1” and
marks the onset of the follicular phase of the menstrual cycle. The
follicular phase encompasses the period of recruitment of multiple
follicles and the emergence and growth of the dominant follicle (Fig.
7.7). During the follicular phase, rising levels of estradiol are associ-
ated with endometrial proliferation. The luteal phase, which begins
on the day after the LH surge, is characterized by formation of the
corpus luteum, secretion of progesterone, estradiol, and inhibin A,
and a coordinated series of changes in the endometrium as it first pre-
pares for implantation and then, with a decline of the corpus luteum
in the absence of pregnancy, loses its blood supply and is shed.
The classic studies of Treloar and colleagues180 reported a
median menstrual cycle length of 28 days, with a normal range
between 25 and 35 days. More recent studies based on data
obtained from mobile tracking apps in large populations of women
often followed for extended periods of time, and some with addi-
tional urinary ovulation tests, have provided more contemporary
data.181–183 In the largest of these studies, data was collected from
1.5 million nonpregnant women across the spectrum of repro-
ductive age and BMI.183 Ninety percent of women had a median

152
cycle length between 21 and 35 days. The median cycle length
was 28 days in 16% of women, with cycle lengths of 27 and 29
days occurring in 12% each. Cycle length was not influenced by
alcohol intake or smoking. A quarter of women had a cycle length
variability of 0 to 1.5 days, with over two-
thirds of women hav-
ing a 6-
day variability between cycles. In this study, shorter cycles
were associated with greater stress, no exercise, and lighter menses.
Cycle variability was highest in women aged 18 to 24 and over
35. Interestingly, women in the highest BMI categories had less
cycle variability than their leaner counterparts. Total cycle length
is much more highly correlated with follicular than luteal phase
length.181 Ovulation occurred between days 13 and 15 in the vast
majority of cycles.183 Younger women were more likely to ovulate
later and older women to ovulate earlier than this range. Luteal
phase duration increased with age and decreased with obesity.
In the follicular phase, the progressive increase in diameter of
the largest follicle as assessed by ultrasound is highly predictable at
approximately 2 mm per day from the time it reaches 11 mm until
ovulation (Fig. 7.8). The accompanying rise in estradiol is associ-
ated with a progressive increase in the thickness of the endome-
trium while the addition of progesterone in the luteal phase results
in increased echogenicity of the endometrium (Fig. 7.8).
Ovarian Feedback and the Dynamics of GnRH
Secretion and Pituitary Responsiveness
GnRH secretion can be measured directly in large animal spe-
cies, and studies have indicated that under physiological circum-
stances, peripheral LH secretion occurs concomitantly with the
secretion of GnRH measured in pituitary portal blood.184–186 LH
has therefore been used as a marker of GnRH pulse frequency
in humans, based on these studies and two additional lines of
evidence. The first is that pulsatile secretion of LH is absent in
patients with congenital isolated GnRH deficiency and can be
restored with pulsatile administration of GnRH.187 The second
is that pulsatile secretion of LH in normal subjects is reversibly
abolished by the administration of a specific GnRH antagonist.92
Thus, the occurrence of LH pulses can be taken as evidence for
the occurrence of a preceding stimulatory GnRH pulse and LH
pulse frequency can be used as a peripheral monitor of the fre-
quency of pulsatile GnRH secretion. Although the glycoprotein-
free alpha subunit (FAS) is secreted from both the gonadotrope
and thyrotrope under the control of GnRH and TRH, the pul-
satile component of FAS secretion is entirely under the control
of GnRH in euthyroid women.92 Thus, FAS can also be used as
a surrogate marker of GnRH pulse frequency. As its clearance
is faster than that of intact LH, it is a preferable marker when
GnRH pulse frequency is rapid or when the clearance of LH is
prolonged. The amplitude of the LH or FAS response to GnRH
depends on both the amplitude of the GnRH signal and on pitu-
itary responsiveness to GnRH. Other techniques must therefore
be used to assess the amplitude of GnRH secretion.
Results of frequent sampling studies (every 5 or 10 minutes
for up to 48 hours) have demonstrated marked variations in the
frequency and amplitude of LH pulses across the normal men-
strual cycle (Fig. 7.9) and their precise regulation in relation to
the preovulatory LH surge.178,187–189
Follicular Phase
The early follicular phase is characterized by an initial rise in
FSH and recruitment of a new cohort of follicles into the grow-
ing pool with increased levels of inhibin B and an early increase in
estradiol. In the early follicular phase (days 14 to 9 from the LH
surge), the mean interpulse interval of GnRH is approximately
90 to 100 minutes.76,188 The early follicular phase of established
reproductive cycles is characterized by a marked slowing of
GnRH pulse frequency during sleep78 (Figs. 7.3 and 7.9). Sleep-
related slowing of pulsatile GnRH secretion may serve the func-
tion of maintaining FSH synthesis during this critical period of
follicle recruitment, but this hypothesis has yet to be tested.
The midfollicular phase is marked by the emergence of the
dominant follicle and a decrease in FSH in response to inhibin B
and rising levels of estradiol and a later rise in inhibin A. In the
midfollicular phase, GnRH pulse frequency increases and the
interpulse interval shortens to approximately 60 minutes. LH
pulse amplitude is markedly attenuated, reflecting the nega-
tive feedback of estradiol secreted from developing follicles on
the amplitude of GnRH pulses and possibly the initial effect of
increased GnRH pulse frequency and its effect on gonadotrope
responsiveness.96,97 Increased estradiol across the follicular phase
results in increasing endometrial proliferation.
The late follicular phase is characterized by an exponential
rise in estradiol and inhibin A with low levels of inhibin B and
FSH. The circhoral frequency of GnRH secretion that began in
the midfollicular phase is maintained through the late follicular
phase. However, LH pulse amplitude begins to increase due to
the stimulatory effects of rising levels of estradiol and possibly
Fig. 7.7 The hormonal, follicular, and endometrial dynamics
of the normal menstrual cycle from the late luteal phase
through menses and the beginning of a new cycle of follicle
development, ovulation, and corpus luteum function, as
indicated. With the support of the changing frequency of
pulsatile gonadotropin-
releasing hormone (GnRH) secretion, the
integrated actions of follicle-
stimulating hormone (FSH; green)
and luteinizing hormone (LH; light blue) are responsible for: (1)
follicle development with secretion of estradiol (E2; light green),
inhibin B (pink) and inhibin A (blue); (2) the preovulatory surge
and ovulation; and (3) secretion of progesterone (Prog; purple),
estradiol and inhibin A from the corpus luteum. Secretion of
estradiol and progesterone results in proliferative and secretory
changes in the endometrium (Endo), preparing it for implantation
should conception occur. In the absence of conception,
endometrial shedding follows the decline in hormone secretion
secondary to demise of the corpus luteum.
LH
FSH
Inhibin A
Inhibin B
E2
Prog
Endo
GnRH
Luteal
phase
Secretory Menses Proliferative Secretory
Luteal
phase
Follicular
phase

7
–8 –6 –4 –2 0
Follicle
diameter
(mm)
Endometrial
thickness
(mm)
Days from ovulation
30
20
10
0
20
15
10
5
0
Fig. 7.8 Transvaginal ultrasound showing that follicular development is associated with a progressive
increase in the diameter of the dominant follicle (marked by arrows, left panels, top to bottom) and an
increase in endometrial thickness during the follicular phase (right panel top and middle). The middle panel
presents data from studies in 42 women with normal menstrual cycles and demonstrates the changes in follicle
diameter (blue lines) and endometrial thickness (brown lines) in relation to the day of ovulation, indicated as 0 on the
x axis. In the luteal phase the appearance of the endometrium is characterized by marked echogenicity (single arrow,
right panel, bottom). (From Adams JM, Hall JE. Increase in the size of the dominant follicle and endometrial thickness
as measured by ultrasound during the follicular phase in 42 normal women, personal communication, 2003.)
0
0 100
200
200
40
20
0
40
20
0
40
20
0
40
20
0
40
20
0
40
20
0
300
40
30
20
10
0
EFP MFP LFP MCS ELP MLP LLP
EFP MFP LFP MCS
MCS
ELP
LFP
MFP
EFP
A B
MLP
LLP
ELP MLP LLP
Interpulse
interval
(minutes)
Pulse
amplitude
(IU/L)
Fig. 7.9 A. Dynamics of pulsatile luteinizing hormone (LH) secretion in relation to LH (red), FSH (teal),
estradiol (green), and progesterone (brown) in the early follicular phase (EFP), midfollicular phase (MFP),
and late follicular phase (LFP), during the midcycle surge (MCS) and in the early luteal phase (ELP),
midluteal phase (MLP), and late luteal phase (LLP) in normal women. The blue rectangle indicates menses.
(Modified from Hall JE, Martin KA, Taylor AE. Body weight and gonadotropin secretion in normal women and
women with reproductive abnormalities. In: Hansel W, Bray GA, Ryan DH, eds. Nutrition and reproduction.
Louisiana State University Press; 1998:378–393; Pennington Center Nutrition Series.) B. Summary of the
dynamic changes in the interpulse interval (top) and amplitude (bottom) of pulsatile LH secretion in
relation to the phases of the menstrual cycle. (Modified from and Hall JE. Neuroendocrine Physiology of
the early and late menopause. Endocrinol Metab Clin North Am. 2004;33[4]:637–659.)

154
inhibin A on gonadotrope responsiveness to GnRH. The marked
increase in estradiol is accompanied by further endometrial
proliferation.
Midcycle Surge
In response to the pituitary actions of the exponential increase
in estradiol, and likely inhibin A, progesterone, and kisspeptin
secretion in the late follicular phase, LH levels in women increase
tenfold over a period of 2 to 3 days while FSH levels increase four-
fold (Fig. 7.9). The midcycle surge of LH is absolutely required
for final maturation of the oocyte and initiation of follicular rup-
ture, which generally occurs 36 hours after the surge. The gonad-
otropin surge is essential for normal reproductive cycles.
The pattern of estrogen exposure is critical to positive feed-
back. Exogenous administration of estradiol to normal women
in the early follicular phase156,157 or to postmenopausal women80
induces an increase in both basal and GnRH-
stimulated LH
secretion that is dependent on the dose and duration of estro-
gen exposure. There is further evidence that the surge occurs
in response to the increase in estradiol rather than the drop in
estradiol that frequently accompanies the onset of the surge.157 In
other words, the surge results from positive feedback rather than
removal of estrogen-
negative feedback.
Other evidence indicates that a small increase in progester-
one augments this surge. Secretion of progesterone is typically
associated with the luteal phase; however, the earliest increase
in progesterone is evident in normal women prior to the LH
surge. Blockade of progesterone receptors by RU486 delays the
surge by up to 3 days despite continued growth of the domi-
nant follicle and rising levels of estradiol.190 In GnRH-
deficient
women, progesterone augments LH pulse amplitude, indicating
that in addition to its well-
known inhibitory effect on GnRH
pulse frequency, progesterone can exert a direct stimulatory
effect at the level of the pituitary. In studies in normal early-
follicular women in whom a graduated estrogen infusion was
initiated in the early follicular phase, it has now been dem-
onstrated that progesterone does not appear to influence the
height of the LH surge per se, as was initially reported,156 but
that it decreases the inter-
individual variability in its timing
relative to the onset of the infusion.157
Although a gonadotropin surge can be generated in response
to a re-
creation of normal preovulatory estradiol and proges-
terone levels, the amplitude of the LH—but not FSH—surge is
less than in normal women. This suggests that there may also be
other ovarian factors required for generation of a surge of normal
amplitude. As discussed above, there is compelling evidence that
inhibin A, which increases dramatically in conjunction with estra-
diol in the late follicular phase,130,163 may play such a role, acting
at the pituitary level.167,171
A key question is whether estrogen-
positive feedback in
women is mediated at the hypothalamus, the pituitary, or both.
In all species, including women, there is evidence for sensitiza-
tion of the pituitary to GnRH stimulation at the time of the
preovulatory surge. While a GnRH surge also appears to be
present in lower animal species, there is still no evidence that a
surge of GnRH is present, or required, in women. Thus, there
are important species specificities to the mechanisms underlying
this critical process.
The classic studies of Yen and colleagues demonstrated that
the responses of LH and FSH to exogenous GnRH administra-
tion are markedly influenced by the stage of the menstrual cycle,
with an exaggerated increase in secretion of both gonadotropins
at the time of the midcycle surge,191 confirming the importance
of the pituitary as a key site of positive feedback. As reviewed
above, animal and in vitro studies demonstrate that estradiol,
in conjunction with progesterone, inhibin A, and possibly kis-
speptin, acts directly at the pituitary to increase gonadotrope
sensitivity to GnRH.98,159,167,171,186 Studies in GnRH-
deficient
women receiving exogenous GnRH replacement provide the
most compelling evidence for the importance of pituitary sensi-
tization to GnRH in generation of the midcycle surge in women.
When GnRH is administered at a dose and frequency that mim-
ics the GnRH pulse frequency in the normal menstrual cycle with
development of a single dominant follicle, an abrupt increase
in LH and FAS pulse amplitude is observed in the absence of
any change in the dose or frequency of GnRH administration
(Fig. 7.10), and a normal LH surge is achieved177 (Fig. 7.11).
These studies indicate that positive feedback can be achieved in
women through pituitary mechanisms alone in the absence of any
increase in GnRH input.
At the onset of both spontaneous and steroid-
induced LH
surges in normal women, complete GnRH receptor block-
ade results in termination of the surge,179,192,193 indicating
that ongoing GnRH secretion is essential for generation of
the gonadotropin surge. However, neither the frequency nor
the overall amount of GnRH is increased in association with the
onset of the gonadotropin surge in normal women. Studies in
normal women in which blood samples were drawn every 5 min-
utes for up to 36 hours at midcycle indicate a striking increase
in LH and FAS pulse amplitude from the late follicular phase to
the early and midportions of the surge with no change in pulse
frequency during this same period178 (Fig. 7.9). To address
the question of whether generation of the surge in women is
associated with an increase in the amplitude of GnRH secreted
with each bolus, submaximal GnRH receptor blockade with a
fixed dose of a GnRH was used allowing competition between
endogenous GnRH and the antagonist to provide a semiquan-
titative estimate of the overall amount of endogenous GnRH
secreted.179 Results of these studies provided no evidence for an
increase in the overall amount of GnRH secreted and, in fact,
suggested that the amount of GnRH at the surge is less than in
the early and late follicular phase. Consistent with this finding,
60
50
40
30
20
10
0
GnRH 75 ng/kg q 60 minutes
LH
(IU/L)
E2 = 131 pg/mL
Prog = 0.6 ng/mL
1000
800
600
400
200
0
0 2 4 6 8 10 12 14 16 18
Time (hours)
20 22 24
FAS
(IU/L)
Fig. 7.10 Luteinizing hormone (LH) and free α-subunit (FAS)
sampled every 5 minutes in a gonadotropin-
releasing hormone
(GnRH)-
deficient woman receiving pulsatile GnRH intravenously,
demonstrating the abrupt increase in LH and FAS pulse amplitude
and mean levels associated with estrogen-
positive feedback in
the absence of any change in the dose or frequency of exogenous
GnRH replacement. (Hall JE, personal communication). E2,
estradiol; Prog, progesterone.

7
further studies have shown that in GnRH-
deficient women, the
replacement dose of GnRH can be reduced by two-
thirds in
the late follicular phase from that required for the development
of a single dominant follicle without compromising the timing
or height of the midcycle surge or the subsequent luteal phase
(Fig. 7.12).51
Taken together, these studies indicate that GnRH is
absolutely required for generation of the midcycle surge in
normal women; however, there is no evidence for an increase
in the amplitude or frequency of GnRH secretion and such
an increase is not required to generate a surge in GnRH-
deficient women receiving pulsatile GnRH replacement.
Consistent with this conclusion, neuroimaging studies in
postmenopausal women in whom a gonadotropin surge was
induced by administration of a graded estradiol infusion show
a marked increase in metabolic activity at the pituitary, but
not the hypothalamus, in association with estrogen-
positive
feedback on LH.113
The termination of the LH surge is associated with a dramatic
decrease in pulse amplitude accompanied by a decrease in pulse
frequency to approximately every 70 minutes178 (Fig. 7.9). The
slowing of pulse frequency that51 accompanies the termination
of the surge is due, at least in part, to the hypothalamic effects of
progesterone.
Thus, in lower animal species, in addition to pituitary sensi-
tization to GnRH, an increase in GnRH occurs in conjunction
with the LH surge. In rodents, rabbits, and sheep, a GnRH surge
is necessary to generate the LH surge; in nonhuman primates a
GnRH surge may not be necessary.46,47 Importantly, in women a
GnRH surge does not appear to occur and is not needed to gen-
erate a normal LH surge.51,178,179
Luteal Phase
Formation of the corpus luteum after ovulation results in secre-
tion of progesterone, estradiol, and inhibin A with inhibitory
effects on both LH and FSH secretion. The slowing of pulsa-
tile GnRH secretion begins during the termination of the mid-
cycle surge and continues through the early, mid, and late luteal
phases (Fig. 7.9). In the late luteal phase, interpulse intervals as
long as 4 to 8 hours are observed. This slowing of the GnRH
pulse generator is due to the effect of progesterone123 but is not
expressed without the additional presence of estradiol.125 In the
luteal phase, LH pulse amplitudes are significantly higher than
in the follicular phase due to progesterone-
induced slowing of
pulsatile GnRH secretion and the inverse relationship between
LH responsiveness to GnRH and GnRH pulse frequency100,101
and possibly due to the direct effect of progesterone at the pitu-
itary to increase LH responsiveness to GnRH.162 The corpus
luteum has a finite lifespan and in the absence of conception the
decrease in progesterone and estradiol results in the shedding of
the endometrium.
Fig. 7.12 The preovulatory surge
in a representative GnRH-
deficient
woman receiving pulsatile GnRH
at a physiologic frequency of every
60 minutes indicating that an LH
surge is generated with no change
in pulse frequency at a dose of 75
ng/kg, unchanged from the late
follicular phase as indicated in the
blue horizontal bar (left panel). The
height of the LH surge is not diminished
despite a reduction in GnRH dose from
75 ng/kg to 25 ng/kg as indicated by
the blue horizontal bar (right panel) in a
subsequent cycle before the onset of
the LH surge. (From Martin KA, Welt CK,
Taylor AE, Smith JA, Crowley WF Jr, Hall
JE. Is GnRH reduced at the midcycle surge
in the human? Evidence from a GnRH-
deficient model. Neuroendocrinology.
1998;67[6]:363–369.)
120
140
Control cycle Dose drop cycle
GnRH
LH
(IU/L)
100
80
60
0
15 15
10 10
5 5
10
0 5 0 5 10 15
20
40
Cycle day centered to ovulation
400
75 ng/kg/bolus
q 90 q 60 q 90 q 4 hour
LH
(IU/L)
300
200
100
300
200
100
0
0
2
0
0 5 10 15 20
Days
PROG
(ng/mL)
FSH
(IU/L)
25
0
10
20
0
100
200
300
400
E
2
(pg/mL)
DF
(cm)
Fig. 7.11 Administration of intravenous pulsatile gonadotropin-
releasing hormone (GnRH) to a GnRH-
deficient woman at a
physiological frequency with follicle development, ovulation, and
normal luteal phase function. Note that the luteinizing hormone (LH)
surge is generated in association with an increase in both the size of
the dominant follicle (DF) and a marked increase in estradiol (E2), but in
the absence of an increase in the dose or frequency of pulsatile GnRH
administration. (Adapted from Hall JE, Martin KA, Whitney HA, Landy
H, Crowley WF. Potential for fertility with replacement of hypothalamic
gonadotropin-
releasing hormone in long term female survivors of cranial
tumors. J Clin Endocrinol Metab. 1994;79:1166–1172.) FSH, follicle-
stimulating hormone.

156
Luteal-Follicular Transition
With declining function of the corpus luteum and declining lev-
els of progesterone, estradiol, and inhibin A, release from nega-
tive feedback permits FSH to rise, an increase that begins before
menses and is critical for recruitment of a new cohort of follicles
into the developing pool (Fig. 7.7). Maintenance of midluteal
phase levels of estradiol prevents this increase in FSH.145,146
Thus, it has been proposed that release from estrogen-
negative
feedback is the key factor in the luteal-
follicular rise in FSH and
that other factors such as the decline in inhibin A secretion from
the corpus luteum may not play a role. However, studies using
tamoxifen to block the estrogen receptor in normal cycles suggest
that inhibin A also plays a role in restraining FSH secretion dur-
ing the normal luteal phase.147
LH pulse frequency increases before the onset of menses
(Fig. 7.13). LH pulse frequency is inversely related to proges-
terone levels189 and administration of midluteal phase levels of
progesterone189 in conjunction with estradiol prevents the nor-
mal luteal-
follicular increase in GnRH pulse frequency in normal
women.125 As discussed above, there is convincing evidence that
the increase in GnRH pulse frequency that occurs between the
luteal and follicular phases facilitates the luteal-
follicular increase
in FSH secretion; FSH is significantly correlated with LH pulse
frequency, while the inverse relationship between FSH and estra-
diol was not significant.189 Importantly an increase in the fre-
quency of exogenous GnRH administration in GnRH-
deficient
women from the slow luteal phase frequency to the follicular
phase frequency is essential to recreate the normal intercycle rise
in FSH (Fig. 7.5).
Thus, while the slow frequency of GnRH secretion in
the luteal phase might be expected to increase FSH synthe-
sis either directly or through a decrease in follistatin and a
concomitant increase in activin signaling, FSH synthesis and
secretion are inhibited by estradiol and inhibin A. With the
demise of the corpus luteum, estradiol and inhibin A levels
fall, as do those of progesterone. FSH increases with release
from negative feedback and with the normal increase in GnRH
pulse frequency.
There is now evidence that the progressive increase in
GnRH pulse frequency from the early to the midfollicular
phase represents a gradual loss of the restraining effects of low
levels of progesterone on the GnRH pulse generator.194 As the
early follicular phase is characterized by sleep-
related inhi-
bition of pulsatile LH secretion, it is intriguing to speculate
that a similar prolonged effect of progesterone is also involved
in sensitizing the hypothalamus to the inhibitory effects of
sleep during this cycle phase. Menstrual cycle abnormalities
or reduced fecundity have been reported in the majority of
studies in women exposed to transmeridian travel or rotating
shifts.195–200 Given the disruption in sleep architecture with
rotating shifts or night work, these studies raise the possibil-
ity that slower sleep-
related GnRH pulse frequency associated
with consolidated sleep is necessary to maintain synthesis of
FSH at this critical time.
Racial Differences in Menstrual Cycle Dynamics
and Fertility
Racial disparities between African American and Caucasian
women in the incidence of breast cancer, leiomyomas, and osteo-
porosis raise the possibility of a greater lifetime exposure to
estrogen in African American women. Estradiol levels are 18%
higher in the late follicular phase and 40% higher in the midlu-
teal and late luteal phases in weight-
matched regularly cycling
African American women who ovulated a single follicle compared
to their Caucasian counterparts.201 In these studies, higher estra-
diol in the face of similar androstenedione levels suggested that
ovarian aromatase activity is higher in African American women
although FSH, the major regulator of ovarian aromatase, was
not elevated. Further studies confirmed that increased circulat-
ing levels of estradiol in African American women are of ovarian
origin with a higher androgen-
to-
estrogen ratio in follicular fluid
and an increase in granulosa cell aromatase expression compared
with Caucasian women.202 The reason for this effect may be due
to population-
specific genetic variation affecting CYP19, which
encodes aromatase, as there were no differences in FSH or AMH
levels or in FSH receptor expression between African American
and Caucasian women.202
There is also evidence that race plays a dramatic role in both
infertility and the results of fertility treatment.203–208 The etiol-
ogy of these differences is undoubtedly multifactorial. The evi-
dence of racial discrepancies in fertility awareness209 and racial
differences in pubertal onset210 and reproductive hormones201,202
suggest that differences in fertility and fertility outcome should
not be attributed to psychosocial influences without further
investigation.
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