【About girl & Pharmacology】Hormonal Contraceptives

Hormonal Contraceptives

Content:

1. Menstrual cycle
2. Hormonal contraception
3. Examples of actual drugs
4. Summary
5. Reference

1. Menstrual Cycle

More about hormone: 【About girl】Hormonal Functions of the Female,  Hormonal control of the menstrual cycle

Follicular phase:

• Hypothalamus release gonadotropin-releasing hormone (GnRH)
• GnRH acts on the anterior pituitary gonadotropic cells 
• Anterior pituitary gonadotropic cells release FSH & LH
• Once released from the pituitary,  FSH travels to the ovary where it binds to immature eggs (oocytes)
• Oocytes initiating their maturation
• As the ovarian follicles grow, they become surrounded by layers of theca and granulosa cells.
• LH stimulates LH receptors expressed on theca cells causing them to produce androgens which then diffuse into granulosa cells
• In response to FSH binding to the FSH receptors convert them to estrogens

First week: Slightly elevated  levels of FSH and LH (FSH > LH)

Day 7: estrogen levels beginning to rise

• Estrogen serves two primary purposes
• causes uterine lining (endometrium), to grow thicker in preparation for possible pregnancy
• endometrial changes are proliferative → proliferative phase
• Initial rise in estrogen levels sends a negative feedback signal to the hypothalamic-pituitary axis
• Suppress further production of FSH and LH.
• Granulosa cells of the growing follicles produce inhibin, which selectively suppresses FSH  secretion
• Multiple large follicles that remain sensitive to decreasing levels of FSH,  only a single dominant follicle continues to grow and produce increasing amounts of estrogen.

• Lining of the uterus continues  to become thicker and spongier with blood-rich tissues
• Estrogen levels reach a critical level as the follicle matures within the ovary
• Estrogen begins to exert positive feedback on LH production
• Provokes a steep surge in LH, and to a lesser degree FSH
• Around day 14, LH reaches its peak 
• triggers the mature follicle to rupture and release the egg into fallopian tube in a process called ovulation

☝End of the follicular phase

Luteal phase👇

• After ovulation, follicle cells that used to hold the egg develop into corpus luteum
• Corpus luteum produce progesterone
• Progesterone: 
• helps the uterine lining to become thicker and more vascular
• stimulates glands in the uterine wall to produce fluids necessary for the nutrition of the potential embryo
• stimulates glands in the cervix to secrete thick mucus that closes off the uterine opening
• becomes a barrier to sperm and bacteria.
• This is secretory phase

Graph: 

• a steep rise in progesterone and a slight bump in estrogen levels, which peak around day 21. 
• corpus luteum secretes high levels of progesterone & lower levels of estrogen
• elevated levels of circulating estrogen, progesterone, and inhibin
• exert a negative feedback  effect on the hypothalamus and anterior pituitary → inhibiting secretion of GnRH, FSH and LH → prevents new follicles from developing

If fertilization of the egg does not occur,

• corpus luteum will start to break down
• levels of both estrogen and progesterone to fall dramatically
• uterine lining to break down
• come out in the form of menstrual bleeding, also called menses
• marks the start of the next follicular phase

2. Hormonal contraception

Hormonal contraception refers to birth control methods that act on the endocrine system of the female to prevent ovulation or fertilization.

Two main types:

• Combined method: contains synthetic forms of both estrogen and progesterone
• Progestin-only method: contains only progestin that is synthetic version of progesterone

Forms:

• Oral tablet: Birth control pill, most widely used
• Patches
• Injections
• Vaginal rings

a. Combination birth control pills:

i. Monophasic

• Pills deliver the same amount of estrogen and progestin each day for the first 21 days, followed by 7 days suspension or 7 days of placebo pills.
• Administration of exogenous estrogen and progestin leads to continuous suppression of LH and FSH output from the pituitary 
• Results in inhibition of ovulation
• The last 7 days of suspension or placebo, allow estrogen and progestin levels to fall dramatically 
• Triggering withdrawal bleeding that mimics the normal menstrual cycle

ii. Multiphasic

• the pills deliver varying levels of estrogen and progestin that intend to mimic the natural hormonal fluctuations & reduce the total exogenous hormone dose per cycle
• With the extended-cycle contraceptive regimens, women can end their menstrual periods altogether by continuously taking combined estrogen-progestin pills beyond the initial 3 weeks. 

b. Progestin-only birth control pills

for short-term hormonal contraception 

for whom exogenous estrogen is contraindicated because of breastfeeding or cardiovascular disease.

Taken continuously, with no hormone-free intervals between cycles leading to consistent suppression of FSH and endogenous progesterone production.  

• That means with the exception of intramuscular depot-medroxyprogesterone, which delivers high dose of progestin, the systemic dose of progestin delivered by all progestin-only products is relatively low.提供高剂量孕激素的肌内长效黄体酮，其它影响小

Result:

less suppression of endogenous estrogen levels, which allows for occasional LH surge that can trigger ovulation. 

Cons:

• Function primarily by thickening cervical mucus and by causing endometrial atrophy
• These changes inhibit egg implantation and make it more difficult for sperm to enter the uterus.

3. Examples of actual drugs

Synthetic derivatives of estrogen:

• Ethinyl 
• Estradiol  
• Mestranol

Synthetic derivatives of  progesterone:

• Desogestrel
• Drospirenone
• Levonorgestrel
• Norgestrel
• Norgestimate
• Norethindrone

4. Summary

5. Reference:

https://youtu.be/TfN9-SamIss

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