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John Rock’s Error M. Gladwell Rock – born in 1890, was in love with the church An inventor of the B.C. Pill Faith & vocation were compatible to him Called.

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Presentation on theme: "John Rock’s Error M. Gladwell Rock – born in 1890, was in love with the church An inventor of the B.C. Pill Faith & vocation were compatible to him Called."— Presentation transcript:

1 John Rock’s Error M. Gladwell Rock – born in 1890, was in love with the church An inventor of the B.C. Pill Faith & vocation were compatible to him Called a “moral rapist” & got a lot of grief from many people, including clergy. Rock was unmoved “John, stick to your conscious” Pill approved by FDA in 1960 Very popular in news media, tall man with impeccable manners and thought his association with pill made it more respectable

2 -Taught OB at Harvard Medical for more than 30 years -Pioneer in in vitro fertilization (IVF) and freezing sperm cells -Two collaborators on the pill Gregory Pincus & Min-Cheuch Chang – worked out mechanism -Rock – guided through clinical trials & gave validity to claim would prevent pregnancy -Testified before FDA -Examiner said Catholic church would NEVER approve - “Young man, don’t you sell my church short.”

3 1968 – Pope Paul VI outlawed oral contraceptives and all other “artificial” methods of B.C. John Rock made an Error not deliberate Became manifest after his death & via science discoveries he couldn’t have anticipated. Error has colored way people thought about contraception ever since. He believed pill was “natural” method of BC because it worked by natural means Progestin – stops ovaries from producing eggs (prep uterus for implantation) favors gestation

4 Pregnant women make progestin so egg can’t be released & threaten pregnancy Pill – progestin not limited to certain part of cycle (sudden surge after ovulation) Steady dose – so no ovulation Also little estrogen hold endometrium together and other tissues Pill’s ingredients duplicated what can be found in the body, had theological significance to ROCK. 1951 – Pope Pius XII sanctioned rhythm method – deemed it natural

5 Rock had Rhythm Method Clinic Limit Sex to safe period that progestin created Pill – using hormone to extend safe period entire month Rock “an adjunct to nature” 1958 – Pope approved Pill for Catholics – as long as contraceptive effects were indirect Led to many arcane arguments Use Pill to achieve rhythm then why not Pill alone etc…..

6 Rock/Pincus came up with 4 week cycle 3 weeks hormone 1 week placebo – allows for menstruation THERE WAS AND IS NO MEDICAL REASON FOR THIS Typical woman – 28 day cycle CYCLE: First E, then E & P flood the uterus. Lining thick and swollen to prep for fertilized egg. Egg not fertilized, hormone levels drop and lining (endometrium) sloughed off in menstrual bleed

7 Pill – no egg released Flux of hormones cause lining to grow are dramatically reduced Effect of Pill’s hormones on endometrium so modest – women could go for months without having to menstruate “a cycle of any desired length could be produced” – Pincus 1958 Picked 4 week cycle so women find menstruating reassuring Rock wanted to be “natural” Packaging & 28 day cycle Drug shaped by dictates of Catholic Church

8 That was his error; Not so natural after all ________________________________________________________ 1986 Bev Strassman (U Mich) – Africa Dogon tribe in Mali. Use no contraception. Wanted to construct reproductive profile of women in tribe to understand female biology before modern age Evolutionary perspective rather than theological one Stayed in Tribe for 2.5 years Put menstruating women in huts at the edge of village Two huts – 3 beds in hut, nighttime hangout (dusk – dawn)

9 736 nights monitored huts First period – age 16 Gives birth 8 or 9 times Onset of menstruation → age 20 & has 7 periods a year 24-34 Pregnant or breast feeding (suppresses ovulation about 20 months) Average 1 period a year 35-menoapuse (50) – average 4 periods a year *Menstruate 100 times in life & live to be 70-80 Western Woman 350-400 X *Exception two sterile women

10 Number of lifetime menses isn’t greatly affected by differences in diet, climate, method of subsistence Prevailing factors – wet nursing or sterility What we think of as normal menses – abnormal in evolutionary terms “Pity gynecologists think women have to menstruate every month” Shift 100 → 400 Periods is significant “incessant ovulation” a serious problem for women’s health?

11 Doesn’t mean women always better off not menstruating Failure to menstruate – signals increased risk of uterine cancer in obese women Female athletes – increased risk of osteoporosis Most women incessant ovulation has no purpose & lots of disadvantages Abdominal pain, mood shifts, migraines, endometriosis, fibroids & anemia greatly increased, as well as risk of some cancers Any change promoting cell growth & division increases cancer risk Ovulation one of those changes

12 Egg bursts through ovary wall Woman gets pregnant and has child – lifetime risk of ovarian cancer drops by 10% with each kid from saving ovaries 12 months of cell division Same argument for endometrial cancer In fact, ovarian & endometrial cancer modern diseases, in part because of 400 menses? In this sense, Pill has natural effect; restrained cell division 10 year on Pill reduces ovarian cancer by 70%, endometrial cancer by 60%

13 Real promise of the Pill not preserve menstrual rhythms of 20 th century, but could DISRUPT THEM Some reproductive specialists against 28 day Pill cycle New contraceptive, Mircette cuts placebo to 2 days Sulak, Texas A&M, women stay on Pill 6-12 weeks before spotting During placebo week, a number of pill users have pelvic pain, bloating, swelling, headaches, etc…Side effects of normal menstruation

14 1980 & 81 – Pike (USC) went to Japan to study at Atomic Bomb Casualties Commission Why Japanese women have 6x less breast cancer than American women? Japanese not genetically protected move to US and increase risk Unknown toxin or virus in west “environment” Breast cancer risk > in the 30’s & 40’s & < with menopause So if toxin – expect increase each year Also, women had ovaries removed had less cancer

15 Made sense amount of E & P women exposed to in life effects Breast cancer risk Breast cells (terminal-duct) where most cancer arises undergoes cell% following exposure to E Mid-late Menstrual period (when ovaries make lost of P) cell division even greater 1 st menstruation How old at menopause How much hormone made in ovaries Weight (fat cells make E)

16 Interestingly, bearing children can be protective against BC (cells resistant to mutations in last two trimesters) JAPAN RESULTS 1 st period ≈ 16.5US = 14 This difference alone explains 40% gap between US & Japan BC rates Other factors not different Age of 1 st pregnancy, number of children BUT WEIGHT Japan = 100 lbs US = 145 Explains 25% difference

17 Also examined blood samples Japan 75% amount of E as US girls (likely because of LF diet) 3 Factors Explain Gap 1 st period, weight, and E levels Pike says understands BC very well. Made Pike think of Pill which had potential to be anti BC treatment Breast different than Reproductive organs Pike thought progestin wasn’t solution: was hormone that caused cell% Pill has no effect on BC

18 Problem with Pill Amount of P & E to make effective contraception more than amount to keep reproductive system healthy & excess P & E raises risk of BC Solution GnRHAs – disrupts signal pituitary sends when effect production of sex hormones Given to men with prostate cancer to halt T production Girls with precocious puberty (age 7 or 8) Also women (child bearing age) to decrease production on E & P from OV

19 Conventional Pill → Little Pregnancy Pike’s Pill (GnRHA) → Little menopause Have to be inhaled nasally; breaks down in the body very fast Menopause has its risks Need E for strong heart & bones; P to keep uterus healthy Add back enough E & P to solve these problems Less than found in Pill Period 4x a year Testing formula on women with high risk for BC

20 Examine changes with mammograms HUGE CHANGES Large clumps → gone 3 women Reducing cell proliferation Reduce risk with Pike Protocol? Sweep “natural” approach aside Risk of (benefit of ) education for women and not getting pregnant increase BC & ovarian C 23 years of uninterrupted ovulation is a brand-new phenomenon

21 1963 – (after Rock’s book published) Vatican officials met with planned parenthood 1964 – summit Notre Dame, looked like church was going to approve Pill Rock – cover on Newsweek Pope – inside Many delays, in 1968, Pope said NO Known Pill could be a cancer drug maybe church would have approved.

22 Sad ending Rock didn’t live to see Pill’s effect on cancer rates Saw (at end of 60’s) Pill wrongly accused of causing blood clots, strokes, heart attacks Mid 70’s-Early 80’s Number of women on Pill decreased 50% Harvard Med took over his reproductive clinic Pension paid $75 a year, had to sell house 1971 – farmhouse in NH 1983 – last public interview, most gratifying part of life “now”

23 The pill doesn't boost breast cancer death risk Reuters HealthFriday, October 12, 2007 -Survival is no better or no worse among breast cancer patients who have used the birth control pill The findings are "broadly reassuring," Dr. Herbert R. Peterson of the UNC- Chapel Hill, one of the study's authors "There just doesn't appear to be any concern about women using the pill at younger ages from the standpoint of breast cancer." Concerns had been raised about oral contraceptives and breast cancer by an analysis of 54 studies, published in 1996, which found an increased risk of the disease among women currently on the pill, Peterson noted. Researchers hypothesized that women on birth control might have more consistent access to healthcare, and thus be more likely to have breast cancers detected early, which would mean they would have a corresponding reduced risk of being diagnosed with advanced disease.

24 To investigate, Peterson and his team looked at use of oral contraceptives and the risk of dying from breast cancer among 4,292 women aged 20 to 54 who had been diagnosed with the disease. The researchers found no increased risk of death associated with use of the pill, duration of use, or any specific oral contraceptive formulation. Women currently taking oral contraceptives were actually at 10% lower risk of dying from the disease. Another large study conducted in 2002 found no increased risk of breast cancer among women currently on the pill, Peterson pointed out. "There are now dozens and dozens of studies looking at the pill and breast cancer risk, and when you pull them all together they're broadly reassuring, both in terms of the risk and in terms of the risk of mortality," he said in an interview. The one unanswered question remains the safety of the pill for women approaching menopause, given the increased risk of breast cancer recently identified for menopausal women taking hormone replacement therapy, Peterson said. "For healthy women over 40 who don't smoke, oral contraceptives continue to be an option for contraception, and for many a good option," he added. Nevertheless, Peterson said, more research needs to be done to confirm that the pill is safe for older women. SOURCE: Obstetrics & Gynecology, October 2007.

25 2114 7 The internal female reproductive organs include the uterus, ovaries, cervix and vagina. These organs are necessary to produce a successful pregnancy. To prevent pregnancy, birth control pills affect how these organs normally function.

26 Follicle Stimulating Hormone (FHS) and Lutenizing Hormone (LH) stimulate the ovary into producing a ripe egg ready for fertilization by sperm during a normal ovulation cycle.

27 During a normal menstrual cycle, hormones stimulate the ovary causing an egg to ripen. The uterine lining thickens preparing itself for implantation of a fertilized egg and the cervical mucus thins to help sperm reach the egg.

28 Estrogen in the body cause the pituitary gland to release LH stimulating the ovary to produce a ripe egg.

29 The lower levels of estrogen in birth control pills suppress FSH and LH "fooling" the pituitary gland into thinking a woman is pregnant. Ovulation will not occur- which prevents pregnancy.

30 The progesterone in birth control pills creates a thick cervical mucus making it difficult for sperm to reach the uterus. It also impedes an egg from attaching itself to the uterine lining (endometrium) because of changes in the cellular structure of the lining.

31 BC METHODS The birth control method you choose should take into account: your overall health how often you have sex the number of sexual partners you have if you want to have children how well each method works (or is effective) in preventing pregnancy any potential side effects your comfort level with using the method

32 BC METHODS Continuous Abstinence – This means not having sexual intercourse (vaginal, anal, or oral intercourse) at any time. It is the only sure way to prevent pregnancy and protect against HIV and other STDs. This method is 100% effective at preventing pregnancy and STDs. HIV/AIDS Louisiana has a serious HIV/AIDS problem. In 2003, the state was in 6 th place nationally in AIDS case rates [per 100,000 population], and 11 th. in the number of AIDS cases reported, according to the Center for Disease Control and Prevention. People with HIV/AIDS reside in every parish in the state, but the Baton Rouge and New Orleans areas have very high concentrations of cases. Metro Baton Rouge ranked 7 th and New Orleans was 9 th in the nation in AIDS case rates in 2003. AIDS Case Rate per 100,000 Population, All Ages, Reported in 2005 LA-21 Whole USA-14

33 BC METHODS Periodic Abstinence or Fertility Awareness Methods – A woman who has a regular menstrual cycle has about seven or more fertile days or days when she is able to get pregnant, each month. Periodic abstinence means you do not have sex on the days that you may be fertile. These fertile days are approximately 5 days before ovulation, the day of ovulation, and one or more days after ovulation. Fertility awareness means that you can be abstinent or have sex but you use a “barrier” method of birth control to keep sperm from getting to the egg. Barrier methods include condoms, diaphragms, or cervical caps, used together with spermicides, which kill sperm. These methods are 75 to 99% effective at preventing pregnancy. Keep in mind that to practice these methods, you need to learn about your menstrual cycle (or how often you get your period). To learn about your cycle, keep a written record of when you get your period, what it is like (heavy or light blood flow), and how you feel (sore breasts, cramps). You also check your cervical mucus and take your basal body temperature daily, and record these in a chart. This is how you learn to predict, or tell, which days you are fertile or “unsafe.” You can ask your doctor or nurse for more information on how to record and understand this information.

34 The Male Condom – Condoms are called barrier methods of birth control because they put up a block, or barrier, which keeps the sperm from reaching the egg. Only latex or polyurethane (because some people are allergic to latex) condoms are proven to help protect against STDs, including HIV. "Natural” or “lambskin” condoms made from animal products also are available, but lambskin condoms are not recommended for STD prevention because they have tiny pores that may allow for the passage of viruses like HIV, hepatitis B and herpes. Male condoms are 84 to 98% effective at preventing pregnancy. Condoms can only be used once. You can buy them at a drug store. Condoms come lubricated (which can make sexual intercourse more comfortable and pleasurable) and non-lubricated (can also be used for oral sex). It is best to use lubrication with non-lubricated condoms if you use them for vaginal or anal sex. You can use KY jelly or water-based lubricants, which you can buy at a drug store. Oil-based lubricants like massage oils, baby oil, lotions, or petroleum jelly will weaken the condom, causing it to tear or break. Always keep condoms in a cool, dry place. If you keep them in a hot place (like a billfold, wallet, or glove compartment), the latex breaks down, causing the condom to tear or break. Latex or polyurethane condoms are the only method other than abstinence that can help protect against HIV and other sexually transmitted diseases (lambskin condoms do not).

35 Oral Contraceptives – Also called “the pill,” contains the hormones estrogen and progestin and is available in different dosages. A pill is taken daily to block the release of eggs from the ovaries. Oral contraceptives lighten the flow of your period and can reduce the risk of pelvic inflammatory disease (PID), ovarian cancer, benign ovarian cysts, endometrial cancer, and iron deficiency anemia. It does not protect against STDs or HIV. The pill may add to your risk of heart disease, including high blood pressure, blood clots, and blockage of the arteries, especially if you smoke. If you are over age 35 and smoke, or have a history of blood clots or breast, liver, or endometrial cancer, your doctor may advise you not to take the pill. The pill is 95 to 99.9% effective at preventing pregnancy. Some antibiotics may reduce the effectiveness of the pill in some women. Talk to your doctor or nurse about a back-up method of birth control if she or he prescribes antibiotics. Most oral contraceptives are swallowed in a pill form. One brand, called Ovcon 35, can either be swallowed or chewed. If it is chewed, you must drink a full glass of liquid immediately after to make sure you get the full dose of medication. There are also extended cycle pills, brand name Seasonale, which have 12 weeks of pills that contain hormones (active) and 1 week of pills that don’t contain hormones (inactive). While taking Seasonale, women only have their period 4 times a year when they are taking the inactive pills. There are many different types of oral contraceptives available, and it is important to talk to your doctor or nurse about which one is best for you. You will need a prescription for oral contraceptives.benign anemia

36 The Mini-Pill – Unlike the pill, the mini-pill only has one hormone, progestin, instead of both estrogen and progestin. Taken daily, the mini-pill thickens cervical mucus to prevent sperm from reaching the egg. It also prevents a fertilized egg from implanting in the uterus (womb). The mini-pill also can decrease the flow of your period and protect against PID and ovarian and endometrial cancer. Mothers who breastfeed can use it because it will not affect their milk supply. The mini-pill is a good option for women who can’t take estrogen, are over 35, or have a risk of blood clots. The mini-pill does not protect against STDs or HIV. Mini-pills are 92 to 99.9% effective at preventing pregnancy if used correctly. The mini-pill needs to be taken at the same time each day. A back-up method of birth control is needed if you take the pill more than three hours late. Some antibiotics may reduce the effectiveness of the pill in some women. Talk to your doctor or nurse about a back-up method of birth control if she or he prescribes antibiotics. You will need to visit you doctor for a prescription and to make sure you are not having problems.

37 Copper T IUD (Intrauterine Device) – An IUD is a small device that is shaped in the form of a “T.” Your health care provider places it inside the uterus. The arms of the Copper T IUD contain some copper, which stops fertilization by preventing sperm from making their way up through the uterus into the fallopian tubes. If fertilization does occur, the IUD would prevent the fertilized egg from implanting in the lining of the uterus. The Copper T IUD can stay in your uterus for up to 12 years. It does not protect against STDs or HIV. This IUD is 99% effective at preventing pregnancy. You will need to visit your doctor to have it inserted and to make sure you are not having any problems. Not all doctors insert IUDs so check first before making your appointment. Progestasert IUD (Intrauterine Device) –This IUD is a small plastic T- shaped device that is placed inside the uterus by a doctor. It contains the hormone progesterone, the same hormone produced by a woman’s ovaries during the monthly menstrual cycle. The progesterone causes the cervical mucus to thicken so sperm cannot reach the egg, and it changes the lining of the uterus so that a fertilized egg cannot successfully implant. The Progestasert IUD can stay in your uterus for one year. This IUD is 98% effective at preventing pregnancy. You will need to visit your doctor to have it inserted and to make sure you are not having any problems. Not all doctors insert IUDs so check first before making your appointment.

38 Intrauterine System or IUS (Mirena) – The IUS is a small T-shaped device like the IUD and is placed inside the uterus by a doctor. Each day, it releases a small amount of a hormone similar to progesterone called levonorgestrel that causes the cervical mucus to thicken so sperm cannot reach the egg. The IUS stays in your uterus for up to five years. It does not protect against STDs or HIV. The IUS is 99% effective. The Food and Drug Administration approved this method in December 2000. You will need to visit your doctor to have it inserted and to make sure you are not having any problems. Not all doctors insert the IUS so check first before making your appointment The Female Condom – Worn by the woman, this barrier method keeps sperm from getting into her body. It is made of polyurethane, is packaged with a lubricant, and may protect against STDs, including HIV. It can be inserted up to 24 hours prior to sexual intercourse. Female condoms are 79 to 95% effective at preventing pregnancy. There is only one kind of female condom, called Reality, and it can be purchased at a drug store.

39 Depo-Provera – With this method women get injections, or shots, of the hormone progestin in the buttocks or arm every 3 months. It does not protect against STDs or HIV. Women should not use Depo-Provera for more than 2 years in a row because it can cause a temporary loss of bone density that increases the longer this method is used. The bone does start to grow after this method is stopped, but it may increase the risk of fracture and osteoporosis if used for a long time. It is 97% effective at preventing pregnancy. You will need to visit your doctor for the shots and to make sure you are not having any problems.

40 Diaphragm, Cervical Cap or Shield – These are barrier methods of birth control, where the sperm are blocked from entering the cervix and reaching the egg. The diaphragm is shaped like a shallow latex cup. The cervical cap is a thimble-shaped latex cup. The cervical shield is a silicone cup that has a one- way valve that creates suction and helps it fit against the cervix. The diaphragm and cervical cap come in different sizes and you need a doctor to “fit” you for one. The cervical shield comes in one size and you will not need a fitting. Before sexual intercourse, you use them with spermicide (to block or kill sperm) and place them up inside your vagina to cover your cervix (the opening to your womb). You can buy spermicide gel or foam at a drug store. Some women can be sensitive to an ingredient called nonoxynol-9 and need to use spermicides that do not contain it. The diaphragm is 84 to 94% effective at preventing pregnancy. The cervical cap is 84 to 91% effective at preventing pregnancy for women who have not had a child and 68 to 74% for women who have had a child. The cervical shield is 85% effective at preventing pregnancy. Barrier methods must be left in place for 6 to 8 hours after intercourse to prevent pregnancy and removed by 24 hours for the diaphragm and 48 for cap and shield. You will need to visit your doctor for a proper fitting for the diaphragm or cervical cap and a prescription for the cervical shield.


42 Contraceptive Sponge - This is a barrier method of birth control that was re- approved by the Food and Drug Administration in 2005. It is a soft, disk shaped device, with a loop for removal. It is made out of polyurethane foam and contains the spermicide nonoxynol-9. Before intercourse, you wet the sponge and place it, loop side down, up inside your vagina to cover the cervix. The sponge is 84 to 91% effective at preventing pregnancy in women who have not had a child and 68 to 80% for women who have had a child. The sponge is effective for more than one act of intercourse for up 24 hours. It needs to be left in for at least six hours after intercourse to prevent pregnancy and must be removed within 30 hours after it is inserted. There is a risk of getting Toxic Shock syndrome or TSS if the sponge is left in for more than 30 hours. The sponge does not protect against STDs or HIV. There is only one kind of contraceptive sponge for sale in the United States, called the Today Sponge, and it can be purchased at a drug store. Women who are sensitive to the spermicide nonoxynol-9 should not use this birth control method.

43 The Patch (Ortho Evra) –This is a skin patch worn on the lower abdomen, buttocks, or upper body. It releases the hormones progestin and estrogen into the bloodstream. You put on a new patch once a week for three weeks, and then do not wear a patch during the fourth week in order to have a menstrual period. The patch is 98 to 99% effective at preventing pregnancy, but appears to be less effective in women who weigh more than 198 pounds. It does not protect against STDs or HIV. You will need to visit your doctor for a prescription and to make sure you are not having problems.

44 The Hormonal Vaginal Contraceptive Ring (NuvaRing) – The NuvaRing is a ring that releases the hormones progestin and estrogen. You squeeze the ring between your thumb and index finger and insert it into your vagina. You wear the ring for three weeks, take it out for the week that you have your period, and then put in a new ring. The ring is 98 to 99% effective at preventing pregnancy. You will need to visit your doctor for a prescription and to make sure you are not having problems. This birth control method is not recommended while breastfeeding because the hormone estrogen may decrease breast milk production. Surgical Sterilization (Tubal Ligation or Vasectomy) – These surgical methods are meant for people who want a permanent method of birth control. In other words, they never want to have a child or they do not want more children. Tubal ligation or “tying tubes” is done on the woman to stop eggs from going down to her uterus where they can be fertilized. The man has a vasectomy to keep sperm from going to his penis, so his ejaculate never has any sperm in it. They are 99.9% effective at preventing pregnancy.

45 Nonsurgical Sterilization (Essure Permanent Birth Control System) – This is the first non-surgical method of sterilizing women. A thin tube is used to thread a tiny spring-like device through the vagina and uterus into each fallopian tube. Flexible coils temporarily anchor it inside the fallopian tube. A Dacron-like mesh material embedded in the coils irritates the fallopian tubes’ lining to cause scar tissue to grow and eventually permanently plug the tubes. It can take about three months for the scar tissue to grow, so it is important to use another form of birth control during this time. Then you will have to return to your doctor for a test to see if scar tissue has fully blocked your tubes. - After 3 years of follow-up studies, Essure has been shown to be 99.8 % effective in preventing pregnancy.

46 Emergency Contraception – This is NOT a regular method of birth control and should never be used as one. Emergency contraception, or emergency birth control, is used to keep a woman from getting pregnant when she has had unprotected vaginal intercourse. “Unprotected” can mean that no method of birth control was used. It can also mean that a birth control method was used but did not work – like a condom breaking. Or, a woman may have forgotten to take her birth control pills, or may have been abused or forced to have sex when she did not want to. Emergency contraception consists of taking two doses of hormonal pills taken 12 hours apart and started within three days after having unprotected sex. These are sometimes wrongly called the “morning after pill.” The pills are 75 to 89% effective at preventing pregnancy. Another type of emergency contraception is having the Copper T IUD put into your uterus within seven days of unprotected sex. This method is 99.9% effective at preventing pregnancy. Neither method of emergency contraception protects against STDs or HIV. You will need to visit your doctor for either a prescription for the pills or for the insertion of the IUD, and to make sure you are not having problems.

47 »The Menstrual Cycle »About every 28 days, some blood and other products of the disintegration of the inner lining of the uterus (the endometrium) are discharged from the uterus, a process called menstruation. During this time a new follicle begins to develop in one of the ovaries. After menstruation ceases, the follicle continues to develop, secreting an increasing amount of estrogen as it does so. follicle

48 »The rising level of estrogen causes the endometrium to become thicker and more richly supplied with blood vessels and glands. »A rising level of LH causes the developing egg within the follicle to complete the first meiotic division (meiosis I), forming a secondary oocyte.meiosis I »After about two weeks, there is a sudden surge in the production of LH. »This surge in LH triggers ovulation: the release of the secondary oocyte into the fallopian tube.fallopian tube

49 –Under the continued influence of LH, the now-empty follicle develops into a corpus luteum (hence the name luteinizing hormone for LH).corpus luteum –Stimulated by LH, the corpus luteum secretes progesterone which continues the preparation of the endometrium for a possible pregnancy inhibits the contraction of the uterus inhibits the development of a new follicle

50 –If fertilization does not occur (usually the case), the rising level of progesterone inhibits the release of GnRH which, in turn, inhibits further production of progesterone. –As the progesterone level drops, the corpus luteum begins to degenerate; the endometrium begins to break down, its cells committing programmed cell death (apoptosis);apoptosis the inhibition of uterine contraction is lifted, and the bleeding and cramps of menstruation begin.

51 Pregnancy Fertilization of the egg takes place within the fallopian tube. As the fertilized egg passes down the tube, it undergoes its first mitotic divisions. By the end of the week, the developing embryo has become a hollow ball of cells called a blastocyst. At this time, the blastocyst reaches the uterus and embeds itself in the endometrium, a process called implantation. With implantation, pregnancy is established.fallopian tube mitotic divisionsblastocyst

52 Pregnancy The blastocyst has two parts: the inner cell mass, which will become the baby, andinner cell mass the trophoblast, which willtrophoblast –develop into the extraembryonic membranes, the amnion placenta, and umbilical cord –and begin to secrete human chorionic gonadotropin (HCG).

53 Pregnancy HCG is a glycoprotein. It is a dimer of the same  subunit (89 aa) used by TSH, FSH, and LH) and unique  subunit (148 aa).glycoproteinTSHFSHLH HCG behaves much like FSH and LH with one crucial exception: it is NOT inhibited by a rising level of progesterone. Thus HCG prevents the deterioration of the corpus luteum at the end of the fourth week and enables pregnancy to continue beyond the end of the normal menstrual cycle.

54 Pregnancy Because only the implanted trophoblast makes HCG, its early appearance in the urine of pregnant women provides the basis for the most widely used test for pregnancy (which can provide a positive signal even before menstruation would have otherwise begun). »As pregnancy continues, the placenta becomes a major source of progesterone, and its presence is essential to maintain pregnancy. Mothers at risk of giving birth too soon can be given a synthetic progestin to help them retain the fetus until it is full-term.progestin

55 Birth Toward the end of pregnancy, Secretion of estrogen by the placenta rises. –This rise is triggered by the fetus itself: The placenta releases CRH which stimulates the pituitary of the fetus to secrete ACTH, which acts on the adrenal glands of the fetus causing them to release the estrogen precursor dehydroepiandrosterone sulfate (DHEA-S).CRHACTH This is converted into estrogen by the placenta.

56 Birth The rising level of estrogen causes the smooth muscle cells of the uterus tosmooth muscle cells –synthesize connexins and form gap junctions. Gap junctions connect the cells electrically so that they contract together as labor junctions –express receptors for oxytocinoxytocin Oxytocin is secreted by the posterior lobe of the pituitary as well as by the uterus. A number of prostaglandins also appear in the mother's blood as well as in the amniotic fluid.prostaglandins Both oxytocin and prostaglandins cause the uterus to contract and labor begins.

57 Birth Three or four days after the baby is born, the breasts begin to secrete milk. Milk synthesis is stimulated by the pituitary hormone prolactin (PRL), andprolactin (PRL) its release from the breast is stimulated by oxytocin. Milk contains an inhibitory peptide. If the breasts are not fully emptied, the peptide accumulates and inhibits milk production. This autocrine action thus matches supply with demand.autocrine

58 Birth-Other Hormones Relaxin-As the time of birth approaches in some animals (e.g., pigs, rats), this polypeptide has been found to: –relax the pubic ligaments –soften and enlarge the opening to the cervix. Relaxin is found in pregnant humans but at higher levels early in pregnancy than close to the time of birth. Relaxin promotes angiogenesis, and in humans it probably plays a more important role in the development of the interface between the uterus and the placenta that it does in the birth process.angiogenesis

59 Birth Activins, Inhibins, Follistatin. These proteins are synthesized within the follicle. Activins and inhibins bind to follistatin. Activins increase the action of FSH; inhibins, as their name suggests, inhibit it. How important they are in humans remains to be seen. However the important role that activin and follistatin play in the embryonic development of vertebrates justifies mentioning themactivin

60 Oral contraceptives: the "pill" The feedback inhibition of GnRH secretion by estrogens and progesterone provides the basis for the most widely-used form of contraception. Dozens of different formulations of synthetic estrogens or progestins (progesterone relatives) — or both — are available. Their inhibition of GnRH prevents the mid-cycle surge of LH and ovulation. Hence there is no egg to be fertilized.

61 Oral contraceptives: the "pill" Usually the preparation is taken for about three weeks and then stopped long enough for normal menstruation to occur. The main side-effects of the pill stem from an increased tendency for blood clots to form (estrogen enhances clotting of the blood).

62 RU-486 RU-486 (also known as mifepristone) is a synthetic steroid related to progesterone. Unlike the synthetic progestins used in oral contraceptives that mimic the actions of progesterone, RU-486 is a progesterone antagonist; that is, it blocks the action of progesterone. It does this by binding more tightly to the progesterone receptor than progesterone itself but without the normal biological effects:

63 RU-486 The RU-486/receptor complex is not active as a transcription factor. Thus genes that are turned on by progesterone are turned off by RU-486. The proteins needed to establish and maintain pregnancy are no longer synthesized. The endometrium breaks down. The embryo detaches from it and can no longer make chorionic gonadotropin (HCG). Consequently the corpus luteum ceases its production of progesterone.

64 RU-486 The inhibition on uterine contraction is lifted. Soon the embryo and the breakdown products of the endometrium are expelled. These properties of RU-486 have caused it to be used to induce abortion of an unwanted fetus. In practice, the physician assists the process by giving a synthetic prostaglandin (e.g., misoprostol [Cytotec®]) 36–48 hours after giving the dose of RU-486. Use of RU-486 is generally limited to the first seven weeks of pregnancy. prostaglandin

65 RU-486 RU-486 has been used for many years in some countries. However, the controversies surrounding abortion in the United States kept it from being authorized for use here until September 2000.

66 Menopause Menstrual cycle continues for many years. But eventually, usually between 42 and 52 years of age, the follicles become less responsive to FSH and LH. They begin to secrete less estrogen. Ovulation and menstruation become irregular and finally cease. This cessation is called menopause. With levels of estrogen now running one-tenth or less of what they had been, the hypothalamus is released from their inhibitory influence (bar). As a result it now stimulates the pituitary to increased activity. The concentrations of FSH and LH in the blood rise to ten or more times their former values. These elevated levels may cause a variety of unpleasant physical and emotional symptoms.hypothalamuspituitary

67 Hormone replacement therapy (HRT) Many menopausal women elect to take a combination of E and P after they cease to make their own. The benefits are: reduction in the unpleasant symptoms of the menopause a reduction in the loss of calcium from bones and thus a reduction in osteoporosis and the fractures that accompany it.osteoporosis It was also believed that HRT reduced the risk of cardiovascular disease. However, a recent study of 16,000 menopausal women was stopped 3 years early when it was found that, in fact, HRT increased (albeit only slightly) not decreased the incidence of cardiovascular disease. Perhaps synthetic selective estrogen response modulators or SERMs (raloxifene is an example) will provide the protective effects without the harmful ones. Stay tuned.

68 Environmental estrogens Some substances that find their way into the environment, such as DDE, a breakdown product of the once widely- used insecticide DDT, DDT itself (still used in some countries (e.g., Mexico), andDDT PCBs, chemicals once used in a wide variety of industrial applications can bind to the estrogen (and androgen) receptors and mimic (weakly) the effects of the hormone. This has created anxiety that they may be responsible for harmful effects such as cancer and low sperm counts.androgen

69 Environmental estrogens However, there is as yet little evidence to support these worries. No epidemiological relationship has been found between the incidence of breast cancer and the levels of these compounds in the body. As for laboratory studies that found a synergistic effect of two of these substances on receptor binding (findings that created the great alarm), these have not been replicated in other laboratories, and the authors of the original report have since withdrawn it as invalid.

70 2002 July 10 th (WHI) clinical trial tracked the long term effects of hormone (HT) trial was being halted three years ahead of schedule. The results showed an unacceptable proportion of women were harmed by the therapy. Data implied that HT did not protect against memory loss and other neurodegenerative conditions such as dementia, and in fact increased their risk of stroke and breast cancer.

71 At the time, some 14 million US women were taking HT to relieve postmenopausal symptoms or to lower their risk for osteoporosis. Numerous studies had suggested that hormone treatment, using synthetic estrogens or a combination of synthetic estrogens and progestins, protected women from many diseases, whereas the absence of estrogen made women more vulnerable.

72 WHI -20,000 participants, was the largest clinical trial to date. With numbers like that it was very difficult to argue that estrogen wasn’t harmful. Was cause to argue estradiol, was protective against damage caused by stroke. Would estradiol influence the extent of injury in rats after we experimentally induced cerebrovascular stroke by blocking blood flow to a major vessel in the brain.

73 Animals with very low levels of estradiol experienced approximately half the amount of injury compared to animals without estrogens. Estradiol had to be present before we performed the stroke injury; otherwise treatment was totally ineffective in protecting the brain. Low doses were as effective as higher doses. Experiment was performed in mice, direct opposition to the WHI findings.

74 Estrogens - pleiotropic hormone which actd on a plethora of physiological functions not directly related to reproduction, therefore also important in male physiology. Estrogens were important players in the immune system, in cardiovascular function, in bone formation and breakdown, in fat distribution and metabolism, learning and memory.

75 Community of estrogen researchers rallied together Why the discrepancies between this major clinical trial and previous studies. Estrogens influenced many genes that regulate cell survival and cell death. Low concentrations of estradiol protected the brain by suppressing apoptosis.

76 Estradiol could change the expression of multiple genes and proteins. Estradiol helps maintain levels of bcl-2, a protein which reduces apoptosis after stroke. Estradiol inhibits caspases, proteins that mediate cell death. Stroke increased the expression of estrogen receptors to allow estrogen to protect the brain and enhance its repair. All of these changes tip the balance toward cell survival and against cell death.

77 WHI study had traced women before stroke had occurred to capture their risk, but didn’t follow women after their stroke to see if women taking estrogen had improved recoveries as models suggested. Men also produce estrogen and are protected after stroke when estrogens are present. Not possible to treat men with estrogen because the hormone has feminizing effects that are not acceptable. Development of compounds that use the same protective mechanisms, but do not have the other effects of estrogen.

78 Cytosolic estrogen receptor discovered in the 1960’s act by transporting estrogens attached to the receptor to the nucleus where the hormone-receptor complex bound to DNA and acted as a transcription factor. 30 years estrogens were thought to act: via a single receptor that acted by binding to the promoter region

79 In 1996 actually two different estrogen receptor subtypes: ER  and ER  ER  - or ER  -knock out mice and found that ER  plays a pivotal role in protecting the brain against cell death. ER  proved not to play a role in protection.

80 Develop drugs that target a specific receptor to allow better outcomes from stroke. Studies mean in terms of the results of the WHI? Two aspects of the clinical study design are worth considering. First, only synthetic hormones were used. Might account for differential actions of these substances compared to endogenous hormones.

81 Second, the average age of women when they started the WHI trial was 63 years old and most of them had not had hormone therapy previous to the trial. Most of them had been estrogen deficient for about 12 years.

82 Investigate what delayed the time of hormone treatment in mice to match that of the WHI. Did not treat mice immediately after ‘menopause,’ but waited for several weeks (the equivalent of several human years), that hormone treatment was totally ineffective.

83 Estradiol acts is by suppressing inflammation, thereby preventing cell death. Waited a few weeks unable to suppress inflammation. Depends upon the presence of ER  The timing or treatment is a critical factor to consider.

84 Different kinds of estrogens and different concentrations of hormone have different effects. Hormonal milieu makes a big different in how estrogens act Completely opposite effects depending upon what other hormones are present and whether they have been there before or after estrogen exposure.

85 Neurogenesis dogma had been that all neurons were born during embryonic and early postnatal development New neurons were born even in adulthood. Estrogen was important in the developing brain of an embryo. Fetal and early postnatal brain, estrogens are factors that mediate Neurogenesis, synapse formation and glial differentiation

86 Estrogens are potent neurogenic factors after stroke injury in the adult brain. Effect depends on both ER  and ER . Uncertain how estradiol works to enhance Neurogenesis. Promise for the use of estrogens in the long-term repair and recovery of brain function

87 Clinical trials such as the WHI are impressive for the number of women they study. But because of prohibitive costs of performing such a large clinical trial, only a limited number of questions can be addressed. In the year following WHI trail 40% of women stopped taking hormone replacement therapy

88 Realized that results should have been interpreted with more caution. Functions depend upon dose, preparation, method of administration, the recipient’s age, genetics and previous exposure to the hormone.

89 Estrogens should be expected to be among the most complex ones to understand: they exhibit a diurnal rhythm, a monthly rhythm that is determined by the menstrual cycle, and they act differently depending upon whether other reproductive hormones are present in high or low concentrations. Estrogens are not the panacea people thought they were, but neither are they always harmful.

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