Female Reproductive Endocrinology I Flashcards by Joel Glotfelty

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

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Male and female gonadal function is dependent on the gonadotropins

LH and FSH

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The secretion of LH and FSH is regulated by

GnRH

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Exerts the fundamental hormonal control of reproductive function by regulating gonadotropin secretion

Hypothalamic release of GnRH

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The mature hypothalamus (specifically, neurons within the preoptic nucleus) regulates the secretion of FSH and LH via the controlled release og

GnRH

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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

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The so-called hypothalamic GnRH pulse-generator is itself regulated in the sexually mature brain by several neurotransmitters including

Endorphins, NP-Y, and adrenergics

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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

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The aforementioned is the physiologic rationale for estrogen-progesterone based

Contraception

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Have very high circulating levels of estrogens; due to carry-over from in utero aromatization of fetal and maternal androgens

Neonates

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Shortly after birth, steroid levels plummet in the baby and remain relatively low throughout

Early childhood

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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

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Adrenarche results in an increase in adrenal

Androgen secretion

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Occurs well before the onset of puberty, and is NOT a prerequisite for puberty to occur

Adrenarche

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What are the two theories for the onset of puberty?

) Hypothalamic maturation theory

2. ) Gonadostat theory

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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

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The hypothalamic maturation theory presumes that the gonads are in a latent, but more or less mature and functional state waiting for

Gonadotropin stimulation

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Some agonadal children manifest the pulsatile release of GnRH and gonadotropins during young adolescence. This supports the

Hypothalamic maturation theory

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In the gonadostat theory, over time, low tonic levels of gonadal steroids exert negative feedback within the

Hypothalamic-pituitary axis

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During puberty, a developmental switch within the gonadal-hypothalamic pituitary axis decreases the sensitivity to negative feedback by gonadal steroids in the

Gonadostat theory

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The result of this change in sensitivity in the gonadostat theory is the pulsatile release of GnRH that stimulates

Gonadotropin release

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There is some direct correlation with increased body weight and the earlier onset of

Puberty

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One protein hormone that may mediate this nutritional link is

-produced by adipocytes

Leptin

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Leptin receptors are located within the

Hypothalamus and certain gonadal cells

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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?

1. ) Follicular (proliferative) phase ( days 1-14) 2. ) Ovulation (day 14) 3. ) 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

1. ) 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

Stimulates theca cell and GC steroidogenesis

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

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