Reproductive Cyclicity and Ovarian Folliculogenesis PDF

Lecture 13 Reproductive Cyclicity & Ovarian Folliculogenesis AGSC310 –Physiology of Reproduction Luis Fernando Schutz, Ph.D. 1  Reproductive cyclicity Learning objectives: Ø Understand the hormonal regul...

Lecture 13 Reproductive Cyclicity & Ovarian Folliculogenesis AGSC310 –Physiology of Reproduction Luis Fernando Schutz, Ph.D. 1  Reproductive cyclicity Learning objectives: Ø Understand the hormonal regulation of the estrous cycle Ø Describe the process of folliculogenesis Ø Understand the process of estradiol synthesis by the antral follicles 2  Phases of Estrous Cycle Phases of estrous cycle ovary in follicular phase ovary in luteal phase v large antral follicle is the v corpus luteum is the dominant dominant structure in the ovary structure in the ovary v no corpus luteum v progesterone is high v estradiol is high, progesterone is low rupture new become corpus luteum 3  Estrous cycle Stages of estrous cycle Ø the two phases of estrous cycle (follicular and luteal phases) are subdivided into four stages: Phases Stages v proestrus follicular phase v estrus i v metestrus luteal phase v diestrus 4  Estrous cycle The estrous cycle corpus luteum secretes P4 dominant follicle secretes E2 Ovulation Ovulation Ovulation Ovulation Relative Hormone Concentration O Relative Hormone Concentration P4 O E2 LH FSH surge Metestrus Diestrus Proestrus Estrus luteal phase follicular phase Estrus Day of Cycle Estrus Stages of the estrous cycle Luteal phase: Follicular phase: Ovulation: corpus luteum is the dominant large antral follicle is the dominant occurs in the metestrus in the structure in the ovary structure in the ovary cow 5 specific to the cow  Folliculogenesis Ovarian folliculogenesis Ø ovarian follicular growth and degeneration occurs continuously throughout the entire estrous cycle animal goes I into anestrus v antral follicles of various sizes develop in response to basal levels of FSH and LH ü antral follicles are present at all stages of the estrous cycle ü antral follicles are classified based on their diameter as: § small (1-5 mm) if § medium (5.1-7.9 mm) § large (>8 mm) 6  Folliculogenesis Ovarian folliculogenesis Ø follicular dynamics involves 4 processes: v recruitment (emergence) v selection (deviation) v dominance v ovulation or v atresia (degeneration) 7  Folliculogenesis Follicular dynamics involves 4 processes: CL CL prestide Tests hemoragian CL CL CL recruitment selection dominance ovulation a group (cohort) of follicles are selected preovulatory follicle ruptures to small antral follicles to become dominant follicle(s) keeps release oocyte start to grow and or undergo atresia growing during ovulation secrete E2 most of the recruited follicles will degenerate (undergo atresia) 11  Folliculogenesis The folliculogenesis is governed by: releases v hypothalamus GnRH gonadotropins stimulates stitiplets Efice T luteum v anterior pituitary Eliakim FSH & LH leutinizing hormone Estradiol (E2) v ovary Inhibin Progesterone (P4) pro gestation 12 corpus luteum produces this  Folliculogenesis The secretion of GnRH Ø is controlled by two separate areas of the hypothalamus, which are composed of clusters of nerve cell bodies tonic center surge center Surge center v Tonic center Tonic center v Surge center 13  Folliculogenesis Tonic center Ø responsible for basal secretion of GnRH v small pulses of GnRH are released over a substantial period of time (days to weeks) over longof time period ü stimulate basal FSH and LH secretion § FSH stimulates follicular recruitment ü have various frequencies and amplitudes depending on the degree of neural activity (rate of firing) in the tonic center ü occur spontaneously ü this pattern of secretion of GnRH in small pulses is called episodic profile 14  Folliculogenesis Surge center Ø responsible for the preovulatory secretion of GnRH v also called the preovulatory center v stimulates a surge of LH, causing final follicular growth and ovulation v secretes basal levels of ovulatory hormone GnRH until it receives the appropriate positive stimulus of estradiol above a threshold concentration in absence of progesterone ü this positive stimulus will result in the release of a great quantity of GnRH 15  Folliculogenesis The hypothalamic centers Ø release of GnRH by tonic and preovulatory centers can be compared to water faucets Release of GnRH from Release of GnRH from the tonic center is the surge center is similar to a leaky faucet similar to opening a Surge from which small faucet fully for a short center Tonic quantities of water drip period of time center over a relatively long time GnRH (pg/ml) GnRH (pg/ml) Preovulatory Tonic GnRH surge GnRH release Hours Hours The surge center is sensitive to positive feedback The tonic center secretes small episodes of and secretes high amplitude, high frequency GnRH in a pulsatile way. This episodic secretion pulses of GnRH in a relatively short period of time is spontaneous and continuous throughout after estradiol reaches a threshold concentration reproductive life 16 doesn't need stimulation constantly drips  Folliculogenesis Concentrations of ovarian steroids determine the release of GnRH Ø during the luteal phase (metestrus and diestrus), the corpus luteum secretes P4 progesterone v P4 will prevent high quantities of GnRH to be released from the tonic and surge center of the hypothalamus – negative feedback ü small quantities of GnRH will only allow basal levels of FSH and LH to be released v follicles will not be able to secrete high amounts of E2 estrodiae ü Low E2 reduces the degree of GnRH neurons firing in the surge center – negative feedback 17  Follicular phase Concentrations of ovarian steroids determine the release of GnRH Ø during the follicular phase (proestrus and estrus), there is no corpus luteum to secrete P4 v P4 will no longer prevent the release of high GnRH v E2 stimulate firing by GnRH neurons in the surge center when is higher than threshold – positive feedback v the preovulatory surge of GnRH occurs, which results in final follicular growth and ovulation E2 & P4 stimulate Preovulatory GnRH surge 18  Follicular phase The follicular phase follicle is most important the structure Ø the steps leading to the LH preovulatory surge are: Luteolysis: P4 GnRH FSH & LH Inhibin FSH proestrual follicular Preovulatory development E2 LH surge 19  Folliculogenesis Regulation and effects of gonadotropins Ø FSH v in the presence of P4, a small amount of FSH is secreted ü this small amount of FSH stimulates recruitment of follicles ü FSH stimulates production of E2, so small follicles begin to grow and secrete E2 ü FSH secretion drops because E2 and inhibin inhibit FSH secretion through negative feedback on the anterior pituitary 0 § the suppression of FSH by the combination of E2 and inhibin is important for the selection of the follicle(s) that will ovulate § most recruited follicles will become atretic because of the lack of FSH whereas the dominant follicle is dependent on LH rather than FSH § in mono-ovulatory species, only one follicle will ovulate 20  Folliculogenesis Regulation and effects of gonadotropins Ø LH v promotes the final growth and maturation of dominant follicles and stimulates ovulation ü P4 reduces the frequency of GnRH pulses released by the surge center ü when luteolysis occurs, P4 drops and the GnRH pulse frequency increases, which will increase LH ü increased LH pulse frequency will result in the preovulatory surge of LH § although the preovulatory surge of LH will stimulate final follicular growth and ovulation and will only come in absence of P4, that does not mean that LH is not secreted throughout the estrous cycle § basal levels of FSH and LH are released throughout the estrous cycle and are necessary for the synthesis of E2 by the antral follicles 21  Folliculogenesis Regulation and effects of gonadotropins FSH LH v important for recruitment and v promotes final growth and maturation secretion of E2 of dominant follicles and ovulation v its release from the anterior pituitary v regulated by GnRH pulse frequency is inhibited by estradiol and inhibin from the hypothalamus, which is released by the antral follicles inhibited by progesterone v dominant and preovulatory follicles v recruited and early selected follicles are LH-dependent, although they still are FSH-dependent respond to basal FSH FSH-dependent LH-dependent CL CL CL CL recruitment early selection late selection dominance 22  Folliculogenesis Regulation of E2 synthesis by the antral follicles Ø E2 is critical for the regulation of folliculogenesis Ø E2 production by the antral follicles: v is regulated by FSH and LH v depends on the communication between cells of the theca interna and granulosa cells Antral follicle Theca Cells Granulosa Cells other inner Antrum (filled layer with fol. fluid) 23  Folliculogenesis Regulation of E2 synthesis by the antral follicles Ø cells of the theca interna produce androgens such as testosterone in response to LH v testosterone is a substrate for E2 production by the granulosa cells LH Theca Cells ü cells of the theca interna have Granulosa Cells LH receptors Antrum Testosterone § when LH binds to theca interna cells, (filled it will convert cholesterol into with fol. testosterone through a cascade of fluid) events 24  Folliculogenesis Regulation of E2 synthesis by the antral follicles Ø granulosa cells convert androgens into E2 in response to FSH E2 ü granulosa cells have FSH FSH receptors Theca Cells § when FSH binds to granulosa cells, it Granulosa Cells will convert androgens into E2 through the action of the enzyme aromatase Antrum Testosterone (filled with fol. fluid) o OBS: granulosa cells of dominant follicles also have LH receptors for final follicular maturation 25  Folliculogenesis Luteolysis (degeneration of corpus luteum) Ø initiates the follicular phase of the estrous cycle v stops the secretion of P4 by the CL, which increases the secretion of gonadotropins by the anterior pituitary v is induced by PGF2⍺ released by the endometrium Its v increasing concentrations of E2 stimulate the release of PGF2 α ü E2 will only stimulate the release of PGF2⍺ if the endometrium has been exposed to P4 for certain period of time (P4 priming of the endometrium), which occurs at late diestrus luteal phase 26  Folliculogenesis Ovarian folliculogenesis occurs in waves 1st wave 2nd wave 1st wave 2nd wave Ovulation produces Ovulation Ovulation Ovulation hair Dominance Selection Dominance Relative Hormone Concentration Selection P4 Recruitment Recruitment E2 Follicle Diameter LH Recruitment Recruitment they can't FSH rid of prog get Proestrus Metestrus Diestrus Estrus Metestrus Diestrus Proestrus Estrus Stages of the estrous cycle Stages of the estrous cycle Ø this is an example of a cow that has 2 follicular waves 27  Folliculogenesis Ovarian folliculogenesis occurs in waves 1st wave 2nd wave 1st wave 2nd wave Ovulation Ovulation Ovulation Ovulation Dominance Selection Dominance Relative Hormone Concentration Selection P4 Recruitment Recruitment E2 Follicle Diameter LH Recruitment Recruitment FSH Metestrus Diestrus Proestrus Estrus Metestrus Diestrus Proestrus Estrus Stages of the estrous cycle Stages of the estrous cycle v follicles of the first follicular wave will not ovulate (will become atretic) because of high P4 (negative feedback) v FSH will stimulate recruitment and will soon be inhibited by E2 and inhibin produced by antral follicles v rising E2 will stimulate the release of PGF2⍺ by the P4-primed endometrium v after luteolysis, P4 decreases and E2, FSH, and LH increase (LH will stimulate final growth and maturation of follicles and ovulation) 28  Folliculogenesis Regulation of folliculogenesis Surge center Tonic center OBS: this is the final follicular wave prior to ovulation 29 endometrium has been primed  Folliculogenesis Regulation of folliculogenesis Surge center Ø Small antral follicles are recruited in response to FSH and start secreting E2 and inhibin Tonic center GnRH FSH Inhibin E2 CL recruitment (emergence) 30  Folliculogenesis Regulation of folliculogenesis Ø Small antral follicles are recruited in response to FSH Surge center and start secreting E2 and inhibin Ø High P4 only allows secretion of basal levels of GnRH Tonic from the tonic center and surge center, which results in center low LH pulse frequency GnRH FSH feedback on Surge center, Inhibin low GnRH and no LH surge E2 CL P4 recruitment (emergence) 31  Folliculogenesis Regulation of folliculogenesis Ø Follicles continue to grow in response to basal FSH (E2 Surge and inhibin are continuously increasing) center Ø E2 and inhibin decrease the release of FSH by the anterior pituitary feedback on Tonic center Ø High P4 continues the negative feedback on surge FSH GnRH center, which results in low LH pulse frequency FSH feedback on Inhibin LH surge E2 CL P4 32  Folliculogenesis Regulation of folliculogenesis Surge center Ø Follicles continue to grow in response to basal FSH (E2 and inhibin are continuously increasing) feedback on Tonic center FSH GnRH FSH feedback on Inhibin LH surge E2 CL P4 selection (deviation) 33  Folliculogenesis Regulation of folliculogenesis Ø Follicles continue to grow and one follicle becomes Surge dominant center Ø Dominant follicle secretes enough E2 to stimulate PGF2⍺ release by the P4-primed endometrium Tonic center Ø PGF2⍺ induces luteolysis and P4 drops (no more GnRH negative feedback on the hypothalamus) FSH no more progesterone Inhibin is surge center happy E2 CL P4 dominance PGF2α released from endometrium 34  Folliculogenesis Regulation of folliculogenesis feedback on GnRH surge release Ø In the absence of P4, E2 is able to stimulate the Surge center preovulatory GnRH surge from the surge center, which will stimulate FSH release and the LH surge from the GnRH Tonic anterior pituitary center ovulation will happen E2 LH Inhibin 35  Folliculogenesis Regulation of folliculogenesis feedback on LH surge release Surge center Ø E2 keeps rising and stimulates estrus behavior GnRH Tonic Ø LH will stimulate final follicular growth and ovulation center E2 LH Inhibin ESTRUS OVULATION 36  Follicular phase Discussion time (bonus points) Ø discuss in small groups (3-4): v what are the 4 processes of folliculogenesis? v what is the difference between the surge and the tonic center of hypothalamus? Which one secretes the preovulatory surge of LH? v which hormone prevents the LH preovulatory surge by the hypothalamus through negative feedback? 37