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Contraception is prevention of conception. This lesson will deal mainly with contraception, but fertility control methods also include post-coital contraceptives and termination of pregnancy(abortion). This lesson will not deal with the issue of abortion except to discuss one drug which isused for this purpose.
Sequence of Events in the Monthly Ovarian Cycle
- The monthly ovarian cycle involves the intricate and coordinated interaction of a number of hormones and factors. The sequential release of these hormones is necessary to ensure that a matureovum is released at the appropriate time.
- At the beginning of the cycle, the plasma levels of both estrogen and progesterone are low andthe endometrium is sloughed (menstruation). In response to the low levels of estrogen andprogesterone, the hypothalamus (an area of the brain) begins to secrete gonadotropin releasing factor(GRF). GRF stimulates the anterior pituitary to release follicle stimulating hormone (FSH) andluteinizing hormone (LH). In response to FSH, a number of ovarian follicles, each containing one ovum, begin to enlarge. After five or six days, one of these follicles develops rapidly and the others regress. In response to FSH, the maturing follicle begins to secrete estrogen, small amounts at first,then larger amounts, until it peaks at day 14 of the cycle. Near day 14, LH secretion peaks andstimulates the maturing ovarian follicle to grow more rapidly; the follicle swells, then bursts, releasingthe ovum. Thus, both FSH and LH are required for ovulation.
- After ovulation, the ovum is picked up by the fimbriae (end of fallopian tubes) into the fallopiantubes and transported to the uterus. It is during the transport through the fallopian tubes thatfertilization occurs.
- During the period that the follicle is undergoing maturation, estrogen and progesterone arepreparing the endometrium (lining of the uterus) for the arrival of the fertilized ovum. During the first14 days of the cycle, the effect of estrogen on the endometrium is one of growth (proliferation), as the lining increases in thickness. Just prior to day 14, the ovary (corpus luteum) begins to secrete increasing amounts of progesterone. Progesterone stimulates the endometrium to secrete nutrients which are needed to support the fertilized ovum as it arrives in the uterus. Progesterone is the hormone supporting the endometrium at this time. After 10 or 12 days, the corpus luteum ceases to function, progesterone secretion diminishes, and the endometrium loses hormonal support leading to sloughing of the endometrium and menstruation. It should be noted that arrival of the fertilized ovum must occur at the appropriate development of the endometrium. If the endometrium is not suitable,implantation will not occur. If pregnancy occurs, the uterus will begin to secrete large amounts of estrogen and progesterone; the progesterone will maintain the integrity of the endometrium and thepregnancy will continue.
Hormonal Contraceptives (Female)
There are several types of hormonal contraceptives that modify the ovarian cycle. The term “oral contraceptive” is usually used to refer to a product containing both an estrogen and aprogestin (progesterone-like compound). The preparations which contain an estrogen and a progestinare the most effective contraceptives developed to date and are also the most widely used.
Types of Hormonal Preparations
- 1. Fixed combinations of an estrogen and a progestin are intended to be taken from the 5th to the25th day of the cycle, counting day 1 as the onset of menses. This is the first preparation thatwas developed in 1955, by Pincus and Rock in Puerto Rico. The first product, Enovid-E, becameavailable in Canada in 1961.
- 2. Multiphasic (biphasic and triphasic) preparations usually contain a fixed amount of an estrogen and variable amounts of a progestin; the progestin increases from week to week. Theadvantages of these preparations are that the hormone dose is kept to a minimum and adverse events are believed to be reduced as compared to a fixed-dose combination. In addition, thehormonal sequence more closely mimics the pattern of hormones released in the normal ovariancycle and this may be a further advantage. These “phasic” preparations are currently the oralcontraceptives of choice.
- 3. Continuous estrogen progestin preparations are products where an estrogen progestincombination product are taken for 28 days each cycle with no drug free period.
- 4. Transdermal Contraceptive patch: These products contain ethinyl estradiol and norelgestromin(progestin) in a patch that is applied to the skin. The drug is delivered at a constant rate for 7 days, thetime the patch is worn. Three patches are used each cycle. The mechanism of action is the same asfor combined estrogen-progestin oral contraceptives.
- 5. Low-dose progestin or the mini-pill contains a synthetic progestin, e.g. norethindrone. A dailydose of progestin is taken as long as the drug is needed. Patient acceptability is less than with the estrogen-progestin combinations. Breakthrough bleeding (bleeding between periods) is often aproblem. Efficacy in preventing pregnancy is also less than with the combination products.
- 6. Norplant is comprised of silicone tubes filled with L-norgestrel (a progestin) which areimplanted under the skin. The drug is released over a period of five years and provides effective contraception during this time. The cost of the drug product and surgical placement isapproximately $700, which is equivalent to using an estrogen-progestin combination product for three years.
- 7. Depoprovera: Injectable progestin injected every three months, provides contraception for about 3months.
1. Estrogen-progestin combinations: Mechanism of Action
- The mechanism of action of estrogen-progestin combination oral contraceptives are essentially the same for the fixed ratio products and the phasic products.
- (a) The estrogen inhibits the release of GNRH from the hypothalamus. The pituitary is notstimulated to release FSH and LH, and without FSH and LH, follicles do not mature and thusovulation is inhibited.
- (b) Under conditions in a normal cycle, the secretion of the endocervical glands is a thin watery mucus in the first 14 days when estrogen is present. Under the influence of progesterone, in thelast half of the cycle, these secretions are thick and not optimal for sperm migration. The oralcontraceptives which contain a progestin render these secretions a thick, scant fluid throughoutthe entire cycle.
- (c) As the oral contraceptives contain both estrogen and a progestin, the preparation of the endometrium is not optimal for implantation of a fertilized ovum.
2. Low-dose progestin and Norplant and DepoProvera: Mechanism of Action
- (a) Progestin inhibits the release of GNRH and thus ovulation.
- (b) The endometrium is not fully developed and is unsuitable for implantation.
- (c) Progestins alter the secretions of the endocervical gland to a scant, thick fluid not optimal forsperm migration.
Choice of Hormonal Preparation
The combined estrogen-progestin products are the preferred agents. In the last decade, the phasic preparations have gained popularity and the total dose of exogenous hormone is reduced. Thesepreparations are essentially 100% effective. The progestin-alone agents are about 98% effective andsome of the adverse events have been a problem. The progestin-alone preparations are most suitable in those individuals where estrogens are contraindicated (should not be used)
1. Low-dose progestin (mini-pill): DepoProvera is similar. Adverse Events
- Menstrual bleeding between periods occurs frequently. This is called breakthrough bleeding.
- Some progestins alter the profile of the plasma lipids. There is an increase in low density lipoproteins (bad cholesterol) and a decrease in high density lipoproteins (good cholesterol). Theoverall result is a small increase in the risk of coronary vascular disease. It should be noted thatsome of the newer agents do not adversely affect the plasma lipids.
2. Norplant: Adverse Events
- Bleeding irregularities – that is, changes in the duration of menstrual bleeding and breakthrough bleeding occurs in about 27% of patients in the first year.
- Weight gain.
- Headache, nervousness and anxiety have been observed by some patients.
- Acne can occur in some patients.
- Muscular pain, breast discharge and abdominal discomfort have been reported by 5% of patientsduring the first year.
- The adverse events listed above demand that patients be carefully selected and counselled before implanting Norplant.
3. Estrogen-progestin combinations: Adverse Events
There are approximately 20 million women in North America taking these preparations each day. It has, therefore, been necessary to carefully evaluate the toxicity of these drugs. A large number of toxicities have been reported with the use of oral contraceptives. They occur infrequently and range from mild to serious in severity.
Mild: Adverse Events of the combo
- Nausea – caused by the estrogen component and usually abates after one or two cycles.
- Edema – the estrogen and progestin cause water retention.
- Headache – migraine is more severe. If headache is severe, the drugs must be stopped.
- Libido – may increase or decrease.
- Menstrual flow may be reduced – there is not a full proliferative phase of the endometrium,and thus less tissue for shedding.
- Weight gain.
- Increased skin pigmentation – estrogen produces increased skin pigmentation which can be aproblem.
- Acne and hirsutism – the progestin is believed to cause these two responses.
- Vaginal and uterine infections are more common – if uterine infections are untreated, sterility can result.
- Post-drug amenorrhea – occurs in a few patients and may persist for months.
- Cholestatic or obstructive jaundice has been reported.
- Changes in carbohydrate metabolism with an increase in glucose tolerance.
- There is a decrease folate absorption, but only a few patients develop anemia.
Serious: Adverse Events of the combo
- Thromboembolic disease is increased in users of oral contraceptives: Estrogens induce the production of some of the factors that are required for blood coagulation(clotting), leading to a condition of increased tendency of the blood to form clots in the veins. The death rate from thromboembolic disease is one per 100,000 woman years for non-users of estrogen-progestin oral contraceptives and three per 100,000 woman years for users (100,000woman years is defined as 100,000 women taking the drug for one year). It can be argued thatthis is a very low incidence, but it is increased.
- Myocardial infarct (heart attacks): Young women do not normally suffer myocardial infarcts unless there are risk factorsinvolved. The estrogen-progestin oral contraceptives are associated with a small risk formyocardial infarct. The risk is greater if the patient is obese or if the patient smokes. Theapproximate risk factors are: users of oral contraceptives is four per 100,000 woman years,and smokers using oral contraceptives is 185 per 100,000 years. The adverse effect is believedto be associated with the progestin component. Some of the newer progestins may be free ofthis effect.
- Cerebrovascular disease (stroke): There is an increased risk for stroke in women taking oral contraceptives. The risk is greater ifthe patient is over 35 years of age, but all ages are affected. The actual risk is not known, butsome studies have quoted a figure of 37 per 100,000 woman years with 10% of these being fatal.
- Hypertension: Cardiovascular disease in users of oral contraceptives is more prevalent in women over 35years of age.
- Cancer: Reduces the risk of endometrial and ovarian cancer. No effect on risk of breast cancer. Hepatic adenomas have been reported. Case reports have suggested that some may haveprogressed to hepatocellular carcinoma.
- The majority of the toxicities were thought to be associated with estrogen; thus; use the lowes tacceptable dose (50 mg/day or less). Recently it has been suggested that the progestin also plays arole.
Contraindications for Combined Estrogen-Progestin
- (a) Thromboembolic disease.
- (b) Cerebrovascular disease.
- (c) Impaired liver function.
- (d) Carcinoma of the breast or estrogen-dependent neoplasia.
- (e) Undiagnosed bleeding.
- (f) Pregnancy or suspected pregnancy. Oral contraceptives during pregnancy may be associatedwith congenital limb deformation, masculinization and crytochism (undescended testes)
Progesterone maintains the endometrium in the last half of the cycle and during pregnancy, shouldpregnancy occur. Mifepristone blocks the effect of progesterone on the endometrium and theendometrium then lacks the support of progesterone and the lining is sloughed (menstruation). Thedrug can be taken after a “missed period” to bring on menstruation. The drug is sold in Canada, but isnot approved for use as a contraceptive.
Large doses of estrogen taken after coitus. Estrogen and a progestin is taken, usually within 24hours, but no later than 72 hours after coitus. The large dose of estrogen ( 3 X the amount in an oralcontraceptive tablet) either delays ovulation or inhibits ovulation. The major problem is the nauseacaused by the estrogen.
Intra-Uterine Device (IUD)
The coil is introduced into the uterus. It is generally believed that the presence of a foreign objectcauses a local tissue reaction and prevents implantation of the fertilized ovum. In addition, the IUDincreases contractions of the uterus and the fertilized ovum is expelled before it can be implanted.
The problems associated with the IUD are:
- (a) Heavy menstrual flow.
- (b) Pelvic discomfort .
- (c) About 10-15% are expelled spontaneously (usually during first two months).
- (d) There is an increase in the incidence of uterine infections.
- The pregnancy rate is 3/100 woman years.
Diaphragm and Spermicidal Jelly
- The diaphragm is a cap filled with a agent which destroys sperm and is placed over the cervix andacts as a physical and chemical barrier to prevent sperm from reaching the ovum.
- Disadvantages of the diaphragm are:
- (a) They must be properly fitted and properly used.
- (b) They must be inserted before coitus and may interrupt the sex act.
- (c) They must remain inserted for 6-8 hours after coitus to allow the spermicide to act.
- The pregnancy rate is 10/100 woman years.
- The condom is a physical barrier worn over the penis.
- Advantage: A good latex condom will prevent the spread of sexual transmitted diseases.
- Disadvantage: They can interfere with the sex act.
- The pregnancy rate is 15/100 woman years; condoms can tear or break and thus lead to contraceptivefailure.
- This is a physical barrier (sleeve) inserted into the vagina. They are not as acceptable as the malecondom, nor as effective.
- Advantages: Prevention of sexually transmitted diseases and pregnancy.
- Disadvantage: Ease of insertion and user acceptability. There is a tendency for these devices todislodge. Although available for about 25 years this product has not had wide acceptance.
- Abstinence a few days before and after ovulation. There is an increase in body temperature atovulation and this is often used to time the period of abstinence. The reason for failure is that time ofovulation is extremely variable and couples must adhere to the abstinence plan.
- The pregnancy rate is 25/100 woman years
- Removal of the penis before ejaculation. This method is not effective since some sperm are releasedbefore ejaculation and sperm may migrate into the vaginal tract if ejaculated near the vaginal opening.
- The pregnancy rate is 25/100 woman years.
This method is not effective in removing sperm from the vaginal tract. In fact, douching may hastensperm migration.
This method is a permanent form of contraception and is best described as tying the fallopian tubulesso that the ovum cannot migrate to the uterus. There is no loss of hormonal balance, thus there shouldbe no effect on sex drive. Some of the newer surgical techniques have been able to reverse theprocess.
This is a simple operation in which the sperm ducts are tied off so that sperm cannot reach the penis. This is considered a permanent form of contraception, except in the odd case where the sperm ductappears to regenerate or the surgery is not done properly. New microsurgery techniques haveimproved the success rate for reversal of the procedure.
Drug Contraceptives for Men
- Male contraceptives, which can be taken orally or injected, have not yet reached the Canadianmarket. Attempts to inhibit spermatogenesis (sperm development) has been difficult and most of thedrugs and processes studied have resulted in, at best, an 80% infertility rate – a figure that isunacceptable if we consider that the drug will be used on a routine basis for contraception.
- The gonadotropin releasing hormone antagonists, which would block both sperm and androgenproduction, are showing some promise as a male contraceptive.
1. Control of spermatogenesis:
As shown in the diagram, GNRH is released by the hypothalamus; GNRH stimulates the anteriorpituitary to release FSH and LH. FSH stimulates the seminiferous tubules to produce sperm. LHstimulates the Leydig cells to produce testosterone, the hormone responsible for male secondary sexcharacteristics. These include body hair growth, sex drive, increased muscle mass and certain typesof behaviour, e.g. aggression. Testosterone feeds back on the hypothalamus and controls the amountof GNRH released. Thus, there is a balance in the system. Attempts to modify this system withhormonal contraception has often upset this balance, leading to changes in sex drive (libido).
- Gossypol is a phenolic compound obtained from cottonseed. The compound destroys elements of the seminiferous tubules, decreasing sperm production, but does not alter sex drive or other functions oftestosterone. The drug has undergone extensive clinical trials in China; 20 mg/day of gossypol fortwo months, followed by 60 mg/week, led to a reduction in sperm count to less than four million/mlin 99% of the subjects (this level of sperm count is considered infertile). Recovery of sperm count ismore apt to occur if the sperm count does not fall too low and the duration of treatment does notexceed two years.
- Hypokalemia (low potassium) has been the major problem reported. This has resulted in transientparalysis. The drug is widely used in China and was undergoing clinical trials in North America but has now been abandoned.
- Estrogens, when administered to men, suppress GNRH release and in turn spermatogenesis. Estrogens have been studied as a male contraceptive. Unfortunately, when estrogens are given tomen, testosterone production decreases as does sex drive, and men develop feminine characteristics. Thus, the subjects were infertile, but they lost interest in sex (this is probably the most effective formof contraception).
- To overcome the deleterious effects of estrogen on secondary sex characteristics, small amounts ofandrogens were added to the regimen. With this combined estrogen-androgen regimen, only 60% ofthe subjects became infertile and adverse effects from the estrogen were too numerous.
4. Androgen-based contraceptives:
As indicated above, androgens can inhibit the release of GNRH and thus spermatogenesis. Exogenous androgens have been studied as male contraceptives. Usually an injectable form of thedrug was administered intramuscularly. In the studies conducted to date, two major problems havebeen encountered: only 80% of the subjects responded with a lowering of sperm count to less thanfour million/ml and the excess androgen enhanced the secondary sex characteristics, includingaggression.
5. Progestin combined with androgen:
In this combination, a synthetic progestin is used to inhibit the release of GNRH. This results in lossof spermatogenesis as well as testosterone production. The loss of testosterone leads to a reduction inthe male secondary sex characteristics. The androgen is added to the regimen to replace the losttestosterone and hence maintain the secondary sex characteristics. This method has shown morepromise than other methods, but finding the appropriate dose of the exogenous androgen is a majorchallenge.
Efficacy of Various Contraceptives
- The following table lists the efficacy of various forms of contraception, expressed as percent failure(pregnancies) per 100 woman years, that is 100 women using the contraceptive for one year. Thefigures include all causes of contraceptive failure, including inappropriate use and patient failures.