Ciclo Menstrual 2024

7 Neuroendocrine Control of the Menstrual Cycle
Janet E. Hall
OUTLINE (also see Chapter 1), that act upstream of GnRH neurons in
the hypothalamus.1–4 In addition, ovarian steroids and inhibins
THE REPRODUCTIVE AXIS act directly at the pituitary level. Negative feedback restraint
of FSH secretion is critical to the development of the single
NEUROENDOCRINE COMPONENTS OF THE REPRODUCTIVE mature oocyte that characterizes human reproductive cycles.
AXIS In addition to negative feedback controls, the menstrual cycle
GONADOTROPIN-RELEASING HORMONES is unique among endocrine systems in its dependence on
Pulsatile Secretion of GnRH estrogen-positive feedback to produce the preovulatory LH
surge that is essential for ovulation.
Neuromodulators of GnRH Secretion
Sleep and Circadian Effects on GnRH Secretion in Women
NEUROENDOCRINE COMPONENTS OF THE
GONADOTROPIN-PRODUCING CELLS OF THE PITUITARY
Gonadotropn Isoforms REPRODUCTIVE AXIS
Effect of Obesity • Genetic findings from patients with congenital deficiencies in gonad-
Differential Control of LH and FSH Secretion otropin secretion have significantly advanced our understanding of
the ontogeny and upstream regulation of GnRH.
OVARIAN FEEDBACK ON THE HYPOTHALAMUS AND • Kisspeptin, neurokinin B, and dynorphin are important regulators
PITUITARY of GnRH synthesis and secretion and transduce gonadal steroid feed-
Negative Feedback back to GnRH neurons.
Positive Feedback • The differential control of LH and FSH requires the integration of
THE NORMAL MENSTRUAL CYCLE GnRH pulse amplitude and frequency with direct pituitary feedback
from estradiol and inhibins.
Clinical Characteristics • Ovarian negative feedback on LH and FSH is primarily, but not
Ovarian Feedback and the Dynamics of GnRH Secretion exclusively, mediated through kisspeptin control of GnRH secretion
and Pituitary Responsiveness with the additional pituitary effect of the inhibin/activin/follistatin
Follicular Phase system on FSH.
Midcycle Surge • Ovarian positive feedback in women and nonhuman primates
Luteal Phase is mediated primarily at the pituitary level with the permissive
Luteal-Follicular Transition involvement of GnRH; in rodents increased kisspeptin-mediated
Racial Differences in Menstrual Cycle Dynamics and Fertility GnRH stimulation is required in addition to direct pituitary effect.
GONADOTROPIN-RELEASING HORMONES
Luteinizing-releasing hormone (LHRH) was isolated, char-
THE REPRODUCTIVE AXIS acterized, and synthesized in 1971.5 The central role of this
Normal reproductive function in women involves repeti- decapeptide in the propagation of the species makes it fit-
tive cycles of follicle development, ovulation, and prepara- ting that Drs. Schally and Guillemin received the Nobel
tion of the endometrium for implantation should conception Prize in Physiology and Medicine in 1977 for its isolation.
occur in that cycle. This pattern of regular ovulatory cycles is It was expected that separate releasing hormones for LH
achieved through precise functional and temporal integration and FSH would be discovered. However, subsequent stud-
of stimulatory and inhibitory signals from the hypothalamus, ies provided evidence that both LH and FSH are secreted in
the pituitary, and the ovary (Fig. 7.1). The reproductive sys- response to LHRH, resulting in the common use of the term
tem functions in a classic endocrine mode. The master hor- gonadotropin-releasing hormone (GnRH) for the decapeptide
mone, gonadotropin-releasing hormone (GnRH), is secreted originally referred to as LHRH.
in a pulsatile fashion from the hypothalamus into the pituitary GnRH neurons differentiate in the olfactory placode, cross the
portal venous system. GnRH regulates the synthesis and sub- cribriform plate into the forebrain, and migrate to the medial basal
sequent release of follicle-stimulating hormone (FSH) and hypothalamus, where they establish connections with the pituitary
luteinizing hormone (LH) from gonadotropes within the portal system in the median eminence as part of the hypotha-
anterior pituitary into the circulation. FSH and LH stimulate lamic tuberoinfundibular system.6 The initial leg of this migratory
the recruitment and development of ovarian follicles, ovula- journey occurs along the scaffold of olfactory, vomeronasal, and
tion, corpus luteum formation, and the coordinated secretion terminal nerves. The importance of this developmental pathway
of estradiol, progesterone, inhibin A, and inhibin B. A key is evidenced in patients with Bosma arhinia microphthalmia syn-
component of this system is the modulatory effect of ovarian drome. In this syndrome, individuals are born without a nose, are
steroids and inhibins on gonadotropin secretion. Ovarian ste- anosmic, and fail to go through puberty due to hypogonadotropic
roids impact the amplitude and/or frequency of GnRH secre- hypogonadism.7 In humans there are approximately 7000 GnRH
tion through their effects on KNDy neurons, discussed below expressing neurons in areas of the brain linked to gonadotropin
142
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CHAPTER 7 Neuroendocrine Control of the Menstrual Cycle 143
associated with other developmental defects. This group of genes

NKB includes Kallmann 1 (KAL1) now known as anosmin 1 (ANOS1),11 7
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
KISS zinc finger 1 (FEZF1),16 fibronectin leucine-rich transmembrane
NKB protein 3 (FLRT3),17 IL-17 receptor D (IL17RD),17 and structural
DYN 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-
GnRH sensitive sex reversal 1 (DAX1), also known as nuclear receptor
Estradiol 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-
Pituitary nal migration factor (NSMF),34 dual specificity phosphatase 6
Inhibin B (DUSP6),17 sprouty homolog 4 (SPRY4),17 and fibroblast growth
Inhibin A
factor 17 (FGF17).17 Finally, the genes involved in gonadotrope
LH
Estradiol stimulation that have been discovered to date in association with
FSH Estradiol 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.
Uterus
Pulsatile Secretion of GnRH
A prominent feature of the reproductive system is the absolute
Ovary 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
Fig. 7.1 Neuroendocrine control of reproduction requires the pulsatile gonadotropin levels.36 Isolated GnRH neurons exhibit an intrin-
secretion of gonadotropin-releasing hormone (GnRH) released into sic pulsatility,37 but there is also a significant body of research
the pituitary portal system to stimulate the synthesis and secretion indicating that external influences modify and coordinate the
of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion of GnRH, influencing both the amplitude and fre-
from pituitary gonadotropes. The gonadotropins, in turn, stimulate quency of pulsatile GnRH secretion.
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),
Neuromodulators of GnRH Secretion
neurokinin B (NKB), and dynorphin (DYN) which are colocalized in the While a number of neurotransmitters are involved in the control
KNDY neurons of the median eminence. Inhibin A, inhibin B, and estradiol of GnRH secretion in animal species, only a few have been shown
also exert negative feedback effects directly at the pituitary. As shown on to have an effect on humans.38 Although there is evidence for
the left, rising levels of estradiol are responsible for the positive feedback at a stimulatory role of the α-adrenergic system in several animal
the pituitary, which generates the preovulatory gonadotropin surge. (From models, it is much less likely that it plays a role in the control
Hall JE, Cacciopa P, NIEHS, personal communication.) of the human menstrual cycle. The role of the dopaminergic
system remains controversial, but studies that have documented
regulation.8 Unlike neurons secreting other hypothalamic releas- an increase in LH pulse frequency in response to a dopamine
ing factors, GnRH neurons do not exist in a defined nucleus but antagonist in women with hypothalamic amenorrhea suggest that
are scattered throughout the medial basal hypothalamus, with dopamine may inhibit GnRH secretion in women.39,40
additional scattered neurons in the preoptic area.9
Over the past three decades, genetic studies in patients with
idiopathic hypogonadotropic hypogonadism (IHH) with con-
Kisspeptin
comitant disruption of the olfactory system resulting in anosmia Knock-out models suggest that there is considerable redundancy in
(Kallmann Syndrome; KS) or without anosmia (normosmic idio- the systems that ultimately control GnRH secretion; however, it is
pathic hypogonadotropic hypogonadism; nIHH), have resulted now firmly established that the kisspeptin pathway is a key upstream
in unprecedented growth in our understanding of the complex modifier of GnRH secretion. As with the genes that are now known
neuroendocrine control of reproduction. Mutations in well over to control the developmental migration of GnRH neurons, a role
50 genes have now been discovered in this rare patient popula- for kisspeptin in reproduction was initially discovered by the com-
tion.10 Validation of their function in animal and cell systems bination of genetic studies in patients with IHH which identified
indicates that these can be broadly classified into four groups. A mutations in the gene encoding the kisspeptin receptor (KISS1R,
number of genes have been discovered that are involved in the formerly known as G-protein coupled receptor 54 [GPR54]) and
early migration and axonal guidance of GnRH neurons on the path knock-out mouse models.18,19 Kisspeptin is an extremely powerful
to their eventual home in the hypothalamus, some of which are stimulator of LH, an action that is blocked by a GnRH antagonist,
144 PART I The Fundamentals of Reproduction
indicating that the effect of kisspeptin on LH is mediated through secretion with increasing evidence that they are also involved in the
control of GnRH secretion.41,42 The kisspeptin system is thought initiation and termination of GnRH secretion that results in its pul-
to play a dominant role in the onset of puberty and mediates estro- satile secretion.62 Gamma-amino butyric acid (GABA) may also be
gen and progesterone negative feedback in the median eminence.2 involved in mediating estrogen-negative feedback on GnRH secre-
Studies of kisspeptin administration in women, performed using tion, particularly in the arcuate/median eminence.63,64
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
RFamide-Related Peptides
and hormonal status.43 The response to kisspeptin is consistently RFaimde-related peptides (RFRP) are the mammalian orthologues
robust in the late follicular, preovulatory, and luteal phases of the of gonadotropin inhibitory hormone (GnIH) which was first dis-
menstrual cycle and in postmenopausal women, while there is some covered in the hypothalami of the quail.65 In humans, RFRP-1 and
inconsistency in the early follicular phase with a lower, and in some RFRP-3 neurons send axonal projections to GnRH neurons.66,67
cases absent, LH response to kisspeptin44 The LH response to RFRPs are secreted into the pituitary portal system68 and their
continuous kisspeptin was similarly low in postmenopausal women receptor, G-protein coupled receptor 147 (GPR147), is present
but increased after two weeks of estrogen replacement in a dose- on gonadotropes as well as in the hypothalamus66 Taken together
dependent fashion, an effect that appears to be mediated at both the with functional data from animal and cellular systems, these find-
pituitary and the hypothalamic level.45 ings suggest that RFRPs function at both the hypothalamus and
In rodents and sheep, there is ample evidence that positive pituitary to regulate the secretion of LH and FSH. Interestingly,
feedback is manifest in the hypothalamus as well as the pituitary there is also evidence that RFRPs increase food intake in sheep
with the generation of a marked increase in GnRH at the time without reducing energy expenditure.67 There is currently limited
of the midcycle gonadotropin surge.46,47 Kisspeptin neurons in data to address the role of these peptides in humans. A three-hour
the anteroventral periventricular nucleus (AVPV) have now been infusion of custom synthesized GnIH resulted in a modest sup-
implicated in this estrogen-positive feedback on GnRH secretion pression of LH secretion in postmenopausal women but failed
in rodents.1 The relationship of the AVPV to the suprachiasmatic to inhibit LH secretion in response to pulses of kisspeptin-10 in
nucleus (SCN) in the rodent provides a potential mechanism for men.69 Additional studies will be required to ascertain its physiol-
the known circadian timing of the proestrus surge in the rodent.48 ogy and potential therapeutic role in men and women.
Despite compelling evidence in lower animal species, it is
likely that kisspeptin control of GnRH does not play a role in the Sleep and Circadian Effects on GnRH Secretion
midcycle surge in women; studies in women demonstrate a pau-
city of kisspeptin neurons in an analogous hypothalamic region49 in Women
and evidence discussed below demonstrates that a GnRH surge Endocrine systems are profoundly influenced by both sleep and
is not required for the generation of a midcycle LH surge in endogenous circadian rhythms, which are intrinsic rhythms
GnRH-deficient women50 and further suggests that a GnRH that persist in the absence of sleep or other environmental cues.
surge is not present in normal women.51 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
Neurokinin B failed to demonstrate an endogenous circadian rhythm of LH or
Neurokinin B (NKB), which is encoded by the tachykinin 3 gene FSH in early follicular phase women (Fig. 7.2) and in postmeno-
(TAC3) and its cognate receptor, NK3R, encoded by TACR3, pausal women, despite the presence of robust circadian rhythms
have also been implicated in the normal control of GnRH secre- of temperature, cortisol, and TSH.70,71
tion through genetic studies in patients with IHH.21 NKB stimu- In contrast, there is compelling evidence that sleep directly
lates LH secretion, acting upstream of the GnRH neuron.52,53 affects the pulsatile secretion of LH and presumably that of
TAC3 and KISS are colocalized in the human as well as in other GnRH. Studies that have separated the effects of sleep from time
species,54 particularly in the arcuate/median eminence. There is of day demonstrate that during puberty in boys and girls, pulsatile
significant evidence that the effect of NKB on GnRH is exerted LH secretion is increased during sleep.72,73 More recent studies
primarily through kisspeptin. NKB agonists stimulate gonado- indicate that LH pulses are most commonly preceded by slow
tropin secretion55 while NKB3 antagonists inhibit LH secretion, wave sleep (SWS)74 and further studies have shown that even
but do not appear to do so in the setting of high estrogen, as in with repeated sleep interruption, 20 min of accumulated sleep is
the preovulatory phase56 Interestingly, the NKB3/NK3R system associated with LH pulse onset in this population.75 These stud-
also plays a role in hot flashes in estrogen-deficient states.56–58 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.
Endogenous Opioids/Dynorphin Paradoxically, with the maturation of the reproductive system
There is substantial evidence for the involvement of endorphins in and the onset of ovulatory menstrual cycles, there is a notable
transducing the negative feedback effects of progesterone on pulsa- slowing of pulsatile LH secretion at night in the early follicu-
tile GnRH secretion from studies using the opioid receptor blocker, lar phase of the cycle.76,77 Sleep reversal studies in women have
naloxone, in women.59,60 However, naloxone binds not only to demonstrated that the early follicular phase of nighttime slowing
the mu receptor but also to the kappa and gamma receptors and is due to sleep rather than the time of day.78 Importantly, within
thus these early studies could not provide mechanistic specificity. sleep, brief periods of wakefulness are associated with the onset
Dynorphin which binds to the kappa-opioid receptor has now been of LH pulses (Fig. 7.3), while SWS is inhibitory to LH pulses.78
identified as the key mediator of progesterone negative feedback.61 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
KNDy Neurons effects of sleep in the early follicular phase.79 In this regard, it is of
In a variety of animal species and humans it has been shown that kis- interest that GnRH pulse frequency, as determined by the pulsa-
speptin, NKB, and dynorphin are coexpressed in cells in the arcuate tile secretion of the gonadotropin-free alpha subunit (FAS), is also
nucleus/median eminence that are now referred to as KNDy neu- slower during sleep than wake in postmenopausal women whose
rons. These neurons express estrogen, progesterone, and androgen gonadal steroid levels are similar to those in early puberty, where
receptors and mediate gonadal steroid negative feedback on GnRH sleep is stimulatory.80 Although the effect of sleep is much less than
monohormonal cells begin to express both βLH and βFSH, while

a population of cells that express growth hormone (GH) also 7
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
Fig. 7.2 Mean + sem of temperature, FSH, LH, FAS, and TSH FAS is unaffected by the absence of gonadal function (Table 7.1).
levels in early follicular phase women (n = 11) during a constant Changes in the isoform composition of FSH in the normal men-
routine of light, position, wake, and nutritional intake over a 24-hour strual cycle are likely to augment the effect of the rise in FSH on
period. These studies indicate the constancy of gonadotropin levels follicle recruitment and development during the luteal-follicular
across the day and night in the absence of sleep with maintenance of transition through a decrease in clearance; in contrast isoform
endogenous circadian rhythms of temperature and TSH. Individual studies changes that increase clearance would curtail the potential effect of
are aligned to the onset of habitual sleep onset for each subject beginning the increase in FSH on follicle recruitment at midcycle.
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
Effect of Obesity
secretion in women. J Clin Endocrinol Metab. 2011;96[5]:1456–1461.) 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 normally cycling women, this finding suggests that the inhibi- in women with polycystic ovary syndrome (PCOS).88 Further
tory effect of sleep on LH pulse frequency is not only related to studies have indicated that the inhibitory effect of obesity on
prior progesterone exposure but that other factors relating to the LH secretion in PCOS is not mediated at the hypothalamus
development of a mature reproductive axis are involved. but is associated with a decrease in both the pituitary response
to GnRH and the half-life of endogenous, but not exogenous,
GONADOTROPIN-PRODUCING CELLS OF THE LH.89,90 The latter finding is consistent with the increase in sul-
PITUITARY fonated isoforms of LH and FSH as a function of increasing BMI
in women with PCOS.86 Recent studies have shown that in obese
LH and FSH are synthesized in gonadotropes, which comprise men and obese women without PCOS, the combination of an
between 7% and 15% of the cells in the pituitary. Immuno insulin and lipid/heparin infusion which results in increased free
histochemical studies in the rat indicate that approximately 70% fatty acids and triglycerides, suppresses LH and FSH.91 Although
of gonadotropes stain for both LH and FSH, while the remainder the characteristics of pulsatile LH secretion were not measured
stains for LH or FSH in approximately equal numbers. As the in this study, the studies described above would suggest that the
animals approach the day of the gonadotropin surge in proestrus, resultant decrease in LH and FSH is mediated at the pituitary.
200
**
Mean LH (IU/L) LH amp (IU/L) LH IPI (minutes)

**
Fig. 7.3 As indicated in the left panel,
100 3
sleep is specifically associated with
slowing of luteinizing hormone (LH)
Min of wakefulness/5 minutes

pulses. The LH interpulse interval (IPI) is
longer and amplitude is higher in normal
0 *** **
women during sleep (blue bars) compared 10
* 2 *
with wake (purple bars), whether sleep **
occurs at night or during the day. As 5
indicated in the right panel, wakefulness is
more likely in the 5 to 10 minutes before 0 1
the onset of an LH pulse (blue bars) than
in a similar period indexed to a random 10
LH point that is not associated with an *
LH pulse (purple bars). (Adapted from 5 0
Hall JE, Sullivan JP, Richardson GS. Brief
–20 –15 –10 –5
wake episodes modulate sleep-inhibited 0 to –15 to –10 to –5 to 0
luteinizing hormone secretion in the early
follicular phase. J Clin Endocrinol Metab. Wake sleep Wake sleep Minutes from onset
2005;90[4]:2050–2055.) night day
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 T1/2 (minutes) Baseline (pg/mL) Mean T1/2 (minutes)
± SEM Mean ± SEM ± SEM 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.)
Differential Control of LH and FSH Secretion TABLE 7.2 Differential Effects of GnRH Pulse Frequency on LH and FSH
Although secreted from a common cell type within the gonad- LH FSH
otrope, LH and FSH have markedly different functions in the Increased frequency
control of ovarian physiology. These differences in function are “In vitro”
reflected in their different patterns of secretion during normal mRNA ↑ →
reproductive cycles. The divergent control of LH and FSH is GnRH-deficient men/women
achieved through a combination of differential control of the Mean ↑ →↓
synthesis and secretion of LH and FSH by the pattern of GnRH Amplitude ↓
stimulation, the preferential control of FSH synthesis by the Decreased frequency
“In vitro”
activin/follistatin system, and differential feedback by ovarian ste- mRNA ↓ ↑
roids and the inhibins at the pituitary. Understanding the control GnRH-deficient men/women
of LH and FSH secretion is critical to our understanding of the Mean ↓ →↑
dynamics of the menstrual cycle. Amplitude ↑
Gonadotropin-Releasing Hormone settings in which gonadal feedback is low.95 In GnRH-deficient

FSH is secreted along with LH in response to acute stimulation men and women, an increase in the frequency of GnRH stimula-
by GnRH, but the relative role of GnRH in the overall control of tion increases mean levels of LH with no appreciable change in
FSH synthesis is much less than for LH. Blockade of the GnRH FSH96,97 (Fig. 7.4), effects that have implications for the patho-
receptor using a specific GnRH receptor antagonist results in physiology of PCOS which is characterized by an increased fre-
90% inhibition of LH secretion, but only 40% to 60% inhibi- quency of pulsatile GnRH stimulation of the pituitary.89 The
tion of FSH.92 Synthesis and secretion of LH and FSH are dif- direct effect of GnRH pulse frequency on GnRH receptor num-
ferentially controlled by the amplitude and frequency of GnRH ber98 underlies the frequency modulation of LH and FSH secre-
stimulation.93,94 LH is highly responsive to increases in the dose tion, at least in part. In addition, increased GnRH pulse frequency
of GnRH, while FSH is relatively insensitive to the GnRH increases follistatin which would attenuate activin stimulation of
dose. A physiological frequency of GnRH results in the synthe- FSH synthesis, as discussed below.99
sis and secretion of FSHβ, LHβ, and free α subunit. However, While an increase in GnRH pulse frequency increases the
increases or decreases in the physiological frequency have differ- synthesis and mean levels of LH, LH pulse amplitude is inversely
ential effects on LH and FSH (Table 7.2). Slow frequencies of related to GnRH pulse frequency.100,101 Studies in GnRH-
GnRH stimulation favor synthesis and secretion of FSH in vitro deficient men and women have shown that slower GnRH pulse
and are associated with an increase in FSH in human studies in frequencies are associated with a higher LH pulse amplitude in
LH mean 10.4 8.9 14.3

nLH mean 10.4 9.0 4.8
7
FSH mean 10.4 9.6 10.7
nFSH mean 10.4 6.4 3.6 Fig. 7.4 The differential effect of increasing
gonadotropin-releasing hormone (GnRH) pulse
GnRH dose (75 ng/kg) 35 frequency on luteinizing hormone (LH) and follicle-
20 stimulating hormone (FSH) as demonstrated in a
30 GnRH-deficient woman receiving intravenous pulsatile
GnRH at intervals indicated by the dotted lines. The
15 25
FSH (IU/L)
study began after 7 days of pulsatile GnRH administration
LH (IU/L)
20 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
10
15 minutes, 60 minutes, and 30 minutes. LH, but not FSH,
increased with the shortest dosing interval. The means of
10 LH and FSH, normalized for the overall amount of GnRH
5
5 administered (nLH and nFSH), suggest that faster GnRH
pulse frequencies are associated with early stages of
0 0 pituitary desensitization. (From Hall JE, Taylor AE, Hayes
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 FJ, Crowley WF Jr. Insights into hypothalamic-pituitary
dysfunction in polycystic ovary syndrome. J Endocrinol
Time (hour) Invest. 1998;21[9]:602–611.)
response to GnRH, while faster frequencies are associated with a high affinity for cell-surface proteoglycans and is presumed to
a decrease in the LH pulse amplitude response to GnRH. This act within the pituitary.104 Activin levels do not appear to vary
decrease in LH amplitude seen with pulse frequencies that are during female reproductive cycles. However, changes in fol-
faster than those encountered in physiological settings96,97 may listatin have been noted during the rat estrus cycle, suggesting
be the earliest sign of the pituitary desensitization that is well rec- that the effects of activin on FSH synthesis and secretion may be
ognized in association with continuous infusions of GnRH or the modulated through changes in follistatin in addition to effects
use of a GnRH agonist. of inhibin.104 As indicated above, follistatin is increased by fast
frequencies of GnRH stimulation and decreased with slower fre-
Autocrine/Paracrine Regulation of Gonadotropins: Activin, quencies99 compatible with the hypothesis that the activin and
follistatin system mediates the effect of GnRH pulse frequency
Inhibin, and Follistatin on FSH. Thus, while GnRH appears to be sufficient for control
Activins, inhibins, and follistatins were first discovered as gonadal of LH synthesis and secretion, the activin-inhibin-follistatin sys-
factors with preferential actions on FSH secretion from pitu- tem and perhaps BMPs play a significant role in conjunction with
itary gonadotropes.102 The inhibins, named for their inhibitory GnRH in regulating the synthesis and secretion of FSH.
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 OVARIAN FEEDBACK ON THE HYPOTHALAMUS AND
contrast, the activins, which stimulate the synthesis and secretion PITUITARY
of FSH, are homodimers of two β-subunits. Activin is secreted
by gonadotropes and other pituitary cell populations. Like other
Negative Feedback
members of the TGF-β superfamily of growth and differentia-
tion factors, activins exert most of their effects by autocrine or
Estrogen
paracrine mechanisms. Activins sequentially interact with one It is well known that low doses of estrogen inhibit gonadotropin
of the two known type-II activin receptors, ActRII or ActRIIB, secretion. Increased gonadotropin levels in patients with aromatase
and the type-1 receptor, activin receptor-like kinase 4 (ALK4).102 deficiency provide the most specific evidence of estrogen-negative
The expression of FSHβ is extremely sensitive to the stimulatory feedback on the control of both LH and FSH in men and
action of activins, which work in concert with and are permissive women.106 This is supported by the marked increase in LH and
to the actions of GnRH through the promotion of transcription FSH levels in postmenopausal and ovariectomized women.107 The
of both FSHβ and the GnRH receptor.103 loss of gonadal feedback in ovariectomized rats is associated with
The inhibins act as specific antagonists of the FSH stimulatory increased expression of LHβ, FSHβ, and α subunit mRNA, an
actions of activin by binding to betaglycan and sequestering the increase in the number of cells expressing LHβ accompanied by
type-II activin receptors. While inhibin is made in the pituitary, an increased in cell size and an increase in total expression per cell,
circulating inhibin derived from the ovary plays a far greater role and an increase in LH and FSH secretion. Administration of low
in the negative control of FSH. In addition, bone morphogenic doses of estradiol reverses these changes,108 as has also been shown
proteins, BMP-6 and BMP-7, are capable of modulating FSH in ovariectomized sheep and monkeys.
synthesis in gonadotropes suggesting that other systems may also There is considerable evidence that supports a primary
be involved in the control of FSH.102,104 hypothalamic site of estrogen-negative feedback on pituitary
Follistatin is a monomeric protein that is distinct from the gonadotropin secretion.38,109 Studies in which GnRH secretion
activin and inhibin family and acts as a virtually irreversible bind- has been measured using a push-pull hypothalamic perfusion
ing protein by complexing with activin and masking the binding technique in rats—or cannulation of the pituitary portal circula-
sites on activin for the type-I and type-II receptors.105 Synthesis tion in sheep and monkeys—indicate that GnRH rises follow-
of follistatin in pituitary folliculostellate cells and gonadotropes is ing ovariectomy and falls with estrogen replacement. Estradiol
controlled by activin and GnRH and may be additionally modu- administration is associated with a decrease in GnRH expres-
lated by gonadal steroids. The follistatin 288 isoform (FS288) has sion in rat hypothalamic tissue slices and in a GnRH neuronal
cell line. Studies in estrogen receptor (ER) knock-out animals is likely that progesterone exerts its effects on GnRH secretion
support an essential role for ERα in estrogen-negative feedback, primarily through its receptors on KNDY neurons.38,127 As indi-
although both forms of the receptor are present in the hypothal- cated above, there is ample evidence that the β-endorphin sys-
amus.109 The major hypothalamic estrogen-negative feedback tem plays a critical role in mediating the effects of progesterone
effect is mediated through neurons upstream of GnRH itself, on GnRH pulse frequency and studies in sheep indicate that the
most importantly the KNDY neurons of the arcuate/median inhibitory effect of progesterone on GnRH secretion is mediated
eminence.1,2 Estrogen-receptive GABA neurons within the pre- by dynorphin, a critical component of KNDY neurons.61
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
Inhibin A and Inhibin B
opioid system is unlikely to be involved in estrogen-negative Evidence for a nonsteroidal gonadal factor with feedback effects
feedback.38 on the pituitary dates to the early 1900s but it was not until the
In women, the mechanisms underlying estrogen-negative mid-1980s that inhibin was isolated and subsequently found to
feedback have generally been investigated in postmenopausal be part of a family of peptides that includes inhibin A, inhibin B,
or ovariectomized women. The quantity of GnRH, estimated activin, and the functionally related protein, follistatin.104 Inhibin
in vivo using submaximal GnRH receptor blockade, is higher B is present in the circulation in men while both inhibin A and
in postmenopausal compared with premenopausal women,110 inhibin B are detected in serum and follicular fluid in women dur-
consistent with the increase in GnRH mRNA that has been ing their reproductive years.128–131
demonstrated in postmenopausal women studied at autopsy.111 Inhibin A is secreted in both the follicular and luteal phases
With the administration of low levels of estradiol, the quan- of the menstrual cycle. During folliculogenesis, peak levels of
tity of GnRH returned to follicular phase levels in postmeno- inhibin A are attained in the preovulatory period and inhibin
pausal women, suggesting that the increase in GnRH in the A is correlated with the size of the dominant follicle in normal
absence of gonadal feedback can be attributed entirely to the cycles,129,130 as is estradiol. Follicular phase inhibin A is primar-
loss of estrogen.112 To further support a hypothalamic site of ily the product of granulosa cells; however, there is some evi-
estrogen-negative feedback in women, neuroimaging studies dence for theca cell production in the mature follicle.132 Studies
have now provided evidence of decreased metabolic activity in of βA inhibin subunit expression132 and measurement of dimeric
the medial basal hypothalamus in association with brief expo- inhibin A in follicular fluid133 are consistent in indicating maximal
sure to relatively low doses of estradiol in postmenopausal follicular phase levels in the preovulatory follicle. However, it is
women.113 Estradiol administration does not decrease GnRH now appreciated that inhibin A is also synthesized and secreted at
pulse frequency in the majority of studies in postmenopausal earlier stages of follicular development, beginning in the mid to
women107 and thus, the negative feedback effect of estradiol on late follicular phase.134 The peak in inhibin A in the luteal phase
the hypothalamus is likely to be mediated through changes in and its decline with luteolysis are consistent with production by
GnRH pulse amplitude. These results in women are similar to the corpus luteum, as expected from the high levels of βA inhibin
those in which GnRH was measured directly in pituitary por- subunit expression in the corpus luteum.132
tal blood in ovariectomized sheep and monkeys and showed In contrast to inhibin A, the pattern of inhibin B in serum suggests
a decrease in GnRH pulse amplitude, but not frequency in that it is primarily secreted from small antral follicles. A correlation
response to estradiol administration.114,115 Autopsy studies of inhibin B levels with the size of the dominant follicle is remark-
in women are consistent with a role for neurons expressing ably absent in women during spontaneous ovulatory cycles,130 sug-
kisspeptin, NKB, substance P, dynorphin, and ERα in medi- gesting that inhibin B is consistent with studies showing that inhibin
ating the negative feedback of estrogen in the medial basal B levels in follicular fluid do not change as a function of follicle size
hypothalamus.49,116,117 or maturity.133 They are also consistent with earlier studies demon-
While the studies detailed above demonstrate a significant strating that expression of βB inhibin subunit mRNA is highest in
hypothalamic effect of estrogen-negative feedback, they do not early antral follicles, with lower levels in the dominant follicle and
exclude a pituitary site of action. In cultured pituitary cells, no evidence of βB-subunit expression in the corpus luteum.132 The
estradiol transiently reduces the LH response to GnRH,118 and latter studies have also shown that inhibin B synthesis is confined to
administration of estradiol to hypothalamic-lesioned monkeys the granulosa cells and is absent in theca cells.
receiving pulsatile GnRH decreased LH secretion.119 Both ERα
and ERβ are present on gonadotropes109,120 and characterization Regulation of Inhibin A and Inhibin B by Gonadotropins. A
of the gonadotrope-specific ERα (ESR1) knock-out mouse has significant body of data has demonstrated an increase in inhibin
now provided definitive evidence of a direct inhibitory effect of B secretion in conjunction with early follicular development
estradiol at the pituitary in the rodent.121 Studies in postmeno- stimulated by physiological levels of FSH. This was initially
pausal women that isolated the pituitary from hypothalamic suggested by the relationship of the rise in FSH during the
input have extended these findings from lower animal species to luteal-follicular transition to the concomitant increase in inhibin
humans by demonstrating that physiological levels of estradiol B. In GnRH-deficient women, replacement of pulsatile GnRH
have a direct pituitary effect on gonadotropin secretion that is at the slower luteal phase frequency of every 4 hours compared
greater for FSH than for LH.122 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
Progesterone follicular growth and an increase in the secretion of inhibin B135
Progesterone has a profound effect on gonadotropin secretion (Fig. 7.5). This study demonstrated the remarkable sensitivity
that manifests at the hypothalamic level through the slowing of of serum inhibin B levels to changes in FSH stimulation within
pulsatile GnRH secretion.123,124 This effect requires estrogen the physiological range during the earliest stages of follicular
priming,125 likely through upregulation of progesterone recep- development.
tors in the hypothalamus.126 In postmenopausal women receiving In studies designed to examine the response to differential
low doses of estradiol, the addition of progesterone uniformly gonadotropin stimulation at different stages of follicle develop-
suppresses GnRH pulse frequency using either LH or FAS as ment, recombinant human LH (rhLH) or FSH (rhFSH) was
markers of GnRH secretion,112 and administration of proges- administered to women following downregulation of endogenous
terone decreases the overall amount of GnRH secretion.110 It GnRH secretion using a potent GnRH agonist.136 Consistent
GnRH pulse
240 minutes 90 minutes
frequency 7
240 minutes
20
15
Fig. 7.5 The increased frequency of pulsatile GnRH during

FSH (IU/L)
the luteal follicular transition facilitates the luteal-follicular

rise in FSH as indicated in this study in GnRH-deficient
10 women, each studied twice. The normal rise in FSH in
200
relation to menses is attenuated when the frequency of
intravenous GnRH (75 ng/kg) remains at the luteal phase
Inhibin B (pg/mL)
frequency of every 240 minutes (teal circles) compared to the
usual increase of every 90 minutes at the time of menses as
5 100 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
0 0 Welt CK, Martin KA, Taylor AE, et al. Frequency modulation
3 2 0 1 2 3 4 5 6 of follicle-stimulating hormone (FSH) during the luteal-follicular
transition: evidence for FSH control of inhibin B in normal
Days from onset of menses women. J Clin Endocrinol Metab. 1997;82[8]:2645–2652.)
with failure to observe LH receptors in small antral follicles, have demonstrated an inverse relationship between increasing
rhLH alone had no effect on follicle growth or hormone secre- FSH and decreasing inhibin B in association with reproductive
tion when administered daily for up to 7 days. However, daily aging.139,141,142
subcutaneous administration of rhFSH resulted in normal early Reproductive aging is associated with a decline in fertility
follicular phase levels of FSH and an increase in inhibin B secre- that begins in the third decade but accelerates rapidly after age
tion that preceded that of estradiol and inhibin A (Fig. 7.6). 35 associated with a decrease in the pool of ovarian follicles.143
Studies using preantral and small antral follicles obtained from It is also at age 35 that an increase in follicular phase FSH is first
ovaries at the time of oophorectomy for nonovarian indications seen. In women 35 or older with regular ovulatory cycles and
indicated that inhibin B is constitutively secreted from preantral follicular phase FSH levels still within the normal range, there
follicles.134 Importantly, FSH does not stimulate the secretion is a small but significant increase in FSH in the early follicular
of inhibin B from granulosa cells. Taken together, these studies phase only; decreased inhibin B levels across the entire follicu-
demonstrate that the increase in inhibin B observed in vivo in lar phase and estradiol levels do not differ from normal women
response to FSH results from an increased number of granulosa in the early follicular phase but increase in the midfollicular and
cells rather than direct stimulation of secretion by FSH. At later late follicular phases.130 In the luteal phase, inhibin B, inhibin A,
stages of follicular development, both LH and FSH stimulate and progesterone are lower in older cycling women while estra-
secretion of inhibin A and estradiol from the dominant follicle diol levels are preserved. While ovulatory cycles are maintained
but have no effect on inhibin B.134 during the early stages of reproductive aging, inhibins B and A
progressively decrease and are associated with a similar progres-
Evidence for an Endocrine Negative Feedback Role for sive increase in FSH and maintenance of estradiol.144 These data
Inhibin A or Inhibin B. Inhibin was initially discovered support an endocrine role for the inhibins independent of estra-
based on its ability to inhibit FSH secretion in pituitary cell diol in the negative feedback control of FSH as well as a key role
cultures.102 Inhibin subunits are expressed in a variety of tissues for FSH in maintaining estradiol levels in the face of a declining
including the adrenal. However, the only significant source of pool of ovarian follicles. In young women with regular ovula-
circulating dimeric inhibins is the gonads and there is compelling tory cycles, it is more difficult to determine whether the inhibins
evidence that the principal mechanism of action of inhibin in contribute to negative feedback on FSH independent of estra-
suppressing pituitary FSH secretion is an endocrine action. In diol and particularly whether inhibin B and/or inhibin A play a
addition, FSH levels decrease in response to the administration role in the midfollicular phase decline in FSH that is critical to
of pharmacological doses of inhibin A administered in the the monofollicular development that characterizes normal repro-
follicular and luteal phases in the rhesus monkey.137,138 The most ductive cycles in women. While the tools to determine the role
compelling line of evidence that inhibin regulates FSH secretion of inhibin directly by either administration or blockade are not
under normal physiological circumstances in women is the failure available, it is possible to investigate the estrogen component of
of physiological levels of gonadal steroids to restore FSH levels FSH negative feedback and thereby infer the physiological role
to normal in postmenopausal women. The model of reproductive of inhibin. Studies in which estradiol levels were maintained by
aging has been used by a number of investigators to refine estradiol administration during the luteal- follicular transition
this evidence. FSH levels increase with age, before increases have been interpreted to suggest that inhibin A is not involved
in LH or decreases in estradiol139,140 and a number of studies in the negative feedback control of FSH in the luteal-follicular
FSH (IU/L) 15
400 10
200 5
0
0
Estradiol (pg/mL)
1500 100
1000
50
Hormone level
500
% Change
0
0 4
800 Inhibin A (IU/mL)
3
600
2
400
1
200
0
Inhibin B (pg/mL) 450
3000
300
Fig. 7.6 Hormone response to recombinant human 2000
follicle-stimulating hormone (FSH; 150 IU daily) for 6 days 150
in normal women after GnRH agonist downregulation 1000
of endogenous gonadotropin secretion. (From Welt CK, 0
Schneyer AL. Differential regulation of inhibin B and inhibin a by 0
follicle-stimulating hormone and local growth factors in human 0 1 2 3 4 5 6
granulosa cells from small antral follicles. J Clin Endocrinol
Metab. 2001;86[1]:330–336.) Time (days)
transition.145,146 An alternative approach is to block the estrogen Gonadotropin Surge Attenuating Factor
receptor. Results of studies using the estrogen receptor blocker,
tamoxifen, indicate that the low levels of estradiol in the early fol- Gonadotropin Surge Attenuating Factor (GnSAF), also known as
licular phase contribute to negative feedback on FSH, mediated gonadotropin surge inhibiting factor (GnSIF), is an ovarian fac-
at a hypothalamic level as shown in GnRH deficient women.147 tor that reduces GnRH- induced LH secretion.152,153 Despite
However, FSH failed to approach menopausal levels indicating many years of investigation, the molecular structure of GnSAF has
that inhibin B is also critical for FSH regulation during the nor- not been completely characterized,152,154,155 which has hampered
mal cycle. Thus, both estradiol and the inhibins are required for efforts to fully understand its regulation and physiological role. Its
FSH restraint during the follicular phase.147 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
Activin/Follistatin models and in women that there is an inverse relationship between
The control of FSH is dependent not only on inhibin and estra- GnSAF bioactivity and follicle size, with the highest concentra-
diol but also on the activin/follistatin system. Activin acts as a tions in small growing follicles,152 suggesting that its primary role
local growth and differentiation factor in the ovary as well as the may be during earlier stages of follicle development.
pituitary.104 During the normal menstrual cycle, total activin A
levels are highest at the midcycle and during the luteal follicular Positive Feedback
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 Role of the Pituitary in Positive Feedback and Generation
activin across the menstrual cycle,149 and no difference in activin
B between the follicular and luteal phases.150 Furthermore, a of the Preovulatory Surge
potential endocrine role of activin can only be considered in the In addition to inhibition of gonadotropin secretion, estrogen
context of follistatin which is synthesized in many tissues as well exerts a stimulatory effect to generate the preovulatory LH
as the pituitary. While activin has been measured in serum, cir- surge. This positive feedback effect is seen in multiple animal
culating activin is irreversibly bound by the circulating isoform species,109 and in women. There are two critical questions that
of follistatin, FS315.151 No mechanisms have been identified form the basis of a mechanistic understanding of gonadotropin
within tissues that would alter neutralization by follistatin, and surge generation: the first is how estrogen can exert both inhibi-
therefore it is almost certain that activin acts in an autocrine and tory and stimulatory effects on LH secretion, and the second is
paracrine (but not endocrine) fashion in the pituitary to regulate whether the site of estrogen-positive feedback is at the pituitary,
FSH secretion. the hypothalamus, or both. The direction of estrogen feedback
is dependent on both the degree of estrogen exposure and its Species Differences in Hypothalamic Input to the
duration with low levels of estradiol administration resulting in 7
decreased LH secretion within 12 to 24 hours, while positive Preovulatory Surge
feedback requires exposure to higher concentrations over a more In the rat and sheep, estrogen-positive feedback on gonadotropin
prolonged duration.156–158 secretion requires an increase in GnRH secretion in addition to
pituitary augmentation of the GnRH signal. In rodents, this increase
Pituitary effect of high levels of estrogen. There is ample in GnRH secretion is dependent on specific circadian signals.175 In
evidence that high levels of estrogen augment the pituitary response rodents, estrogen-negative feedback occurs in the arcuate nucleus of
to GnRH across species. Studies in animal models demonstrate the medial basal hypothalamus, and kisspeptin neurons in the region
an increase in the number of cells expressing the gonadotropin coexpress NKB and dynorphin. In contrast, positive feedback occurs
subunits, an increase in GnRH receptor number, an impact on the in the anteroventral periventricular nucleus (AVPV), where kiss-
function of ion channels in the plasma membrane, and regulation peptin neurons do not express NKB and dynorphin.1,3
of both gene expression and second messenger systems within Generation of the preovulatory surge in nonhuman primates
gonadotropes.98,159,160 Studies in LβT2 pituitary cells indicate that appears to be fundamentally different from that in the rodent—
activin may act in concert with estrogen to increase GnRH receptors while there may be some alteration in GnRH input, this is not
on pituitary gonadotropes103 while NPY secretion from the median controlled in the preoptic area (the site of the AVPV), it is not
eminence may contribute to pituitary sensitization through changes tied to circadian signals, and the gonadotropin surge does not
in the affinity of the GnRH receptor for its ligand.161 require an increase in GnRH.47
As in nonhuman primates, an increase in GnRH secretion is
Pituitary effect of progesterone. In GnRH-deficient women not required for the generation of a normal gonadotropin surge in
receiving pulsatile GnRH with or without progesterone indicate women176,177; moreover, there is no evidence for augmentation of
that low levels of progesterone as seen in the periovulatory period, GnRH secretion or even an altered pattern of GnRH stimulation
increase LH pulse amplitude through a direct pituitary action.162 associated with generation of the surge in women.51,178,179 Taken
This effect is independent of the indirect effects of progesterone together, these data suggest that the gonadotropin surge in normal
on the amplitude of LH pulses associated with slowing of GnRH women requires ongoing pulsatile GnRH stimulation but is other-
stimulation of the pituitary.100,101 wise mediated through the marked increase in pituitary sensitivity
to GnRH. Thus, while an increase in GnRH is required for gen-
Inhibin A augments the effect of high estrogen levels at the eration of the gonadotropin surge in rodents and sheep, GnRH
pituitary. Inhibin A is elevated in women before ovulation,130,163 appears to play a permissive role in generation of the preovulatory
and there are several lines of evidence suggesting that it may play LH surge in normal women as it does in nonhuman primates.46,47
a role in positive feedback at the pituitary level. Inhibin A increases
GnRH receptors by three-to sixfold in pituitary cell cultures,164 and THE NORMAL MENSTRUAL CYCLE
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 • Normal reproductive function in women involves repetitive cycles of
A on the percentage of LH positive cells and the percent of LH follicle development, ovulation, and preparation of the endometrium
positive cells that bind GnRH is greater than the effect of estradiol; for implantation should conception occur during that cycle.
however, inhibin A has a less pronounced effect than estradiol on • Increased FSH stimulation during the luteal-follicular transition
positive feedback effects downstream of the LH receptor.167 leads to the recruitment of a cohort of follicles as well as the emer-
gence and growth of a dominant follicle.
Pituitary effects of kisspeptin. An emerging body of data • Secretion of estradiol and inhibin from the ovary is required to limit
suggests that there may be a pituitary role for kisspeptin in ongoing FSH stimulation while rising levels of estradiol in combination
addition to its well-studied hypothalamic role.168 Kisspeptin has with other potential factors are essential to the gonadotropin surge.
been found in the pituitary portal system in rodents and sheep169; • The corpus luteum secretes progesterone and estradiol to prime the
however, it does not change dynamically, suggesting that uterus for implantation and its demise allows FSH to rise with the
kisspeptin may not be directly involved in pituitary regulation. beginning of a new cycle.
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 Clinical Characteristics
estrogen acting through the ERα receptor.170 Kisspeptin induces By convention, the first day of menses is designated “Day 1” and
transcription of LHβ and FSHβ gene expression in LβT2 cells171 marks the onset of the follicular phase of the menstrual cycle. The
and increases GnRHR expression in this same cell type.172 Kissr1 follicular phase encompasses the period of recruitment of multiple
in the pituitary is enhanced in female mice during the estradiol- follicles and the emergence and growth of the dominant follicle (Fig.
induced LH surge,171 possibly through the effect of the increased 7.7). During the follicular phase, rising levels of estradiol are associ-
secretion of GnRH at midcycle in rodents (see below) and its ated with endometrial proliferation. The luteal phase, which begins
stimulatory effect on kissr1.172 While kisspeptin positive cells on the day after the LH surge, is characterized by formation of the
were demonstrated in the anterior pituitary in the monkey, corpus luteum, secretion of progesterone, estradiol, and inhibin A,
they were not shown to be colocalized to the gonadotrope,173 and a coordinated series of changes in the endometrium as it first pre-
pointing to potential species differences. KISS1R is present in the pares for implantation and then, with a decline of the corpus luteum
human pituitary174; however, further information is not available in the absence of pregnancy, loses its blood supply and is shed.
to determine whether alterations may contribute to pituitary The classic studies of Treloar and colleagues180 reported a
sensitization to GnRH in the setting of high estradiol levels at median menstrual cycle length of 28 days, with a normal range
the time of the midcycle surge. between 25 and 35 days. More recent studies based on data
In summary, high levels of estrogen have a profound effect on obtained from mobile tracking apps in large populations of women
the pituitary to increase LH secretion through increases in GnRHR often followed for extended periods of time, and some with addi-
as well as its downstream effects. This pituitary effect of high levels tional urinary ovulation tests, have provided more contemporary
of estrogen is likely augmented by elevated inhibin A, the direct data.181–183 In the largest of these studies, data was collected from
pituitary effects of low levels of progesterone, and possibly through 1.5 million nonpregnant women across the spectrum of repro-
a pituitary effect of elevated kisspeptin on LH secretion. ductive age and BMI.183 Ninety percent of women had a median
GnRH
Luteal Follicular Luteal
phase phase phase
Fig. 7.7 The hormonal, follicular, and endometrial dynamics

of the normal menstrual cycle from the late luteal phase LH
through menses and the beginning of a new cycle of follicle FSH
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) Inhibin A
and luteinizing hormone (LH; light blue) are responsible for: (1) Inhibin B
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), E2
estradiol and inhibin A from the corpus luteum. Secretion of Prog
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, Endo
endometrial shedding follows the decline in hormone secretion
secondary to demise of the corpus luteum. Secretory Menses Proliferative Secretory
cycle length between 21 and 35 days. The median cycle length of GnRH in euthyroid women.92 Thus, FAS can also be used as
was 28 days in 16% of women, with cycle lengths of 27 and 29 a surrogate marker of GnRH pulse frequency. As its clearance
days occurring in 12% each. Cycle length was not influenced by is faster than that of intact LH, it is a preferable marker when
alcohol intake or smoking. A quarter of women had a cycle length GnRH pulse frequency is rapid or when the clearance of LH is
variability of 0 to 1.5 days, with over two-thirds of women hav- prolonged. The amplitude of the LH or FAS response to GnRH
ing a <6-day variability between cycles. In this study, shorter cycles depends on both the amplitude of the GnRH signal and on pitu-
were associated with greater stress, no exercise, and lighter menses. itary responsiveness to GnRH. Other techniques must therefore
Cycle variability was highest in women aged 18 to 24 and over be used to assess the amplitude of GnRH secretion.
35. Interestingly, women in the highest BMI categories had less Results of frequent sampling studies (every 5 or 10 minutes
cycle variability than their leaner counterparts. Total cycle length for up to 48 hours) have demonstrated marked variations in the
is much more highly correlated with follicular than luteal phase frequency and amplitude of LH pulses across the normal men-
length.181 Ovulation occurred between days 13 and 15 in the vast strual cycle (Fig. 7.9) and their precise regulation in relation to
majority of cycles.183 Younger women were more likely to ovulate the preovulatory LH surge.178,187–189
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
Follicular Phase
the largest follicle as assessed by ultrasound is highly predictable at The early follicular phase is characterized by an initial rise in
approximately 2 mm per day from the time it reaches 11 mm until FSH and recruitment of a new cohort of follicles into the grow-
ovulation (Fig. 7.8). The accompanying rise in estradiol is associ- ing pool with increased levels of inhibin B and an early increase in
ated with a progressive increase in the thickness of the endome- estradiol. In the early follicular phase (days 14 to 9 from the LH
trium while the addition of progesterone in the luteal phase results surge), the mean interpulse interval of GnRH is approximately
in increased echogenicity of the endometrium (Fig. 7.8). 90 to 100 minutes.76,188 The early follicular phase of established
reproductive cycles is characterized by a marked slowing of
Ovarian Feedback and the Dynamics of GnRH GnRH pulse frequency during sleep78 (Figs. 7.3 and 7.9). Sleep-
related slowing of pulsatile GnRH secretion may serve the func-
Secretion and Pituitary Responsiveness tion of maintaining FSH synthesis during this critical period of
GnRH secretion can be measured directly in large animal spe- follicle recruitment, but this hypothesis has yet to be tested.
cies, and studies have indicated that under physiological circum- The midfollicular phase is marked by the emergence of the
stances, peripheral LH secretion occurs concomitantly with the dominant follicle and a decrease in FSH in response to inhibin B
secretion of GnRH measured in pituitary portal blood.184–186 LH and rising levels of estradiol and a later rise in inhibin A. In the
has therefore been used as a marker of GnRH pulse frequency midfollicular phase, GnRH pulse frequency increases and the
in humans, based on these studies and two additional lines of interpulse interval shortens to approximately 60 minutes. LH
evidence. The first is that pulsatile secretion of LH is absent in pulse amplitude is markedly attenuated, reflecting the nega-
patients with congenital isolated GnRH deficiency and can be tive feedback of estradiol secreted from developing follicles on
restored with pulsatile administration of GnRH.187 The second the amplitude of GnRH pulses and possibly the initial effect of
is that pulsatile secretion of LH in normal subjects is reversibly increased GnRH pulse frequency and its effect on gonadotrope
abolished by the administration of a specific GnRH antagonist.92 responsiveness.96,97 Increased estradiol across the follicular phase
Thus, the occurrence of LH pulses can be taken as evidence for results in increasing endometrial proliferation.
the occurrence of a preceding stimulatory GnRH pulse and LH The late follicular phase is characterized by an exponential
pulse frequency can be used as a peripheral monitor of the fre- rise in estradiol and inhibin A with low levels of inhibin B and
quency of pulsatile GnRH secretion. Although the glycoprotein- FSH. The circhoral frequency of GnRH secretion that began in
free alpha subunit (FAS) is secreted from both the gonadotrope the midfollicular phase is maintained through the late follicular
and thyrotrope under the control of GnRH and TRH, the pul- phase. However, LH pulse amplitude begins to increase due to
satile component of FAS secretion is entirely under the control the stimulatory effects of rising levels of estradiol and possibly
30 20
Endometrial thickness
Follicle diameter
15
20
(mm)
(mm)
10
10
5
0 0
–8 –6 –4 –2 0
Days from ovulation
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.)
MCS
200 0
Interpulse interval (minutes)
0 100
40 40
LFP 20 20 ELP
200
0 0
40 40 300
MFP MLP
20 20 EFP MFP LFP MCS ELP MLP LLP
0 0
40
Pulse amplitude (IU/L)
40 40
20 20 30
0 0
EFP LLP 20
10
0
EFP MFP LFP MCS ELP MLP LLP
A B
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.)
inhibin A on gonadotrope responsiveness to GnRH. The marked GnRH 75 ng/kg q 60 minutes

increase in estradiol is accompanied by further endometrial
60 E2 = 131 pg/mL
proliferation.
50 Prog = 0.6 ng/mL
LH (IU/L)
Midcycle Surge 40
In response to the pituitary actions of the exponential increase 30
in estradiol, and likely inhibin A, progesterone, and kisspeptin
secretion in the late follicular phase, LH levels in women increase 20
tenfold over a period of 2 to 3 days while FSH levels increase four- 10
fold (Fig. 7.9). The midcycle surge of LH is absolutely required
for final maturation of the oocyte and initiation of follicular rup- 0
ture, which generally occurs 36 hours after the surge. The gonad-
1000
otropin surge is essential for normal reproductive cycles.
FAS (IU/L)
The pattern of estrogen exposure is critical to positive feed- 800
back. Exogenous administration of estradiol to normal women
in the early follicular phase156,157 or to postmenopausal women80 600
induces an increase in both basal and GnRH- stimulated LH
secretion that is dependent on the dose and duration of estro- 400
gen exposure. There is further evidence that the surge occurs
200
in response to the increase in estradiol rather than the drop in
estradiol that frequently accompanies the onset of the surge.157 In 0
other words, the surge results from positive feedback rather than 0 2 4 6 8 10 12 14 16 18 20 22 24
removal of estrogen-negative feedback.
Other evidence indicates that a small increase in progester- Time (hours)
one augments this surge. Secretion of progesterone is typically Fig. 7.10 Luteinizing hormone (LH) and free α-subunit (FAS)
associated with the luteal phase; however, the earliest increase sampled every 5 minutes in a gonadotropin-releasing hormone
in progesterone is evident in normal women prior to the LH (GnRH)-deficient woman receiving pulsatile GnRH intravenously,
surge. Blockade of progesterone receptors by RU486 delays the demonstrating the abrupt increase in LH and FAS pulse amplitude
surge by up to 3 days despite continued growth of the domi- and mean levels associated with estrogen-positive feedback in
nant follicle and rising levels of estradiol.190 In GnRH-deficient the absence of any change in the dose or frequency of exogenous
women, progesterone augments LH pulse amplitude, indicating GnRH replacement. (Hall JE, personal communication). E2,
that in addition to its well-known inhibitory effect on GnRH estradiol; Prog, progesterone.
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 women receiving exogenous GnRH replacement provide the
initiated in the early follicular phase, it has now been dem- most compelling evidence for the importance of pituitary sensi-
onstrated that progesterone does not appear to influence the tization to GnRH in generation of the midcycle surge in women.
height of the LH surge per se, as was initially reported,156 but When GnRH is administered at a dose and frequency that mim-
that it decreases the inter-individual variability in its timing ics the GnRH pulse frequency in the normal menstrual cycle with
relative to the onset of the infusion.157 development of a single dominant follicle, an abrupt increase
Although a gonadotropin surge can be generated in response in LH and FAS pulse amplitude is observed in the absence of
to a re-creation of normal preovulatory estradiol and proges- any change in the dose or frequency of GnRH administration
terone levels, the amplitude of the LH—but not FSH—surge is (Fig. 7.10), and a normal LH surge is achieved177 (Fig. 7.11).
less than in normal women. This suggests that there may also be These studies indicate that positive feedback can be achieved in
other ovarian factors required for generation of a surge of normal women through pituitary mechanisms alone in the absence of any
amplitude. As discussed above, there is compelling evidence that increase in GnRH input.
inhibin A, which increases dramatically in conjunction with estra- At the onset of both spontaneous and steroid-induced LH
diol in the late follicular phase,130,163 may play such a role, acting surges in normal women, complete GnRH receptor block-
at the pituitary level.167,171 ade results in termination of the surge,179,192,193 indicating
A key question is whether estrogen- positive feedback in that ongoing GnRH secretion is essential for generation of
women is mediated at the hypothalamus, the pituitary, or both. the gonadotropin surge. However, neither the frequency nor
In all species, including women, there is evidence for sensitiza- the overall amount of GnRH is increased in association with the
tion of the pituitary to GnRH stimulation at the time of the onset of the gonadotropin surge in normal women. Studies in
preovulatory surge. While a GnRH surge also appears to be normal women in which blood samples were drawn every 5 min-
present in lower animal species, there is still no evidence that a utes for up to 36 hours at midcycle indicate a striking increase
surge of GnRH is present, or required, in women. Thus, there in LH and FAS pulse amplitude from the late follicular phase to
are important species specificities to the mechanisms underlying the early and midportions of the surge with no change in pulse
this critical process. frequency during this same period178 (Fig. 7.9). To address
The classic studies of Yen and colleagues demonstrated that the question of whether generation of the surge in women is
the responses of LH and FSH to exogenous GnRH administra- associated with an increase in the amplitude of GnRH secreted
tion are markedly influenced by the stage of the menstrual cycle, with each bolus, submaximal GnRH receptor blockade with a
with an exaggerated increase in secretion of both gonadotropins fixed dose of a GnRH was used allowing competition between
at the time of the midcycle surge,191 confirming the importance endogenous GnRH and the antagonist to provide a semiquan-
of the pituitary as a key site of positive feedback. As reviewed titative estimate of the overall amount of endogenous GnRH
above, animal and in vitro studies demonstrate that estradiol, secreted.179 Results of these studies provided no evidence for an
in conjunction with progesterone, inhibin A, and possibly kis- increase in the overall amount of GnRH secreted and, in fact,
speptin, acts directly at the pituitary to increase gonadotrope suggested that the amount of GnRH at the surge is less than in
sensitivity to GnRH.98,159,167,171,186 Studies in GnRH-deficient the early and late follicular phase. Consistent with this finding,
further studies have shown that in GnRH-deficient women, the normal women; however, there is no evidence for an increase
replacement dose of GnRH can be reduced by two-thirds in in the amplitude or frequency of GnRH secretion and such 7
the late follicular phase from that required for the development an increase is not required to generate a surge in GnRH-
of a single dominant follicle without compromising the timing deficient women receiving pulsatile GnRH replacement.
or height of the midcycle surge or the subsequent luteal phase Consistent with this conclusion, neuroimaging studies in
(Fig. 7.12).51 postmenopausal women in whom a gonadotropin surge was
Taken together, these studies indicate that GnRH is induced by administration of a graded estradiol infusion show
absolutely required for generation of the midcycle surge in a marked increase in metabolic activity at the pituitary, but
not the hypothalamus, in association with estrogen-positive
feedback on LH.113
75 ng/kg/bolus The termination of the LH surge is associated with a dramatic
400 400 decrease in pulse amplitude accompanied by a decrease in pulse
q 90 q 60 q 90 q 4 hour frequency to approximately every 70 minutes178 (Fig. 7.9). The
FSH (IU/L)
300 300
LH (IU/L)
slowing of pulse frequency that51 accompanies the termination

200 200 of the surge is due, at least in part, to the hypothalamic effects of
progesterone.
100 100 Thus, in lower animal species, in addition to pituitary sensi-
tization to GnRH, an increase in GnRH occurs in conjunction
0 0
DF (cm)
with the LH surge. In rodents, rabbits, and sheep, a GnRH surge

2 is necessary to generate the LH surge; in nonhuman primates a
0 GnRH surge may not be necessary.46,47 Importantly, in women a
PROG (ng/mL)
GnRH surge does not appear to occur and is not needed to gen-
300
E2 (pg/mL)
20 erate a normal LH surge.51,178,179

200
10 Luteal Phase
100
Formation of the corpus luteum after ovulation results in secre-
tion of progesterone, estradiol, and inhibin A with inhibitory
0 0
effects on both LH and FSH secretion. The slowing of pulsa-
0 5 10 15 20 25 tile GnRH secretion begins during the termination of the mid-
Days cycle surge and continues through the early, mid, and late luteal
phases (Fig. 7.9). In the late luteal phase, interpulse intervals as
Fig. 7.11 Administration of intravenous pulsatile gonadotropin- long as 4 to 8 hours are observed. This slowing of the GnRH
releasing hormone (GnRH) to a GnRH-deficient woman at a pulse generator is due to the effect of progesterone123 but is not
physiological frequency with follicle development, ovulation, and expressed without the additional presence of estradiol.125 In the
normal luteal phase function. Note that the luteinizing hormone (LH) luteal phase, LH pulse amplitudes are significantly higher than
surge is generated in association with an increase in both the size of in the follicular phase due to progesterone-induced slowing of
the dominant follicle (DF) and a marked increase in estradiol (E2), but in pulsatile GnRH secretion and the inverse relationship between
the absence of an increase in the dose or frequency of pulsatile GnRH LH responsiveness to GnRH and GnRH pulse frequency100,101
administration. (Adapted from Hall JE, Martin KA, Whitney HA, Landy and possibly due to the direct effect of progesterone at the pitu-
H, Crowley WF. Potential for fertility with replacement of hypothalamic itary to increase LH responsiveness to GnRH.162 The corpus
gonadotropin-releasing hormone in long term female survivors of cranial luteum has a finite lifespan and in the absence of conception the
tumors. J Clin Endocrinol Metab. 1994;79:1166–1172.) FSH, follicle- decrease in progesterone and estradiol results in the shedding of
stimulating hormone. the endometrium.
Control cycle Dose drop cycle Fig. 7.12 The preovulatory surge
140 in a representative GnRH-deficient
GnRH woman receiving pulsatile GnRH
120 at a physiologic frequency of every
60 minutes indicating that an LH
100 surge is generated with no change
in pulse frequency at a dose of 75
LH (IU/L)
80 ng/kg, unchanged from the late

follicular phase as indicated in the
60 blue horizontal bar (left panel). The
height of the LH surge is not diminished
40 despite a reduction in GnRH dose from
75 ng/kg to 25 ng/kg as indicated by
20 the blue horizontal bar (right panel) in a
subsequent cycle before the onset of
0 the LH surge. (From Martin KA, Welt CK,
15 10 5 0 5 10 15 10 5 0 5 10 15 Taylor AE, Smith JA, Crowley WF Jr, Hall
JE. Is GnRH reduced at the midcycle surge
Cycle day centered to ovulation in the human? Evidence from a GnRH-
deficient model. Neuroendocrinology.
1998;67[6]:363–369.)
Fig. 7.13 Follicle-stimulating hormone (FSH) and 15

luteinizing hormone (LH) in a normal woman who
FSH (IU/L)
underwent blood sampling every 10 minutes 10
over a 2-day period during the luteal-follicular
transition. This study was conducted beginning 12 5
days after the subject’s preovulatory LH surge and
3 days before menses. Note the rise in FSH that is 0
evident before menses and is associated with an 30
increase in the frequency of pulsatile LH secretion.
LH (IU/L)
The horizontal bars indicate sleep and the inverted 20
triangles indicate statistically identified pulses.
(Adapted from Hall JE, Schoenfeld DA, Martin KA, 10
Crowley WF Jr. Hypothalamic gonadotropin-releasing
hormone secretion and follicle-stimulating hormone 0
dynamics during the luteal-follicular transition. J Clin 0 4 8 12 16 20 24 28 32 36 40 44
Endocrinol Metab. 1992;74[3]:600–607.) Time (hours)
Luteal-Follicular Transition shifts.195–200 Given the disruption in sleep architecture with

rotating shifts or night work, these studies raise the possibil-
With declining function of the corpus luteum and declining lev- ity that slower sleep-related GnRH pulse frequency associated
els of progesterone, estradiol, and inhibin A, release from nega- with consolidated sleep is necessary to maintain synthesis of
tive feedback permits FSH to rise, an increase that begins before FSH at this critical time.
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 Racial Differences in Menstrual Cycle Dynamics
Thus, it has been proposed that release from estrogen-negative and Fertility
feedback is the key factor in the luteal-follicular rise in FSH and Racial disparities between African American and Caucasian
that other factors such as the decline in inhibin A secretion from women in the incidence of breast cancer, leiomyomas, and osteo-
the corpus luteum may not play a role. However, studies using porosis raise the possibility of a greater lifetime exposure to
tamoxifen to block the estrogen receptor in normal cycles suggest estrogen in African American women. Estradiol levels are 18%
that inhibin A also plays a role in restraining FSH secretion dur- higher in the late follicular phase and 40% higher in the midlu-
ing the normal luteal phase.147 teal and late luteal phases in weight-matched regularly cycling
LH pulse frequency increases before the onset of menses African American women who ovulated a single follicle compared
(Fig. 7.13). LH pulse frequency is inversely related to proges- to their Caucasian counterparts.201 In these studies, higher estra-
terone levels189 and administration of midluteal phase levels of diol in the face of similar androstenedione levels suggested that
progesterone189 in conjunction with estradiol prevents the nor- ovarian aromatase activity is higher in African American women
mal luteal-follicular increase in GnRH pulse frequency in normal although FSH, the major regulator of ovarian aromatase, was
women.125 As discussed above, there is convincing evidence that not elevated. Further studies confirmed that increased circulat-
the increase in GnRH pulse frequency that occurs between the ing levels of estradiol in African American women are of ovarian
luteal and follicular phases facilitates the luteal-follicular increase origin with a higher androgen-to-estrogen ratio in follicular fluid
in FSH secretion; FSH is significantly correlated with LH pulse and an increase in granulosa cell aromatase expression compared
frequency, while the inverse relationship between FSH and estra- with Caucasian women.202 The reason for this effect may be due
diol was not significant.189 Importantly an increase in the fre- to population-specific genetic variation affecting CYP19, which
quency of exogenous GnRH administration in GnRH-deficient encodes aromatase, as there were no differences in FSH or AMH
women from the slow luteal phase frequency to the follicular levels or in FSH receptor expression between African American
phase frequency is essential to recreate the normal intercycle rise and Caucasian women.202
in FSH (Fig. 7.5). There is also evidence that race plays a dramatic role in both
Thus, while the slow frequency of GnRH secretion in infertility and the results of fertility treatment.203–208 The etiol-
the luteal phase might be expected to increase FSH synthe- ogy of these differences is undoubtedly multifactorial. The evi-
sis either directly or through a decrease in follistatin and a dence of racial discrepancies in fertility awareness209 and racial
concomitant increase in activin signaling, FSH synthesis and differences in pubertal onset210 and reproductive hormones201,202
secretion are inhibited by estradiol and inhibin A. With the suggest that differences in fertility and fertility outcome should
demise of the corpus luteum, estradiol and inhibin A levels not be attributed to psychosocial influences without further
fall, as do those of progesterone. FSH increases with release investigation.
from negative feedback and with the normal increase in GnRH
pulse frequency.
There is now evidence that the progressive increase in TOP REFERENCES
GnRH pulse frequency from the early to the midfollicular Biro FM, Pajak A, Wolff MS, et al. Age of menarche in a longitudinal US
Cohort. J Pediatr Adolesc Gynecol. 2018;31(4):339–345.
phase represents a gradual loss of the restraining effects of low
Clarke SA, Dhillo WS. Kisspeptin across the human lifespan: evidence
levels of progesterone on the GnRH pulse generator.194 As the from animal studies and beyond. J Endocrinol. 2016;229(3):R83–98.
early follicular phase is characterized by sleep-related inhi- Gahete MD, Vázquez- Borrego MC, Martínez- Fuentes AJ, Tena-
bition of pulsatile LH secretion, it is intriguing to speculate Sempere M, Castaño JP, Luque RM. Role of the Kiss1/Kiss1r sys-
that a similar prolonged effect of progesterone is also involved tem in the regulation of pituitary cell function. Mol Cell Endocrinol.
in sensitizing the hypothalamus to the inhibitory effects of 2016;438:100–106.
sleep during this cycle phase. Menstrual cycle abnormalities Garcia-Galiano D, Pinilla L, Tena-Sempere M. Sex steroids and the
or reduced fecundity have been reported in the majority of control of the Kiss1 system: developmental roles and major regulatory
studies in women exposed to transmeridian travel or rotating actions. J Neuroendocrinol. 2012;24:22–33.
Grieger JA, Norman RJ. Menstrual cycle length and patterns in a global its impact on the gene expression of gonadotropin subunits. Gen Comp
cohort of women using a mobile phone app: retrospective cohort study. Endocrinol. 2017;246:382–389. 7
J Med Internet Res. 2020;22:e17109. Siegel DR, Sheeder J, Polotsky AJ. Racial and ethnic disparities in fertility
Hewitt SC, Korach KS. Estrogen receptors: new directions in the new awareness among reproductive-aged women. Womens Health Rep (New
millennium. Endocr Rev. 2018;39:664–675. Rochelle). 2021;2(1):347–354.
Humphries LA, Chang O, Humm K, Sakkas D, Hacker MR. Influence of Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA.
race and ethnicity on in vitro fertilization outcomes: systematic review. Neurokinin 3 receptor antagonism reveals roles for neurokinin B in
Am J Obstet Gynecol. 2016;214(2):212.e1–212.e17. the regulation of gonadotropin secretion and hot flashes in postmeno-
Li K, Urteaga I, Wiggins CH, et al. Characterizing physiological and pausal women. Neuroendocrinology. 2018;106(2):148–157.
symptomatic variation in menstrual cycles using self-tracked mobile- Sun BZ, Kangarloo T, Adams JM, et al. The relationship between pro-
health data. NPJ Digit Med. 2020;3(1):79. gesterone, sleep, and LH and FSH secretory dynamics in early postme-
Lippincott MF, Chan YM, Rivera Morales D, Seminara SB. Continuous narchal girls. J Clin Endocrinol Metab. 2019;104(6):2184–2194.
kisspeptin administration in postmenopausal women: impact of Wide L, Naessén T, Sundström-Poromaa I, Eriksson K. Low-and fully
estradiol on luteinizing hormone secretion. J Clin Endocrinol Metab. N-glycosylated gonadotropins circulating in women with polycystic
2017;102(6):2091–2099. ovary syndrome. J Endocr Soc. 2021;5(7):bvab080.
Louden ED, Poch A, Kim HG, Ben-Mahmoud A, Kim SH, Layman LC.
Genetics of hypogonadotropic Hypogonadism- Human and mouse Visit Elsevier eBooks+ (eBooks.Health.Elsevier.com) for
genes, inheritance, oligogenicity, and genetic counseling. Mol Cell a complete set of references.
Endocrinol. 2021;534(111334):111334.
Mijiddorj T, Kanasaki H, Sukhbaatar U, Oride A, Hara T, Kyo S. Mutual
regulation by GnRH and kisspeptin of their receptor expression and
REFERENCES 23. Chan YM, de Guillebon A, Lang-Muritano M, et al. GNRH1 muta-
1. Garcia-Galiano D, Pinilla L, Tena-Sempere M. Sex steroids and the tions in patients with idiopathic hypogonadotropic hypogonadism.
control of the Kiss1 system: developmental roles and major regula- Proc Natl Acad Sci U S A. 2009;106(28):11703–11708.
tory actions. J Neuroendocrinol. 2012;24:22–33. 24. Muscatelli F, Strom TM, Walker AP, et al. Mutations in the DAX-1
2. Mittelman-Smith MA, Williams H, Krajewski-Hall SJ, et al. Arcuate gene give rise to both X-linked adrenal hypoplasia congenita and
kisspeptin/neurokinin B/dynorphin (KNDy) neurons mediate the hypogonadotropic hypogonadism. Nature. 1994;372(6507):672–676.
estrogen suppression of gonadotropin secretion and body weight. 25. Dodé C, Levilliers J, Dupont JM, et al. Loss-of-function mutations
Endocrinology. 2012;153(6):2800–2812. in FGFR1 cause autosomal dominant Kallmann syndrome. Nat
3. Lehman MN, Hileman SM, Goodman RL. Neuroanatomy of the Genet. 2003;33(4):463–465.
kisspeptin signaling system in mammals: comparative and develop- 26. Kim HG, Herrick SR, Lemyre E, et al. Hypogonadotropic hypo-
mental aspects. Adv Exp Med Biol. 2013;784:27–62. gonadism and cleft lip and palate caused by a balanced translo-
4. Goodman RL, Coolen LM, Anderson GM, et al. Evidence that cation producing haploinsufficiency for FGFR1. J Med Genet.
dynorphin plays a major role in mediating progesterone negative 2005;42(8):666–672.
feedback on gonadotropin- releasing hormone neurons in sheep. 27. Pitteloud N, Acierno JS Jr, Meysing A, et al. Mutations in fibroblast
Endocrinology. 2004;145(6):2959–2967. growth factor receptor 1 cause both Kallmann syndrome and nor-
5. Conn PM, Crowley Jr WF. Gonadotropin-releasing hormone and mosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad
its analogues. N Engl J Med. 1991;324(2):93–103. Sci U S A. 2006;103(16):6281–6286.
6. Stamou MI, Cox KH, Crowley WF Jr. Discovering genes essen- 28. Falardeau J, Chung WCJ, Beenken A, et al. Decreased FGF8 signal-
tial to the hypothalamic regulation of human reproduction using a ing causes deficiency of gonadotropin-releasing hormone in humans
human disease model: adjusting to life in the “-omics” era. Endocr and mice. J Clin Invest. 2008;118(8):2822–2831.
Rev. 2015;36(6):603–621. 29. Dodé C, Teixeira L, Levilliers J, et al. Kallmann syndrome: muta-
7. Shaw ND, Brand H, Kupchinsky ZA, et al. SMCHD1 mutations tions in the genes encoding prokineticin-2 and prokineticin recep-
associated with a rare muscular dystrophy can also cause isolated tor-2. PLoS Genet. 2006;2(10):e175.
arhinia and Bosma arhinia microphthalmia syndrome. Nat Genet. 30. Cole LW, Sidis Y, Zhang C, et al. Mutations in prokineticin 2 and
2017;49(2):238–248. prokineticin receptor 2 genes in human gonadotrophin-releasing
8. Rance NE, Young 3rd WS, McMullen NT. Topography of neurons hormone deficiency: molecular genetics and clinical spectrum. J
expressing luteinizing hormone-releasing hormone gene transcripts Clin Endocrinol Metab. 2008;93(9):3551–3559.
in the human hypothalamus and basal forebrain. J Comp Neurol. 31. Tornberg J, Sykiotis GP, Keefe K, et al. Heparan sulfate
1994;339(4):573–586. 6-O-sulfotransferase 1, a gene involved in extracellular sugar modi-
9. Dudas B, Merchenthaler I. Three-dimensional representation of fications, is mutated in patients with idiopathic hypogonadotrophic
the neurotransmitter systems of the human hypothalamus: inputs of hypogonadism. Proc Natl Acad Sci U S A. 2011;108(28):11524–11529.
the gonadotrophin hormone-releasing hormone neuronal system. J 32. Kim HG, Ahn JW, Kurth I, et al. WDR11, a WD protein that inter-
Neuroendocrinol. 2006;18(2):79–95. acts with transcription factor EMX1, is mutated in idiopathic hypo-
10. Louden ED, Poch A, Kim HG, Ben-Mahmoud A, Kim SH, Layman gonadotropic hypogonadism and Kallmann syndrome. Am J Hum
LC. Genetics of hypogonadotropic Hypogonadism- Human and Genet. 2010;87(4):465–479.
mouse genes, inheritance, oligogenicity, and genetic counseling. 33. Meyer BF. Functional consequences of AXL sequence variants
Mol Cell Endocrinol. 2021;534(111334):111334. in hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A.
11. Ballabio A, Camerino G. The gene for X-linked Kallmann syn- 2014;99:1452–1460.
drome: a human neuronal migration defect. Curr Opin Genet Dev. 34. Miura K, Acierno JS Jr, Seminara SB. Characterization of the
1992;2(3):417–421. human nasal embryonic LHRH factor gene, NELF, and a muta-
12. Kim HG, Kurth I, Lan F, et al. Mutations in CHD7, encoding a tion screening among 65 patients with idiopathic hypogonadotropic
chromatin- remodeling protein, cause idiopathic hypogonado- hypogonadism (IHH). J Hum Genet. 2004;49(5):265–268.
tropic hypogonadism and Kallmann syndrome. Am J Hum Genet. 35. de Roux N, Young J, Misrahi M, et al. A family with hypogonado-
2008;83(4):511–519. tropic hypogonadism and mutations in the gonadotropin-releasing
13. Pingault V, Bodereau V, Baral V, et al. Loss-of-function mutations hormone receptor. N Engl J Med. 1997;337(22):1597–1602.
in SOX10 cause Kallmann syndrome with deafness. Am J Hum 36. Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E. Hypophysial
Genet. 2013;92(5):707–724. responses to continuous and intermittent delivery of hypopthalamic
14. Young J, Metay C, Bouligand J, et al. SEMA3A deletion in a fam- gonadotropin-releasing hormone. Science. 1978;202(4368):631–633.
ily with Kallmann syndrome validates the role of semaphorin 3A 37. Wetsel WC, Valença MM, Merchenthaler I, et al. Intrinsic pul-
in human puberty and olfactory system development. Hum Reprod. satile secretory activity of immortalized luteinizing hormone-
2012;27(5):1460–1465. releasing hormone-secreting neurons. Proc Natl Acad Sci U S A.
15. Hanchate NK, Giacobini P, Lhuillier P, et al. SEMA3A, a gene 1992;89(9):4149–4153.
involved in axonal pathfinding, is mutated in patients with Kallmann 38. Herbison AE. Multimodal influence of estrogen upon gonadotropin-
syndrome. PLoS Genet. 2012;8(8):e1002896. releasing hormone neurons. Endocr Rev. 1998;19(3):302–330.
16. Kotan LD, Hutchins BI, Ozkan Y, et al. Mutations in FEZF1 cause 39. Berga SL, Loucks AB, Rossmanith WG, Kettel LM, Laughlin GA,
Kallmann syndrome. Am J Hum Genet. 2014;95(3):326–331. Yen SS. Acceleration of luteinizing hormone pulse frequency in
17. Miraoui H, Dwyer AA, Sykiotis GP, et al. Mutations in FGF17, functional hypothalamic amenorrhea by dopaminergic blockade. J
IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individu- Clin Endocrinol Metab. 1991;72(1):151–156.
als with congenital hypogonadotropic hypogonadism. Am J Hum 40. Perkins RB, Hall JE, Martin KA. Neuroendocrine abnor-
Genet. 2013;92(5):725–743. malities in hypothalamic amenorrhea: spectrum, stability, and
18. de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom response to neurotransmitter modulation. J Clin Endocrinol Metab.
E. Hypogonadotropic hypogonadism due to loss of function of the 1999;84(6):1905–1911.
KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A. 41. Gottsch ML, Cunningham MJ, Smith JT, et al. A role for kiss-
2003;100(19):10972–10976. peptins in the regulation of gonadotropin secretion in the mouse.
19. Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as Endocrinology. 2004;145(9):4073–4077.
a regulator of puberty. N Engl J Med. 2003;349(17):1614–1627. 42. Navarro VM, Castellano JM, Fernández- Fernández R, et al.
20. Topaloglu AK, Tello JA, Kotan LD, et al. Inactivating KISS1 Characterization of the potent luteinizing hormone-releasing activ-
mutation and hypogonadotropic hypogonadism. N Engl J Med. ity of KiSS-1 peptide, the natural ligand of GPR54. Endocrinology.
2012;366(7):629–635. 2005;146(1):156–163.
21. Topaloglu AK, Reimann F, Guclu M, et al. TAC3 and TACR3 43. Clarke SA, Dhillo WS. Kisspeptin across the human lifes-
mutations in familial hypogonadotropic hypogonadism reveal a key pan: evidence from animal studies and beyond. J Endocrinol.
role for Neurokinin B in the central control of reproduction. Nat 2016;229(3):R83–R98.
Genet. 2009;41(3):354–358. 44. Chan YM, Butler JP, Sidhoum VF, Pinnell NE, Seminara SB.
22. Bouligand J, Ghervan C, Tello JA, et al. Isolated familial hypogo- Kisspeptin administration to women: a window into endogenous
nadotropic hypogonadism and a GNRH1 mutation. N Engl J Med. kisspeptin secretion and GnRH responsiveness across the menstrual
2009;360(26):2742–2748. cycle. J Clin Endocrinol Metab. 2012;97(8):E1458–E1467.
157.e1
157.e2 PART I The Fundamentals of Reproduction
45. Lippincott MF, Chan YM, Rivera Morales D, Seminara SB. 66. Ubuka T, Morgan K, Pawson AJ, et al. Identification of human
Continuous kisspeptin administration in postmenopausal women: GnIH homologs, RFRP-1 and RFRP-3, and the cognate recep-
impact of estradiol on luteinizing hormone secretion. J Clin tor, GPR147 in the human hypothalamic pituitary axis. PLoS One.
Endocrinol Metab. 2017;102(6):2091–2099. 2009;4(12):e8400.
46. Karsch FJ, Bowen JM, Caraty A, Evans NP, Moenter SM. 67. Smith JT, Clarke IJ. Gonadotropin inhibitory hormone function in
Gonadotropin-releasing hormone requirements for ovulation. Biol mammals. Trends Endocrinol Metab. 2010;21(4):255–260.
Reprod. 1997;56(2):303–309. 68. Smith JT, Young IR, Veldhuis JD, Clarke IJ. Gonadotropin-
47. Plant TM. A comparison of the neuroendocrine mechanisms inhibitory hormone (GnIH) secretion into the ovine hypophyseal
underlying the initiation of the preovulatory LH surge in the portal system. Endocrinology. 2012;153(7):3368–3375.
human, old world monkey and rodent. Front Neuroendocrinol. 69. George JT, Hendrikse M, Veldhuis JD, Clarke IJ, Anderson RA,
2012;33(2):160–168. Millar RP. Effect of gonadotropin-inhibitory hormone on luteinizing
48. Simonneaux V, Bahougne T. A multi-oscillatory circadian system hormone secretion in humans. Clin Endocrinol. 2017;86(5):731–738.
times female reproduction. Front Endocrinol. 2015;6:157. 70. Lavoie HB, Marsh EE, Hall JE. Absence of apparent circadian
49. Rometo AM, Krajewski SJ, Voytko ML, Rance NE. Hypertrophy rhythms of gonadotropins and free alpha-subunit in postmenopausal
and increased kisspeptin gene expression in the hypothalamic infun- women: evidence for distinct regulation relative to other hormonal
dibular nucleus of postmenopausal women and ovariectomized rhythms. J Biol Rhythms. 2006;21(1):58–67.
monkeys. J Clin Endocrinol Metab. 2007;92(7):2744–2750. 71. Klingman KM, Marsh EE, Klerman EB, Anderson EJ, Hall JE.
50. Martin KA, Hall JE, Adams JM, Crowley WF Jr. Comparison of Absence of circadian rhythms of gonadotropin secretion in women.
exogenous gonadotropins and pulsatile gonadotropin-releasing hor- J Clin Endocrinol Metab. 2011;96(5):1456–1461.
mone for induction of ovulation in hypogonadotropic amenorrhea. 72. Boyar RM, Rosenfeld RS, Finkelstein JW, et al. Ontogeny of
J Clin Endocrinol Metab. 1993;77(1):125–129. luteinizing hormone and testosterone secretion. J Steroid Biochem.
51. Martin KA, Welt CK, Taylor AE, Smith JA, Crowley WF Jr, Hall JE. 1975;6(5):803–808.
Is GnRH reduced at the midcycle surge in the human? Evidence from 73. Boyar RM, Wu RH, Roffwarg H, et al. Human puberty:
a GnRH-deficient model. Neuroendocrinology. 1998;67(6):363–369. 24-hour estradiol in pubertal girls. J Clin Endocrinol Metab.
52. Ramaswamy S, Seminara SB, Plant TM. Evidence from the agonadal 1976;43(6):1418–1421.
juvenile male rhesus monkey (Macaca mulatta) for the view that the 74. Shaw ND, Butler JP, McKinney SM, Nelson SA, Ellenbogen
action of neurokinin B to trigger gonadotropin-releasing hormone JM, Hall JE. Insights into puberty: the relationship between
release is upstream from the kisspeptin receptor. Neuroendocrinology. sleep stages and pulsatile LH secretion. J Clin Endocrinol Metab.
2011;94(3):237–245. 2012;97(11):E2055–E2062.
53. Young J, George JT, Tello JA, et al. Kisspeptin restores pulsatile 75. Shaw ND, Butler JP, Nemati S, et al. Accumulated deep sleep is a
LH secretion in patients with neurokinin B signaling deficiencies: powerful predictor of LH pulse onset in pubertal children. J Clin
physiological, pathophysiological and therapeutic implications. Endocrinol Metab. 2015;100(3):1062–1070.
Neuroendocrinology. 2013;97(2):193–202. 76. Filicori M, Santoro N, Merriam GR, Crowley WF Jr.
54. Navarro VM. New insights into the control of pulsatile GnRH Characterization of the physiological pattern of episodic gonado-
release: the role of Kiss1/neurokinin B neurons. Front Endocrinol. tropin secretion throughout the human menstrual cycle. J Clin
2012;3:48. Endocrinol Metab. 1986;62:1136–1144.
55. Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson 77. Soules MR, Steiner RA, Cohen NL, Bremner WJ, Clifton DK.
RA. Interactions between neurokinin B and kisspeptin in mediat- Nocturnal slowing of pulsatile luteinizing hormone secretion in
ing estrogen feedback in healthy women. J Clin Endocrinol Metab. women during the follicular phase of the menstrual cycle. J Clin
2016;101(12):4628–4636. Endocrinol Metab. 1985;61(1):43–49.
56. Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA. 78. Hall JE, Sullivan JP, Richardson GS. Brief wake episodes modulate
Neurokinin 3 receptor antagonism reveals roles for neurokinin B sleep-inhibited luteinizing hormone secretion in the early follicular
in the regulation of gonadotropin secretion and hot flashes in post- phase. J Clin Endocrinol Metab. 2005;90(4):2050–2055.
menopausal women. Neuroendocrinology. 2018;106(2):148–157. 79. Sun BZ, Kangarloo T, Adams JM, et al. The relationship between
57. Rance NE, Dacks PA, Mittelman- Smith MA, Romanovsky AA, progesterone, sleep, and LH and FSH secretory dynamics in early
Krajewski-Hall SJ. Modulation of body temperature and LH secre- postmenarchal girls. J Clin Endocrinol Metab. 2019;104(6):2184–2194.
tion by hypothalamic KNDy (kisspeptin, neurokinin B and dynor- 80. Shaw ND, Gill S, Lavoie HB, Marsh EE, Hall JE. Persistence of
phin) neurons: a novel hypothesis on the mechanism of hot flushes. sleep-associated decrease in GnRH pulse frequency in the absence
Front Neuroendocrinol. 2013;34(3):211–227. of gonadal steroids. J Clin Endocrinol Metab. 2011;96(8):2590–2595.
58. Jayasena CN, Comninos AN, Stefanopoulou E, et al. Neurokinin B 81. Childs GV, Unabia G, Rougeau D. Cells that express luteiniz-
administration induces hot flushes in women. Sci Rep. 2015;5(1):8466. ing hormone (LH) and follicle-stimulating hormone (FSH) beta-
59. Quigley ME, Sheehan KL, Casper RF, Yen SS. Evidence for an subunit messenger ribonucleic acids during the estrous cycle: the
increased opioid inhibition of luteinizing hormone secretion in major contributors contain LH beta, FSH beta, and/or growth hor-
hyperprolactinemic patients with pituitary microadenoma. J Clin mone. Endocrinology. 1994;134(2):990–997.
Endocrinol Metab. 1980;50(3):427–430. 82. Wide L, Naessén T, Sundström-Poromaa I, Eriksson K. Low-and
60. Shoupe D, Montz FJ, Lobo RA. The effects of estrogen and pro- fully N-glycosylated gonadotropins circulating in women with poly-
gestin on endogenous opioid activity in oophorectomized women. J cystic ovary syndrome. J Endocr Soc. 2021;5(7):bvab080.
Clin Endocrinol Metab. 1985;60(1):178–183. 83. Stanton PG, Burgon PG, Hearn MT, Robertson DM. Structural
61. Goodman RL, Holaskova I, Nestor CC, et al. Evidence that the and functional characterisation of hFSH and hLH isoforms. Mol
arcuate nucleus is an important site of progesterone negative feed- Cell Endocrinol. 1996;125(1–2):133–141.
back in the ewe. Endocrinology. 2011;152(9):3451–3460. 84. Wide L, Eriksson K, Sluss PM, Hall JE. Serum half-life of pitu-
62. Lehman MN, Coolen LM, Goodman RL. Minireview: kisspeptin/ itary gonadotropins is decreased by sulfonation and increased by
neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a cen- sialylation in women. J Clin Endocrinol Metab. 2009;94(3):958–964.
tral node in the control of gonadotropin-releasing hormone secre- 85. Smith PL, Baenziger JU. Molecular basis of recognition by the
tion. Endocrinology. 2010;151(8):3479–3489. glycoprotein hormone-specific N-acetylgalactosamine-transferase.
63. Pielecka-Fortuna J, Moenter SM. Kisspeptin increases gamma- Proc Natl Acad Sci U S A. 1992;89(1):329–333.
aminobutyric acidergic and glutamatergic transmission directly to 86. Wide L, Naessén T, Sundström-Poromaa I, Eriksson K. Sulfonation
gonadotropin-releasing hormone neurons in an estradiol-dependent and sialylation of gonadotropins in women during the menstrual
manner. Endocrinology. 2010;151(1):291–300. cycle, after menopause, and with polycystic ovarian syndrome and
64. Cheong RY, Czieselsky K, Porteous R, Herbison AE. Expression of in men. J Clin Endocrinol Metab. 2007;92(11):4410–4417.
ESR1 in glutamatergic and GABAergic neurons is essential for nor- 87. Sharpless JL, Supko JG, Martin KA, Hall JE. Disappearance of
mal puberty onset, estrogen feedback, and fertility in female mice. J endogenous luteinizing hormone is prolonged in postmenopausal
Neurosci. 2015;35(43):14533–14543. women. J Clin Endocrinol Metab. 1999;84(2):688–694.
65. Tsutsui K, Saigoh E, Ukena K, et al. A novel avian hypotha- 88. Taylor AE, McCourt B, Martin KA, et al. Determinants of abnormal
lamic peptide inhibiting gonadotropin release. Biochem Biophys Res gonadotropin secretion in clinically defined women with polycystic
Commun. 2000;275(2):661–667. ovary syndrome. J Clin Endocrinol Metab. 1997;82(7):2248–2256.
CHAPTER 7 Neuroendocrine Control of the Menstrual Cycle 157.e3
89. Pagán YL, Srouji SS, Jimenez Y, Emerson A, Gill S, Hall JE. Inverse 111. Rance NE, Uswandi SV. Gonadotropin-releasing hormone gene
relationship between luteinizing hormone and body mass index in expression is increased in the medial basal hypothalamus of post- 7
polycystic ovarian syndrome: investigation of hypothalamic and pitu- menopausal women. J Clin Endocrinol Metab. 1996;81(10):3540–3546.
itary contributions. J Clin Endocrinol Metab. 2006;91(4):1309–1316. 112. Gill S, Lavoie HB, Bo-Abbas Y, Hall JE. Negative feedback effects
90. Srouji SS, Pagán YL, D’Amato F, et al. Pharmacokinetic factors of gonadal steroids are preserved with aging in postmenopausal
contribute to the inverse relationship between luteinizing hor- women. J Clin Endocrinol Metab. 2002;87(5):2297–2302.
mone and body mass index in polycystic ovarian syndrome. J Clin 113. Ottowitz WE, Dougherty DD, Fischman AJ, Hall JE. [18F]2-fluoro-
Endocrinol Metab. 2007;92(4):1347–1352. 2-deoxy-D-glucose positron emission tomography demonstration
91. Chosich J, Bradford AP, Allshouse AA, Reusch JEB, Santoro N, of estrogen negative and positive feedback on luteinizing hormone
Schauer IE. Acute recapitulation of the hyperinsulinemia and hyperlip- secretion in women. J Clin Endocrinol Metab. 2008;93:3208–3214.
idemia characteristic of metabolic syndrome suppresses gonadotropins: 114. Evans NP, Dahl GE, Glover BH, Karsch FJ. Central regulation of
metabolic syndrome and the HPG Axis. Obesity. 2017;25(3):553–560. pulsatile gonadotropin- releasing hormone (GnRH) secretion by
92. Hall JE, Whitcomb RW, Rivier JE, Vale WW, Crowley Jr WF. estradiol during the period leading up to the preovulatory GnRH
Differential regulation of luteinizing hormone, follicle-stimulating surge in the ewe. Endocrinology. 1994;134(4):1806–1811.
hormone, and free alpha-subunit secretion from the gonadotrope by 115. Chongthammakun S, Terasawa E. Negative feedback effects of
gonadotropin-releasing hormone (GnRH): evidence from the use of estrogen on luteinizing hormone-releasing hormone release occur
two GnRH antagonists. J Clin Endocrinol Metab. 1990;70(2):328–335. in pubertal, but not prepubertal, ovariectomized female rhesus
93. Marshall JC, Dalkin AC, Haisenleder DJ, Paul SJ, Ortolano GA, monkeys. Endocrinology. 1993;132(2):735–743.
Kelch RP. Gonadotropin-releasing hormone pulses: regulators of 116. Rometo AM, Rance NE. Changes in prodynorphin gene expression
gonadotropin synthesis and ovulatory cycles. Recent Prog Horm Res. and neuronal morphology in the hypothalamus of postmenopausal
1991;47:155–187; discussion 188–189. women: dynorphin mRNA in the hypothalamus of postmenopausal
94. Kaiser UB. Molecular mechanisms of the regulation of gonadotro- women. J Neuroendocrinol. 2008;20(12):1376–1381.
pin gene expression by gonadotropin-releasing hormone. Mol Cells. 117. Rance NE. Menopause and the human hypothalamus: evidence for
1998;8:647–656. the role of kisspeptin/neurokinin B neurons in the regulation of
95. Gross KM, Matsumoto AM, Bremner WJ. Differential control of estrogen negative feedback. Peptides. 2009;30(1):111–122.
luteinizing hormone and follicle-stimulating hormone secretion by 118. Frawley LS, Neill JD. A reverse hemolytic plaque assay for micro-
luteinizing hormone-releasing hormone pulse frequency in man. J scopic visualization of growth hormone release from individual
Clin Endocrinol Metab. 1987;64(4):675–680. cells: evidence for somatotrope heterogeneity. Neuroendocrinology.
96. Spratt DI, Finkelstein JS, Butler JP, Badger TM, Crowley WF Jr. 1984;39(5):484–487.
Effects of increasing the frequency of low doses of gonadotropin- 119. Nakai Y, Plant TM, Hess DL, Keogh EJ, Knobil E. On the sites of
releasing hormone (GnRH) on gonadotropin secretion in GnRH- the negative and positive feedback actions of estradiol in the control
deficient men. J Clin Endocrinol Metab. 1987;64(6):1179–1186. of gonadotropin secretion in the rhesus monkey. 1978. Am J Obstet
97. Hall JE, Taylor AE, Hayes FJ, Crowley WF Jr. Insights into Gynecol. 2005;193(5):1764; discussion 1765.
hypothalamic-pituitary dysfunction in polycystic ovary syndrome. J 120. Hewitt SC, Korach KS. Estrogen receptors: new directions in the
Endocrinol Invest. 1998;21(9):602–611. new millennium. Endocr Rev. 2018;39:664–675.
98. Bédécarrats GY, Kaiser UB. Differential regulation of gonadotropin 121. Singh SP, Wolfe A, Ng Y, et al. Impaired estrogen feedback and
subunit gene promoter activity by pulsatile gonadotropin-releasing infertility in female mice with pituitary-specific deletion of estrogen
hormone (GnRH) in perifused L beta T2 cells: role of GnRH recep- receptor alpha (ESR1). Biol Reprod. 2009;81(3):488–496.
tor concentration. Endocrinology. 2003;144(5):1802–1811. 122. Shaw ND, Histed SN, Srouji SS, Yang J, Lee H, Hall JE.
99. Kirk SE, Dalkin AC, Yasin M, Haisenleder DJ, Marshall JC. Estrogen negative feedback on gonadotropin secretion: evidence
Gonadotropin-releasing hormone pulse frequency regulates expression for a direct pituitary effect in women. J Clin Endocrinol Metab.
of pituitary follistatin messenger ribonucleic acid: a mechanism for dif- 2010;95(4):1955–1961.
ferential gonadotrope function. Endocrinology. 1994;135(3):876–880. 123. Filicori M, Butler JP, Crowley Jr WF. Neuroendocrine regulation
100. Finkelstein JS, Badger TM, O’Dea LS, Spratt DI, Crowley WF. of the corpus luteum in the human. evidence for pulsatile progester-
Effects of decreasing the frequency of gonadotropin- releasing one secretion. J Clin Invest. 1984;73(6):1638–1647.
hormone stimulation on gonadotropin secretion in gonadotropin- 124. Soules MR, Steiner RA, Clifton DK, Cohen NL, Aksel S, Bremner
releasing hormone-deficient men and perifused rat pituitary cells. J WJ. Progesterone modulation of pulsatile luteinizing hormone secre-
Clin Invest. 1988;81(6):1725–1733. tion in normal women. J Clin Endocrinol Metab. 1984;58(2):378–383.
101. O’Dea LS, Finkelstein JS, Schoenfeld DA, Butler JP, Crowley Jr 125. Nippoldt TB, Reame NE, Kelch RP, Marshall JC. The roles of
WF. Interpulse interval of GnRH stimulation independently modu- estradiol and progesterone in decreasing luteinizing hormone pulse
lates LH secretion. Am J Physiol. 1989;256(4 Pt 1):E510–E515. frequency in the luteal phase of the menstrual cycle. J Clin Endocrinol
102. Bilezikjian LM, Justice NJ, Blackler AN, Wiater E, Vale WW. Cell- Metab. 1989;69(1):67–76.
type specific modulation of pituitary cells by activin, inhibin and fol- 126. Scott CJ, Pereira AM, Rawson JA, et al. The distribution of proges-
listatin. Mol Cell Endocrinol. 2012;359(1–2):43–52. terone receptor immunoreactivity and mRNA in the preoptic area
103. Norwitz ER, Xu S, Jeong KH, et al. Activin A augments GnRH- and hypothalamus of the ewe: upregulation of progesterone receptor
mediated transcriptional activation of the mouse GnRH receptor mRNA in the mediobasal hypothalamus by oestrogen: progesterone
gene. Endocrinology. 2002;143(3):985–997. receptor in the sheep brain. J Neuroendocrinol. 2000;12(6):565–575.
104. Welt C, Sidis Y, Keutmann H, Schneyer A. Activins, inhibins, and 127. Kepa JK, Jacobsen BM, Boen EA, et al. Direct binding of progester-
follistatins: from endocrinology to signaling. a paradigm for the new one receptor to nonconsensus DNA sequences represses rat GnRH.
millennium. Exp Biol Med (Maywood). 2002;227(9):724–752. Mol Cell Endocrinol. 1996;117(1):27–39.
105. Bilezikjian LM, Blount AL, Donaldson CJ, Vale WW. Pituitary 128. Lambert-Messerlian GM, Hall JE, Sluss PM, et al. Relatively low
actions of ligands of the TGF-beta family: activins and inhibins. J levels of dimeric inhibin circulate in men and women with polycystic
Reprod Fertil. 2006;132(2):207–215. ovarian syndrome using a specific two-site enzyme-linked immuno-
106. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K. sorbent assay. J Clin Endocrinol Metab. 1994;79(1):45–50.
Aromatase deficiency in male and female siblings caused by a novel 129. Muttukrishna S, Fowler PA, Groome NP, Mitchell GG, Robertson
mutation and the physiological role of estrogens. J Clin Endocrinol WR, Knight PG. Serum concentrations of dimeric inhibin during
Metab. 1995;80(12):3689–3698. the spontaneous human menstrual cycle and after treatment with
107. Hall JE, Gill S. Neuroendocrine aspects of aging in women. exogenous gonadotrophin. Hum Reprod. 1994;9(9):1634–1642.
Endocrinol Metab Clin North Am. 2001;30(3):631–646. 130. Welt CK, McNicholl DJ, Taylor AE, Hall JE. Female reproductive
108. Gharib SD, Wierman ME, Shupnik MA, Chin WW. Molecular biol- aging is marked by decreased secretion of dimeric inhibin. J Clin
ogy of the pituitary gonadotropins. Endocr Rev. 1990;11(1):177–199. Endocrinol Metab. 1999;84(1):105–111.
109. Couse JF, Korach KS. Estrogen receptor null mice: what have we 131. Lau CP, Ledger WL, Groome NP, Barlow DH, Muttukrishna S.
learned and where will they lead us? Endocr Rev. 1999;20(3):358–417. Dimeric inhibins and activin A in human follicular fluid and oocyte-
110. Gill S, Sharpless JL, Rado K, Hall JE. Evidence that GnRH decreases cumulus culture medium. Hum Reprod. 1999;14(10):2525–2530.
with gonadal steroid feedback but increases with age in postmeno- 132. Roberts VJ, Barth S, el-Roeiy A, Yen SS. Expression of inhibin/
pausal women. J Clin Endocrinol Metab. 2002;87(5):2290–2296. activin subunits and follistatin messenger ribonucleic acids and
157.e4 PART I The Fundamentals of Reproduction
proteins in ovarian follicles and the corpus luteum during the human 153. Dafopoulos K, Kotsovassilis CG, Milingos S, et al. Changes in
menstrual cycle. J Clin Endocrinol Metab. 1993;77(5):1402–1410. pituitary sensitivity to GnRH in estrogen-treated post-menopausal
133. Schneyer AL, Fujiwara T, Fox J, et al. Dynamic changes in the women: evidence that gonadotrophin surge attenuating factor plays
intrafollicular inhibin/activin/follistatin axis during human follicular a physiological role. Hum Reprod. 2004;19(9):1985–1992.
development: relationship to circulating hormone concentrations. J 154. Karligiotou E, Kollia P, Papaggeli P, et al. FSH modulatory effect on
Clin Endocrinol Metab. 2000;85(9):3319–3330. human granulosa cells: a gene-protein candidate for gonadotrophin
134. Welt CK, Schneyer AL. Differential regulation of inhibin B and surge-attenuating factor. Reprod Biomed Online. 2011;23(4):440–448.
inhibin A by follicle-stimulating hormone and local growth factors 155. Hendriks ML, Lambalk CB, Helder MN, de Koning J. Purification
in human granulosa cells from small antral follicles. J Clin Endocrinol of a candidate gonadotrophin surge-inhibiting/attenuating factor
Metab. 2001;86(1):330–336. (GnSIF/AF) showing MAPK as a possible target: purified GnSIF/
135. Welt CK, Martin KA, Taylor AE, et al. Frequency modulation AF showing bioactivity. Mol Reprod Dev. 2011;78(4):292–304.
of follicle-stimulating hormone (FSH) during the luteal-follicular 156. Liu JH, Yen SS. Induction of midcycle gonadotropin surge by ovar-
transition: evidence for FSH control of inhibin B in normal women. ian steroids in women: a critical evaluation. J Clin Endocrinol Metab.
J Clin Endocrinol Metab. 1997;82(8):2645–2652. 1983;57(4):797–802.
136. Welt CK, Smith ZA, Pauler DK, Hall JE. Differential regulation of 157. Taylor AE, Whitney H, Hall JE, Martin K, Crowley Jr WF. Midcycle
inhibin A and inhibin B by luteinizing hormone, follicle-stimulating levels of sex steroids are sufficient to recreate the follicle-stimulating
hormone, and stage of follicle development. J Clin Endocrinol Metab. hormone but not the luteinizing hormone midcycle surge: evidence
2001;86(6):2531–2537. for the contribution of other ovarian factors to the surge in normal
137. Stouffer RL, Dahl KD, Hess DL, Woodruff TK, Mather JP, women. J Clin Endocrinol Metab. 1995;80(5):1541–1547.
Molskness TA. Systemic and intraluteal infusion of inhibin A or 158. Shaw ND, Srouji SS, Histed SN, Hall JE. Differential effects of
activin A in rhesus monkeys during the luteal phase of the menstrual aging on estrogen negative and positive feedback. Am J Physiol
cycle. Biol Reprod. 1994;50(4):888–895. Endocrinol Metab. 2011;301(2):E351–E355.
138. Molskness TA, Woodruff TK, Hess DL, Dahl KD, Stouffer RL. 159. Turzillo AM, Nolan TE, Nett TM. Regulation of gonadotropin-
Recombinant human inhibin- A administered early in the men- releasing hormone (GnRH) receptor gene expression in
strual cycle alters concurrent pituitary and follicular, plus subse- sheep: interaction of GnRH and estradiol. Endocrinology.
quent luteal, function in rhesus monkeys. J Clin Endocrinol Metab. 1998;139(12):4890–4894.
1996;81(11):4002–4006. 160. Clarke IJ. Multifarious effects of estrogen on the pituitary gonad-
139. Klein NA, Battaglia DE, Fujimoto VY, Davis GS, Bremner WJ, otrope with special emphasis on studies in the ovine species. Arch
Soules MR. Reproductive aging: accelerated ovarian follicular Physiol Biochem. 2002;110(1–2):62–73.
development associated with a monotropic follicle- stimulating 161. Xu M, Hill JW, Levine JE. Attenuation of luteinizing hormone
hormone rise in normal older women. J Clin Endocrinol Metab. surges in neuropeptide Y knockout mice. Neuroendocrinology.
1996;81(3):1038–1045. 2000;72(5):263–271.
140. Reame NE, Wyman TL, Phillips DJ, de Kretser DM, Padmanabhan 162. Couzinet B, Brailly S, Bouchard P, Schaison G. Progesterone stimu-
V. Net increase in stimulatory input resulting from a decrease in lates luteinizing hormone secretion by acting directly on the pitu-
inhibin B and an increase in activin A may contribute in part to the itary. J Clin Endocrinol Metab. 1992;74(2):374–378.
rise in follicular phase follicle-stimulating hormone of aging cycling 163. Groome NP, Illingworth PJ, O’Brien M, et al. Measurement of
women. J Clin Endocrinol Metab. 1998;83(9):3302–3307. dimeric inhibin B throughout the human menstrual cycle. J Clin
141. Burger HG, Cahir N, Robertson DM, et al. Serum inhibins A and Endocrinol Metab. 1996;81(4):1401–1405.
B fall differentially as FSH rises in perimenopausal women. Clin 164. Laws SC, Beggs MJ, Webster JC, Miller WL. Inhibin increases and
Endocrinol. 1998;48(6):809–813. progesterone decreases receptors for gonadotropin-releasing hor-
142. Santoro N, Banwell T, Tortoriello D, Lieman H, Adel T, Skurnick mone in ovine pituitary culture. Endocrinology. 1990;127(1):373–380.
J. Effects of aging and gonadal failure on the hypothalamic-pituitary 165. Wrathall JH, McLeod BJ, Glencross RG, Beard AJ, Knight PG.
axis in women. Am J Obstet Gynecol. 1998;178(4):732–741. Inhibin immunoneutralization by antibodies raised against synthetic
143. Richardson SJ. 1 The biological basis of the menopause. Baillieres peptide sequences of inhibin alpha subunit: effects on gonado-
Clin Endocrinol Metab. 1993;7(1):1–16. trophin concentrations and ovulation rate in sheep. J Endocrinol.
144. Burger HG. The endocrinology of the menopause. J Steroid Biochem 1990;124(1):167–176.
Mol Biol. 1999;69(1–6):31–35. 166. Wu JC, Sealfon SC, Miller WL. Gonadal hormones and
145. le Nestour E, Marraoui J, Lahlou N, Roger M, de Ziegler D, gonadotropin- releasing hormone (GnRH) alter messenger ribo-
Bouchard P. Role of estradiol in the rise in follicle-stimulating hor- nucleic acid levels for GnRH receptors in sheep. Endocrinology.
mone levels during the luteal-follicular transition. J Clin Endocrinol 1994;134(4):1846–1850.
Metab. 1993;77(2):439–442. 167. Ghosh BR, Wu JC, Strahl BD, Childs GV, Miller WL. Inhibin
146. Lahlou N, Chabbert-Buffet N, Christin-Maitre S, Le Nestour E, and estradiol alter gonadotropes differentially in ovine pitu-
Roger M, Bouchard P. Main inhibitor of follicle stimulating hor- itary cultures: changing gonadotrope numbers and calcium
mone in the luteal-follicular transition: inhibin A, oestradiol, or responses to gonadotropin- releasing hormone. Endocrinology.
inhibin B? Hum Reprod. 1999;14(5):1190–1193. 1996;137(11):5144–5154.
147. Welt CK, Pagan YL, Smith PC, Rado KB, Hall JE. Control of 168. Gahete MD, Vázquez-Borrego MC, Martínez-Fuentes AJ, Tena-
follicle-stimulating hormone by estradiol and the inhibins: critical Sempere M, Castaño JP, Luque RM. Role of the Kiss1/Kiss1r sys-
role of estradiol at the hypothalamus during the luteal-follicular tem in the regulation of pituitary cell function. Mol Cell Endocrinol.
transition. J Clin Endocrinol Metab. 2003;88(4):1766–1771. 2016;438:100–106.
148. Muttukrishna S, Fowler PA, George L, Groome NP, Knight PG. 169. Smith JT, Rao A, Pereira A, Caraty A, Millar RP, Clarke IJ.
Changes in peripheral serum levels of total activin A during the Kisspeptin is present in ovine hypophysial portal blood but does not
human menstrual cycle and pregnancy. J Clin Endocrinol Metab. increase during the preovulatory luteinizing hormone surge: evi-
1996;81(9):3328–3334. dence that gonadotropes are not direct targets of kisspeptin in vivo.
149. Demura R, Suzuki T, Tajima S, et al. Human plasma free activin Endocrinology. 2008;149(4):1951–1959.
and inhibin levels during the menstrual cycle. J Clin Endocrinol 170. Richard N, Galmiche G, Corvaisier S, Caraty A, Kottler ML.
Metab. 1993;76(4):1080–1082. KiSS-1 and GPR54 genes are co-expressed in rat gonadotrophs and
150. Vihko KK, Bläuer M, Kujansuu E, et al. Activin B: detection by an differentially regulated in vivo by oestradiol and gonadotrophin-
immunoenzymometric assay in human serum during ovarian stimu- releasing hormone. J Neuroendocrinol. 2008;20(3):381–393.
lation and late pregnancy. Hum Reprod. 1998;13(4):841–846. 171. Witham EA, Meadows JD, Hoffmann HM, et al. Kisspeptin regu-
151. Schneyer AL, Rzucidlo DA, Sluss PM, Crowley Jr WF. lates gonadotropin genes via immediate early gene induction in
Characterization of unique binding kinetics of follistatin and activin pituitary gonadotropes. Mol Endocrinol. 2013;27(8):1283–1294.
or inhibin in serum. Endocrinology. 1994;135(2):667–674. 172. Mijiddorj T, Kanasaki H, Sukhbaatar U, Oride A, Hara T, Kyo
152. Fowler PA, Sorsa-Leslie T, Harris W, Mason HD. Ovarian gonad- S. Mutual regulation by GnRH and kisspeptin of their receptor
otrophin surge-attenuating factor (GnSAF): where are we after 20 expression and its impact on the gene expression of gonadotropin
years of research? J Reprod Fertil. 2003;126(6):689–699. subunits. Gen Comp Endocrinol. 2017;246:382–389.
CHAPTER 7 Neuroendocrine Control of the Menstrual Cycle 157.e5
173. Ramaswamy S, Gibbs RB, Plant TM. Studies of the localisation of of the estrogen/progesterone-stimulated surge-like release of lutein-
kisspeptin within the pituitary of the rhesus monkey (Macaca mulatta) izing hormone and follicle-stimulating hormone in postmenopausal 7
and the effect of kisspeptin on the release of non-gonadotropic pitu- women. J Clin Endocrinol Metab. 1992;75(4):993–997.
itary hormones. J Neuroendocrinol. 2009;21(10):795–804. 193. Dubourdieu S, Charbonnel B, D’Acremont MF, Carreau S, Spitz
174. Muir AI, Chamberlain L, Elshourbagy NA, et al. AXOR12, a novel IM, Bouchard P. Effect of administration of a gonadotropin-
human G protein-coupled receptor, activated by the peptide KiSS- releasing hormone (GnRH) antagonist (Nal-Glu) during the peri-
1. J Biol Chem. 2001;276(31):28969–28975. ovulatory period: the luteinizing hormone surge requires secretion
175. Krajnak K, Rosewell KL, Wise PM. Fos-induction in gonadotropin- of GnRH. J Clin Endocrinol Metab. 1994;78(2):343–347.
releasing hormone neurons receiving vasoactive intestinal polypep- 194. McCartney CR, Gingrich MB, Hu Y, Evans WS, Marshall JC.
tide innervation is reduced in middle-aged female rats. Biol Reprod. Hypothalamic regulation of cyclic ovulation: evidence that the
2001;64(4):1160–1164. increase in gonadotropin-releasing hormone pulse frequency during
176. Martin K, Santoro N, Hall J, Filicori M, Wierman M, Crowley Jr the follicular phase reflects the gradual loss of the restraining effects
WF. Clinical review 15: management of ovulatory disorders with of progesterone. J Clin Endocrinol Metab. 2002;87(5):2194–2200.
pulsatile gonadotropin-releasing hormone. J Clin Endocrinol Metab. 195. Miyauchi F, Nanjo K, Otsuka K. Effects of night shift on plasma
1990;71(5). 1081A–1081G. concentrations of melatonin, LH, FSH and prolactin, and menstrual
177. Hall JE, Martin KA, Whitney HA, Landy H, Crowley WF. Potential irregularity. Sangyo Igaku. 1992;34(6):545–550.
for fertility with replacement of hypothalamic gonadotropin- 196. Ahlborg G Jr, Axelsson G, Bodin L. Shift work, nitrous oxide expo-
releasing hormone in long term female survivors of cranial tumors. sure and subfertility among Swedish midwives. Int J Epidemiol.
J Clin Endocrinol Metab. 1994;79:1166–1172. 1996;25(4):783–790.
178. Adams JM, Taylor AE, Schoenfeld DA, Crowley Jr WF, Hall JE. 197. Bisanti L, Olsen J, Basso O, Thonneau P, Karmaus W. Shift
The midcycle gonadotropin surge in normal women occurs in the work and subfecundity: a European multicenter study. European
face of an unchanging gonadotropin-releasing hormone pulse fre- Study Group on infertility and subfecundity. J Occup Environ Med.
quency. J Clin Endocrinol Metab. 1994;79(3):858–864. 1996;38(4):352–358.
179. Hall JE, Taylor AE, Martin KA, Rivier J, Schoenfeld DA, Crowley 198. Chung FF, Yao CCC, Wan GH. The associations between men-
WF Jr. Decreased release of gonadotropin-releasing hormone dur- strual function and life style/working conditions among nurses in
ing the preovulatory midcycle luteinizing hormone surge in normal Taiwan. J Occup Health. 2005;47(2):149–156.
women. Proc Natl Acad Sci U S A. 1994;91(15):6894–6898. 199. Stocker LJ, Macklon NS, Cheong YC, Bewley SJ. Influence of shift
180. Treloar AE, Boynton RE, Behn BG, Brown BW. Variation of work on early reproductive outcomes: a systematic review and meta-
the human menstrual cycle through reproductive life. Int J Fertil. analysis. Obstet Gynecol. 2014;124(1):99–110.
1967;12(1 Pt 2):77–126. 200. Fernandez RC, Marino JL, Varcoe TJ, et al. Fixed or rotating night
181. Sohda S, Suzuki K, Igari I. Relationship between the menstrual cycle shift work undertaken by women: implications for fertility and mis-
and timing of ovulation revealed by new protocols: analysis of data carriage. Semin Reprod Med. 2016;34(2):74–82.
from a self-tracking health app. J Med Internet Res. 2017;19(11):e391. 201. Marsh EE, Shaw ND, Klingman KM, et al. Estrogen levels are
182. Li K, Urteaga I, Wiggins CH, et al. Characterizing physiological higher across the menstrual cycle in African- American women
and symptomatic variation in menstrual cycles using self-tracked compared with Caucasian women. J Clin Endocrinol Metab.
mobile-health data. NPJ Digit Med. 2020;3(1):79. 2011;96(10):3199–3206.
183. Grieger JA, Norman RJ. Menstrual cycle length and patterns in a 202. Shaw ND, Srouji SS, Welt CK, et al. Evidence that increased ovar-
global cohort of women using a mobile phone app: retrospective ian aromatase activity and expression account for higher estradiol
cohort study. J Med Internet Res. 2020;22:e17109. levels in African American compared with Caucasian women. J Clin
184. Moenter SM, Caraty A, Locatelli A, Karsch FJ. Pattern of Endocrinol Metab. 2014;99(4):1384–1392.
gonadotropin- releasing hormone (GnRH) secretion leading up 203. Wellons MF, Fujimoto VY, Baker VL, et al. Race matters: a system-
to ovulation in the ewe: existence of a preovulatory GnRH surge. atic review of racial/ethnic disparity in society for assisted reproduc-
Endocrinology. 1991;129(3):1175–1182. tive technology reported outcomes. Fertil Steril. 2012;98(2):406–409.
185. Levine JE. New concepts of the neuroendocrine regulation of 204. Owen C, Goldstein E, Clayton J, Segars J. Racial and ethnic health
gonadotropin surges in rats. Biol Reprod. 1997;56(2):293–302. disparities in reproductive medicine: an evidence-based overview.
186. Clarke IJ. Two decades of measuring GnRH secretion. Reprod Suppl. Semin Reprod Med. 2013;31(05):317–324.
2002;59:1–13. 205. McQueen DB, Schufreider A, Lee SM, Feinberg EC, Uhler ML.
187. Crowley Jr WF, Filicori M, Spratt DI, Santoro NF. The physiology Racial disparities in in vitro fertilization outcomes. Fertil Steril.
of gonadotropin-releasing hormone (GnRH) secretion in men and 2015;104(2):398–402.e1.
women. Recent Prog Horm Res. 1985;41:473–531. 206. Humphries LA, Chang O, Humm K, Sakkas D, Hacker MR.
188. Reame N, Sauder SE, Kelch RP, Marshall JC. Pulsatile gonado- Influence of race and ethnicity on in vitro fertilization outcomes:
tropin secretion during the human menstrual cycle: evidence for systematic review. Am J Obstet Gynecol. 2016;214(2):212.e1–212.e17.
altered frequency of gonadotropin-releasing hormone secretion. J 207. Office of the Surgeon General (OSG). The Surgeon General’s
Clin Endocrinol Metab. 1984;59(2):328–337. Call to Action to Improve Maternal Health. Washington (DC): US
189. Hall JE, Schoenfeld DA, Martin KA, Crowley Jr WF. Hypothalamic Department of Health and Human Services; 2020.
gonadotropin-releasing hormone secretion and follicle-stimulating 208. Behrman RE, Butler AS. Institute of medicine (US) committee
hormone dynamics during the luteal-follicular transition. J Clin on understanding premature birth and assuring healthy outcomes.
Endocrinol Metab. 1992;74(3):600–607. In: Preterm Birth: Causes, Consequences, and Prevention. Washington
190. Batista MC, Cartledge TP, Zellmer AW, Nieman LK, Loriaux DL, (DC): National Academies Press (US); 2007.
Merriam GR. The antiprogestin RU486 delays the midcycle gonad- 209. Siegel DR, Sheeder J, Polotsky AJ. Racial and ethnic disparities
otropin surge and ovulation in gonadotropin-releasing hormone- in fertility awareness among reproductive-aged women. Womens
induced cycles. Fertil Steril. 1994;62(1):28–34. Health Rep (New Rochelle). 2021;2(1):347–354.
191. Wang CF, Lasley BL, Lein A, Yen SS. The functional changes 210. Biro FM, Pajak A, Wolff MS, et al. Age of menarche in a longitudi-
of the pituitary gonadotrophs during the menstrual cycle. J Clin nal US cohort. J Pediatr Adolesc Gynecol. 2018;31(4):339–345.
Endocrinol Metab. 1976;42(4):718–728.
192. Kolp LA, Pavlou SN, Urban RJ, Rivier JC, Vale WW, Veldhuis JD.
Abrogation by a potent gonadotropin-releasing hormone antagonist

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7 Neuroendocrine Control of the Menstrual Cycle

associated with other developmental defects. This group of genes

monohormonal cells begin to express both βLH and βFSH, while

Mean LH (IU/L) LH amp (IU/L) LH IPI (minutes)

Min of wakefulness/5 minutes

Gonadotropin-Releasing Hormone settings in which gonadal feedback is low.95 In GnRH-deficient

LH mean 10.4 8.9 14.3

20 at a dose of 75 ng/kg and a frequency of every 90 minutes.

Fig. 7.5 The increased frequency of pulsatile GnRH during

the luteal follicular transition facilitates the luteal-follicular

Fig. 7.7 The hormonal, follicular, and endometrial dynamics

inhibin A on gonadotrope responsiveness to GnRH. The marked GnRH 75 ng/kg q 60 minutes

slowing of pulse frequency that51 accompanies the termination

with the LH surge. In rodents, rabbits, and sheep, a GnRH surge

20 erate a normal LH surge.51,178,179

80 ng/kg, unchanged from the late

Fig. 7.13 Follicle-stimulating hormone (FSH) and 15

Luteal-Follicular Transition shifts.195–200 Given the disruption in sleep architecture with

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Ciclo Menstrual 2024

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7 Neuroendocrine Control of the Menstrual Cycle

associated with other developmental defects. This group of genes

monohormonal cells begin to express both βLH and βFSH, while

Mean LH (IU/L) LH amp (IU/L) LH IPI (minutes)

Min of wakefulness/5 minutes

Gonadotropin-­Releasing Hormone settings in which gonadal feedback is low.95 In GnRH-­deficient

LH mean 10.4 8.9 14.3

20 at a dose of 75 ng/kg and a frequency of every 90 minutes.

Fig. 7.5 The increased frequency of pulsatile GnRH during

the luteal follicular transition facilitates the luteal-­follicular

Fig. 7.7 The hormonal, follicular, and endometrial dynamics

inhibin A on gonadotrope responsiveness to GnRH. The marked GnRH 75 ng/kg q 60 minutes

slowing of pulse frequency that51 accompanies the termination

with the LH surge. In rodents, rabbits, and sheep, a GnRH surge

20 erate a normal LH surge.51,178,179

80 ng/kg, unchanged from the late

Fig. 7.13 Follicle-­stimulating hormone (FSH) and 15

Luteal-­Follicular Transition shifts.195–200 Given the disruption in sleep architecture with

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Gonadotropin-Releasing Hormone settings in which gonadal feedback is low.95 In GnRH-deficient

the luteal follicular transition facilitates the luteal-follicular

Fig. 7.13 Follicle-stimulating hormone (FSH) and 15

Luteal-Follicular Transition shifts.195–200 Given the disruption in sleep architecture with