L14: Female Contraception

Question 1

What are the reversible family planning methods for women in order of decreasing effectiveness?

Answer 1

1. Implant
2. IUD (intra-uterine device)
3. Injectable
4. Pill
5. Patch
6. Ring
7. Female condom
8. Withdrawal
9. Fertility awareness

Question 2

What are the irreversible family planning methods for women?

Answer 2

Female sterilization (blocking fallopian tubes)

Question 3

What is the main target of contraceptives?

Answer 3

The endocrine system, in order to be able to modify the release of sperm or oocytes (and to prevent the fertilization of oocytes).

Question 4

What are the major components of the endocrine system pertaining to contraception? What hormone do they release?

Answer 4

1. Hypothalamus: releases GnRH (Gonadotropin releasing hormone)
2. Anterior pituitary: releases LH (Luteinizing hormone) and FSH (Follicle-stimulating hormone)
3. Ovaries or testis: gametogenisis (ovaries will produce eggs and testis will produce sperm) and gonadal hormone production (ovaries will release estrogen and progesterone, testis will release testosterone)

Question 5

Describe the hypothalamic-pituitary-ovarian axis when in negative feedback conditions.

Answer 5

1. The hypothalamus secretes GnRH which stimulates the anterior pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from specific gonadotropic cells.
2. LH and FSH circulate and reach the ovaries with different responses depending on the stage (where you are relative to puberty, or depending on what goes on in the ovaries at that time).
3. LH and FSH stimulate the ovary to release estrogen and progesterone which simulates folliculogenesis and secondary sex characteristics (breast development and maturation, broadening of hips, and pubic hair growth).
4. A constant release of progesterone and estrogen have a negative feedback on the hypothalamus and the pituitary which causes the reduction of GnRH from the hypothalamus and the reduction of LH and FSH release from the pituitary.

Question 6

Describe the positive feedback in the hypothalamic-pituitary-ovarian axis.

Answer 6

The increase of estradiol above a certain threshold (surge) stimulates GnRH release and the LH surge which stimulates oocyte release.

Question 7

What is the shape of the GnRH, FSH and LH release? Why is it important?

Answer 7

The pulsatile secretion of GnRH is what allows the increased secretion of LH and FSH from the anterior pituitary. It is not a constant level of chemical messenger.

Question 8

What does FSH regulate?

Answer 8

Follicular growth and maturation of the follicles in the ovaries.

Question 9

Describe the cycle of follicular development.

Answer 9

Women are born with all of their follicles. During puberty, they develop into primary follicles, and then secondary follicles (the primary follicles in the ovary increase in size and develop into the oocyte, and then the secondary follicles). When they become mature follicles, the oocyte gets ovulated (into fallopian tube where it can be fertilized by a sperm cell) and the follicle becomes the corpus luteum.

Question 10

What specialized cells surround the developing oocyte? What is their main role?

Answer 10

Surrounding the maturing oocytes inside a follicle there are a lot of specialized cells like the Granulosa cells and the Theca cells. These cells are making the steroid hormones, and it’s the interaction of these two cells that generate sufficient estrogen and progesterone.

Question 11

How do Theca and Granulosa cells make estrogen and progesterone?

Answer 11

1. In the theca cells, cholesterol side chains are cleaved to make pregnenolone and then progesterone. Cleavage is induced by FSH. Pregnenolone is turned into testosterone.
2. The Granulosa cells make estradiol from testosterone via aromatase when aromatase is induced by FSH.
   It is important to have the right amount of cholesterol to make hormones.

Question 12

What does LH do?

Answer 12

LH acts on Theca cells to increase steroid synthesis and synthesis of FSH receptors such that the Theca cells can have a magnified response to FSH.

Question 13

What type of receptors do estrogen and progesterone interact with? Where do they bind?

Answer 13

Nuclear hormone receptors.

Nuclear hormone receptors bind to hormone response elements (HRE) in our genome that have an estrogen receptor response element or a progesterone receptor response element. There can be many co-repressors and co-activators that bind to the nuclear hormone receptors as well. When bound they have an effect on transcription.

Question 14

What are the isoforms of the estrogen receptors (nuclear hormone receptor- hER)? What is their purpose?

Answer 14

Alpha and beta isoforms which have different DNA binding domains (DBD binds the HRE) and different ligand binding domains (LBD).
Purpose: having different domains allows for more selective estrogen receptor ligands and modulators to interact differentially with ER-alpha or ER-beta. Estrogen can interact and stimulate both alpha and beta isoforms.

Question 15

How does estrogen act on the endometrium?

Answer 15

Estrogens bind to receptors on the endometrium so that endometrium cells proliferate and become more receptive to implantation of the fertilized oocyte.

Question 16

Describe the progesterone receptor.

Answer 16

There’s only one progesterone receptor but it is alternatively spliced to make 2 isoforms (A & B).

Question 17

Do estrogen and progesterone only cause genomic changes?

Answer 17

No, they may bind cell membrane receptors that don’t cause genomic changes.

Question 18

When do women ovulate?

Answer 18

Women ovulate 1 oocyte per menstrual cycle usually every 28 days.

Question 19

What can a woman use to treat their fertility problems?

Answer 19

Drugs for ovulation induction.

Question 20

What is hormone replacement therapy used for?

Answer 20

Used if the ovary stops functioning and doesn’t make estrogens and progesterone, then estrogens in the body decrease. This is menopause.

Question 21

What can estrogen and progesterone drugs be used for?

Answer 21

1. Fertility control: contraception and ovulation induction
2. Hormone replacement therapy
3. Cancer chemotherapy: to interact with receptors on cancer cells
4. Other

Question 22

Explain the human menstrual cycle.

Answer 22

1. The primary follicle develops into a mature follicle which ovulates (follicular rupture) under stimulation of the LH surge. Anterior pituitary hormones LH and FSH increase at the time of follicular rupture.
2. The estradiol peak lines up with the LH surge (because estradiol surge has positive feedback on LH production), while progesterone increases after ovulation. Ovulation occurs mid-cycle.
3. After ovulation, the corpus luteum forms and produces hormones important for preparing the endometrial lining of the uterus. If the woman gets impregnated (oocyte is fertilized) the uterine endometrium is important to create a favourable environment for the fertilized zygote implant. If the woman is not pregnant, the corpus luteum degenerates which causes the the endometrium lining to degenerate and the woman undergoes menstruation.

Question 23

What is the fertility awareness based method?

Answer 23

There is an increase in basal body temperature associated with ovulation. The fertilization awareness based method is based on measuring the temperature and detecting ovulation with a thermometer. Due to Progesterone release after ovulation, temperature increases, so women are more fertile. But relying on this calendar as a contraceptive method is not very effective.

Question 24

What is a combination oral contraceptive (COC)?

Answer 24

Contains analogs of estrogen (ex: ethinyl estradiol, estradiol valerate, 17beta-estradiol) and progesterone (ex: Levonorgesterel).

Question 25

Why do COCs contain analogs of estrogen and progesterone rather than estrogen and progesterone themslves?

Answer 25

Because the analogs have longer half lives than the endogenous hormones.

Question 26

Why have COC side effects decreased over the years?

Answer 26

The amount of ethinyl estradiol in the pills was decreased.

Question 27

How has the methods of administration of the pill changed over the years?

Answer 27

The pill used to be monophasic, meaning each tablet contains a fixed amount of estrogen and progestin. Now the pills are multiphasic which means that the concentrations vary during the cycle to try to mimic natural hormones. Other regiments also exist: - The basic one is 21 days on the pill and 7 days hormone-free for Menses. - 24 days on the pill, two days only on estrogen, 2 days hormone-free - 84 days on the pill, 7 days hormone-free (people have realized that it is not necessary to menstruate every month, so they have Menses every 3 months or so).

Question 28

What are the effects of oral contraceptives on the menstrual cycle?

Answer 28

1. The pill is giving low and continuous amounts of estrogen and progesterone. This eliminates the positive feedback that comes with an estrogen increase that would normally increase the release of FSH and LH from the anterior pituitary which causes the follicle to rupture (ovulation). 2. Also, the continuous amounts of estrogen and progesterone wont allow for follicular development and the endometrium lining doesn't develop as much. 3. There's also an effect on the ability of the sperm to swim to the oocyte by changing the composition of the proteins the sperm has to swim through to decrease the rate of fertilization.

Question 29

What is the reversibility of the pill?

Answer 29

Completely reversible. When women stop taking the pill, only 10-15% of women were not able to have children which is analogous to the rate of infertility in couples in the general population.

Question 30

Why would the failure rate of the pill vary? What are the different failure rates?

Answer 30

The failure rate of the pill can vary because failure is related to poor compliance (if a woman takes the pill irregularly, forgets to take the pill, or takes drugs that prevent the constant amount of estrogen and progesterone). - The typical use failure rate in the first year is 9%. - The perfect use failure rate is 0.3%. - If you skip 1-5 tablets the pregnancy rate is 2.6% - If you skipped 6-19 pills the pregnancy rate goes up to 42%.

Question 31

What type of drug-drug interactions can affect oral contraceptive methods?

Answer 31

1. The induction of CYP450s due to other drugs taken by the woman. 2. Drugs that alter entero-hepatic (intestine-liver) circulation

Question 32

What happens to the pill when CYP450s are induced by other drugs?

Answer 32

The induction of CYP450s due to drugs taken by the woman can have an effect on the metabolism of analogs present in the pill. Ex: anti-epileptic drugs.

Question 33

What happens to the pill when the entero-hepatic (intestine-liver) circulation is altered by other drugs?

Answer 33

Ex: antibacterial drug (antibiotic) In normal circumstances, when you take the pill, it gets conjugated (metabolized in the liver) and released into the GI tract (intestines). Then, the bacteria in the GI tract cleaves off the glucuronide that was conjugated on to the drug and the drug can get reabsorbed into the liver. When you take antibiotics it kills some of the bacteria that would normally help remove the glucuronide that was conjugated on to the drug (example glucuronidases) in the GI tract, so now the body isn't able to recycle estrogen or progesterone from the pill. Instead, the pill analogs are excreted, and the woman will have lower levels of the analogs in her body, which interferes with the contraception and can cause the normal menstrual cycle to come back. This is why women are often recommended to use another method of contraception while taking antibiotics.

Question 34

What are the advantages of Oral contraception?

Answer 34

1. Periods are more regular 2. Can be used by women over the age of 40 3. May decrease menstrual cramps, acne, bleeding, anemia and breast tenderness 4. Does not interfere with sexual intercourse 5. Reduces risk of ovarian, endometrial, and uterine cancer 6. Increases bone density (estrogen), which is good, as risks of fractures increase with age.

Question 35

What are the disadvantages/contraindications of Oral contraception?

Answer 35

1. Increased risk of venous thromboembolism (blood clots) 2. MAY be a slight increase in breast cancer. Use of oral contraceptives in BRCA1/2 carriers is controversial but appears to be associated with a decreased risk of ovarian cancer and no increase in breast cancer. 3. Increased risk for smokers >=35 because increased risk of mortality

Question 36

Describe the contraceptive patch (Evra).

Answer 36

A skin patch: steroids can penetrate the skin which may be a better option for women who don't want to take a pill every day or for women who easily forget. The steroids are delivered from the patch through to the skin and into the circulation so that they can be delivered to the hypothalamus and other tissues in the body.

Question 37

What is the difference between the pearl index (another way of calculating the failure rate) of oral contraceptive vs the patch? Why?

Answer 37

Pearl index of patch = 0.88 which is half of the rate of pregnancy experienced by oral contraceptive users after 6 cycles. This is most likely because the patches are more continuous and there is better compliance from people as people do not need to remember that much.

Question 38

How do contraceptive implants work? How effective is it? What is an advantage?

Answer 38

A capsule can be implanted in different places in the body (a common place in the arm) and it can deliver low continuous of estrogen and progesterone. Most of them contain a progesterone analog such as Levonorgestrel. It's 99% effective. There is no LH surge when using the contraceptive implant therefore there is no ovulation. An advantage is that it does not interfere with sexual intercourse.

Question 39

How do intra-uterine devices work? What are the 2 types? What is the effectiveness?

Answer 39

It's inserted into the uterus. It delivers some form of active ingredient locally in the uterus. The Copper-T IUD delivers copper but the progestin IUD delivers progesterone and are more common. Both of these types are 99% effective.

Question 40

Name 2 emergency contraceptives (the morning after pill).

Answer 40

1. Plan B- Levonorgesterol (progesterone analog) | 2. Ulipristal acetate (selective progesterone receptor modulator)

Question 41

What does Plan B do? When does it have to be taken? What is the percent efficacy and what does it depend on?

Answer 41

1. May temporarily block ovulation 2. Prevents fertilization 3. Prevent a fertilized egg from implanting in the uterus 4. Has to be taken within 72h of unprotected sex 5. 1 or 2 doses should be taken to induce a withdrawal bleed 6. 75-79% effective depending on the timing after intercourse and the ability to induce a withdrawal bleed

Question 42

What is an alternative to taking a morning after pill?

Answer 42

The ingredients of the morning after pill are similar to oral contraceptive pills so you can take a few contraceptive pills, depending on the formula, to have the same effect as Plan B.

Question 43

What is Ulipristal acetate? What is its efficacy? How long is it effective for?

Answer 43

- A partial antagonist and partial agonist for the progesterone receptor - Similar efficacy to progestin only morning after pill (plan B) - Effective for up to 5 days after intercourse