FEMALE REPRODUCTIVE SYSTEM

FEMALE REPRODUCTIVE SYSTEM

TO REVIEW THE COMPONENTS OF THE FEMALE REPRODUCTIVE SYSTEM TO CHARACTERIZE THE GENERAL ORGANIZATION OF THE OVARIES TO UNDERSTAND THE HORMONAL REGULATION OF OOGENESIS, OVULATION, AND THE UTERINE CYCLE

Hormones of the Female Reproductive Cycle

Control the reproductive cycle Coordinate the ovarian and uterine cycles

Hormones of the Female Reproductive Cycle

Key hormones include:
FSH
Stimulates follicular development

LH
Maintains structure and secretory function of corpus luteum

Estrogens
Have multiple functions

Progesterones
Stimulate endometrial growth and secretion

FEMALE REPRODUCTIVE SYSTEM

OVARIES OVIDUCT (UTERINE TUBES) UTERUS VAGINA

Female Reproductive Organs

Ovary: female gonad Uterine Tubes (fallopian tube, oviduct) - three parts: infundibulum, ampulla, isthmus

The Female Reproductive System in Midsagital View

Figure 28.13

The Ovaries and Their Relationships to the Uterine Tube and Uterus

Figure 28.14a, b

The Uterine Tubes

Figure 28.17a-c

The Uterus
Muscular organ
Mechanical protection Nutritional support Waste removal for the developing embryo and fetus

Supported by the broad ligament and 3 pairs of suspensory ligaments

Uterine Wall Consists of 3 Layers:

Myometrium outer muscular layer Endometrium a thin, inner, glandular mucosa Perimetrium an incomplete serosa continuous with the peritoneum The site of implantation of developing embryo And 3 parts: fundus, body, and cervix

Female Accessory Sex Organs: Uterus

Uterine endometrium has two layers: - basal layer - functional layer: built up and shed each cycle

The Uterus

Figure 28.18a, b

The Uterus

Figure 28.18c

The Uterine Wall

Figure 28.19a

The Uterine Wall

Figure 28.19b

The Uterine Cycle

To be discussed below

Figure 28.20

Functions of the Ovary

Production of a mature oocyte, capable of fertilization and embryonic development. Production of ovarian steroids (estradiol, progesterone). Production of gonadal peptides (inhibin, activin).

Structural Organization of the Ovary

The main functional unit of the ovary is the follicle. Follicles are composed of the oocyte, granulosa cells, and theca cells.

Stages of Follicular Growth

Follicles are present in a number of different stages of growth: - primordial follicles (resting) - primary, secondary, and antral follicles - preovulatory (Graafian) follicles

The Corpus Luteum

After the preovulatory follicle ovulates (releases its egg), it forms the corpus luteum.

FEMALE REPRODUCTIVE SYSTEM

OVIDUCT (UTERINE TUBES)
INFUNDIBULUM, AMPULLA, ISTHMUS, UTERINE

UTERUS
FUNDUS, BODY (CORPUS), CERVIX

Oogenesis and Oocyte Maturation

Recall that germ cells must go through meiosis in order to produce unique haploid cells. From one spermatogonia, end up with four spermatozoa. Oocytes must also go through meiosis, but they do it during the course of follicular development. Primordial follicles contain primary oocytes that are arrested in prophase I, prior to the first meiotic division (diploid). How do they go through the rest of meiosis?

Oocyte Maturation
Oocytes remain in prophase I until the preovulatory surge of LH, which initiates completion of the first meiotic division. The primary oocyte does not split into two cells, but instead gives off a very small first polar body, containing half of the chromosomes.

LH surge

zona pellucida

first polar body

Oocyte Maturation
Thus, the ovulated egg is actually not completely mature (hasnt completed meiosis II). Maturation goes to completion only if the oocyte is fertilized. Fertilization causes completion of meiosis II, and expulsion of a second polar body. Meiosis of the oocyte results in only one gamete.
fertilization

first polar body

first polar body second polar body

FEMALE REPRODUCTIVE SYSTEM

OVARY
GERMINAL EPITHELIUM TUNICA ALBUGINEA - thin connective tissue capsule underlying germinal epithelium

The Ovarian Cycle

CORTEX
- surrounds the medulla and contains maturing follicles

MEDULLA
- central connective tissue containing vascular supply and nervous innervation

FEMALE REPRODUCTIVE SYSTEM

OVARY

The Ovarian Cycle

3 to 5 million OOGONIA differentiate into PRIMARY OOCYTES during early development OOCYTES becomes surrounded by squamous (follicular) cells to become PRIMORDIAL FOLLICLES most PRIMORDIAL FOLLICLES undergo atresia leaving 400,000 at birth

oocytes at birth arrested at Meiosis I (prophase)

FEMALE REPRODUCTIVE SYSTEM

OVARY
THREE STAGES OF OVARIAN FOLLICLES CAN BE IDENTIFIED FOLLOWING PUBERTY: (each follicle contains one oocyte) (1) PRIMORDIAL FOLLICLES - very prevalent; located in the periphery of the cortex - a single layer of squamous follicular cells surround the oocyte OOGENESIS (2) GROWING FOLLICLES - three recognizable stages: (a) early primary follicle (b) late primary follicle (c) secondary (antral) follicle (3) MATURE (GRAAFIAN) FOLLICLES - follicle reaches maximum size

FEMALE REPRODUCTIVE SYSTEM

OVARIAN FOLLICLES
(1) PRIMORDIAL FOLLICLES

(2) GROWING FOLLICLES

(a) early primary follicle

- follicular cells still unilaminar but now are cuboidal in appearance

- oocyte begins to enlarge

(b) late primary follicle

- multilaminar follicular layer; cells now termed granulosa cells - zona pellucida appears; gel-like substance rich in GAGs

- surrounding stromal cells differentiate into theca interna and theca externa

(b) secondary (antral) follicle

- cavities appear between granulosa cells forming an antrum

- follicle continues to grow - formation of cumulus oophorus and corona radiata

(3) MATURE (GRAAFIAN) FOLLICLES

FEMALE REPRODUCTIVE SYSTEM

OVARIAN FOLLICLES
late primary follicle

FEMALE REPRODUCTIVE SYSTEM

OVARIAN FOLLICLES

GRANULOSA (FOLLICULAR) CELLS

OOCYTE

ZONA PELLUCIDA

FEMALE REPRODUCTIVE SYSTEM

OVARY

CORTEX MEDULLA

CORPUS LUTEUM

FEMALE REPRODUCTIVE SYSTEM

CORTEX GERMINAL EPITHELIUM TUNICA ALBUGINEA PRIMORDIAL FOLLICLES

OVARY

 OVARY

GERMINAL EPITHELIUM

FEMALE REPRODUCTIVE SYSTEM

TUNICA ALBUGINEA

FEMALE REPRODUCTIVE SYSTEM

OVARY
OVARY
H&E

PRIMORDIAL FOLLICLES

EARLY 1

FEMALE REPRODUCTIVE SYSTEM

OVARY
OVARY
H&E

CORPUS ALBICANS EARLY PRIMARY FOLLICLES

PRIMORDIAL FOLLICLE

FEMALE REPRODUCTIVE SYSTEM

OVARY
LATE PRIMARY FOLLICLE multilaminar

FEMALE REPRODUCTIVE SYSTEM

OVARY
MATURE (GRAAFIAN) FOLLICLE zona pellucida cumulus oophorus corona radiata theca interna and externa
theca interna cells begin to produce androgens that are converted to estrogens

FEMALE REPRODUCTIVE SYSTEM

HORMONAL REGULATION OF OOGENSIS AND OVULATION
HYPOTHALAMUS release of GnRF which stimulates release of LH and FSH from the adenohypophysis (ANTERIOR PITUITARY)

Neuroendocrine Regulation of Ovarian Functions

CNS
hypothalamus

GnRH Pituitary LH E2, P inhibin, activin OVARY FSH

Follicle

Development Ovulation
Luteinization

Effects of GnRH on Gonadotropins

GnRH is released in a pulsatile manner, stimulating the synthesis and release of LH and FSH. GnRH acts through its receptor on the pituitary gonadotroph cells, stimulating production of phospholipase C. Recall that IP3 pathway causes gonadotropin release, while the DAG/PKC pathway causes gonadotropin synthesis.

Actions of FSH on Granulosa Cells

FSH

AC
ATP cAMP PKA CREB CRE

Gs

Gene Expression
Steroidogenic
enzymes LH Receptor Inhibin Subunits Plasminogen

Regulation of Estradiol Production

Recall the two-cell theory of estradiol production (lecture 4): - LH acts on theca cells to produce androgens - FSH acts on granulosa cells to increase aromatase activity, resulting in conversion of androgens to estrogens (granulosa cells lack 17 hydroxylase activity)

Ovarian Estradiol Production

LH Theca cells

androgens
aromatase

Granulosa cells

FSH

estradiol

Regulation of Progesterone Production

Progesterone is produced from theca cells, mature granulosa cells, and from the corpus luteum. In this case, gonadotropins induce expression of - steroidogenic acute regulatory protein - P450 side chain cleavage

Actions of Estradiol
Estradiol plays an important role in feedback regulation of gonadotropin release. Low estradiol levels exert negative feedback (via inhibition of GnRH release) Question: what happens to LH and FSH levels if you remove the ovary (increase, decrease, no change)? Answer:

Actions of Estradiol
High estradiol levels exert positive feedback (via increase in GnRH receptors, stimulation of GnRH release, increased pituitary response to GnRH, and effects on LH) - increase in stimulatory neurotransmitters regulating GnRH neurons (ie, norepinephrine) - decrease in inhibitory neurotransmitters (ie, beta endorphin) - increased activity of GnRH neurons - increased expression of GnRH receptors - increased expression of LH gene

Actions of Estradiol
Estradiol also has important actions in a number of other tissues: - causes proliferation of uterine endometrium - increases contractility of uterine myometrium - stimulates development of mammary glands - stimulates follicle growth (granulosa cell proliferation) - effects on bone metabolism, hepatic lipoprotein production, genitourinary tract, mood, and cognition Effects are mediated through the intracellular estrogen receptors (alpha and beta), and possible membrane effects.

Actions of Progesterone
Progesterone exerts positive and negative feedback effects on gonadotropin synthesis and release. Progesterone also acts on many tissues: - stimulates secretory activity of the uterine endometrium - inhibits contractility of the uterine myometrium - stimulates mammary growth The actions of progesterone are mediated through an intracellular P receptor, which acts as a transcription factor.

Regulation of Follicle Growth

Primordial follicles can rest for many decades before being recruited for growth by an unknown mechanism. The recruitment of primordial follicles and subsequent growth to the small antral follicle stage can occur without gonadotropin stimulation (gonadotropin-independent). Small antral follicles (and larger) must be stimulated by FSH and LH in order to continue growth to the preovulatory stage (gonadotropin dependent).

Regulation of Follicle Growth

Each day many follicles begin to grow (recruitment). Each cycle, only one follicle is selected for continued development to the preovulatory stage, by an unknown mechanism. This follicle is called the dominant follicle The remaining recruited follicles become atretic and degenerate.

Regulation of Follicle Growth

recruitment

selection

preovulatory

follicle
atresia

Follicular Ovulation
As the preovulatory follicle grows, it produces increasing amounts of estradiol. When the preovulatory follicle is mature, plasma estradiol levels are very high. High estradiol levels exert positive feedback on the hypothalamus and pituitary, resulting in LH and FSH surges. These preovulatory gonadotropin surges cause ovulation of the preovulatory follicle (follicular rupture and release of the egg for fertilization).

Mechanism of Gonadotropin-induced Ovulation

The preovulatory LH and FSH surges induce expression of enzymes in the preovulatory follicle which break down the follicle wall. Tissue-type plasminogen activator: results in breakdown of fibrin. Metalloproteinases: result in breakdown of collagen. Result: follicle wall is ruptured, resulting in release of the oocyte into the peritoneal cavity.

Formation of the Corpus Luteum

After the follicle ovulates, the remaining granulosa cells and theca cells luteinize. Luteinization: accumulation of cholesterol and lipid, cells swell. Luteinized cells switch the ovary from predominant production of estradiol to production of progesterone and estradiol. This prepares the uterine endometrium for pregnancy.

FEMALE REPRODUCTIVE SYSTEM

HORMONAL REGULATION OF OOGENSIS AND OVULATION
FOLLICULAR PHASE
10-20 primordial follicles begin to develop in response to FSH and LH levels FSH and LH stimulate theca and granulosa production of estrogen and progesterone surge of LH induces ovulation

The Menstrual Cycle

OVULATION

LUTEAL PHASE
theca and granulosa cells transform into the corpus luteum and secrete large amounts of progesterone if fertilization does not occur, corpus luteum degenerates ... if fertilization does occur, HCG released from the embryo maintains corpus luteum

FEMALE REPRODUCTIVE SYSTEM

The Menstrual Cycle
HORMONAL REGULATION OF OOGENSIS AND OVULATION
OVULATION:

sharp surge in LH with simulataneous increase in FSH Meiosis I resumes; oocyte and surrounding cumulus break away and are extruded
oocyte passes into oviduct

ECTOPIC IMPLANTATIONS

The Menstrual Cycle

Women have ovulatory cycles of about 28 days in length. Day 1 of the cycle is defined as the first day of menstruation. There are two phases of the cycle, named after ovarian and uterine function during that phase: - first two weeks: follicular or proliferative stage - second two weeks: luteal or secretory stage The preovulatory gonadotropin surges occur in the middle of the cycle (around day 14).

The Menstrual Cycle: The Ovary

Follicular phase: small antral follicles develop, a dominant follicle is selected and grows to the preovulatory stage. Midcycle: the gonadotropin surges cause ovulation of the dominant follicle. Luteal phase: the corpus luteum forms and becomes functional, secreting large amounts of progesterone, followed by estradiol (results in negative feedback, not positive feedback, because P increases before E2). If pregnancy does not take place, the corpus luteum regresses, and P and E2 levels decrease.

The Menstrual Cycle: The Uterus

Proliferative stage: increasing estradiol levels stimulate proliferation of the functional layer of the uterine endometrium. - Results in increased thickness of the endometrium. - Increased growth of uterine glands (secrete mucus) and uterine arteries. Secretory stage: progesterone acts on the endometrium. - uterine glands become coiled and secrete more mucus - uterine arteries become coiled (spiral arteries)

The Menstrual Cycle: The Uterus

If pregnancy doesnt occur, P and E2 levels decrease at the end of the secretory stage. - vasospasm of arteries causes necrosis of tissue - loss of functional layer with bleeding of uterine arteries (menstruation)

FEMALE REPRODUCTIVE SYSTEM

CORPUS LUTEUM
FORMED FROM FOLLICLE WALL WHICH REMAINS FOLLOWING OVULATION TRANSFORMED CELLS SECRETE ESTROGENS AND PROGESTERONE: (1) GRANULOSA LUTEIN CELLS - large, light cells derived from granulosa cells (2) THECA LUTEIN CELLS - strands of small cells derived from theca interna

FEMALE REPRODUCTIVE SYSTEM

CORPUS LUTEUM
(1) GRANULOSA LUTEIN CELLS (2) THECA LUTEIN CELLS CORPUS LUTEUM
H&E

(1) (2)

FEMALE REPRODUCTIVE SYSTEM

OVIDUCT
TRANSMITS OVA FROM OVARY TO UTERUS MEIOSIS II IN PROGRESS AND ULTIMATELY ARRESTS UNLESS FERTILIZED SITE OF FERTILIZATION MUCOSA
EPITHELIUM AND LAMINA PROPRIA

MUSCULARIS
INNER CIRCULAR; OUTER LONGITUDINAL
INCREASES AS APPROACH UTERUS

SEROSA

FEMALE REPRODUCTIVE SYSTEM

OVIDUCT
SIMPLE COLUMNAR EPITHELIUM TWO CELL TYPES: (1) CILIATED (2) PEG CELLS (NONCILIATED)

FEMALE REPRODUCTIVE SYSTEM

UTERUS
PERIMETRIUM, MYOMETRIUM, ENDOMETRIUM

FEMALE REPRODUCTIVE SYSTEM

UTERUS
ENDOMETRIUM undergoes cyclic changes which prepare it for implantation of a fertilized ovum TWO LAYERS: (1) FUNCTIONAL LAYER (stratum functionalis)
- BORDERS UTERINE LUMEN - SLOUGHED OFF AT MENSTRATION - CONTAINS UTERINE GLANDS

(2) BASAL LAYER (stratum basale)

- RETAINED AT MENSTRATION - SOURCE OF CELLS FOR REGENERATION OF FUNCTIONAL LAYER
STRAIGHT AND SPIRAL ARTERIES

FEMALE REPRODUCTIVE SYSTEM

HORMONAL REGULATION OF UTERINE CYCLE
(1) PROLIFERATIVE PHASE (2) SECRETORY PHASE (3) MENSTRUAL PHASE concurrent with follicular maturation and influenced by estrogens concurrent with luteal phase and influenced by progesterone commences as hormone production by corpus luteum declines

FEMALE REPRODUCTIVE SYSTEM

UTERUS
PROLIFERATIVE PHASE

cells in basal layer begin to proliferate to regenerate functional layer

spiral arteries begin to lengthen and revascularize developing layer functional layer becomes thicker than basal layer during late proliferative phase

developing uterine glands are tubular in arrangement

FEMALE REPRODUCTIVE SYSTEM

UTERUS
PROLIFERATIVE PHASE

tubular uterine glands

simple columnar lining

FEMALE REPRODUCTIVE SYSTEM

UTERUS
PROLIFERATIVE PHASE
UTERUS
H&E

tubular uterine glands

simple columnar lining

PROLIFERATIVE PHASE

UTERINE GLANDS

FEMALE REPRODUCTIVE SYSTEM

UTERUS
SECRETORY PHASE

functional layer thickens

glands become coiled and accumulate large quantities of secretory product

FEMALE REPRODUCTIVE SYSTEM

UTERUS
SECRETORY PHASE
UTERUS
H&E

SECRETORY PHASE

functional layer thickens

glands coiled
COILED UTERINE GLANDS

FEMALE REPRODUCTIVE SYSTEM

UTERUS
SECRETORY PHASE

functional layer thickens

glands become coiled and accumulate large quantities of secretory product

FEMALE REPRODUCTIVE SYSTEM

VAGINA
MUCOSA
STRATIFIED SQUAMOUS EPITHELIUM LAMINA PROPRIA

---------------- no glands ---------------MUSCULARIS

INNER CIRCULAR OUTER LONGITUDINAL

ADVENTITIA

FEMALE REPRODUCTIVE SYSTEM

LABIA MINORUM
LABIA MINORUM
H&E

Endocrinology of Pregnancy
To maintain the uterine endometrium and inhibit contraction of myometrium, must maintain plasma progesterone levels during pregnancy. Early in pregnancy, this is accomplished by the action of human chorionic gonadotropin (hCG) on the corpus luteum (first 8 weeks of pregnancy). Later in pregnancy, progesterone is produced by the placenta.

Early Embryonic Development

After fertilization, the embryo spends the first four days in the oviduct (fallopian tube). The developing embryo then goes to the uterus, and implants in the uterine endometrium on Day 6 (blastocyst stage of development). By day 6, the trophoblast cells of the embryo begin to produce hCG. In a normally developing embryo, hCG levels (in maternal circulation) will double every 3 days, reaching peak at about 2 months of pregnancy.

Actions of Human Chorionnic Gonadotropin (hCG)

hCG binds to the LH receptor in the corpus luteum, maintaining luteal steroidogenesis during the first 8 weeks of pregnancy. In addition, hCG may act to stimulate testosterone production from the developing testes in male embryos.

Role of the Fetal-Placental-Maternal Unit in Steroid Production

Later in pregnancy, the placenta becomes the major steroidogenic organ of pregnancy. However, the placenta requires maternal LDL as a source of cholesterol for progesterone production. The placenta also produces estrogens during pregnancy (primarily estriol). However, the placenta is dependent upon the maternal and fetal adrenal as a source of androgens for aromatization to estrogen. Estrogens may be important in increasing uterine blood flow to the fetus, and in the maturation of fetal organ systems.

Parturition: The Process of Childbirth

The mechanisms signaling the onset of labor are not clearly understood, although several theories exist. Potential role of progesterone?: - decreasing progesterone prior to labor would allow uterine contractions to occur - however, there is no decline in progesterone before labor in humans - some studies suggest there is a decline in uterine progesterone receptors, resulting in decreased progesterone action, leading to labor

Potential Role of Oxytocin in Parturition?

Oxytocin causes uterine contraction. However, oxytocin levels do not increase until after labor starts, according to more recent studies. Oxytocin may play a role in uterine contraction following labor, resulting in decreased blood loss.

Potential Role of Relaxin in Parturition?

Relaxin acts on the cervix, causing dilatation and softening. In some animals relaxin increases before labor starts. In humans, relaxin is high beginning early in pregnancy and stays elevated until labor. Relaxin does act to soften connective tissues, such as the ligaments connecting the pelvic bones, to allow increase in size of the birth canal. Relaxin also decreases uterine contractility during pregnancy.

Potential Role of Prostaglandins in Parturition

Prostaglandins cause dilation and softening of the cervix. Prostaglandins also cause uterine contractions. The levels of prostaglandins increase in fetal membranes before the onset of labor. It is believed that some (unknown) signal from the fetus causes increased prostaglandin production from fetal membranes, which then act on the uterus and cervix to initiate labor.

Lactation
Lactation is the delivery of milk from the mammary gland. There are four main stages of lactation, controlled by different hormones: - milk synthesis in alveolar cells - secretion of milk from alveolar cells to alveolar lumen - maintainance of established milk production and release into alveolar lumen - milk ejection: movement of milk from alveoli into the duct system and out of the breast

Lactation: Milk Synthesis

Milk Synthesis: Production of breast milk is stimulated by increased levels of prolactin (pituitary) and human placental lactogen (from the placenta) during pregnancy. Milk release from alveolar cells is inhibited by the high levels of progesterone and estrogen during pregnancy. Estrogen and progesterone also act with prolactin to increase alveolar duct growth during pregnancy.

Lactation: Lactogenesis
Lactogenesis: secretion of milk from alveolar cells into the alveoli of the breast. Stimulated by prolactin, and occurs after parturition when estradiol and progesterone levels are decreased.

Lactation: Galactopoiesis and Milk Ejection

Galactopoiesis: the maintenance of established milk production, caused by prolactin. Milk Ejection: movement of milk from alveolar ducts into the main duct system and out of the breast. Induced by oxytocin. Oxytocin causes contraction of myoepithelial cells in the breast, causing milk release.

Regulation of Oxytocin and Prolactin During Lactation

There is a positive feedback effect of breastfeeding on the production of oxytocin and prolactin. Oxytocin levels increase due to suckling of the breast by the infant. In addition, sight, sound, or thought of the infant can also increase oxytocin levels, causing milk ejection. Prolactin release is also increased by suckling of the breast by the infant (but not by audiovisual stimuli). Associated with suppression of dopamine release.

Hormonal Induction of Labor

Estrogen
From ovaries

Oxytocin
From fetus and mothers post pit

(+)

Induces oxytocin receptors on uterus

Stim uterus to contract Stim placenta to make PGs Stim more vigorous contractions of uterus Physical/emotional stress
(+)

Positive feedbac k

Baby in utero

(+)

Milk Letdown Reflex

Suckling stim pressure receptors, which lead to efferents to mothers hypothalamus

Hypo Pit oxytocin stim breast myoepithelial cells to contract

(+) Feedback cycle continues till suckling stops.

Alveolar glands respond by releasing milk