Lecture 14: Contraception for Women

Where are contraceptions least used?

123 million women, mostly in developing countries, who are not using contraception despite expressing a desire to limit children.

What do CNS estrogen receptors control?

CNS controls estrus behaviour with estrogren.

What chemicals are used in terms of contraception?

Chemicals used are similar to endogenous compounds (estrogen and progesterone)

Describe contraceptive implants.

Contraceptive implants contain a progesterone analogue such as levonrgestrel. Implants are 99% effective, cost $450-900 every five years. Can be used in countries with less access to medical care and physicians. The steroid comes out of capsule in a sustained fashion to wipe out the LH surge.

What are oral contraceptives effect on hypothalamus?

Effects on hypothalamus are progesterone decreasing GnRH pulses.

What % of pregnancies are unintended?

Estimated 38% of all pregnancies occurring around the world every year are unintended and around 6/10 result in induced abortion.

What are the negative feedback mechanisms for estradiol?

Estradiol above a certain threshold shuts down LH and FSH release.

How does FSH act with its receptor?

FSH is in a complex with its receptor. Two subunits form a dimer and interact with the FSH receptor.

Describe gonadotropin releasing hormone (GnRH)

GnRH is a peptide hormone, pulsatile release, stimulates LH and FSH release

What is Plan B?

Plan B is 2 progestin only pills taken as morning after pills. Ovral, alesse, nordettte, levlen and triphasil are all examples.

What are the two isoforms of estrogen receptors? How does this effect estrogen response?

The two isoforms are alpha and beta. They are tissue specific. Multiple estrogen receptor ligands can interact with certain isoforms. Co factors interact with specific isoforms. Usually cause genomic mechanism response(slow) but can also activate non-genomic mechanisms (which are very rapid)

Describe the hypothalamic-pituitary axis in regards to fertility

Hypothalamus secretes gonadotropin releasing hormone (GnRH) which travels to anterior pituitary. The anterior pituitary releases luteinizing hormone (LH) and follicle stimulating hormone (FSH) to gonads. The gonads (testies/ovary) will cause gametogenesis and gonadal hormone production.

When would contraceptive patches be less effective?

IN women over 198 pounds

What are the advantages of intra-uterine devices?

IUD's require no attention. Fertility returns immediately upon removal. They do not interfere with sexual intercourse. Some copper IUDs need to be changed only every 10 years. Progestin IUDs need to be changed every 2-5 years. They can be used while breast feeding.

What are the mechanisms of action on hormones by oral contraceptives?

There are changes in LH and FSH. In normal cycle you can see a LH surge, during contraceptive use there is no LH or FSH surge. Menstruation in between when withdrawn contraceptive use. NO ovulation. You can see the changes in estrogen and progesterone in actual people, contraceptive flattens out levels so there is no cycling.

What are oral contraceptives actions on the body?

Oral contraceptives act in higher brain centres, decreasing signalling to hypothalamus and thus decreasing signalling to pituitary and ovary. The main effect is to cause no ovulation. Also effects fallopian tube motility, cervical mucus( hostile to sperm) and the endometrium doesn't build up.

Describe the female reproductive tract.

1 egg is ovulated every month, released and picked up in fallopian tubes (carried down towards uterus). Sperm will swim up the uterus and meet the egg in fallopian tubes. The fertilized egg implants in the uterus. We can interfere with ovulation, transportation, fertilization or implantation.

How does steroidgenesis occur?

Cholesterol is acted on by sidechain cleavage enzyme that converts it to progesterone then further to testosterone, then aromatase enzyme convert testosterone to estradiol.

What are the disadvantages of intra-uterine devices?

Copper IUDs could increase menstrual outflow by about 2fold Need access to medical care because they must be inserted by a physician.

Describe drug drug interactions in regards to contraceptives and P450's

Drugs inducing P450's activity (barbituaates pheytoin, rifampicin) cause decrease estrogen and progesterone circulating levels that can cause LH surge.

Describe estrogens and progestins as drugs.

Drugs used for, fertility control (contraception and ovulation induction), hormone replacement therapy, cancer chemotherapy and other.

What does oral contraceptives flattening levels of estrogen/progesterone cause?

When we flatten estradial levels there is no LH peak and thus no ovulation. When we flatten progesterone levels the endometrium will not built up and therefore is not receptive for the embryo.

What are the advantages of contraceptive implants?

Works up to 7 years or until removal. Fertility returns rapidly upon removal of the implant. Helps to protect against uterine cancer. Used safely after child birth and while breastfeeding. Does not interfere with sexual intercourse.

Is the oral contraceptive reversible?

Yes, when a woman stops the oral contraceptive she starts to cycle again after 1-2 months

Describe lutenizaing hormone and follicle stimulating hormone (LH and FSH)

Both have alpha and beta units, a common alpha subunit and distinct beta subunit. Both are peptide hormones, pulsatile message and act on cells in ovary to stimulate steroidogenesis and maturation of the ovarian follicle.

describe Japan vs US contraceptive use.

Impact of culture on contraceptive use. In Japan very few people use oral contraceptive, while it is much more common in the US

How effective is the morning after pill?

It is 75-97% effective, depending on the time you take it after intercourse. The pregnancy chance increases the longer it takes to take it.

When are oral contraceptives given?

Both pills are given continuously throughout the month or given sequentially throughout the month.

Why would you change the structure of estradiol or progesterone in an oral contraceptive?

Change structure of progesterone/estradiol to administer orally (effective with longer half life)

Where are estrogen receptors located?

CNS, hypothalamus, anterior pituitary, distributed in fat, mammary glands, myometrium (cells of uterine lining, for proliferation) and bones (for bone maturation)

Where does progesterone act? What does this cause?

CNS: sleep, EEG patterns, Thermoregulation(warmer) Hypothalamus and anterior pituitary. Myometrium (antagonized effects of estrogen) Mammary gland

What happens if you forget to take the pill one day?

Chances of getting pregnant are higher. If you forget 1-5 times there is a 2-6% chance of pregnancy if you forget 6-19 times there is a 42% chance of pregnancy. It depends on how many you miss and when you miss them.

What are oral contraceptives effect on pituitary?

Effects on pituitary are decreased pituitary responsiveness to GnRH. Estrogen suppresses FSH release thus decreasing follicle growth and progesterone suppresses mid cycle LH surge.

What is estrogens actions?

Estrogen is transported to cell with steroid hormone binding globulins and get through the membrane because it is very lipophilic. Estrogen binds to estrogen receptor inside the cell and removes the heat shock proteins (chaperones). The receptor translocates to nucleus and interacts with estrogen response elements and with other co-regulators and transcription factors. Genes are activated and produce effects associated with estrogen.

What is ethinyl estradiol?

Ethinyl estradiol is an oral contraceptive that looks/acts like estradiol (has aromatic ring)

What is Evra?

Evra is a contraceptive patch

Describe a copper-T intra-uterine device.

Ex Tcu380a, Paragard 99% effective and cost $250-750 every 10 years

Describe a progesterone intra-uterine device.

Ex mirena (levonorgestrel) or Progestasert (progesterone) 99% effective, cost $250-400 every year

Describe steroid hormone receptor homologies.

Exactly the same as corticosteroid receptor. Two forms of estrogen receptor alpha and beta, they have different locations in the body (could be an area of targeting). Progesterone receptor also exists. Distinct ligand binding domains, androgen LBD is very different from the estrogen receptor LBD but some domains have more homology. All contain a DNA binding domain and NH2 terminal.

What does FSH regulate?

FSH regulates: Follicle growth and maturation, primary follicles (granulosa cell layer secreting steroids) grow to secondary follicle (antrum forming) to form the maturing follicle and then the corpus luteum Cholesterol side chain cleavage enzyme: FSH increases amount of this enzyme Aromatase activity in the granulosa cell: Estrogen has an aromatic ring made by aromatase (converts androgens like testosterone to estradiol)

What are fertility control methods?

Female sterilization, male sterilization, inter-uterine devices (IUD), pill, injectables, condoms, other. All are population specific.

What are the absolute contraindications for oral contraceptives?

History of breast cancer or blood clots. Liver or kidney disease, unexplained uterine bleeding, and pregnancy. Smokers over the age of 35 have increased mortality rate.

What are the contra-indications of intra-uterine devices?

History of tubal pregnancy. Severe pain with periods at present. An allergy to copper (for copper IUDS) A gonorrhoea or chlamydia infection. Abnormal pap smear that suggests precancerous changes in cervix. Pregnancy or suspicion of pregnancy. A current problem with abnormal vaginal bleeding. Severe anaemia.

How does the morning after pill work?

If fertilization has not yet occurred it can block fertilization. If fertilization has occurred it can block implantation. the pill must be taken within 72 hours of unprotected sex and one or two doses should be taken to induce a withdrawal bleed.

How do anti-bacterial drugs effect contraceptives.

In normal GI tract (has important flora) estrogen and progesterone are metabolized in the liver and secreted in bile to the GI tract where bacteria will cleave off conjugates (have beta-glucoronidase enzyme to remove glucoronide) and estrogen and progestin are reabsorbed (they're lipophilic) and re enter ciculation. If the bacteria are killed (with antibiotic) there are decreased levels of estrogen and progesterone. Anti-bacterial drugs mess up entero-hepatic circulation.

Describe the normal cycle of progesterone and estrogen.

In the normal cycle: Peak in estrogen is associated with peak in LH Peak in progesterone associated with peak in FSH Positive feed back when estradiol passes a certain threshold and triggers the LH surge, LH secretion increases estradiol causing high peak in estradiol which shuts down LH secretion. This mid cycle LH surge is crucial because it stimulates follicle rupture and ovulation

What are Intra-uterine devices?

Intra-uterine devices are contraceptives inserted into the uterus by a physician. They block implantation and may contain a drug. They can be uncomfortable, trigger more bleeding or fallout.

How does LH act?

LH acts on the theca cells to regulate steroid synthesis and to increase the number of FSH receptors (intricate relationship between FSH and LH)

What is levonorgestrel?

Levonorgestrel is an oral contraceptive that looks/acts like progesteone (no aromatic ring)

What are the relative contraindications for oral contraceptives?

Light periods, high blood pressure, diabetes, migraine, severe headaches, depression, sickle cell disease, and fibroids

What are the contra-indications of contraceptive implants?

Liver disease, breast cancer, unexplained uterine bleeding, blood clots

Describe effectivness of fertility control methods.

Look at pregnancy rates after 1 year of exposure per 100 women. With no birth control methods chance of pregnancies is 85%. With spermicide only chance is 26%. Periodic abstinence (abstinence when ovulation occurs) is 25%. Withdrawal is 19%. Rates only become effect with condom use. Male condom 14%, female condom 21%. Vaginal ring (medicated) 1-2%, IUD less than 1-2%, oral contraceptives 0.5-5% (0.5% if taken everyday and no other drugs taken that could interfere)

What can oral contraceptive pills contain?

Oral contraceptive pills can contain both estrogen and progesterone or pills with only progesterone.

Should there be a mandatory monthly bleeding cycle while taking contraceptives?

Originally thought yes when pill first designed but now there are pills that allow 3 month cycles so it may not matter.

Describe world birth control statistics.

Many countries have less than 25% of women using contraception. Few countries (NA, Europe, China, Australia) have more than 65% of women using contraception

What do oral contraceptives do?

Oral contraceptive maintain levels of estrogen/progesterone through the day by flattening out estrogen/progesterone in circulation.

Describe oral contraceptive pills.

Oral contraceptive pills are 99-98% effective, with a 0.5% failure rate. Cost ~$25-45 per month. Include a wide range of formulations, most contain estrogen and progestin.

What do contraceptive patches contain? How do they work?

Patch contains 6 mg norelgestromin and 0.75 mg ethinyl estradiol. the patch delivers continuous sytemic doses of hormones (per day), 150 ug norelgestromin and 20 ug ethinyl estradiol

Why would contraceptive patches be used over oral contraceptives?

Patches have few side effects. Although a direct comparison to oral contraceptive delivery dose cannot be made.

Describe periodic abstinence.

Periodic abstinence is related to the human menstrual cycle. It has a 25% failure rate. Temperature is monitored to know time of ovulation or time in menstruation (associated with a 0.5 degree increase in temp). Menstruation occurs with lower levels of FSH, LH, estradiol and progesterone. Ovulation triggered by LH surge. Progesterone will build up the endometrial linings.

Describe progesterone action.

Progesterone interacts in the same way as estrogen with their receptors, trigger changes in gene expression. Two gene splicing products, PR-A and PR-B, as well as other faster mechanisms.

What is one of the main components in contraceptives?

Progesterone is one of the main components in contraceptives.

Describe the compliance of patches compared to oral contraceptives.

Superior compliance with patch than with oral contraceptive. Patch compliance is unaffected by age. Lower compliance with oral contraceptive in younger compared to older subjects.

What systemic effects does progesterone have?

Systemic effects of progesterone are, glucose/protein/water and electrolyte metabolism.

What are the systemic effects of estrogen?

Systemic effects: protein/carbohydrate/lipid metabolism, water and electrolyte balance and blood clotting

What are the benefits of oral contraceptives?

The benefits are you can control family planning, periods are more regular, it can be used for woman over 40 (unless smoking) may decrease premenstrual syndrome (PMS), menstrual cramps, acne, bleeding, anemia, ovarian cysts and breast tenderness. It does not interfere with intercourse and reduces the rise of ovarain endometrial and uterine cancer, ovarian cysts, pelvic inflammatory disease (bleed less during menstruation), iron deficiency anemia, ectopic pregnancy and fibrocystic breast disease.

What was a big change in oral contraceptives throughout history?

There were many changes in the combinations of estrogen and progesterone. Formulations changed, and the dose was reduced, especially of estradiol.

Describe the efficacy of contraceptive patches.

They have high efficacy. Overall pearl index of 0.88. After 6 cycles, overall probability of pregnancy is 0.5 of that of oral contraceptive users.

What is Uliprital acetate?

Ulipritale acetate is a selective progesterone receptor modulator (SPRM) antagonist/agonist. It works like progestin morning after pill, can be effective for up to 5 days after intercourse.

Describe world fertility rates.

in African continent and central america fertility rate is very high (more than 6) in Canada fertility rate is low (less than 2)