Estrous and Menstrual Cycles Ansc 631 Spring 2014

Home , Corpus hemorrhagicum, Corpus luteum, Estrous cycle, Menstruation (mammal), Ovarian follicle

ESTROUS AND

MENSTRUAL CYCLES

ANSC 631

SPRING 2014 What are you expected to learn?

 What is an estrous cycle?  How does it differ from a menstrual cycle?  What organs are involved?  What hormones are needed?  How/where estrogen and progesterone are synthesized?  What endometrial changes occur during the estrous and menstrual cycles?  Menstruation: why and how  What happens in a fertile cycle

Outline for Presentations • Estrous and Menstrual Cycles • Gonadotropin Regulation of Follicular Recruitment and Development • Follicular Steroidogenesis • Growth Factors and Follicular Development • Ovulation • Corpus Luteum Formation, Function and Angiogenesis • Luteal Peptides, Cytokines and Growth Factors • Prolactin and Ovarian Function • Luteolysis. Reproductive cyclicity provides females with repeated opportunities to become pregnant What was normal in ancient times?

Reproductive cycles: Animals vs Women

Animals Women Estrous cycle The physiological Menstrual cycle The events between successive physiological events between periods of sexual receptivity successive menstruations &/or ovulation – Day 0 is day of (~28d) – Day 1 in day of onset onset of estrus of menses

Anestrus Without cyclicity - caused by pregnancy, season, Amenhorrea lack of menstruation lactation, stress (under- – caused by pregnancy, nutrition, environment) lactation, stress, pathologies If no conception in a cycle, another cycle begins to provide a new opportunity to establish pregnancy Estrus = heat = period of sexual receptivity

–Estrus is a noun. (estrus)

–Estrous is an adjective (estrous)

Cyclicity - categorized according to frequency of occurrence throughout the year

 Polyestrus  cattle, swine, rodents

 Seasonally polyestrus  sheep, goat, mare, deer

 Monoestrus  dogs, foxes

Senger 2003 Classifications of Estrus Physiological Estrus – Follicle Growth, Estrous behavior, LH surge and ovulation with outcome being synchronized mating and ovulation to maximize chances for fertilization of oocytes and establishment of pregnancy. Characteristics - Increase in estrogens from mature Graffian Follicles - Increase in GnRH synthesis by peptidergic neurons in hypothalamus - Increase in GnRH pulse frequency - Increase in GnRH Receptors on Gonadotrophs in Anterior Pituitary - LH surge and Ovulation

Psychological Estrus – Estrous behavior without ovulation 1. Estrogens – effects in area of hypothalamus (work with cats identified nuclei for estrous behavior without ovulation) Pre-optic area - +++ Arcuate Nucleus - ++ Mammalary Body - +

2. GnRH – Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro- GlyNH2 Receptor Binding Lordosis

3. Oxytocin – Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-GlyNH2 a. Smooth muscle contractions – sperm transport, lactation, parturition b. Bonding mother and offspring sexual partners

Hypothalamic Divisions

Yen 2004; Reprod Endocrinol 3-73 Characteristics of Psychological Estrus

Increased activity: walking, vocalization, mounting, accept male for mounting/mating

Example: Post-partum Estrus in Sows a. Estrous Behavior 2 to 3 days post-partum b. No Ovulation c. Cause: Likely prepartum estrogens

Post-Partum Estrus Sow - 2-3 days – Psychological Esrus Only - Post-weaning estrus – 72 to 96 h is fertile

Mare 7-10 days post-partum – fertile

Beef Cows 60-80 days postpartum due to suckling intensity

Dairy Cows 2X Day Milking – 14 Days Postpartum is short cycle usually 21-25 Days Postpartum for normal cycles

Ewes – Normally Lamb During Anestrus Season

Mouse and Rat – Day 1 postpartum – fertile and followed by delayed implantation

Humans – Variable due to suckling intensity and nutrition DELAYED IMPLANTATION • Embryonic diapause, temporary suspension of blastocyst development in mammals due to suppression of cell proliferation. • Obligate diapause occurs in every gestation of some species, e.g., season to time birth with favorable time of year for nutrients • Facultative diapause is associated with metabolic stress, usually lactation, to prevent concident lactation and pregnancy. Mechanisms for Optimizing Timing of Birth

3) Delayed implantation (Chiroptera, Carnivora, Xenarthra, Cetartiodactyla)

Obligate

Ursus americanus

Zona Pellucida

Facultative Many Rodents Mechanisms for Optimizing Timing of Birth

4) Embryonic diapause (Macropodids) DELAYED IMPLANTATION IN WALLABY

JANUARY BREED AND NEW YOUNG TO TEAT TO SUCKLE AND INDUCE FACULTATIVE DELAYED IMPLANTATION (LACTATION/SUCKLING INDUCED)

CORPUS LUTEUM PRODUCING LITTLE PROGESTERONE

TREATMENT WITH BROMOCRYPTINE TO DECREASE PROLACTIN AND DELAYED IMPLANTATION CAN BE INTERRUPTED

JUNE-JULY OBLIGATE DELAY DUE TO SEASON/PHOTOPERIOD

DECEMBER POUCH YOUNG OUT + ABOUT 28 DAYS AND FEMALE RETURNS TO ESTRUS

JANUARY BREED AND REPRODUCTIVE CYCLE BEGINS AGAIN Figure 1 Strategies for photoperiodic modulation of diapause employ melatonin and prolactin for contrasting purposes.

Lopes F L et al. Reproduction 2004;128:669-678

LIF – Leukemia Inhbiting Factor ErbB – EGF Receptor EGF – Epidermal Growth Factor Anandamide -

A. Spontaneous Ovulators – Women, Domestic Animals – Endogenous hormonal changes adequate to stimulate ovulatory surge of LH and ovulation.

B. Spontaneous Ovulator with Induced CL Formation – Rodents – Spontaneous Ovulation; Mating Induced CL Formation

C. Induced Ovulator – Mating or stimulation of vaginal-cervical area results in noradrenergic stimulation of hypothalamic GnRH centers to cause release of ovulatory surge of LH - rabbit, mink, cats. In rabbits, ovulation about 10 h post-mating or stimulation of vaginal-cervical area. In domestic cats, multiple matings usually required for full ovulatory response.

D. Seasonal Ovulators 1. Monestrus – bears, dogs (most big breeds) ovulate once per year 2. Long-Day Breeders – horse is seasonally polyestrus species 3. Short-Day Breeders – ewe is seasonally polyestrus species Hormones of the Estrous and Menstrual Cycles

A. Luteotropic Hormones – LH, hCG, prolactin that act directly on CL to stimulate progesterone (P4) secretion.

B. Luteolyic Hormone – Prostaglandin F2-alpha (PGF) that acts on CL to cause cessation of secretion of progesterone and physical destruction of luteal cells. Luteolytic PGF is from uterine epithelia in subprimate mammals and from intra- ovarian sources in most primates, so menstrual cycle in uterine independent while estrous cycles are usually uterine dependent.

C. Antiluteolytic Hormones – Interferon tau (ruminants), estradiol and prolactin (pigs), prolactin and lactogenic hormones (mice)

D. Luteal Protective – Prostaglandin E2 may antagoinize luteolytic effects of PGF2-alpha Stages of the Estrous Cycle

A. Estrus: High Estrogens from Mature Graffian Follicles and LH Surge 1. Follicle Maturation 2. Oocyte Maturation 3. Estrous Behaviour (Psychological Estrus) and Mating 4. Estrogen-Induced Ovulatory Surge of LH (Physiological Estrus) 5. Ovulation 6. Initial Luteinization of Granulosa and Theca Cells 7. Decreased Vaginal and Rectal Temperatures 0.25 to 0.75 degrees C Increased blood flow to perineum area Monitor time of ovulation 8. Increase in cervical mucus Unique crystallization patter of mucus – ferning pattern

9. pH of vagina increases to 6.8 from 7.1 to 7.4

10. Increased antimicrobial actions Increase in Lysozyme – bacteriacidal Increase in Lactoferrin – bacteriostatic

11. Pheromones for attracting male a. Cow – acetaldehyde (Bill Klemm, TAMU) b. Rhesus Monkey

Copulin – short-chain fatty acids: acetic acid, proprionic acid, isobutyric acid, butyric acid, and isovaleric acid

c. Microflora of vagina produce pheromones

12. Swelling of sexual skin - Vulva

Metestrus: Ovulation and Corpus Hemmorhagicum (Corpora Hemmorhagica) 1. Circulating Estrogens and Progesterone are LOW 2. Uterine cells expressing receptors for progesterone (PGR), estradiol (ESR1) and Oxytocin (OXTR) Diestrus: Corpus Luteum (Corpora Lutea) and Progesterone 1. Circulating Progesterone is HIGH

2. Large luteal cells of CL synthesize and store, depending on species, oxytocin-neurophysin (ruminants) and relaxin (pig) In sheep and cow: OXY production: Days 0-3 transcription (maybe in response to LH surge Days 4-7 translation of OXT-Neurophysin mRNA Days 8-14 storage of OXY-Neurophysin Days15-17 pulsatile release of OXT and Neurophysin

3. Steroid Receptors in Uterine Endometrium Uterine epithelia and stromal cells: NO OXTR Uterine epithelia lose ESR1 Uterine epithelia lose PGR after Days 11 to 12 Uterine stromal cells express PGR and low or no ESR1

4. Preparation of the Uterus for Pregnancy – Uterine luminal and glandular epithelial cells begin to express proteins important to development of embryo/conceptus (conceptus is embryo and its associated membranes) Late Diestrus – Corpus Luteum Regression 1. Steroid Receptors in Uterine Endometrium Uterine Epithelia have increasing expression of ESR1 and then OXTR

2. Increase in estrogens from developing follicles stimulate more ESR1 and OXTR in uterine epithelia

3. Oxytocin released from CL and/or Posterior Pituitary in Ruminants and Posterior Pituitary and/or Uterus in sows and mares

4. Oxytocin-induced luteolytic pulses of PGF2a

5. Corpus Luteum Regression Proestrus – Corpus Albicans (Corpora Albicantia) and Mature Graffian Follicles

1. Circulating Estradiol Increasing 2. Circulating Progesterone Decreasing to basal levels 3. GnRH Pulse Frequency increasing from 1 pulse/2 to 4 h to approximately hourly pulses Fig. 7-3

Regulation of Corpus Luteum Function

Species Luteotrophic Complex Human LH

Sheep LH & GH

Pig Estradiol Pseudopreg. Estradiol, LH Rabbit Pseudopreg. Estradiol, Prolactin & LH Rat/Mouse Organs involved in female reproductive cycle

hypothalamus anterior pituitary

Oviduct uterus

ovary corpus luteum endometrium Ovarian Cycles: Uterine-Dependent and Uterine-Independent Major hormones regulating the female reproductive cycle

Hormone Site of production  gonadotropin-releasing hypothalamus hormone - GnRH

 luteinizing hormone - LH anterior pituitary (gonadotrophs)  follicle stimulating hormone - FSH

 estradiol 17 (E2) ovarian follicle

 Progesterone (P4) corpus luteum

After ovulation, cells of dominant follicle give rise to the CL The female hypothalamo-pituitary ovarian axis

Hypothalamus

Feedback hormones GnRH

Pituitary Steroids

Inhibin Activin

Follistatin Gonadotrophins (LH, FSH)

Steroids / Uterus ovary Estrous cycles consist of two major phases

Follicular phase Luteal phase

Ovarian FOLLICLES - CORPORA LUTEA – dominant structures in the dominant ovarian ovary structures ESTROGEN is the PROGESTERONE is the dominant hormone dominant hormone

Follicles grow Corpus luteum develops / regresses

The estrous cycle has 4 stages

 Proestrus – formation of ovulatory follicles + E2 secretion

 Estrus – sexual receptivity + peak E2 secretion + ovulation

 Metestrus – CL formation + early P4 secretion

 Diestrus – substantial secretion of P4 Phases / stages of the estrous cycle Most animals - short follicular phase

Senger 2003 Hormone cyclicity in menstrual cycle

Positive feedback of peak E2 induces preovulatory LH surge

GnRH, FSH and LH • Pulsatile secretion • Changing frequency & amplitude In Women – Menstrual cycle

Differs from estrous cycle

 no defined period of sexual receptivity

 a period of endometrial sloughing (menstruation)

 timeline for the description of the cycle begins and ends with menses, not ovulation or estrus

 Lack of cyclicity = amenhorrea – absence of cyclicity for an extended period of time in women of reproductive age (in athletes-loss of body fat; lactation (prolactin ↓ GnRH frequency and amplitude; menopause; undernutrition; stress)

Ovarian follicle numbers with age

Women with regular 100000 menses B B 10000 BB 1000 J perimenopausal F F women B 100 F F F 10 F F postmenopausal women 1

Primordial Follicles / Ovary Follicles/ Primordial 0 0 10 20 30 40 50 60 Age in Years

Richardson et al., JCEM, 1987  In women, the proliferative or follicular phase and the secretory or luteal phases of the menstrual cycle are of equal length.

 The phases of the menstrual cycle are named for the changes that occur in the endometrium.

 Follicular phase (estradiol dominated) = proliferative phase

 Luteal phase (progesterone dominated) = secretory phase

Summary – comparison events that occur between estrous and menstrual cycles

Senger 2006 Steroidogenesis

• Ovary (Follicles and Corpus Luteum) • Conceptus • Fetal Adrenal • Placenta

20a-Hydroxysteriod Dehydrogenase 20a-HSD

H3C H3C O OH Prolactin Inhibits Enzyme

20a-HSD NADPH NADP

O Progesterone 20a-dihydroprogesterone

Does not support pregnancy or decidualization in rodents FSH

FSH is a glycoprotein. Each monomeric unit is a protein molecule with a sugar attached to it; two of these make the full, functional protein. Its structure is similar to LH, TSH, and hCG. The protein dimer contains 2 polypeptide units, labelled alpha and beta subunits. The alpha subunits of LH, FSH, TSH, and hCG are identical, and contain 92 amino acids. The beta subunits vary. FSH has a beta subunit of 118 amino acids (FSHB) that confers its specific biologic action and is responsible for interaction with the FSH- receptor.The sugar part of the hormone is composed of fucose, galactose, mannose, galactosamine, glucosamine, and sialic acid, the latter being critical for its biologic half- life. The half-life of FSH is 3-4 hours.

HORMONES FROM GRANULOSA CELLS OF FOLLICLE AND SERTOLI CELLS OF TESTES THAT REGULATE FSH SECRETION

Inhibin: a peptide inhibitor of FSH synthesis and secretion participates in regulation of estrous and menstrual cycles. Structure: contains an alpha and beta subunit linked by disulfide bonds. Two forms of inhibin differ in their beta subunits (A or B), while alpha subunits are identical. Inhibin belongs to the transforming growth factor-β (TGF- β) superfamily. ********************************************************** Activin: a peptide stimulator of FSH synthesis and secretion participates in regulation of estrous and menstrual cycles Structure: two beta subunits identical to the two beta subunits (A or B) of inhibin, allowing for the formation of three forms of activin: A, AB, and B; linked by a single covalent disulfide bond. ********************************************************** Follistatin: a single chain gonadal protein that inhibits FSH synthesis and release by binding and antagonizing Activin.

LH is a dimeric glycoprotein with 2 polypeptide units, alpha and beta, connected by two disulfide bridges alpha subunits of LH, FSH, TSH, and hCG are identical, and contain 92 amino acids. beta subunits: LH beta subunit of 121 amino acids confers specific biologic action and binding to LH receptor. This beta subunit identical to beta sub unit of hCG and both bind LH receptor, but hCG beta subunit contains an additional 24 amino acids half-life of LH is 20 minutes, shorter than that of FSH (3-4 hours) or hCG (24 hours). PROLACTIN

Prolactin is a single chain polypeptide of 199 amino acids with a molecular weight of about 24,000 daltons. Its structure is similar to that of growth hormone and placental lactogen. The molecule is folded due to the activity of three disulfide bonds. Prolactin Inhibiting Factor

Dopamine

pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly CONH2

GnRH OXYTOCIN

Oxytocin-Neurophysin

Maturase

Oxytocin + Neurophysin

Circulation To Target Tissues Relaxin: A Hormone with Diverse Actions in Rats

Sherwood, O. D. Endocr Rev 2004;25:205-234

Corpus luteum Progesterone receptors, PGR Estrogen receptor alpha, ESR1

Ovulation Atresia

Preovulatory Theca (androgens) Androgen Estrogen Developing Follicles FSH Granulosa cell (progesterone receptors LH receptors estrogen)

Secondary Androgen Estrogen Primary Oocyte FSH receptors Primordial

Steroidogenesis Before LH Surge

EP FSH FSHR A

Ch P A2 GL P450scc Arom E2 3-HSD BM

TI ChP450scc P A2 E2 17a-HSD EP 3-HSD LHCGR TE

LH A: Antrum; GL: Granulosas; BM; Basement Memb TI: Theca Int. TE: T Ext.; C: Capillaries Ch: Cholesterol; P: Progesterone; A2: Endrogen; E2: Estradiol Luteal Steroidogenesis

EP LHCGR and FSHR

Large Luteal Cells

(Some Species) Ch A E P450scc P17 a-HSD 2 Arom 2 3-HSD

Ch A E P450scc P17 a-HSD 2 Arom 2 3-HSD Small Luteal Cells EP LHCGR

Ch: Cholesterol; P: Progesterone; A2: Endrogen; E2: Estradiol Estrogen production in the ovary: collaboration between two cell types

aromatase Primary steps leading to the pre-ovulatory LH surge • In early follicular phase GnRH pulse frequency increases • Causes LH & FSH secretion

• Increase in E2 production Portal vessels • E2 stimulates: • increase in GnRH Receptors on Gonadotrophs; •increase in GnRH pulse frequency •surge in GnRH leads to ovulatory surge of LH • The follicle then starts to secrete inhibin – negative inhibitor of FSH CL

bovine human LH surge

Primates Fig. 9-2 Stigma of Ovarian Follicle of Chicken Fig. 9-2 Fig. 9-2 LH SURGE, OVULATION AND FERTILIZATION Fig. 8-6 Events in Proteolytic Cascade for Ovulation • LH and PGE2 induce plasminogen activator (PA) • Plasminogen is in follicular fluid • PA converts Plasminogen to Plasmin, a serine protease • Plasmin converts procollagenase to collegenase • Combined effects of plasmin and collagenase lead to rupture of stigma and ovulation Adamts1 -A Disintegrin-like and PROAPOPTOTIC CASPASE Metalloproteinase with ADAPTOR PROTEIN Thrombospondin Type 1 motif1

TSG6 - TNF-Alpha-induced Protein 6

PCAP – pituitary activating adenyl cyclase Tumor Necrosis Factor-stimulated Gene 6 IαI- Inter-alpha trypsin inhibitor SHAP – IαI + hyaluronan (HA)

Follicle Wall and Ovulation • Stigma of Follicle – Avascular area at apex of follicle – Proteases act to cause rupture of basement membrane – Follicular fluid exits and takes oocyte and cumulus cells with it into oviduct – Bernoulli’s Law – Contractions of ovary generated by actin and myosin fibers in area of theca externa aids in expulsion of oocyte and cumulus cells • Alpha adrenergic receptors on theca externa respond to norepinephrine to enhance contractions

– Mature Graffian Follicle MINUS oocyte and cumulus cells becomes corpus hemmorhagicum and with hyperplasia and hypertrophy of large and small luteal cells they give rise to the corpus luteum that produces progesterone MECHANISM OF OVULATION – SEE PAPER BY ESPEY • LH, FSH and PGE2 act via LHCGR, FSHR and EPs to increase cAMP and Protein Kinase A that: – 1. Stimulates production of plasminogen activator by GC and plasminogen activator converts plasminogen into plasmin (serine protease) and procollegenase to collagenase

– 2. Plasmin and Collagenase act on basement membrane and extracellular matrix of follicle to cause rupture and release of oocyte and cumulus cells

– 3. Ovulation is due to softening of cell wall, decrease in pressure in follicle, rupture of cell wall and as follicular fluid escapes it creates a negative pressure that pulls oocyte and cumulus mass with it into the infundibulum of the oviduct Fig. 8-13

Follicular Pressure Does Not Increase Ovarian Histology • Corpus hemorrhagicum (CH)/Corpora hemorrhagica – newly ruptured follicle – essentially a blood clot • Corpus luteum (CL)/Corpora lutea – LH stimulates formation from theca interna and granulosa – temporary endocrine gland • progesterone • Corpus albicans (CA)/Corpora albicantia – remains after CL regresses LH Surge- Induced Events: The Oocyte and Follicle • Inhibition of androgen and estrogen production – Inhibition of C21 steroid 17α hydroxylase – Aromatase enzyme inhibited – Progesterone production increases – Loss of FSHR on GC – TC and GC become small and large luteal cells, respectively • Hyperplasia • Hypertrophy • Endoplasmic reticulum develops in complexity • Mitochondria develop with complex cristae to enhance conversion of cholesterol to pregnenolone for P4 production • Increase in cholesterol esters

LH Surge-Induced Events: Oocyte and Follicle • LHCGR and Prolactin receptors increase in luteal cells to enhance LDL and HDL receptors for uptake of cholesterol

• Progesterone Production Increases

• Increased production of PGE2 by luteal cells Structural Changes During Luteinization

TC LC Antrum BV O GC Small versus Large Luteal Cells • LARGE LUTEAL CELLS FROM GC – GREATER THAN 22 MICRONS – HIGH BASAL P4 OUTPUT – LITTLE ABUNDANT ROUGH ENDOPLASMIC RETICULUM • OXYTOCIN-NEUOPHYSIN • RELAXIN – FEW LHCGR – ABUNDANT FP (PGF RECEPTORS) Small versus Large Luteal Cells • SMALL LUTEAL CELLS FROM TC – 8 TO 22 MICRONS – LOW BASAL P4 OUTPUT – ABUNDANT LHCGR – INCREASE P4 IN RESPONSE TO LH – SMOOTH ENDOPLASMIC RETICULUM • NO OXYTOCIN-NEUOPHYSIN • NO RELAXIN – FEW FP (PGF RECEPTORS) Ovulation: Morphological and Cytological Changes • Increase in Blood Flow to Follicle – Histamines – PGE2 – Increased Vascular Permeability to Proteins • Platelet Activating Factor • Increased influx of plasminogen into follicular fluid

• Granulosa Cells – Loss of junctional complexes between corona radiata cells and oocyte – Increase in hyaluronic acid and water in cumulus GC – High cAMP due to FSH, LH and PGE2 – Plasminogen Activator Enzyme activity increases to convert plasminogen to plasmin (active protease) and collegenase Oocyte Maturation

• Pre-Meiosis: Prophase I arrest – Oocyte-corona radiata cell communication via gap junctions – High cAMP in oocyte blocks meiosis • Adenosine – Increases conversion of ATP to cAMP via adenyl cyclase • Hypoxanthine – decreases activity of phsphodiesterase that converts cAMP to AMP – Maturation Promoting Factor Inactive – RNA synthesis – maternal RNA LH SURGE-INDUCED EVENTS • Changes in cytoplasmic mass – Increase deposition of nutrients into oocyte by corona radiata cell just before loss of gap junctions – Nuclear Envelope Breakdown – Breakdown of centrioles and chromosomes migrate to periphery of oocyte – Chromosomes individualize – Chromosomes condense due to increase in histone I kinase – Microtubule organizing center forms (Centriole and Microtubules) – Chromosomes align on equatorial plane at Metaphase I – Polar Body I extruded – Metaphase II arrest – Nuclear Envelope Forms Oocyte Maturation (Continued)

• Protein Synthesis – Zona Pellucida Proteins • ZP1 – Cross-linking • ZP2 – Sperm Trap • ZP3 – Sperm Receptor – Cortical Granules • Proteases – destroy sperm binding sites • Colloidal Molecules: Hyaluronic Acid and Glycosaminoglycans – bind water and increase space between vitelline membrane and zona pellucida • Structural Proteins – unknown function

Fig. 8-17 FERTILIZATION MEDIATED EVENTS • Fertilization – Increase in intracellular Ca++ in oocyte – Germinal Vesicle Breakdown – Microtubule Organizing Center with Spindle forms – Metaphase II Completed – Polar Body II extruded into perivitelline space – Syngamy between male and female pronuclei – Pairing of paternal and maternal chromosomes – Nuclear envelope forms – Zygote forms – 1- cell embryo

TIMING OF EVENTS AFTER LH SURGE IN EWES

• 8-12H: PROPHASE I COMPLETED • 12-20H: METAPHASE II • 21-24H: POLAR BODY I EXTRUDED TO PERIVITELLINE SPACE • 24-30H: METAPHASE II AND OVULATION • 30-36H: FERTILIZATION Fig. 8-16 Summary

 FSH & LH levels rise during early follicular phase stimulating growth of early antral follicles

 During mid follicular phase, selection and emergence of dominant follicle occurs. Corresponds to an increase in E2 secretion.

 Increasing estrogen levels stimulate GnRH, which results in preovulatory surges of LH & FSH leading to ovulation.

 Following ovulation, the corpus luteum secretes large amounts of P4. The P4 inhibits GnRH synthesis and secretion by neurons in the hypothalamus.