Female Reproductive Endocrinology II Flashcards
In the selected follicle, fully differentiate into androgen producing cells, producing androstenedione and testosterone
Theca cells
Also, GC cells in the selected follicle begin to express high levels of
CYP19 (P450 aramotase) and 17B-HSD
The enzymes that convert androgens into E2
CYP19 (P450 aramotase) and 17B-HSD
During the advanced phase of antral follicle growth, a developmental switch occurs; whereby we see an increase in the production of
E2
This transient elevation in serum E2 exerts a positive feedback effect on the production and release of
FSH and LH from the pituitary
Rising FSH during the late follicular phase induces the expression of
LH receptors within the GC of the selected follicle
Therefore, the selected follicle can now respond to
FSH and LH
The rise in FSH and LH during the late follicular phase of the cycle supports further growth and differentiation of
Previously recruited younger follicles
The rise in FSH and LH during the late follicular phase of the cycle supports a robust increase in
Steroidogenesis by the selected follicle
The rise in FSH and LH during the late follicular phase of the cycle supports initial luteinization of the
Selected follicle
Inhibin B secretion drops just prior to mid-cycle; this releases its feedback inhibition on the pituitary peptide
Activin
Activin is expressed within gonadotropes, and activin stimulates
FSH secretion
The feedback dynamics between the selected follicle and the hypothalamus pituitary lead to the
Preovulatory gonadotropin surge
The combination of preovulatory levels of E2, rising progesterone, and an increase in inhibin A production by the (luteinizing) GC within the preovulatory follicle, and ultimately the corpus luteum, disrupts the patterns of
GnRH pulsatility
This results in negative feedback at the level of the hypothalamus on the secretion of both
FSH (E2 dependent) and LH (P4 dependent)
Note that the hypothalamus expresses
-mediate negative feedback on gonadotropin secretion
Estrogen receptor-alpha (ERa) and progesterone receptor
This results in a profound decline in gonadotropin secretion upon ovulation, and this continues through the
Luteal phase
During the luteal phase, we see a negative feedback on LH secretion via chronic stimulation by
Progesterone
It is this cyclical nature of E2, progesterone, and gonadotropin secretion, with inhibins and activin, that controls
Female Cyclicity
In antral follicles, theca cells are stimulated by LH to produce
Androstenedione and (some) testosterone
GC cells are then stimulated by FSH to
Aromatize these androgens
A product of GC within preantral and small antral follicles, and thus represents the number of follicles which reach somewhat advanced stages of development
AMH
Therefore, AMH is a marker of healthy growing follicles and this correlates with
Fertility
Following this peak in a woman’s mid-20s, AMH declines to undetectable levels around age
40-45 years
What this all means is that the depletion of the ovarian follicular reserve, and serum AMH levels are
Related
Indicates the greatest number of healthy growing follicles and hence, maximum fertility
Peak AMH
The decline in fertility which begins in a woman’s early 30s is reflected by the precipitous decline in
AMH
In a woman less than 38 years old with normal follicular status, serum AMH levels should be between
2.0-6.8 ng/mL
Dependent upon the gonadotropin surge, and LH is a main player
Ovulation
Can be considered the”ovulation gonadotropin”
LH
LH and FSH stimulate the terminal differentiation of GC; whereby GC switch from almost the exclusive production of E2 to the production of
E2 and progesterone (luteinization)
This change in steroidogenesis begins immediately prior to ovulation with the expression of LH receptors within the
GC of the dominant follicle q
A thermogenic hormone; this accounts for the biphasic 0.5 ˚F rise in basal body temperature that occurs upon ovulation and during the luteal phase
Progesterone
LH also stimulates the production of
Prostaglandins
Collectively, the aforementioned molecules dissociate some of the intercellular connections that join
GC
Increases in the follicular vasculature are also involved; these angiogenic effects appear to be mediated by
Prostaglandins, cytokines, and growth factors
The oocyte is ovulated with an attached surrounding layer of GC called the
Cumulus GC
Thus, the ovulated complex is referred to as the
Oocyte-cumulus complex
Upon ovulation, changes in cAMP signaling in the GC and oocyte signal the oocyte to complete the
First meiotic division
This can be identified microscopically by the extrusion of the first
Polar body into the ooplasm
A haploid product of meiosis I that contains one set of 23 paired chromosomes; this structure fragments and disappears
1st polar body
The oocyte-cumulus complex is extruded into the region of the fimbrae of the
Oviduct (Fallopian tube)
The remnant of what was the preovulatory follicle is just the
GC and theca cells
The remnant of what was the preovulatory follicle is stimulated by LH to terminally differentiate into the
Corpus Luteum
In general, in response to LH, luteal cells produce
E2 and progesterone
Indicates that ovulation has occurred
Luteal progesterone
A woman who has ovulated can predict a meager rise in basal body temperature through the
Mid-luteal phase of her cycle
Targets the uterus, and has a quiescing effect on the myometrium (uterine muscle)
Progesterone
The corpus luteum also produces
Inhibin A
Like inhibin B during the early-mid follicular phase, inhibin A exerts negative feedback on
Gonadotropin secretion
In the event of fertilization, elevated progesterone is absolutely required for
Implantation
Has proliferative and angiogenic effects within the endometrium
-also required for implantation
E2
If pregnancy does not occur, LH levels decline, and without LH, the corpus luteum undergoes
Degeneration (luteolysis)
Mediated by prostaglandins and other factors
Luteolysis
The fertile endometrium undergoes cycles of
Proliferation, differentiation, and tissue breakdown
The endometrium has which two main layers?
- ) Functional upper layer
2. ) Deep basal layer
During the proliferative (i.e. follicular) phase of the cycle, the endometrium is stimulated by
E2
Within the functional endometrium, E2 induces the expression of
ERa, progesterone receptors (PR), and growth factors
This enables regeneration (due to shedding from the previous cycle) and proliferation of the
Endometrium
Recall that the secretory (i.e. luteal) phase of the cycle begins following
Ovulation
During the early secretory phase, the endometrium is targeted by
E2 and progesterone
Results in the development of a rich blood supply that supports the endocrine and paracrine mechanisms required for implantation of the blastocyst
E2 and Progesterone’s effects on the endometrium in early secretory phase
With rising progesterone levels during the mid secretory phase, we see a down-regulation of
PR and ERa
During the mid-phase, also causes changes in gene expression within the endometrium that induce decidualization
-prepares endometrium for implantation
Progesterone
Consider that optimal conditions for implantation exist for approximately
6-10 days post LH surge
During the late secretory phase, the uterus is essentially a refractory tissue; it briefly assumes the properties of a
Pregnant Uterus
Should implantation occur, a complex cascade of events is initiated through interactions between the embryo and the decidua which maintain the
Pregnant Uterus
Results from the precipitous drop in progesterone and E2 that occurs during the late\ luteal phase
Menstruation
The processes which enable the endometrial breakdown in fact begin due to progesterone-stimulated changes in gene expression during the
Early secretory phase
Primes the endometrium to shed
Progesterone
In the absence of progesterone and E2 support, the upper 2/3 of the functional layer sheds off, the uterus again assumes the
Steroid-responsive phenotype
Diagnosed as the inability of a couple to conceive after one year of unprotected intercourse
Infertility
Indicates that a woman has never conceived
Primary infertility
Type of infertility where a woman has conceived previously
Secondary infertility
The incidence of diagnosed female infertility is approximately
13%
The absence of menses by age 13 without normal growth or secondary sexual development; or no menses by age 15 with normal growth and secondary sexual development
Primary amenorrhea
Having had one or more consecutive cycles with the absence of 3 consecutive cycles for 6 consecutive months
Secondary Amenorrhea
Defects in the mechanisms leading to ovulation and/or the luteal phase are classified as
Functional causes of infertility
Pelvic and cervical anomalies are classified as
Structural causes of infertility
The basic premise for treating infertility is to support enhanced follicular growth so that several preovulatory follicles develop for
Retrieval or Ovulation
The basic idea is to exogenously manipulate the hormonal regulation of the
Menstrual Cycle
First,neuroendocrine function is controlled by the use of either a
GnRH agonist or antagonist
A so-called selective estrogen receptor modulator (ER antagonist within the hypothalamus) which releases GnRH from feedback inhibition by E2
Clomiphene
Therefore, the short term effect of Clomiphene is that of a
GnRH antagonist
Can be given on days 3-5 of the cycle for 5 days, and this results in spikes of GnRH secretion
Clomiphene
These GnRH spikes subsequently drive FSH secretion leading to enhanced follicular growth and the formation of several
Preovulatory follicles
These follicles functionally differentiate as would occur naturally, and thus produce
E2 and inhibins
In the event of a GnRH suppression protocol, a GnRH pulsatility is disrupted using either an antagonist (e.g., clomiphene) or agonist such as
Leuprolide
Recall that the chronic loss of GnRH pulsatility, as occurs with GnRH antagonists or agonists, attenuates
FSH secretion
This causes the down-regulation of the
Pituitary drive
Once down-regulation has been established (as determined by a serum E2 < 50 pg/ml), we administer
Recombinant FSH (rFSH)
After a few days of rFSH treatment, follicle growth is assessed by
Transvaginal ultrasound
So long as ≥ 3 follicles with a diameter of ≥ 17 mm are detected, the processes leading to ovulation are induced by giving
hCG
Oocytes are aspirated from the large follicles guided by transvaginal ultrasound at around
36 hours post hCG
Keep in mind that with the development of several preovulatory follicles, and the exposure of these follicles to a hefty dose of LH (i.e. hCG), comes the normal pattern of increased
E2 secretion, luteinization (P4 secretion), and endometrial priming
Under normal circumstances, fertilization occurs within the
Oviduct
The oocyte can be fertilized up to approximately
24 hours post ovulation
During the fertilization process, a single sperm burrows through the outer cumulus GC and binds to the
Zona pellucida of the oocyte
The cortical reaction within the oocyte occurs as follows: sperm binding stimulates its incorporation into the ooplasm, and this is followed by which three things?
- ) Oocyte membrane hyperpolarization
- ) Increased intracellular [Ca2+]
- ) Cortical granule hardening
These cellular changes prevent additional sperm-oocyte interactions, known as
Polyspermia
