Female Reproductive System

Question 1

Cross section of female reproductive organs

Answer 1

1. OVARIES- PRIMARY SEX ORGAN OF FEMALE MAKE OOCYTES AND HORMONES (ESTROGEN, PROGESTERONE)
2. OVIDUCT- TRANSPORT SPERM TO EGG AND ZYGOTE TO UTERUS
3. UTERUS- SITE OF IMPLANTATION WHERE EMBRYO AND FETUS GROW

Question 2

Oogenesis overview

Answer 2

OOGENESIS= FORMATION, DEVELOPMENT AND MATURATION OF FEMALE GAMETE OR OOCYTE
2. PURPOSE IS TO REDUCE # CHROMOSOMES IN 1/2 AND ALLOW FOR GENETIC RECOMBINATIONS VIA CROSSOVER
3. OCCURS IN OVARY
4. STAGES= OOGONIA, PRIMARY OOCYTE, SECONDARY OOCYTE, OVUM
5. PROCESS IS SPREAD OUT OVER MANY YEARS UNLIKE
SPERMATOGENESIS

Must occur inside of follicles. Otherwise, the individual is infertile

Question 3

FOLLICULOGENESIS

Answer 3

Primordial follicle starts with 1 layer of very flat epithelial cells.

They eventually become cuboidal, at which point, it is a primary follicle.

The growing follicle has Thecal cells which surround the follicle as it grows, adding more layers of cells around the oogonium/oocyte

There is an empty space (antrum) inside of the secondary follicle

The tertiary follicle ruptures open, the secondary oocyte comes out with some follicle cells around it. The rest of the follicle becomes the corpus luteum, which produces progesterone. The life span of the corpus luteum is about 10 days after which it becomes the corpus albicans, which is essentially connective tissue and is no longer functional.

Question 4

Oogenesis and Folliculogenesis Combined

Answer 4

Question 5

Sperm fertilize a:

Answer 5

secondary oocyte. not an ovum. Oogenesis is not complete until female is pregnant.

Question 6

Oocyte Factors

Answer 6

BIDIRECTIONAL CROSS TALK BETWEEN THE OOCYTE AND FOLLICLE CELLS IS NECESSARY FOR DEVELOPMENT OF BOTH OOCYTE AND FOLLICLE

FIG(alpha) (FACTOR IN THE GERMLINE a),A TRANSCRITPION FACTOR PRODUCED BY OOCYTES, IS NECESSARY FOR FORMATION OF PRIMORDIAL FOLLICLES
KO MICE LACKING FIG(alpha) FAIL TO PRODUCE PRIMORDIAL FOLLICLES AND GERM LINE IS RAPIDLY DEPLETED

OOCYTES SECRETE GDF9 (GROWTH AND DIFFERENTATION FACTOR 9) – STIMULATE GROWTH OF FOLLICLE CELLS (mitosis) AND IS NECESSARY FOR TRANSITION OF PRIMARY FOLLICLE TO A SECONDARY FOLLICLE (growing follicle)
KO MICE W/O GDF9 - ALL FOLLICLES ARREST AS PRIMARY FOLLICLES

Question 7

Fig(alpha) and GDFP9 KO DATA

Answer 7

Knockout mice made with mutuations on the Fig(alpha) gene were infertile

Knockout mice made with mutation son the gene for GDF9 only had primary oocytes and were infertile

Question 8

Timeline for Oogenesis

Answer 8

peak number of oocytes is about 5 months into prenatal development (7million)

At birth, the individual has approximately 2 million oocytes

At puberty, there are typically less than one million oocytes left. (somewhere between 40,000 and 400,000)

REPRODUCTIVE DOGMA

Question 9

Jonathan Tilly

Answer 9

Revisited the reproductive dogma and found that stem cells in the ovaries of females are capable of forming oocytes after birth. These stem cells may come from bone marrow.

He published an article in Nature.

Zou et al Nature Cell 11:631 Production of offspring from a germline stem cell line derived from neonatal ovaries

Used neonatal and adult mouse ovaries

Isolated female germline stem cells!

Established line of FGSC and grew FGSC in vitro over a year

Put GFP marker in FGSC and transplanted to ovaries of infertile mice

Mated infertile females with transplants and offspring were born!!

Question 10

WHAT CAN GO WRONG DURING PRODUCTION OF OOCYTES?

Answer 10

NON-DISJUNCTION- OOGENESIS

POLYCYSTIC OVARY DISEASE- FOLLICULOGENESIS

Absence of PTEN in oocytes induces premature global follicular activation

Question 11

POLYCYSTIC OVARY DISEASE- FOLLICULOGENESIS

Answer 11

Caused by too much testosterone in relation to estrogen and progesterone. Failure to shed follicles leads to fluid-filled sacs in ovary, making it swollen.

Question 12

Absence of PTEN in oocytes induces premature global follicular activation

Answer 12

PTEN = Phosphatase and tensin homolog

Phosphatase and tensin homolog (PTEN) is a protein that, in humans, is encoded by the PTEN gene.[2] Mutations of this gene are a step in the development of many cancers.
PTEN acts as a tumor suppressor gene through the action of its phosphatase protein product. This phosphatase is involved in the regulation of the cell cycle, preventing cells from growing and dividing too rapidly.[3] It is one of the targets of an oncomiR, MIRN21.

In humans. 1% of women suffer from premature ovarian failure – follicle reserve is exhausted by age 40

Normally, 10-12 primordial follicles become primary follicles in an ovarian cycle. Without PTEN, too many become primary each cycle, depleting the supply of follicles prematurly.

Question 13

New Hope For The Oocytes of Women Facing Cancer

Answer 13

Men battling cancer - freeze a sperm ejaculate and use it to fertilize oocytes later. Protects their fertility.

What about women with cancer?

Best option is to create embryos, freeze them and later let them implant in uterus. Works about 40% of time

Can also freeze oocytes and later fertilize them – but oocytes are harder to freeze – works about 3% of the time.

Some labs are trying to culture and mature follicles in vitro This has been done for the mouse- may be very hard for humans it would take a long time for maturation.

Question 14

STRUCTURE OF THE UTERUS

Answer 14

1. STRUCTURE OF UTERUS
   A. ENDOMETRIUM- CLOSEST TO LUMEN. LINED BY
   EPITHELIUM.CONTAINS LOTS OF BLOOD VESSELS AND GLANDS
   B. MYOMETRIUM; LAYERS OF MUSCLE
2. ENDOMETRIUM UNGERGOES ROUNDS OF GROWTH AND SLOUGHING
3. DURING PUBERTY, UTERUS ALSO BEGINS TO UNDERGO CYCLIC CHANGES
4. THERE ARE 4 PHASES OF THE UTERINE CYCLE/CONTINUOUS PROCESS

Question 15

UTERINE CYCLE

Answer 15

• *MENSTRUAL PHASE/ DAYS 1-5 OF CYCLE**
  1. STRATUM FUNCTIONALIS (OUTER PART OF ENDOMETRIUM) IS NECRTOTIC DUE TO LACK OF CIRCULATION ; CELLS GET SLOUGHED OFF
  2. CELLS OF ENDOMETRIUM AND BLOOD FROM VESSELS ARE LOST AT THIS TIME
  3. STRATUM BASALE - NEXT TO MYOMETRIUM- UNDERGOES MINIMAL CHANGES/HAS ITS OWN ARTERIES, NOT SPIRAL
  4. ESTROGEN AND PROGESTERONE LEVELS ARE LOW
• *FOLLICULAR (PROLIFERATIVE) PHASE DAYS 6-14**
  1. COINCIDES W/ GROWTH OF OVARIAN FOLLICLES
  2. ENDOMETRIUM IS REPAIRED AND GROWS BACK
  3. EPITHELIAL CELLS FROM REMNANT IN STRATUM BASALE PROLIFERATE AND MIGRATE SO ENDOMETRIUM THAT WAS SLOUGHED OFF GETS REPLACED
  4. STROMA CELLS ALSO DIVIDE SO ENDOMETRIUM INCREASES IN THICKNESS
• *SECRETORY OR LUTEAL PHASE DAYS 15-27**
  1. COINCIDES WITH GROWTH OF C.L.
  2. GLANDS BECOME WIDE AND COILED; SECRETION INCREASES. A RICH MEDIUM AWAIT OVUM
  3. SECRETE GLYCOGEN AND MUCOID MATERIAL
  4. IF OVUM IS FERTILIZED, IT IMPLANTS ABOUT DAY 20

ISCHEMIC PHASE DAYS 27-28/ LASTS ABOUT 24 HRS
2. SMC AROUND SPIRAL ARTERIES CONTACT INTERMITTENTLY
3. CAUSES CIRULATION TO STOP -TISSUE IN FUNCTIONALIS GETS NECROTIC AND DIES
4. STRAIGHT ARTERIES IN STRATUM BASALE DO NOT CONSTRICT SO THIS LAYER OK
5. DECREASED SECRETION OF PROGESTERONE BY C.L. CAUSES VESSELS IN FUNCTIONALIS TO CONSTRICT
6. LEADS TO SLOUGHING OF ENDOMETRIUM SO WE ARE BACK TO BEGINNING OF CYCLE
7. PROSTAGLANDINS INCREASE IN UTERUS AND CAUSE VASOCONSTRICTION
A. IF PG CONCENTRATION INCREASES TOO MUCH UTERINE MUSCLES CONTRACT -CAN BE PAINFUL
B. PAIN CAN BE ALLEVIATED BY TAKING DRUGS THAT BLOCK PG SYNTHESIS, E.G. ASPIRIN

Question 16

Menstrual Blood Banks:

Answer 16

Menstarual bllood bank

A com,pant called Cyro-Cell is ffering to bank mentraul bllod stem cells
Cryo-Cell charges a sum of $499 (£238) for processing and a year’s storage of menstrual stem cells.
The woman is sent a “discreet” collection kit in the post, comprising a menstrual cup, collection tubes and a prepaid return shipment to Cryo-Cell.
According to the company, menstrual stem cells - which come from the womb lining shed during a woman’s period - have the advantage of being easily harvested in a painless, non-invasive manner as compared to some other stem cell sources such as bone marrow.
And their use gets round the ethics of using stem cells taken from embryos.
Yet like other stem cells, early lab work suggests they too have the potential to turn into many other types of cell, including heart, nerve, bone, cartilage and fat, Cryo-Cell claims.
And they are in a plentiful supply.
Speaking on behalf of the company, stem cell expert Dr Stephen Noga, director of the Cellular Therapeutics Program, at Sinai Hospital of Baltimore, said: “Even one menstrual cycle has the potential to produce millions of stem cells.

Question 17

Inter-relationship of the ovarian and uterine cycle

Answer 17

FSH

1. PROMOTES MATURATION OF OVARIAN FOLICLES
2. 5-12 FOLICLES RECRUITED TO GROW/CYCLE
3. STIMULATE TI CELLS TO MAKE ESTROGEN

LH

1. SURGES 24 HRS BEFORE OVULATION
2. NEEDED FOR FINAL MATURATION OF FOLLICLE
3. CONVERTS RUPTURED FOLLICLE TO CL
4. STIMULATED CL TO PRODUCE PROGESTERONE

ESTROGEN

1. FSH CAUSES TI TO PRODUCE ESTROGEN
2. CAUSES LINING OF UTERUS TO THICKEN AND SECRETE
3. HIGH CONC INHIBITS FSH RELEASE
4. MODERATE CONC PROMOTES LH SYSTHESIS

PROGESTERONE

1. MADE BY CL - GRANULOSA LUTEIN CELLS
2. THICKENS AND MAINTAINS LINNG OF UTERUS
3. HIGH CONCENTRATION INHIBITS FSH AND LH PRODUCTION

Progesterone levels have to be high for the endometrium to stay built up. The corpus luteum makes progesterone, which feeds back to the anterior pituitary gland and stops production of FSH and LH so that the ovarian cycle doesn’t start again yet. Progesterone levels drop when the corpus luteum degrades to the corpus albicans and the outer endometrium layer sloughs off.

HCG - 1. PRODUCED BY IMPLANTING BLASTOCYST -
2. RESCUES CL -PROGESTERONE STAYS HIGH

Question 18

HCG

Answer 18

Human chorionic gomadotropin

Secreted by implanted blastocyst (embryo) makes corpus luteum continue producing progesterone (keeps it alive) so the uterine endometrium stays, allowing the embryo to implant.

Without HCG, the endometrium layer sloughs off, and the embryo cannot implant and dies.

Question 19

What Regulates the release of FSH and LH?

Answer 19

Kisspeptin (formerly known as metastin) is a protein that in humans is encoded by the KISS1 gene. Kisspeptin is a G-protein coupled receptor ligand for GPR54.[1] Kiss1 was originally identified as a human metastasis suppressor gene that has the ability to suppress melanoma and breast cancer metastasis.[2] It recently became clear that kisspeptin-GPR54 signaling has an important role in initiating secretion of gonadotropin-releasing hormone (GnRH) at puberty, the extent of which is an area of ongoing research.[3][4]

Kisspeptin - protein secreted by cells in hypothalamus

Kisspeptins stimulate release of gonadotropin releasing hormone from other neurons in hypothalamus

GnRHs in turn stimulate release of FSH and LH from anterior pituitary

Kisspeptin–>Gomadotropin release hormone (GnRH)–>FSH+LH produced

Question 20

Birth Control Pills

Answer 20

use progesterone analogs to raise progesterone levels, putting the woman in a state of pseudo pregnancy. It blocks ovulation. Have to be careful when you start hormonal contraceptives because if taken after the follicle develops and ruptures (oocyte cumulus complex, etc). the oocyte and follicle could be kept alive by the progesterone and pregnancy can ensue.