Menstrual Cycle

Menstrual Cycle Participants

Hypothalamus – pulsatile GnRH secretion, "on/off" switch

Pituitary – responds to GnRH, secretes FSH and LH

"fine-tuned" by ovarian hormones"

Ovary – secretes estrogen, progesterone, and androgen

egg is picked up by contra-lateral fallopian tube 20% of the time
eggs are in the cortex of the ovary (contrast to sperm, which are in the center of the testicle)

Uterus – menstrual cycle’s end organ

endometrium is hormonally responsive: grows (follicular), differentiates (luteal), sloughs

Features of the Menstrual Cycle

Controlled by ovary, can be called Ovarian Cycle.

cycle » 26-35 days long

first day of bleeding = day 1, menses occurs on days 1-4.

divided by ovulation into 2 phases:

(1) Follicular (proliferative) Phase – estrogen secreted from ovary Þ growth and maturation of follicle, cessation of menstrual flow, growth of uterine lining

variable length, ends with ovulation

(2) Luteal Phase–follicular cells transformed (luteinized) to form corpus luteum (CL)

corpus luteum secretes estrogen and progesterone

progesterone Þ secretory changes in uterus in preparation for implantation or menstruation, maturation of oocyte

always 14 days long

Folliculogensis

Follicular development

Gonadotropin-independent follicular maturation – during female reproductive life, follicles continually undergo limited maturation and atresia

process is independent of gonadotropin (FSH/LH)

Follicular recruitment – rising gonadotropin levels at start of cycle recruit cohort of follicles that began gonadotropin-independent follicular maturation.

Dominant follicle selection – among the recruited follicles, one dominant follicle emerges

dominant follicle causes atresia of the other recruited follicles (see mechanism below).

Anatomy of Follicular development

Primordial follicle – oocyte arrested in diplotene stage of prophase I due to oocyte maturation inhibitor

primordial follicle is surrounded by one layer of granulosa cells

Primary follicle – due to follicular recruitment, flattened granulosa cells become cuboidal and form gap junctions

Secondary (Preantral) follicle – oocyte enlarges and is surrounded by three zones:

(1) zona pellucida – mucopolysaccharides

(2) granulosa – avascular layer relying on precursors from theca for steroidogenesis – mitosisÞ multilayered

(3) theca interna–vascular layer with access to peripheral hormonal precursors; begins to organize over granulosa

Antral (Graafian) follicle – fluid accumulates between granulosa cells Þ cavity

fluid provides means to maintain follicular microenvironment

oocyte gets surrounded by cumulus oophorus (granulosa cells) that communicates with it and provides nutrients
theca interna differentiates, and theca externa grows over it

Pre-ovulatory follicle – the dominant follicle destined to ovulate, completed by day 9

Note: though the oocyte is in rest throughout this whole process, it is a site of significant RNA activity

Two Cell Theory

Principles of Two Cell Theory

Theca cells get stimulated by LH – cholesterol from peripheral circulation Þ androgen

Granulosa cells get stimulated by FSH – androgen from theca cells Þ estrogen

estrogenic environment (1) further enhances aromatase activity (androgenÞ estrogen) and (2) promotes further follicular growth. Androgenic environment has opposite effects (promotes atresia).

selection of dominant follicle depends on ability of follicle to establish and maintain estrogenic microenvironment

Dominant follicle selection – Molecular mechanism

Keep this in mind: At beginning of follicular phase theca cells have LH-R and granulosa cells have FSH-R. By end of follicular phase theca cells still have LH-R, but granulosa cells have both FSH-R and LH-R.

Early follicular phase – low estrogen and progesterone levelsÞ Ý Pituitary FSH/LH

LH Þ androgen synthesis in theca cells

FSH Þ estrogen synthesis in granulosa cells

Mid-follicular phase – Ý FSH Þ Ý number of FSH-Rs on granulosa cells and Ý granulosa cell mitosis Þ dominant follicle is more responsive to FSH Þ faster synthesis of estradiol Þ maintenance of follicular estrogenic microenvironment and Ý serum [estradiol] Þ suppression of pituitary FSH secretion

Ý estradiol levels also Ý Estrogen-Rs and Ý FSH-Rs on granulosa cells; Ý LH-Rs on theca cells; and slighly Ý LH secretion by pituitary

Note: a small number of LH-Rs also appear on granulosa cells due to estrogen/FSH levels; these play a role in production of preovulatory progesterone

Late follicular phase – rising peripheral [estradiol] further suppresses pituitary FSH

dominant follicle continues responding to FSH despite falling peripheral FSH due to high number of FSH-Rs

the other follicles, which have low content of FSH-Rs, create androgenic environment Þ atresia

thus, dominant follicle indirectly destroys the other follicles

at the same time, FSH begins inducing LH-Rs on granulosa cells

Inhibin and Activan – factors made by granulosa cells, found in follicular fluid

Inhibin (folliculostatin) – produced in response to FSH, acts at level of pituitary to suppress FSH secretion

inhibin B functions in follicular phase; inhibin A functions in luteal phase (same a -chain, different b -chains)

paracrine effects: Epidermal Growth Factor ß inhibin production, Insulin-like Growth Factor Ý inhibin production

Activan – stimulates FSH release; composed of two b -chains identical to those in inhibin – not well understood

Uterine responses to ovarian folliculogenesis – stimulation of endometrial lining by Ý peripheral estradiol levels Þ repair and regeneration of the functionalis layer from the basalis layer that remains after menstruation

these changes are, in part, responsible for cessation of menstrual bleeding

Estrogen causes endometrial mitosis, Progesterone causes growth of secretory glands

Ovulation – happens over a period of approximately 36 hours leading to release of oocyte

LH Surge – due to estradiol (need critical plasma estradiol level of at least 200 pg/ml sustained for at least 2 days)

Rapidly rising estradiol level from mature dominant follicle triggers surge of LH secretion for 48 hours Þ oocyte resumes meiosis because LH neutralizes oocyte maturation inhibitor (prophase I to metaphase II upon release, 2^nd division completes upon fertilization)Þ oocyte released after about 36 hours from start of LH surge

LH surge Þ synthesis/enhancement of prostaglandins and proteolytic enzymes to participate in oocyte release

LH surge Þ lutenization (transformation) of granulosa cells and differentiation of theca cells Þ corpus luteum (CL)

FSH Surge – due to estradiol and preovulatory progesterone; occurs simultaneous to LH surge

Ý LH-R production in granulosa cells necessary for an adequate luteal phase

activates plasminogen Þ plasmin (egg release) and hyaluronidase (expandes cumulus mass surrounding oocyte)

Oocyte Release – occurs as result of thinning and breakdown of follicular wall, not an explosive event

LH/FSH surge Þ rapid accumulation of follicular fluid Þ expansion of follicular cyst without change in pressure

Ý elasticity mediated by progesterone

LH/progesterone Þ proteolytic enzymes digest collagen in follicular wall

LH surge Þ prostaglandins Þ lysosomal enzymes digest wall and smooth muscle contracts

no prostaglandins = no egg release

Oocyte released covered in sticky cumulus mass which is necessary for tubal pickup

Fertilization occurs 24-48 hours following egg release

The loci of the LH surge are in the pituitary and the hypothalamus. The pituitary gonadotrophs (LH/FSH), appropriately primed by the preceding pattern of gonadal steroid exposure (estradiol/progesterone), respond at this time to GnRH with heightened sensitivity. The LH molecules released are more active, probably because of posttranslational modulation of their sialic acid content by estradiol. In addition, a peak of peripheral plasma GnRH levels preceds the LH/FSH peak, most likely due to the gonadal steroids augmenting flow of GnRH from the hypothalamus to the pituitary. Estradiol and progesterone may be acting in part by decreasing inhibitory endorphinergic activity on the GnRH neurons.

Luteal Phase – corpus luteum (CL) exists for exactly 14 days

Cellular changes – granulosa and theca interna cells enlarge and differentiate and accumulate yellow pigment (lutein)

Capillaries from theca layer penetrate granulosa layer filling cyst with blood, allowing LDL access (steroid synthesis)
corpus luteum synthesizes all classes of steroids: androgen, estrogen, progesterone

Corpus luteum – Lifespan of a healthy corpus luteum is 14 days (continued function requires tonic LH stimulation)

Progesterone levels rise and remain elevated throughout lifespan of the corpus luteum
it acts locally (ovary) to suppress further follicular recruitment, and centrally to suppress LH secretion
Mechanism for corpus luteum decline/demise is unknown (estrogen may play a role)

Uterine changes – Endometrium, which previously underwent mitosis by estrogen stimulation, now undergoes progressive and discrete secretory changes under progesterone stimulation

In case of pregnancy: implantation occurs about 6-7 days after ovulation, during peak glandular secretions

adequate endometrial maturation is necessary to assure implantation and early placentation

hCG (human chorionic gonadotropin) secretion from trophoblast formed at implantation is required for corpus luteum "rescue" and continued hormone secretion beyond 14-day span
hormonal support of early pregnancy by corpus luteum is essential until placental development can take over
occur 2-4 weeks after the first missed menstrual period or 6-8 weeks after the last menstrual period

In absence of pregnancy: corpus luteum involutes Þ no hormone production Þ shedding of endometrial lining

Summary of Hormonal Changes during Menstrual Cycle

Summary of Ovulation

Summary of the Menstrual Cycle

Follicular Phase

FSH Þ Ý estradiol Þ ß FSH/LH release; Ý FSH/LH synth and storage (low levels of E2)

E2 surge Þ Ý Ý expression of GnRH receptors Þ Ý Ý LH release (overrides inhibition) Þ progesterone Þ FSH surge

FSH surge is slower and later than LH surge

Luteal Phase

progesterone Þ ß GnRH pulses Þ ß expression of GnRH receptors Þ ß FSH/LH release

corpus luteum involution triggers LH/FSH rise in follicular phase