What are the main functions of the ovaries?
-Oogenesis, or the production of female gametes during the fetal period
-Maturation of the oocyte when it is ready for fertilization
-ovulation of the mature oocyte
-production of the female sex steroid hormones, estrogen and progesterone, and the peptide hormones inhibin and activin
Give an overview of the products of oogenesis
Oogenesis begins during embryonic development as diploid oogonia (46,2N) that undergo many mitoses so that females are typically born with 2-4 million diploid primary oocytes (46, 4N) (no new oocytes are procued after birth). These primary oocytes are arrested in prophase of meiosis I (and 99.99% of which undergo degeneration) until ovulation occurs and meiosis I completes to produce haploid secondary oocytes (23, 2N), which again arrest in metaphase. Meiosis II is completed at fertilization (or the 2ndary ooccytes degenerate) to produce an haploid ovum (23, N)
When does the follicular phase of human oocyte maturation occur?
Days 1-14 of a typical cycle (this part can vary in length but the luteal phase is fixed at 14 days)
What are the developmental stages of the follicular phase of human oocyte maturation?
1. Primordial follicle
2. Primary follicle
3. Preantral/early antral follicles
4. Mature follicle (1st Meiosis completes)
What is the role of theca cells during oocyte maturation?
providing signal transduction between granulosa cells and oocytes during development by the establishment of a vascular system, providing nutrients, and providing structure and support to the follicle as it matures.
The theca cells are also responsible for the production of androstenedione, and indirectly the production of 17β estradiol, also called E2, by supplying the neighboring granulosa cells with androstenedione that with the help of the enzyme aromatase can be used as a substrate for this type of estradiol. FSH induces the granulosa cells to make aromatase that converts the androgens made by the theca interna into estradiol.
What is the role of granulosa cells during oocyte maturation?
These are the cells directly lining the ovarian follicle and have a primary function of hormone production (estrogen, progesterone, inhibin, and activin)
These proliferate with oocyte maturation
What happens on Day 14 of the menstrual cycle?
Ovulation- a mature secondary oocyte (23,2N) is released from the follicle to the ovarian surface as meiosis I is completed
What occurs during days 14-25 of the menstrual cycle?
The luteal phase, which occurs post-ovulation, and is marked by the formation of the corpus luteum (which regresses after 10 days- days 25-28- if no fertilization occurs)
What hormones does the corpus luteum secrete?
progesterone!! (the elevation of progesterone is indicative of ovulation), and some estrogen, inhibin, and activin
What is the main source of the cholesterol needed to make steroid hormones?
LDL from the liver
What are the female sex steroid hormones?
-Estrogens (17B-estradiol (E2), Estrone (E1), and Estriol (E3))
What are estrone and estriol?
Estrone is a weak estrogen and a precursor of E2, while Estriol (E3) is even weaker than E1 and is a metabolite of E2.
17B-Estradiol is the major estrogen in the body
What organs make 17B-Estradiol?
Ovaries (directly produce 17B-estradiol),
Adrenal glands, placenta,
adipose tissue (contains aromatase to convert testosterone and androstenedione)
What cells in the ovaries produce progesterone?
-corpus luteum (after ovulation)
When do theca cells produce progesterone?
during the follicular phase and up to ovulation
When does the corpus luteum produce progesterone?
This is the main source of progesterone- post-ovulation
How is progesterone produced in the ovary theca cells?
LH from the anterior pituitary stimulates cholesterol desmolase (CYP11A1) stored in the mitcohondria of the theca cells to produce pregnenolone from cholesterol, which is then transformed to progesterone via 3B-HSD.
NOTE: LH also inhibits 17a-hydroxylase (inhibits conversion of pregnenolone to 17-hydroxypregnenlone)
at high levels to shut down production of testosterone and 17B-estradiol
How is 17B-Estradiol made (1 of 2)?
1) Cholesterol is converted to pregnenolone via cholesterol desmolase via LH infuence
2) Pregnenolone is converted to 17-Hydroxypregnenolone via 17a-hydroxylase
3) 17-Hydroxypregnenolone is converted to DHEA via 17,20-lyase
4) DHEA is converted to Androstenedione via 3B-HSD
All in the theca cells
What things can happen to androstenedione?
It can be converted to testosterone by diffusing into granulosa cells and via 17B-HSD or
it can be converted to estrone in the theca cells via aromatase
How is testosterone converted to 17B-estradiol in the ovaries?
Via aromatase under positive influence of FSH from the anterior pituitary
Estrogen production is age-dependent. Give a brief outline of the levels of estrogen in the body at various points in life.
Estrogen production starts at an early embryonic age (8-12 weeks) and is thought to be very important in the development of internal female organs. By birth estrogen levels fall significantly until about 2-3 mo of age when a transient "minipuberty" occurs which is thought to stimulate brain development. Levels then drop again to near zero until puberty, where they remain high until about 45 yers of age, which sees a progressive decreased in estrogen secretion by the ovaries and a small compensation by the adipose tissues
Describe the Hypothalamic-Pituitary-Gonadal Axis
The Hypothalamus produces pulsatile GnRH which promotes secretion of LH and FSH from the anterior pituitary to act on the ovaries to produce testosterone, estrogen, progesterone, activin, and inhibin
Describe what is happening in this graph
During childhood, levels of FSH and LH are very low until puberty which is met with a 5-10x increase in the gonadotropins. During menopause, the decreased producton of estrogen produces a lack of negative feedback on the production of FSH and LH and their levels surge up to 10x where they remain high into the 60s until slowly decreasing until death
How do the LOW levels of estradiol affect production of FSH, LH, and GnRH during the early and middle follicular phase of ovulation?
Low levels of estradiol inhibit production of GnRH and mainly LH from the anterior pituitary, whereas inhibin production during this phase from the ovaries inhibits FSH
What occurs immeditealy prior to ovulation?
Estradiol production from the ovaries increases causing a positive feedback on production of GnRH from the hypothalamus and up-regulation of GnRH receptors and increased LH (mainly) and FSH production in the anterior pituitary. LH increases causes the ovulatory surge and induces ovulation of the mature oocyte and formation of the corpus luteum
What happens to the levels of GnRH, LH, and FSH during the luteal phase?
Progesterone begins to be produced in higher quantities from the corpus luteum which has a negative feedback on both GnRH and LH and inhibin from the ovaries inhibits the production of FSH
How does estrogen circulate in the body?
What are the main carriers of estrogen in the blood?
high affinity specific binding (45-70%): Beta globulins like sex steroid-binding globulin (SSBG) and
low affinity binding (30-50%): Albumin
How does estrogen act in the long-term?
Estrogen is membrane permeable and diffuses into the cytoplasm where it binds to nuclear receptors ERa and ERb which transport it to the nucleus to initiate RNA transcription
What are the fast responses of estrogen mediated by?
There are receptors, both membrane-bound and cytosolic, that bind estrogen and mediate secondary messenger cascades
How does estrogen affect bone?
Preserves bone density (upregulates osteroprotegerin)
How does estrogen affect cholesterol levels?
decreases LDL cholesterol but increases HDL
How does estrogen affect the heart?
It is cardioprotective- Estrogen is believed to have a positive effect on the inner layer of arterial intima, helping to keep blood vessels flexible. That means they can relax and expand to accommodate blood flow.
How does estrogen affect blood vessels?
It has anti-atherosclerotic effects and reduces plaque formation
How does estrogen affect the brain?
Estrogen helps to maintain body temp, may delay memory loss, and helps the brain prepare for sexual development
What are the effects of estrogen on the breast, uterus, ovaries, and vagina?
Estrogen stimulates maturation of all of these
How does progesterone affect the uterus?
It prepares the uterus for implantation of the fertilized ovum and pregnancy during the luteal phase by stimulating endometrial glandular secretions and spiral artery development
-produces thick cervical mucus, which inhibits sperm entry into the uterus
-causes uterune smooth muscle relaxation (preventing contractions) and decreases myometrial excitability
The best time for fertilization is within 12-24 hrs of ovulation
Where are inhibin and activin made?
What are the functions of inhibin?
Negative feedback on FSH secretion to reduce estrogen production
What are the functions of activin?
Positive feedback on the anterior pituitary to stimulate FSH secretion resulting in increased estrogen production
How does estrogen affect prolactin secretion?
it promotes but blocks its action at the breast
What does progesterone do to body temp?
increases it (post-ovulation, body temp is high)
How does progesterone affect estrogen receptors?
it down-regulates them