Female Reproductive Endocrinology I Flashcards
Traditionally defined as gonadal activation: the abilities of:
1) the testes to produce steroid hormones and viable sperm, and
2) the ovaries to produce steroid hormones and ovulate one viable oocyte (egg) during each menstrual cycle.
Puberty
Male and female gonadal function is dependent on the gonadotropins
LH and FSH
The secretion of LH and FSH is regulated by
GnRH
Exerts the fundamental hormonal control of reproductive function by regulating gonadotropin secretion
Hypothalamic release of GnRH
The mature hypothalamus (specifically, neurons within the preoptic nucleus) regulates the secretion of FSH and LH via the controlled release og
GnRH
The mature hypothalamus secretes GnRH in a pulsatile manner at defined intervals, this causes the pituitary gonadotropes to produce and secrete
FSH and LH in a pulsatile manner
The so-called hypothalamic GnRH pulse-generator is itself regulated in the sexually mature brain by several neurotransmitters including
Endorphins, NP-Y, and adrenergics
Prolonged extremes in steroid hormone production, and/or pharmacologically elevated and/or clamped serum androgen, estrogen, or progesterone concentrations, will disrupt the GnRH pulse generator; thus perturbing
LH and FSH secretion
The aforementioned is the physiologic rationale for estrogen-progesterone based
Contraception
Have very high circulating levels of estrogens; due to carry-over from in utero aromatization of fetal and maternal androgens
Neonates
Shortly after birth, steroid levels plummet in the baby and remain relatively low throughout
Early childhood
Somewhere around 7-9 years-old, the adrenal cortex begins to functionally mature into an active steroidogenic tissue. This process of adrenal maturation is referred to as
Adrenarche
Adrenarche results in an increase in adrenal
Androgen secretion
Occurs well before the onset of puberty, and is NOT a prerequisite for puberty to occur
Adrenarche
What are the two theories for the onset of puberty?
- ) Hypothalamic maturation theory
2. ) Gonadostat theory
An unknown signal induces the maturation of GnRH secreting neurons within the medial preoptic nucleus; hence, turning-on the GnRH pulse-generator in the
Hypothalamic maturation theory
The hypothalamic maturation theory presumes that the gonads are in a latent, but more or less mature and functional state waiting for
Gonadotropin stimulation
Some agonadal children manifest the pulsatile release of GnRH and gonadotropins during young adolescence. This supports the
Hypothalamic maturation theory
In the gonadostat theory, over time, low tonic levels of gonadal steroids exert negative feedback within the
Hypothalamic-pituitary axis
During puberty, a developmental switch within the gonadal-hypothalamic pituitary axis decreases the sensitivity to negative feedback by gonadal steroids in the
Gonadostat theory
The result of this change in sensitivity in the gonadostat theory is the pulsatile release of GnRH that stimulates
Gonadotropin release
There is some direct correlation with increased body weight and the earlier onset of
Puberty
One protein hormone that may mediate this nutritional link is
-produced by adipocytes
Leptin
Leptin receptors are located within the
Hypothalamus and certain gonadal cells
Elevated leptin concentrations have been correlated with the early onset of
Menarche
The hypothesis being that with greater fat stores, more leptin is secreted, and that leptin then acts as a metabolic green light to
Neuroendocrine and gonadal tissues to start puberty
Defined by the ovulation of one mature, viable oocyte during each 28-day menstrual cycle
Female fertility
The menstrual cycle is functionally and clinically divided into which three phases?
- ) Follicular (proliferative) phase ( days 1-14)
- ) Ovulation (day 14)
- ) Luteal (secretory) phase (days 15-28)
Regulated by GnRH, pituitary gonadotropins, as well as growth factor-mediated autocrine and paracrine interactions within the ovary
Ovulation
Together, the aforementioned establish the feedback loops within the
Ovarian-hypothalamic-pituitary axis
The feedback loops in the ovarian-hypothalamic-pituitary axis control
Female cyclicity and fertility
The ovary has several distinct anatomical components. The key functional structures are spheroid tissues known as
Folliicles
House growing oocytes
Follicles
Each follicle contains one
Oocyte
Hormone factories that make estrogens, progestins, and androgens, as well as a host of protein hormones, growth hormones, and cytokines
Follicles
Follicular steroidogenesis fosters the growth and maturation of the
-maintains neuroendocrine feedback loops
Oocyte
In addition to one oocyte, each follicle contains which two cell populations
- ) Theca cells
2. ) Granulosa cells (GC)
Surround the basal lamina and are the outer-most layer of follicle cells
Theca Cells
The theca cell layers, i.e. theca externa and theca interna are
Vascularized
The basal lamina (rich in structural proteins: collagens, laminins, etc.) separates the theca cells from the
GCs
More-or-less an inner-most structure, and is surrounded by GC
Oocyte
The oocyte contains the maternal genetic component. This 4n is arrested in
Meiosis I
Comprise the regions between the follicles
Ovarian interstitial cells
The largest and most mature follicles
Selected, preovulatory, or Graafian Follicles
The largest and most mature follicles (referred to as selected, preovulatory, or Graafian follicles) contain a large antrum that is filled with
Follicular fluid
The hypothalamic GnRH pulse-generator is affected by changes in circulating
Steroid hormone concentrations
Slow GnRH pulse frequency is associated with stimulating
FSH secretion
Rapid, high amplitude GnRH pulse frequency is associated with stimulating
LH secretion
Targets the theca cells and GCs
LH
Stimulates theca cell and GC steroidogenesis
LH
Furthermore, LH causes the changes in GC function and cytoarchitecture that enable
Ovulation
Also, LH stimulates the terminal differentiation of GC and theca cells; a process identified as
Luteinization
Luteinization of the selected follicle begins immediately prior to
Ovulation
Following ovulation, LH stimulates the luteinized GC and theca cells within the
Corpus Luteum
Following ovulation, LH stimulates the luteinized GC and theca cells within the corpus luteum to produce and secrete appreciable amounts of
Progesterone and estrogens
Enables GC to convert aromatizable androgens into estrogens
FSH
Do not contain FSH receptors
Theca cells
FSH stimulates steroidogenesis in
GCs
FSH also regulates GC mitosis during
Follicular growth (folliculogenesis)
Importantly, the mitogenic actions of FSH are mediated by growth factors, cytokines, and steroid hormones that are often secreted by ovarian cells in response to
FSH and/or LH
A key signal transduction mechanism that mediates the responsiveness of follicle cells to FSH and LH
cAMP/PKA-dependent signal transduction cascade
Failure of the neuroendocrine system to secrete sufficient levels of FSH and/or LH necessary to stimulate ovarian function is known as
Hypogonadotropic Hypogonadism
Note that serum gonadotropin levels may appear deceivingly normal, but do not undergo the cyclical rises necessary to support
Follicular development, steroidogenesis, and/or ovulation
Women with hypogonadotrophic hypogonadism have low\ serum estradiol, due to reduced
FSH and/or LH levels
A cohort of ovarian follicles is recruited to begin the growth and maturation process during the
Follicular phase of each menstrual cycle
The entire process of follicular growth occurs over a period of approximately
3-4 menstrual cycles
A new cohort of follicles is recruited to begin growing during each
Menstrual cycle
The anatomical sequence of follicular growth is:
Primordial, primary, secondary, tertiary, and preovulatory (dominant or Graffian)
Prior to being recruited into a growing cohort, follicles remain in an arrested, immature state of development. These are the
Primordial follicles
Immature follicles each contain an oocyte that is surrounded by one layer of
Non-steroidogenic GC (pre-GC)
Prior to the onset of puberty, Oocytes within these follicles are arrested in
Meiotic Prophase I (4n)
Recruitment is defined by the entry of primordial follicles into the growth phase; in other words, the differentiation of primordial follicles into
Primary and then secondary follicles
As follicular differentiation begins, the first cells to grow and functionally differentiate are the
GC and oocyte
This initial growth phase occurs independent from
FSH
The recruitment of a cohort of follicles is counter-modulated by
Antimullerian Hormone (AMH)
Required to sustain the growing follicle in the advanced secondary stages and beyond
FSH and (later) LH
Probably represent a transitional phase from FSH-independence to FSH-dependence
Young secondary follicles
Not present until the later secondary stage of follicular development
Theca Cells
The appearance of morphologically distinct theca cells occurs concaminant with follicular vascularization and appears to require
LH
As mentioned, very early follicular growth occurs independent from gonadotropin support; however, it appears that maturation of the previously recruited preantral follicles requires a
Jolt of LH and FSH
This jolt occurs via the
Preovulatory gonadotropin surge
A profound and transient increase in serum FSH and LH just prior to ovulation
Preovulatory gonadotropin surge
Functions as a counter-modulator by reducing the sensitivity of GC within small follicles to FSH
Antimüllerian hormone
In response to FSH and LH, the cohorts of young follicles undergo further growth and differentiation. Growth stops during the mid-to-late
Luteal phases
-resumes again during the next follicular phase
This stop-and-go pattern of follicular growth and maturation of a given follicular cohort continues until the dominant follicle is
Ovulated
The non-selected sister follicles undergo
Atresia
As a recruited cohort of follicles begins to grow, serum FSH and LH levels are
Waning (from the previous cycle)
Without FSH stimulation, there is very low production of
estradiol-17B (E2)
Exert a negative feedback effect on the hypothalamic/pituitary axis; resulting in a further suppression of FSH and LH secretion
Low Serum E2 levels
Basically, during the early follicular phase of the cycle, FSH and LH levels are decreasing, and this downward slope in the level of FSH and LH secretion is sustained by
Low serum E2 levels
Sometime around the tertiary/antral stage of development, one follicle within the recruited cohort is selected to
-will eventually ovulate
Differentiate
Within the selected follicle, GC express more FSH receptors, and also begin to produce the peptide
Inhibin B
Increase during the mid-follicular phase and fall at mid-cycle
Inhibin B levels
Blocks the secretion of FSH by the pituitary
-hence FSH levels are further suppressed via the selected follicle
Inhibin B
One theory is that the selected follicle contains enough FSH receptors so that it can continue to utilize the modicum of available
Serum FSH
Meanwhile, the remaining (non-selected) sister follicles within the growing cohort cannot bind FSH, and are thus
FSH-starved
In response to being FSH starved, all of the non selected follicles within the growing cohort begin to die by the process of apoptosis which leads to
Follicular atresia
The selected follicle can respond to the very low concentrations of available FSH because its GC contain a lot of
FSH receptors
In response to FSH, these GC secrete
Inhibin B
As the selected follicle grows, its antrum becomes engorged with
Follicular fluid