sex steroids and ovulation and cycle shit

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  Without reproduction our species wouldn’t survive so it needs control 

• These are tropic hormones under the hypothalamic/anterior pituitary axis

• GnRH is released from the hypothalamus

  • GnRH (gonadotropin releasing hormone) signals the anterior pituitary to release FSH and LH. These are both gonadotropins. 

    • In short, GnRH tells the anterior pituitary to release gonadotropins, hence its name

    • Gonads are ovaries in females and testes in males. They have two functions…

      • Production of gametes, the haploid cells of reproduction. Ovaries produce oocytes and testes produce sperm

      • Endocrine functions. 

        • Ovaries produce estrogens (female reproductive hormones) such as estradiol, the most abundant estrogen. There are other estrogens

        • Testes produce androgens such as testosterone, which are male-characteristic steroid hormones. There are other androgens

        • These hormones are secreted beginning at puberty

          • secreted throughout life in men (though there is a peak in the 20s). 

          • In women, ovulation starts at puberty but ends at menopause

    • ONLY THE GONADS HAVE RECEPTORS FOR THESE HORMONES - FSH and LH

• GnRH turns on the system, and is released from the hypothalamus. The reason why we dont make sperm before puberty is because GnRH isnt produced in the first decade of life. At the start of puberty, the hypothalamic neurons make GnRH. This tells the anterior pituitary to release FSH and/or LH. 

• The testes are composed of a densely packed array of seminiferous tubules. The walls of these tubules are a multilayered epithelium, outside of which lay stem cells that divide, forming another stem cell and a sperm, providing continual production of sperm starting at puberty. 

  • The seminiferous tubules are surrounded by sertoli cells, which provide nourishment to the tubules, and promote spermatogenesis– approximately several hundred sperm per day. Sperm are pushed through the tubule and stored in the epididymis where they sit. 

  • The sertoli cells have receptors for FSH, which trigger the sertoli cells to promote spermatogenesis. Thus, FSH binding to sertoli cells → spermatogenesis

  • In the spaces between the sertoli cells are leydig cells, which have receptors for LH. When LH binds, testosterone is released from the leydig cell. 

    • Testosterone is produced in high levels, spills out of the testes, binds to carrier proteins, and circulates around the body. This molecule is responsible for male secondary sex characteristics (muscle development, body mass, larynx, pubic hair, etc.)

    • The highest level of  testosterone is in the testes. The leydig cells are located in between the sertoli cells which wrap around the tubules, so the sertoli cells get the highest level of testosterone of any cell in the body

• Testosterone, androgens, estrogens are all lipophilic steroid hormones derived from cholesterol 

• Leydig cells have androgen receptors on the nuclear membrane. The testosterone-receptor complex acts as a transcription factor.

• Sertoli cells are highly androgen dependent. The reason why men have more skeletal muscle is male skeletal muscle has more androgen receptors coupled with there being more testosterone in men. 

• Sertoli cells require testosterone from the leydig cell

• Thus, FSH and LH secretion promotes spermatogenesis and release of a protein hormone called inhibin from the sertoli cells

• Let’s cover the negative feedback mechanisms

  • Testosterone binds to the anterior pituitary cells, preventing them from releasing LH but not FSH

  • Testosterone binds to the hypothalamus and prevents it from releasing GnRH

  • Thus, testosterone directly inhibits LH and indirectly inhibits FSH and LH

  • Inhibin is senses by the anterior pituitary, inhibiting FSH release

• Although sperm accumulate mutations that increase the risk of birth defects, older men can still have children due to spermatogenesis even in old age

• Pretty similar to men

• Hypothalamus releases GnRH, which tells the anterior pituitary to release FSH and/or LH.

  • These hormones target the ovarian follicles, which lie within the ovary

  • The two cell types in the ovarian follicle are the granulosa and theca cells

  • The granulosa is analogous to the sertoli cell, which surrounds and nourishes the developing gamete. It is stimulated by estrogen. Testosterone can be converted to estrogen in one enzymatic step– this conversion is stimulated/carried out by the granulosa cell. Granulosa cells only have estrogen receptors, not testosterone receptors. 

    • Positive feedback: a loop is formed between estrogen, testosterone, and granulosa cell. The more testosterone → estrogen, the more the granulosa cells trigger more conversion

    • The granulosa cells, similar to the sertoli cells, secretes inhibin release, which inhibits FSH release from the anterior pituitary

  • The theca cell is analogous to the leydig cell in the testes. It is stimulated by LH, and releases testosterone. 

  • The steroid hormone that escapes the ovary is estrogen, which travels through the blood on carrier proteins and goes on to inhibit FSH release from the anterior pituitary and GnRH release from the hypothalamus. 

    • Thus, estrogen directly inhibits FSH and indirectly inhibits both FSh and LH

  • This hormone cycling creates the menstrual cycle/ovarian cycle in women

• Let’s just focus on the Ovary in upper right hand corner

  • There are follicles in the ovary, each of which contains one oocyte surrounded by a layer of granulosa cells. 

  • When a baby girl is born, she is endowed in each of the two ovaries, several hundred primary follicles (one oocyte covered by a single layer of granulosa cells). 

  • The yellow is the granulosa cells and the red dot is the oocyte

1. Starting at birth, each day a small number of the primary follicles/oocytes develop into secondary follicles. These secondary follicles have MANY layers of granulosa cells surrounded by a layer of theca cells. When the theca cells appear, the follicle is now secondary. 

2. If FSH and LH are at the right levels, the follicle will undergo further development from secondary. 

3. It grows larger (adding more granulosa/theca cells), fluid is secreted and a cavity forms with the fluid and the oocyte suspended by a stalk of granulosa cells. This follicle is called a graffian follicle, as seen in the image above. The follicle grows so much that the ovary begins to bulge.

4. If the hormone levels are right, then continued secretion of the fluid builds osmotic pressure. There are also digestive enzymes being secreted on the outside of the follicle to break down the ovary’s sheath/connective tissue, weakening it. The buildup of pressure then causes the rupture of follicles, pushing the oocyte and granulosa cells out of the ovary into the abdominal cavity. This event is called ovulation. 

5. The oocyte then travels through a funnel-shaped tube with finger processes that are cilliated, and beat to carry the oocyte into the oviduct/fallopian tubes, which leads to the uterus. Fertilization occurs in the oviduct. Ovulation occurs around the middle of the 28 day cycle, roughly day 14, but it is +/- a couple days. 

6. The oocyte in the oviduct can last about one day before it dies of old age/gets phagocytosed, so sperm has to be present within this one day. (Note that sperm can last in the vagina→cervix for about a week to 10 days.The mucous that blocks the cervix/protects against infection clears around ovulation.). Thus, having intercourse within 10 days of ovulation can lead to pregnancy

7. Let’s say fertilization occurs by sperm penetrating egg membrane. The result is a diploid zygote

8. Back in the ovary, the remnant of the follicle, consisting of granulosa and theca cells in the ovary continues to grow under the influence of the hormones, mainly luteinizing hormone (LH). The follicle forms the corpus luteum. The reason why LH has its name is because it forms the corpus luteum!

9. The corpus luteum means “yellow body”. It is the remnant of a follicle, and is an endocrine organ that secretes estrogen and progesterone. The corpus luteum has a fixed lifespan– 10 days if fertilization doesn’t occur, where it just withers away into scar tissue. 

10. This cycle repeats, as the development of the oocytes happens every day starting at birth to the tune of 30 oocytes per day and 900 a month. To progress to the secondary follicle phase, the hormones in the anterior pituitary need to be at the appropriate levels, which are only present at puberty. Thus, for the first 10 years or so the oocytes that start this developmental process simply die off:(

11. The cause of menopause is the depletion of viable oocytes that are capable of cycling. 

12. For each cycle, usually only one oocyte bursts. The case of fraternal twins is when two oocytes burst instead of one

• Now lets look at the hormone graphs

• FSH is follicle stimulating hormone– it stimulates the growth of the follicle. 

  • Transforming between primary → secondary → graffian requires FSH

• Granulosa cells produce the estrogen, which exerts negative feedback on the gonadotropins, LH and FSH

• At first, we have estrogen being secreted at low levels, and because of these low levels, the levels of FSH and LH are kind of flat because estrogen is inhibiting FSH and LH. There is some level of FSH, which stimulates the initial slow growth of the follicle. The granuloa cells, using testosterone 

• X-axis is days of the ovarian cycle

1. At day 1 or 2, estrogen levels are low, FSH and LH are kind of flat. Estrogen inhibits FSH and LH. There is some FSH which stimulates slow growth. Granulosa cells provide estrogen using testosterone from the theca cells. 

2. Around day 5-6, slow growth of the follicle causes a gradual increase of estrogen concentration

3. By day 7-10, the rate of estrogen production increases, triggering the production of more estrogen. Remember the positive feedback loop. There is more negative feedback of FSH and LH. 

4. Around day ~12, under conditions of rapidly rising estrogen, the normal negative feedback on FSH and LH is overpowered, and switches to positive feedback. So, instead of inhibiting FSH and LH, it promotes large surge in LH and a smaller surge in FSH. This event is called the LH surge.

5. After the LH surge, ovulation is triggered. The follicle ruptures to expel the oocyte at around day 14. The switch to positive feedback is reversed, and there is now a rapid drop in LH and FSH as there is still high estrogen– the falling phase of the LH surge. Estrogen levels fall after ovulation a little bit due to the follicle secreting estrogen being damages

6. Ovulation is a trigger for the follicle remnants to grow into the corpus luteum, which is an endocrine organ that produces estrogen and progesterone. This replenishes the estrogen that was lost in ovulation, and increases the concentration of progesterone to high levels in the second half of the cycle

7. The endometrial lining of the uterus, the endometrium, is sensitive to estrogen and progesterone

   1. Estrogen causes the endometrium to grow in thickness. The endometrium has  an inner lining of the uterus with a basal layer of stem cells that remain there all the time. Over the course of the cycle starting day 3-4, these basal cells proliferate, and the inner/functional layer which lays above the basal layer gets thicker and thicker as a response to estrogen. 

   2. Thus, there is a continual growth of the endometrium after about the first week. It grows because if fertilization occurs, the zygote needs a place to implant itself and develop 

   3. Cells cant grow and survive without blood supply, so spiral arteries come up from the basal layer and supply blood to the endometrium as a result of estrogen. 

   4. Progesterone causes differentiation of the exocrine glands that secrete a glycogen rich mucous onto the outer layer of the endometrium to provide the zygote for energy during implantation and division. 

   5. Around day 24-25, cells in the endometrium produce a strong vasoconstrictor, prostaglandin, paracrine hormone. These vasoconstrictors WOULD cause the spiral arteries to cut off blood supply to the endometrium BUT estrogen inhibits the production of the prostaglandin. So as long as estrogen is high, the prostaglandin is inhibited, blood flows through the arteries, and there is growth.

   6. If fertilization occurs, it wouldve been by around day 14, and it takes about 7-10 more days for the zygote to show up in the uterine cavity and implant when the endometrium is at its thickest in the figure

   7. If fertilization did not occur, the corpus luteum pumping estrogen and progesterone dies after its lifespan of 7-10 days expires. Remember that this organ secretes estrogen and progesterone, so those hormones fall. O 

   8. As estrogen and progesterone fall, the inhibition of prostaglandins end, and the vasoconstrictor effects starve the endometrium of blood flow, killing the tissue via necrosis. The endometrium falls apart and regress along with the prostaglandin-secreting cells, so secretion ends and prostaglandin levels fall, causing bleeding as the vasoconstriction wears off. 

   10. Bleeding marks the beginning of the cycle, day 0

“The beauty of all this is that the endometrium is thickening and growing each cycle to accommodate the implantation of the zygote should one appear but if the zygote doesnt appear, the endometrium will regress back to its original shape and thickness like in day 3 and start the process all over again. It can’t just keep growing.”

• Let’s talk more about what would happen if fertilization DID occur. 

  • Does the corpus luteum still die?

    • No, because if fertilization occurs and there is successful implantation, the implanted embryo will secrete a “chorionic” gonadotropin – the chorion is an extraembryonic membrane formed by the embryo when it implants.

    • The chorion is an endocrine organ that secretes a chorionic gonadotropin hormone similar to LH in structure and effects. 

    • The chorionic gonadotropin has powerful effects in supporting the ovarian follicle, extending the corpus luteum’s lifespan from 7-10 days (because the estrogen it secretes inhibits the gonadotropin/prostaglandin it needs to survive) to 9 months (all of pregnancy as a result of the gonadotropins support). 

    • If implantation occurs and the corpus luteum survives, the embryo and follicle are maintained, and estrogen and progesterone levels are maintained by the corpus luteum. 

      • This also helps with hormone-driven growth of the uterus during pregnancy

    • The secretion of chorionic gonadotropin happens soon after fertilization, so its a good marker in pregnancy tests