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Parts of the system

Gonads Ovaries Internal genitalia: Uterine tubes Uterus Vagina External genitalia

Female reproductive endocrinology

Layers of the uterus wall

Endometrium (with uterine glands) Myometrium Perimetrium The thickness of the endometrium changes during the menstrual cycle

Function of the system

Oogenesis Conception - reception of sperm and transport of sperm and ovum Gestation - maintenance of the fetus Parturition Lactation

Characteristics
Ovaries function until menopause testes function until old age (only slight decline) Periodic preparation for fertilization and pregnancy and intermittent release of ova continuous production of spermatozoa

Ovary
Two roles gametogenic endocrine The gametogenic potential is established early in the fetus Endocrine role of the ovary is not realized until puberty

Ovary
Cortex Contains follicles in different stages of development Medulla Interstitial, steroid producing cells Stromal cells (connective tissue)

Cellular components of the ovary

The ovary consists of epithelial and mesenchymal components Mesenchymal tissue differentiates into interstitial tissue This tissue is the primary source of hormones Also associated with germinal elements of the ovary Provides nutritive environment for the oocytes Epithelial tissue differentiates into granulosa cells

Follicle
Each contains an oocyte Concentric layers of cells Granulosa cells Thecal cells There is a basal membrane between granulosa and thecal cells Follicle is embedded in stroma

Cellular layers of the follicle

Oogenesis before birth

Oogonia (6-7 million) Undifferentiated stem cells in the fetus During the prenatal period, oogonia develop into primary oocytes At birth only primary oocytes are present

Oogenesis - at birth
Primary oocytes (2 million at birth) Primary oocyte is covered by single-layer of flattened granulosa cells = primary follicle a.k.a primordial follicle

Primordial follicles
Lie in the periphery (cortex) of the ovary They are separated from each other by stromal and interstitial tissues Majority of primary follicles remain arrested in development state

Primordial follicles
A small population of primary follicles starts developing towards more differentiated form: secondary follicle Still in embryonic ovary, primordial follicles begin reduction division of meiosis

What happens to the primary follicles

Before puberty: the developing population of primary follicles degenerates before reaching the secondary follicle stage (atresia) After puberty: one of the simultaneously differentiating primary follicles will reach the fully mature form in every 28 days ( ovulation), the other simultaneously maturing primary follicles will degenerate

What happens to the primary follicles

By menopause: no primary follicle is left (400 have reached the fully mature stage, the rest has degenerated)

Secondary oocytes (secondary follicles) mature ovum

Secondary follicle
After puberty, in every ovulatory cycle 6-12 primary follicles are selected for development of secondary follicles Increase in oocyte size and in granulosa cell layers around each oocyte Granulosa cells secrete mucoid material that forms the zona pellucida around each oocyte

Secondary follicle
Usually only one will develop into a mature follicle The rest will become atretic and disappear The follicle that is selected for maturation is thought to be the one whose granulosa cells acquire high levels of aromatase and LH receptor

Purposes of ovarian follicle

Preserve resident oocyte Mature oocyte at the right time Produce best surrounding for development of healthy oocyte Release oocyte at right time Produce quality corpus luteum after implantation Preserve hormonal conditions for gestation

Cyclic behavior of female reproductive system

The cause of cyclicity - hypothalamus Periodic changes in the frequency of GnRH bursts Ovarian cycle Uterine (menstrual cycle)

Periodic changes in the frequency of GnRH bursts from the hypothalamus

Periodic changes in FSH and LH release from pituitary

Periodic changes in ovarian function (ovarian cycle) periodic release of ovum periodic changes in the secretion of estrogens and progesterone

Periodicity in the possibility of fertilization and implantation

- periodic changes in the uterus (uterine cycle, a.k.a. menstrual cycle) - periodic changes in the cervix - periodic changes in the vagina - periodic changes in the breasts

Ovarian cycle or follicular maturation

Primary oocyte (meiotic arrest, diploid) During each ovarian cycle, primary oocytes complete first meiotic division First meiotic division is completed shortly before ovulation Followed by extrusion of the first polar body and formation of the secondary oocyte

Ovarian cycle

Ovarian cycle
Granulosa cells continue to increase in number Interstitial tissue next to follicle arranges concentrically and forms a theca Next to follicle - theca interna Outer layer of interstitial cells - theca externa Theca is separated from granulosa cells by basal membrane The follicle grows and the antrum is formed

Ovarian cycle continued

The granulosa cells that remain stuck to the ovum become the corona granulosa Those that touch the theca around it become the membrana granulosa

Ovarian cycle - ovulation

Cumulus oophorus is severed and ejected Coronal granulosa becomes the corona radiata (surrounding layer of granulosa cells) Fully mature preovulatory follicle : Graffian follicle A bridge of granulosa cell connects the coronal granulosa with the membrana granulosa: the cumulus oophorus

Follicular maturation through the ages

Before puberty Non-cyclic gonadotropin-independent Starts during intrauterine life lasts till menopause After puberty, before menopause Continuous, gonadotropin-dependent maturation

Follicular maturation before puberty

Non-cyclic gonadotropin-independent 250 days Primordial follicles mature continuously to early antral phase but never reach complete maturation because there is no FSH and LH secretion from the pituitary

Follicular maturation after puberty

Continuous, gonadotropin-independent maturation If the follicles that reached a certain degree of maturation are exposed to gonadotropins, they will enter the next phase of development, which is Cyclic gonadotropin-dependent maturation Gonadotropin secretion is cyclic gonadotropindependent maturation shows a cyclic pattern; Period length: average 28 days (20 to 40 days)

Follicular phase:
primary oocytes enlarge granulosa cells proliferate and differentiate (express FSH and estrogen receptors) zona pellucida thecal cells appear and proliferate (express LH receptors) follicular cells (granulosa cells + thecal cells) secrete estrogen and inhibin antrum appears FSH-mediated rescue of 1-25 follicles Gonadotropindependent

A single follicle becomes dominant and grows more rapidly, completes the first meiotic division preovulatory follicle (Graafian follicle) rupture ovulation secondary oocyte in the abdomen (zona pellucida, corona radiata) Gonadotropinindependent

Gonadotropindependent

Luteal phase Corpus Luteum

After release of ovum it fills up with blood:corpus
follicular remnant (mainly outer layer of granulosa cells) corpus hemorrhagicum c. luteum: secretes estrogen and progesterone survives for 14 days (in pregnancy: for 12 weeks) c. albicans

hemorrhagicum

Granulosa cells increase in number and clotted blood is absorbed Granulosa cells accumulate a lot of cholesterol Luteinization process forms the corpus luteum

Ovarian hormones
Steroids Estrogens Androgens Progesterone Peptides

Ovarian steroid hormones

Produced in both interstitial and follicular cells Derivatives of cholesterol (coming from LDL-lipoproteins and de novo synthesis)

Feedback regulation of gonadal steroids

Estrogens
Chemical structure: C18 Source: follicular cells corpus luteum placenta adrenal cortex adipose tissue (DHEA androstenedione E1)

Synthesis of steroid hormones in the ovary

Synthesis of steroid hormones in the ovary

First step happens in mitochondria All the rest in smooth ER Reduction in number of carbon atoms Estrogens are primarily synthesized in granulosa cells Androgens are primarily synthesized in thecal cells

Synthesis of steroid hormones in the ovary

Estrogens in circulation

Estrogens in circulation
Estradiol Secreted by the ovary Estrone Derived from peripheral conversion of estradiol and androstenodione Estriol Liver metabolite of estrone

Transport of estrogens in blood

Mostly carrier-bound (albumin, sex hormone-binding globulin) Two peaks Before ovulation Mid-luteal peak Levels of estrogen and progesterone are much higher in the follicular fluid than in the plasma!

Metabolism of gonadal hormones

Metabolized to glucuronides and sulfates Recycled in enterohepatic circulation Excreted in urine

Physiological role of estrogens

Intracellular receptor Mostly genomic but also some nongenomic

Physiological role of estrogens Reproductive system

Development and maintenance of uterus, uterine tubes, vagina, external genitalia and breasts Cyclic changes in the endometrium, cervix, vagina Growth of the ovarian follicles Motility of the uterine tubes

Physiological role of estrogens Reproductive system

Pregnancy: uterine muscle mass , excitability , breasts Female secondary sex characteristics (fat deposits, etc) Estrous behavior in animals, increased libido in humans

Physiological role of estrogens Metabolism

Protein metabolism: anabolism- (in cattle, chicken, etc.) Lipid metabolism: LDL , plasma cholesterol Salt and water retention (by stimulating angiotensin) edema

Physiological role of estrogens Other metabolic

Bone Maintenance of bone mass Liver Clotting factor synthesis ( thrombosis)

Physiological role of estrogens Circulatory

Physiological role of estrogens Brain

Trophic effects Protective against neurodegenerative diseases, ischemic insults, etc Role in modulating memory, cognition, motor skills, mood, etc

Physiological role of estrogens Endocrine effects

Suppression of FSH Suppression/stimulation of LH PRL

Progesteron
The most distinctive hormone between males and females Chemical structure: C21 Source: c. luteum placenta follicles (small amount) adrenal cortex

Transport of progesterone in blood

2% free 80% albumin-bound 18% corticosteroid-binding protein (transcortin) -bound

Physiological role of progesterone

Intracellular receptors RU-486 Progesterone receptor antagonist Binds to receptor but does not allow the chaperone protein to detach from the receptor DNA binding of the receptor-ligand complex is inhibited

Physiological role of progesterone

Cyclic changes in the endometrium, cervix, and vagina Myometrium excitability (smooth muscle contractility in general constipation, venous varicosities) Estrogen receptor number in endometrium Breasts: supports the secretory function during lactation Thermogenesis

Physiological role of progesterone

Inhibits LH secretion Sodium excretion (inhibits aldosterone receptors) followed by compensatory increases in aldosterone secretion ( mild water retention) Precursor for steroids in all steroid-producing tissues

Progesterone as a precursor of steroid hormones

Role of progesterone
Progesterone is the ovarian hormone of pregnancy It is responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

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Physiological roles of ovarian steroid hormones

In the follicular phase, estrogens are the main steroidal products of the ovaries During the luteal phase,progesterone is the main product of the of the post-ovulatory follicle

Peptide hormones of the ovary

Relaxin Relaxes pelvic joints Softens and dilates cervix Sperm mobility - in males

Peptide hormones of the ovary

Inhibin Selective inhibitory control of FSH Activin Selective stimulaton of FSH Cell differentiation

Peptide hormones of the ovary

Follistatins Inhibit FSH secretion Gonadotropin surge attenuating factor Prevents premature LH surge POMC hormones Vasopressin and oxytocin (in luteal cells)

Menstrual phase Hormonal control of ovulation

estrogens, progesterone , prostaglandins necrosis of the endometrial lining uterus contractions ( dysmenorrhea) After 3-5 days: arterioles constrict again bleeding stops

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Follicular phase
GnRH and lack of negative feedback from estrogen, progesterone and inhibin Rising FSH and LH Follicular growth IGF-1 Estrogen secretion Inhibin

Proliferative phase
regeneration of endometrial lining in response to estrogens: - endometrium regenerates -uterine glands enlarge length become coiled -blood vessels grow arterioles become coiled blood supply -progesterone receptors synthesized

Autocrine Stimulation of follicular growth

Negative feedback on FSH

Systemic effects on uterus, vagina, breasts, etc.

Ovulation
Outer layer of granulosa cells starts expressing LH receptors The sensitivity of the hypothalamus to estrogens changes temporarily, estrogens have positive feedback on hypothalamic GnRH FSH surge

Luteal phase
LH: maintains corpus luteum stimulates progesterone and estrogen secretion FSH and LH levels decrease (negative feedback of estrogens, progesterone, inhibin) Luteolytic factors produced by c. luteum (oxytocin, prostaglandins) luteolysis estrogen, progesterone, inhibin new cycle starts

LH surge final maturation of the oocyte local PG

vascular changes swelling collagenase digests follicle wall ovulation follicular cells luteal cells

Secretory phase
In response to estrogens and (mainly) progesterone changes in the endometrium to prepare for possible implantation of the blastocyst Endometrium: Increase in vascularization glands become more coiled, secretory activity large amounts of nutrients secreted (glycogen)

Hormonal control of uterine (menstrual) cycle

Estrogen: myometrium endometrium , progesterone receptors Progesterone endometrium transformation, myometrium contractility

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Pathophysiology did you know?

PMS Menopause Contraceptive drugs

PMS - symptoms
CNS Depression, irritability, emotional lability Food cravings Insomnia Other Water retention weight gain Headache, breast tenderness, lower abdominal discomfort

PMS causes
Cyclic disregulation of homeostasis low plasma calcium low calcium in CSF neural symptoms Increased interstitial osmolarity in kidney water reabsorption Ca2+

Menopause
Climacteric period Period of increasing ovarian failure Cycles become increasingly infrequent and finally cease completely Caused by the end of ovarian follicle supply

Menopause
Hormonal changes: - Estrogens and progesterone - Inhibin - FSH and LH

Menopause symptoms
Due to the diminished ovarian estrogen secretion Vaginal dryness Genital atrophy Hot flushes Psychological, emotional symptoms Decrease in bone density; Fractures (osteoporosis) Increased incidence of cardiovascular diseases

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Menopause therapy
Estrogen replacement (plus progesterone to reduce the risk of uterus carcinoma) NO LONGER!!! Phytoestrogens

Did you know?

Secondary amenhorrhea may be a consequence of strenuous exercise (female athletes) Decreased body fat composition ratios and weight loss have been linked to menstrual disturbances and early menopause The effect is reversible with weight gain Post-pill amenorrhea (10% prevalence) it is not a direct consequence of hormonal contraception, but it is due to androgen excess or hyperprolactinemia

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