Hormone Action Flashcards
B. Hormone Action
The major hormones of the menstrual cycle are the ovarian steroids
estrogen and progesterone
the pituitary gonadotropins
FSH and LH. Each of these hormones has discrete actions upon a variety of
tissues that ultimately lead to the menstrual cycle. It is important to remember that hormones never
act alone; the action of most hormones is modulated by other hormones. For instance
both estrogen and
progesterone stimulate the endometrium to produce the hormone prostaglandin F20.. However
stimulation is only attained if the endometrium is exposed to estrogen and progesterone in a sequential
fashion. This interdependence of hormone action upon interactions with other hormones can become
bewildering to understand. Thus
the major hormones of the menstrual cycle will be examined
individually.
- Androgens
1.33
For years
androgens were considered as detrimental to follicle development
association of anovulation and poor oocyte quality with elevated androgen levels in polycystic ovary
patients. However
various androgens
dihydrotestosterone (DHT
the highly active form of testosterone) have been shown to stimulate
growth and development of mammalian ovarian folicles.
It is now recognized that follicle development is positively impacted by the effects of androgens
during the early and intermediate stages of folicular maturation. Androgens produced by the thecal
cells of developing folicles facilitate the transcription of genes involved in the control of primordial
follicle recruitment and activation and of genes involved in the promotion of subsequent follicle
development.
The effects of androgens peak at the pre-antral and antral stages of follicle development.
Androgens primarily act on granulosa cells (GC) via the androgen receptor (AR) and enhance
FSH-driven GC differentiation and thus follicle development. AR expression peaks in GC at the pre-
antral and antral stages of follicle development that are also particularly FSH-dependent.
The drop in AR expression in mature follicles reduces the action of androgens and thus FSH-
stimulated cell proliferation and differentiation and has been postulated as having a role in the
processes of follicular selection and atresia.
Effective androgen action on follicle development appears to be limited to a therapeutic range
outside of which
like other hormones
- Estrogen
17B-estradiol (E2) (Table 3) is secreted by the GC of developing follicles. There are two other
estrogens; estrone (Ei) produced by the ovary and adipose tissue and estriol (E) produced by the
placenta during pregnancy.
At puberty
E2 stimulates the final development and the subsequent maintenance of the reproductive
tract. In response to the increase in circulating estradiol at puberty
the oviduct will enlarge and
develop ciliated epithelium
and the uterus will increase in size threefold
growth.
E2 also establishes the female secondary sex characteristics. It is responsible for adult female
breast development
widening of the pelvis
long bone growth during puberty and then epiphyseal fusion to terminate bone growth.
Menarche is the occurrence of a first menstrual period in the female adolescent. The onset of
pulsatile hypothalamic production of GnRH at puberty stimulates the pituitary to produce FSH and LH
that
in turn
FOLLICULAR PHASE
Blood vessels
Menstrual
period
Plasma steroids
(arbitrary units)
15r
10F
OVARIAN
FOLLICLE
DAY
OVARIAN
PHASE
Estrogen
Progesterone
FOLLICULAR
5
10
ovulation
- Progesterone (Latin = for pregnancy’)
15
LUTEAL
20
LUTEAL PHASE
> inhibition of myometrial activity
25
Figure 13. Uterine and endocrine hormone patterns of the menstrual cycle.
(Printed with permission from Swain et al.
2003.)
Rising estradiol levels have a negative regulatory effect on GnRH secretion and release of the
gonadotropins from the pituitary. However
rather than acting on GnRH neurons directly
that estradiol acts on neurons containing ER-alpha receptors that regulate the transcription of kiss1
the gene that encodes the peptide kisspeptin. The kisspeptin releasing neuron influences GnRH
secretion by acting through KISS-1 receptors present on GnRH neurons (Barbieri
2014). Kisspeptin
stimulates GnRH release.
Gland
During the menstrual cycle Ez acts as a mitogen on the uterine endometrium by stimulating the
proliferation of epithelial cells
glands and stroma cells. It stimulates a myriad of cytoplasmic enzymes
that prepare the endometrium to become a secretory tissue in response to progesterone and also
increases the excitability of the myometrium (Figure 13).
> stimulation of the oviducts and uterus to become secretory
28
The two major hormonal actions associated with progesterone are
Prepares the uterus for pregnancy and
when a woman becomes pregnant
(Table 3).
Under the influence of progesterone
the size (hypertrophy) and number of endometrial glands markedly
increase (Figure 13). Progesterone also changes the metabolic activity of the endometrium with the
production of nutritive substances
especially glycogen
A secondary effect of progesterone
related to pregnancy
lobules within the breast preparing for lactation.
Progesterone also has a generalized stimulatory effect on systemic metabolism. This stimulation
is particularly noticeable just after ovulation
when it causes a subtle increase in basal (resting) body
temperature (BBT). The elevation of progesterone during the early luteal phase will raise the BBT by
0.3-0.5°C (0.5-1.0°F) and can be used clinically as an indicator of ovulation.
Progesterone levels are low during the first part of the follicular phase of the menstrual cycle and start
to rise approximately 48 hours prior to the initiation of the LH surge (Figure 13). Granulosa cells
undergoing luteinization secrete large amounts of progesterone leading to an increase in measurable
systemic progesterone levels. These differentiating GC express the progesterone receptor
Suggesting a role for progesterone in ovulation and luteinization.
A premature increase in progesterone levels can induce changes to follicular and endometrial cell
function potentially impacting oocyte quality and/or endometrial receptivity.
Table 3. Estrogen and Progesterone Sites of Action
Target Tissue
Oviducts
Uterus
Endometrium
Myometrium
Cervical mucus
Mammary Gland
Other
Estradiol
Maintenance
↑ Muscular contractions
Maintenance
Proliferation
↑ Blood supply
↑ Contractions
LViscosity
Growth of ducts
Control of LH & FSH
↑ Follicular development
Adapted from Hodge et al.
1987
- Follicle-stimulating hormone (FSH)
Progesterone
L Muscular contractions
Secretion
↑ Blood supply
J Contractions
↑ Viscosity
Growth of alveoli
Control of LH & FSH
↑ Basal body temp
FSH is responsible for stimulation of granulosa cells. Pituitary FSH binds to FSH membrane receptors
(FSHR) on the GC of the follicle and stimulates pre-ovulatory follicle growth and estradiol production
by triggering cytodifferentiation and proliferation of the GC. FSH also stimulates several steroidogenic
enzymes including aromatase and 38-HSD. FSHR expression on target cells is essential for
modulation of ovarian function by FSH and is required in mature follicles to avoid death by atresia.
FSH levels begin to rise during the last few days of the preceding menstrual cycle (Figure 14
(16))
due to declining steroid production by the CL and a dramatic fall in inhibin A levels. Low sex
steroid levels release the negative feedback on GnRH pulsatile secretion that leads to an elevation
of FSH secretion. Elevated FSH levels recruit and support (cyclic recruitment) the development of a
cohort of folicles in each ovary
one of which is destined to ovulate during the upcoming menstrual
cycle. Once menses ensues
FSH levels begin to decline due to the negative feedback of rising
estrogen levels and the negative effects of inhibin B produced by the GC of the developing folicle.
FSH levels surge mid-cycle
like LH levels
effect of inhibin B.
FSH levels early in the menstrual cycle have been used for many years as a biomarker of ovarian
reserve. The blood test assessed both FSH and estradiol levels and is preferably performed on cycle
day 3 when estradiol levels
that affect FSH levels via negative feedback control (see below)
generally low.
(arbitrary units)
40
30-
DAY
20
10
OVARIAN
FOLLICULE
OVARIAN
PHASE
LH
- Luteinizing hormone (LH)
FSH
FOLLICULAR
10
Ovulation
8)
13
20
14
LUTEAL
25
PA
Figure 14. Patterns of the pituitary gonadotropins during the menstrual cycle.
(Printed with permission from Swain et al.
2003.)
Pituitary LH binds to LH membrane receptors (LHR) on the thecal cells and stimulates androgen
production. These androgens are metabolized by the GC to produce estradiol (two cell theory
Figure 8).
LH levels increase slowly throughout the follicular phase of the menstrual cycle. Mid-cycle
a
surge of LH secretion is triggered by a dramatic rise of estradiol produced by the preovulatory
folicle (Figure 14). The dominant folicle is almost always more than 15 mm in diameter to
produce the critical concentration of estradiol needed to initiate the positive neuroendocrine
feedback on the anterior pituitary.
FSH and LH bind to their G-protein coupled receptors FSHR and LHCGR (LHR) respectively
bringing about the activation of adenyl cyclase
inactivation of intracellular cAMP
protein kinase A (PKA) levels. This in turn releases the block on meiotic progression. It is also
recognized that signaling events controlled by the gonadotropins in ovarian GCs also involve
many additional signaling molecules
including SRC tyrosine kinase
(PKBIAKT)
and mitogen-activated protein kinases (MAPKS) (Fan et al.
is expressed predominantly by thecal and mural granulosa cells (see above) and thus paracrine
signaling and intercellular communications must be essential for cumulus-oocyte complex
response to the LH surge.
The LH surge (Figure 14) initiates final maturational changes in the oocyte
ovulation
stimulates luteinization of the folicle. After the formation of the CL
LH stimulates luteal
progesterone production.
- Gonadotropin-releasing hormone (GnRH)
GnRH produced by the hypothalamus controls the secretion of the gonadotropins
LH and FSH.
The cel bodies of the GnRH neurons are located in the preoptic nucleus of the brain (Table 2).
These neurons fire in an episodic fashion that
in turn
gonadotropin release. The responsiveness of the pituitary to GnRH is dependent upon the
frequency and duration of the GnRH pulses. Slow GnRH plasticity favors FSH secretion whereas
fast pulse frequencies support LH secretion. If systemic serum LH is monitored at short intervals
this pulsatile pattern is evident. However
due to the longer metabolic half-life of FSH
pattern of release is not measurable in the systemic circulation.
The release of GnRH in a pulsatile manner is essential for stimulation of the gonadotropin
secreting cells in the anterior pituitary. Failure of this mechanism renders the pituitary
unresponsive.
Posterior pituitary
Oxytocin
FSH
Oestrogen
Granulosa
cell
Graafian
folicles
(+)
LH
Progesterone
Ovum
Anterior pituitary
prolactin
Corpus luteum
Ovary
Blood
vessols
38/154
Oocyte
Oestrogen
Progeslerone
