Endocrine Feedback Mechanisms Flashcards
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C. Endocrine Feedback Mechanisms
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2
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Control of the reproductive hormones during the menstrual cycle is centered upon a delicate endocrine
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3
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feedback mechanism between the hypothalamus
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the pituitary
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gonadotropins stimulate estrogen and progesterone production that is controlled
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in turn
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actions of estrogen and progesterone to suppress the tonic secretion of the gonadotropins. This
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relationship between the gonadotropins and steroids is an example of a classic endocrine negative
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feedback system (Figure 15; Knobil
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1974).
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The feedback regulation between the pituitary and ovary is very complex. In its simplest terms it can
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be viewed as involving the following sequence of events;
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a. As the levels of the gonadotropins increase
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the production and release of estrogen and progesterone
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increases.
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b
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13
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As the systemic concentrations of estrogen and progesterone increase
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these steroids begin to inhibit
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gonadotropin secretion that leads to a diminution in gonadotropin secretion.
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c. The drop in gonadotropins would decrease the production of the steroids.
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d. As the systemic concentrations of estrogen and progesterone decrease
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the negative inhibition of the
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gonadotropins is removed. Gonadotropin concentrations would increase again and the cycle of
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negative feedback control would repeat.
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This oscillating cycle is the basis of the endocrine mechanism used to control the menstrual cycle
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(Figure 13)
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However
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the constantly changing ovarian folicle development. Furthermore
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the inhibitory actions of estrogen
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and progesterone upon the gonadotropins difer.
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23
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Estrogen inhibits the synthesis and release of LH at the level of the pituitary. Progesterone
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on the
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other hand
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appears to act primarily on the hypothalamus by decreasing the duration and ampitude
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of GnRH release.
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The control of FSH secretion by steroids differs from LH in that the tonic secretion of FSH is more
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sensitive to negative feedback by estradiol. Therefore
small concentrations of estrogen can
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selectively inhibit FSH release. Pituitary FSH may also be controlled by non-steroidal ovarian
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hormones such as inhibin
activin
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1. Activins and Inhibins
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Activins
inhibins
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members of the TGFB superfamily of extracellular signaling molecules.
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Activin and inhibin are chemicaly composed of two disulfide-linked dimers. The dimers are peptide
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subunits designated as alpha and beta subunits. There are 3 forms of activin and 2 forms of
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inhibin (Table 4).
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The intra-ovarian roles of activins and inhibins are multiple and complex and are the theme of
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continued investigation (Knight et al.
2012).
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a. Inhibins antagonize activin by binding to receptors and preventing activin from forming active
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signaling complexes. They can also antagonize BMP activity by competing for endocrine receptor
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binding. They are principally produced in the ovary by the granulosa and thecal cells and
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selectively inhibit the secretion of FSH by the pituitary
suggesting that inhibin plays a role in the
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ovarian negative feedback control of FSH secretion. Somatic (thecal
granulosa
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express the inhibin co-receptor betaglycan.
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The data available confirm that inhibin B is mainly produced in the follirular nhaneę by r
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antral and small antral follicles
while inhibin A appears to be the pred
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during the late follicular and luteal phases by preovulatory follicles
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respectively.
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Early folicular phase inhibin B levels decrease with age
reflecting the increase in early follicular
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phase FSH levels and recruitment of diminished cohorts of follicles with ovarian ageing. The roles
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of activin
follistatin
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Table 4. Chemical Composition of Activin and Inhibin
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Inhibin regulates FSH levels by preventing the upregulation of GnRH receptors on pituitary
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gonadotropes.
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Hormone
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Activin
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Inhibin
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Name
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Activin A
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Activin AB
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Activn B
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Inhibin A
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Inhibin B
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Dimers
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BetaA - BetaA
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Betaa - Betas
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Betag- Betas
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Alpha - Betaa
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40/154 d
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Alpha - Betas
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ute
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b. Activins were first isolated from ovarian follicular fluid of cows and pigs and have pleiotropic
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reproductive and metabolic actions. They share 65% homology and overlapping biological
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activities
but also display some divergent functions due to differential expression and receptor
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utilization and affinities. They are also produced by a wide range of extra-gonadal tissues and are
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primarily considered to act as local autocrine and paracrine signaling molecules.
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In the ovary
activins are recognized as important factors in the induction and maintenance of the
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FSHR. Activin A has been measured during the normal menstrual cycle with higher levels in the
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early folicular phase
at midcycle
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contribute to the increase in FSH levels during these particular periods.
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Ovarian somatic cells express activin receptors and signaling receptors.
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The activins stimulate FSH secretion by the pituitary
as well as follicular development and
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function
and inhibit thecal cell androgen production. They exert their stimulatory action on FSH
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levels through paracrine mechanisms in the pituitary.
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2. Follistatin
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Follistatin is a single chain glycoprotein found throughout the body and may act simply as a binding
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protein and serve to modulate the interactions of activins with their signaling receptors.
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In the developing embryonic ovary
changes in follistatin-activin signaling may have linically
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important implications in determining the size of the primordial follicle pool.
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In the adult ovary
follistatin inhibits FSH secretion and is therefore involved in folliculogenesis
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and ovarian steroidogenesis regulation
primarily by modulating activin activity.
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3. Antimüllerian hormone (AMH)
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AMH is produced exclusively by the GC in preantral and small antral follicles (4-6 mm).
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AMH levels vary across the menstrual cycle based on "ovarian age" rather than "chronological
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age." Lower levels that show minimal variation are found in the "aging ovary
" and higher levels
with a rise in AMH during the follicular phase are measured in the "younger ovary" (Prunskaite-
of t'
Hyyrylainen et al., 2014). AMH levels are therefore thought to reflect the g'
ovarian reserve and have been used as a diagnostic measure of
treatment prognosis for infertility patients. AMH may be measured at aıy wnung th.
menstrual cycle and has been shown to correlate with oocyte yield and clinical pregnancy rates
and live birth (Ligon et al., 2019).
AMH has been proposed to have a role in regulating primordial folicle activation in mice. Other
evidence indicates that both AMH and inhibin B can act as paracrine modulators of follicular
development and dominant follicle selection. The role of AMH in the ovarian negative feedback
system, however, has not been established clearly (reviewed in Sowers et al., 2009).
4. Other factors
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The TGFB family members BMPs and GDF9 have also emerged as important players in ovarian
physiology and female fertility. BMPs contribute to folliculogenesis by inhibiting luteinization of GCs
whereas GDF9 suppresses LH receptor expression in GCs (Otsuka et al., 2011).
5. LH Surge
Most endocrine systems are modulated by negative feedback. However, the LH surge is controlled
by what appears to be a positive feedback mechanism. As with the negative feedback of LH,
estrogen is also the primary hormone responsible for the LH surge.
Sustained high levels of estrogen seen in the late follicular phase of the menstrual cycle
stimulate a neuro-endocrine reflex release of LH (Messinis, 2006). This action of estrogen is
at both the level of the hypothalamus (.e., GnRH release) and the pituitary. Since a
sustained elevation in estrogen only occurs in the menstrual cycle as a result of the development
of the Graafian follicle, the LH surge will only naturally occur in the presence of the
preovulatory folicle.
Progesterone does not have the ability to stimulate an LH surge; in fact, progesterone
antagonizes the positive feedback effect of estrogen. This action guarantees that an LH surge
1.41
does not occur during the luteal phase of the menstrual cycle or during pregnancy, when
progesterone is increasing. This inhibition of the LH surge is also thought to be the major
mechanism of action for oral progestin contraceptives.
97
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2. Follistatin
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Follistatin is a single chain glycoprotein found throughout the body and may act simply as a binding
100
protein and serve to modulate the interactions of activins with their signaling receptors.
101
In the developing embryonic ovary
changes in follistatin-activin signaling may have linically
102
important implications in determining the size of the primordial follicle pool.
103
In the adult ovary
follistatin inhibits FSH secretion and is therefore involved in folliculogenesis
104
and ovarian steroidogenesis regulation
primarily by modulating activin activity.
105
3. Antimüllerian hormone (AMH)
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AMH is produced exclusively by the GC in preantral and small antral follicles (4-6 mm).
107
AMH levels vary across the menstrual cycle based on "ovarian age" rather than "chronological
108
age." Lower levels that show minimal variation are found in the "aging ovary
" and higher levels
with a rise in AMH during the follicular phase are measured in the "younger ovary" (Prunskaite-
of t'
Hyyrylainen et al., 2014). AMH levels are therefore thought to reflect the g'
ovarian reserve and have been used as a diagnostic measure of
treatment prognosis for infertility patients. AMH may be measured at aıy wnung th.
menstrual cycle and has been shown to correlate with oocyte yield and clinical pregnancy rates
and live birth (Ligon et al., 2019).
AMH has been proposed to have a role in regulating primordial folicle activation in mice. Other
evidence indicates that both AMH and inhibin B can act as paracrine modulators of follicular
development and dominant follicle selection. The role of AMH in the ovarian negative feedback
system, however, has not been established clearly (reviewed in Sowers et al., 2009).
4. Other factors
41/ 154
The TGFB family members BMPs and GDF9 have also emerged as important players in ovarian
physiology and female fertility. BMPs contribute to folliculogenesis by inhibiting luteinization of GCs
whereas GDF9 suppresses LH receptor expression in GCs (Otsuka et al., 2011).
5. LH Surge
Most endocrine systems are modulated by negative feedback. However, the LH surge is controlled
by what appears to be a positive feedback mechanism. As with the negative feedback of LH,
estrogen is also the primary hormone responsible for the LH surge.
Sustained high levels of estrogen seen in the late follicular phase of the menstrual cycle
stimulate a neuro-endocrine reflex release of LH (Messinis, 2006). This action of estrogen is
at both the level of the hypothalamus (.e., GnRH release) and the pituitary. Since a
sustained elevation in estrogen only occurs in the menstrual cycle as a result of the development
of the Graafian follicle, the LH surge will only naturally occur in the presence of the
preovulatory folicle.
Progesterone does not have the ability to stimulate an LH surge; in fact, progesterone
antagonizes the positive feedback effect of estrogen. This action guarantees that an LH surge
1.41
does not occur during the luteal phase of the menstrual cycle or during pregnancy, when
progesterone is increasing. This inhibition of the LH surge is also thought to be the major
mechanism of action for oral progestin contraceptives.
