Female Hormonal Contraceptives

A functional account about progestogens, androgens and oestrogens has already been given in Chapter 5. It included the metabolic, morphological and endocrine effects of these three different steroids. It will be an impossible task to write about all brands of the hormonal contraceptives available worldwide. Many good brands are licensed in certain but not other countries. Accordingly, this chapter is not meant to give a detailed account of such different variations, or the instructions on how to use different contraceptives. It is written with the following objectives in mind, avoiding repetition of previously discussed issues:

Despite the great advances in the field of family planning over the last 30 years, oestrogens and progestogens remained the cornerstones for hormonal contraceptives, though newer means for their delivery have been introduced. Beside the oral route, transdermal, transvaginal and intrauterine routes have been used effectively, and with great acceptance by women. Progestogens played the major part in hormonal contraception, and are mostly derived from three parent steroid molecules which are estranes, gonanes and pregnanes. These molecules differ in relation to their half lives, and their antioestrogenic effect. Furthermore, gonanes have 17 carbon atoms, whereas estranes have 18. The range of progestogens used includes norethindrone, norethindrone acetate, ethynodiol diacetate, norgestrel, levonorgestrel, norethynodrel, desogestrel, norgestimate, and gestodene. The last three are derived from the gonane molecule, and are known as the third generation progestins. Other gonane derivatives include norgestrel and levonorgestrel. Estranes include norethindrone, norethindrone acetate, ethynodiol diacetate, and lynestrenol. Pregnanes include medroxyprogesterone acetate and megestrol acetate, and they have no androgenic activity. They are used in the injectable forms of hormonal contraceptives. The sequence of ascending androgenicity of the different progestogens used is: ethynodiol diacetate, norethindrone, norethindrone acetate, norgestimate and desogestrel, in that order. Levonorgestrel and gestodene have the highest androgenicity in all groups. This information is of great value when selecting a specific brand of contraceptive pill, especially when dealing with hyperandrogenic patients. Furthermore, progestogens of lower androgenic capability are less likely to oppose the oestrogen induced hepatic production of sex hormone binding globulin and high density lipoprotein (HDL). A new spironolactone analogue (drospirenone) which has anti-mineralocorticoid, anti-androgenic and progestational activities has been used in oral contraceptive pills, mainly for women with polycystic ovary syndrome and premenstrual dysphoric disorder.

In contrast to the long list of progestins, only two oestrogens are used in the majority of combined hormonal contraceptives; ethinyl oestradiol and mestranol. Ethinyl oestradiol is pharmacologically active, whereas mestranol has to be converted into oestradiol first before gaining biologically activity. Oral contraceptives currently in the market contain 20 - 35 micrograms of oestrogen. Pills with 50 µg ethinyl oestradiol are still available, but are used for the management of certain gynaecological problems when high doses of oestrogen are needed, rather than for regular contraceptive purposes. Unlike all the other routes, orally taken ethinyl oestradiol is absorbed rapidly from the intestines and undergoes rapid metabolism in the liver during the first hepatic pass which reduces its biological efficacy by almost 40%. It has plasma half life of 10-27 hours, with a longer half-life in tissues, such as the endometrium. This first hepatic pass affects different liver functions, including increased production of clotting factors, sex hormone binding globulin, transcortin, thyroid binding globulins, as well as changes in the lipid profile. This may have direct positive or negative effects on different individuals, depending on their own circumstances, such as patients with hypothyroidism on thyroxine replacement therapy. Such hepatic first pass does not occur with the transdermal route, which can be of benefit especially for patients at risk of thromboembolism.

Oral contraceptives can be used either in a combined oestrogen and progestogen form, or as progestogens only pills. Regular brands of the combined form have 21 pills, either in monophasic, biphasic or triphasic combinations. Monophasic pills have the oestrogen and progestogen in a fixed dose in the same pill for the whole 21 days. Biphasic and triphasic brands have oestrogen and progestogen pills in two or three different doses to be taken in sequence respectively. The idea behind these different combinations was to reduce the total amount of hormones used, and to simulate the variations in oestrogen and progesterone which occur during a natural ovulatory cycle. Newer brands of oral contraceptives have been manufactured to reduce the hormone free period by increasing the number of pills to be taken each cycle. Brands with 24 or 26 instead of 21 pills have been marketed. The main objective behind this regimen was to have better control of the bleeding episodes, and to reduce the premenstrual symptoms suffered by the patients during the hormone free period. Such brands are sold in the United States, but are not licensed yet in the United Kingdom. An extended protocol to use oral contraceptive pills for 84 days before having a withdrawal bleeding proved useful for patients with endometriosis and severe premenstrual syndrome. Seasonale (Duramed Pharmaceuticals, Inc) is a brand which contains 30 µg ethinyl oestradiol and 150 µg levonorgestrel. Yet again, despite the wide increase in the number of brands of combined hormonal contraceptives currently available, suppression of ovulation and local uterine changes remained to be the most important modes of action. These are affected through the synergistic effects of both oestrogen and progestogen. Nonetheless, in most cases the contraceptive efficacy is linked to the progestogen part, with oestrogen controlling regular bleeding.

Unlike oestrogens, progestogens can be used separately to provide adequate contraception. Progestogens only pills have been available for a long time, and are sometimes known as mini pills. They are mainly used when oestrogen is contraindicated. This is especially so in cases at risk of cardiovascular diseases and venous thromboembolism. They are also a good choice for lactating women requiring contraception, as they do not affect milk production, and do not influence the infant’s growth or development. Unlike the combined forms, they should be used continuously and at the same time every day without a break. Different brands are available and their main contraceptive effects have been related to the following points:

· They increase cervical mucus viscosity which reduces transcervical sperm migration into the uterine cavity. This effect is maximal four hours after intake. The pills should be taken at the same time every day, as serum levels fall to baseline levels within 24 hours after ingestion. Other precautions should be taken for 48 hours if taking a pill is delayed for more than 3 hours.

· They can inhibit activation of the enzymes necessary for sperm capacitation which is required for ovum penetration.

· They slow ovum transport through the fallopian tubes, which may increase the risk of tubal pregnancies.

· They reduce embryos implantation due to their progestational histological effects on the endometrium. Progestogens deplete their own receptors and oestrogen receptors in the endometrium. Biochemically, progestogens reduce the production of glycogen in the endometrium, and accordingly reduce the ability of the blastocyst to survive in the uterine cavity.

· Small doses of progestogens as used in the progestogen only pills do not usually inhibit ovulation, and many women continue to ovulate normally. Occasionally, only the LH surge is affected despite growth of the follicles to a mature size. This explains the increased risk of functional ovarian cysts seen in patients using progestogen only pills.

The two main injectable forms are depo-medroxyprogesterone acetate (depoprovera) and combined injectable contraceptives (CICs), both being long acting contraceptives. Depoprovera can be used in a dose of 150 mg every 3 months. Its blood level peaks approximately 10 days after drug administration, and sustain high blood levels capable of inhibiting ovulation by direct action at the hypothalamus and pituitary gland. It also has a strong progestational effect at the level of the endometrium. Amenorrhoea is common after the third dose in almost 50% of the users, with the majority of the remaining group having irregular bleeding episodes (1). After one year of use, about 75% of the users will be amenorrhoeic. It may take up to 200 days for the drug to clear off the circulation following a single injection, as documented in the Depoprovera Product Monograph (2). This slow decline in the level of serum progestogen is responsible for the long period of amenorrhoea and delayed return of fertility. It took 9 months after the last injection on average for women to conceive as reported in the same Monograph (2). In comparison to intrauterine contraceptive devices (IUCD) and oral contraceptives, 92% of women conceived within 2 years after discontinuing depoprovera, 93% after IUCD and 95% after stopping the pill (2). Partial reactivation of the hypothalamo-pituitary-ovarian axis may allow basic folliculogenesis to restart leading to development of mature follicles, with failure of the LH surge mechanism. This will prevent the final act of ovulation, or may lead to abnormal ovulation and dysfunctional uterine bleeding. Being a strong antioestrogen, it has been associated with the development of osteoporosis. This effect has been quantified by the Product Monograph alluded to before (2), which reported 5-6% reduction in the spine and hip bone mass density after 5 years of depoprovera use. This decline was more pronounced during the first two years of medication. This effect was not carried through during the postmenopausal years as shown by a World Health Organisation study, which showed similar bone mass density in women who did or did not use depoprovera (3). Furthermore, young women in their teenage years are more likely to regain their bone mass density within 12 months after stopping medication. An advantage of depoprovera is that it has no androgenic effect. Furthermore, it does not affect the level of triglycerides or total cholesterol (4), and has no significant detrimental effect on the liver function, coagulation factors, fibrinolysis, or blood pressure. Alterations in carbohydrate metabolism similar to those imposed by the oral contraceptive pill can follow depoprovera administration, but to a lesser extent and with minor clinical significance (5). More information about depoprovera has been given in Chapter 5. Another injectable progestogen is Noristerat, which is made of 200 mg norethisterone enanthate. It should be given by deep intramuscular injection on the fifth day of the cycle for short term effective contraception, when patient’s compliance is not guaranteed regarding the pill. It can be repeated after eight weeks if necessary. It has similar mode of action to depoprovera, but menstrual irregularities are less common.

Combined injectable contraceptives (CICs) contain both oestrogen and progestogen, and are given by monthly intramuscular injections. Their mode of action is similar to that of the combined oral contraceptive pill, with similar range of side effects and contraindications, but without the first hepatic pass. They offer better cycle control and quicker return of fertility after suspending medication than the progestogen only injections. There are three main types of CICs including Cyclofem, Mesigyna and Deladroxate. Cyclofem (cyclo-provera) contains 25 mg depo-medroxyprogesterone acetate, plus 5 mg oestradiol cypionate. Mesigyna is made up of 5 mg oestradiol valerate and 50 mg norethisterone enanthate. Deladroxate contains 10 mg of oestradiol enanthate and 150 mg dihydroxyprogesterone acetophenide. The first dose should be given within the first 5 days of menstruation, and repeat injections administered every 28 days. They offer an error margin of 5 days only. Because of their depo effect, ovulation and fertility usually return 2-3 months after the last administered dose (6). A recent Cochrane database systemic review showed that more women using CICs had normal bleeding, and fewer of them stopped using them because of bleeding reasons than progestin-only users (7). Another advantage of CICs is that there is low incidence of amenorrhoea, after their prolonged use. Despite all these advantages, this method is not very popular yet, and is not licensed in many countries. Nevertheless, it can be very useful in developing countries as it needs less compliance than the oral contraceptive pill.

Research in subdermal implants started in 1967 which resulted in the introduction of Norplant in 1983 in Finland, before being used in other countries. It was licensed for 5 years, but has been withdrawn from the UK in 1999. Another discontinued brand was Jadelle, which was made of two rods each containing 75 mg levonorgestrel. The only licensed brand in the UK now is Implanon, which is a single subdermal 4 cm rod with 68 mg etonogestrel dispersed in ethylene vinyl acetate core. It is covered by 0.06 mm rate-controlling membrane. During the initial stages, it releases 60 - 70 µg/day, which declines to 25 - 30 µg/day by the end of the third year. It is licensed to be used for 3 years after insertion, and should be inserted subdermally usually in the upper arm under aseptic conditions. The same incision used for removing the old rod can be use to insert the new one. It has the same mode of action as depoprovera, and almost similar indications as well. There is also increased risk of irregular uterine bleeding, which makes the commonest cause for removing the rod. In all, good cycle control was reported by only 28% of women over a period of 3 years (8). Other statistics showed 30-40% amenorrhoea throughout the 3 years, 30% infrequent bleeding and 10-20% prolonged bleeding episodes. Its contraceptive and cycle control efficacy is decreased if hepatic enzymes inducing drugs such as rifampin, carbamezapine, phenobarbitol and St. John’s Wort are used at the same time.

In recent years transdermal combined oestrogen and progestogen contraceptive patches became available. They have the same mode of action and efficacy as the combined pill, regarding suppression of ovulation, cycle control and cervical mucous viscosity (10). They have an extra advantage, as the absorbed hormones do not pass through the liver first. This reduces the production of all oestrogen dependent hepatic factors, which occurs following the first pass through the liver. A once-weekly Evra patch (Janssen-Cilag Ltd) can be used for 3 weeks starting on the first day of menstruation, followed by one patch-free week. Each patch delivers 33.9 µg ethinyl oestradiol and 203 µg norelgestromin daily into the systemic circulation. To reduce the risk of ovulation the patch should be changed every 7 days irrespective whether menstruation has not started or bleeding has not stopped yet. A new patch may need to be replaced in less than 2% of the cases because of complete detachment. Contraindications for using combined oral contraceptives are valid for the patch as well. Furthermore, one follow up study showed that women younger than 20 years of age were less likely to use the patch properly, compared to the contraceptive pill (11). This method is more suitable for women in their twenties or thirties who are not very compliant with the daily routine of the oral contraceptive pill, and are not keen on other methods.

1. The mirena system (Bayer) is a levonorgestrel impregnated intrauterine system which is becoming widely used for contraceptive purposes, as well as for control of excessive menstrual blood loss. It is made of a polymer cylinder containing 52 mg of levonorgestrel mounted on a T-shaped frame. It releases 20 µg of levonorgestrel every day into the uterine cavity, through a hormone rate limiting membrane covering the device. It acts as a contraceptive through the same 4 mechanisms described for other progestogens earlier on in this chapter. It does not inhibit ovulation in the majority of cases. There is occasionally an initial period of abnormal uterine bleeding which usually settles within 3 months. Patients should be counselled accordingly to prevent unnecessary premature removal of the device. Eventually, the amount of blood loss and bleeding days will be reduced, and 20% of women may become amenorrhoeic after one year (12). This beneficial effect has been used to avoid surgery with reasonable results in patients with uterine fibroids. Few studies showed reduction in blood loss and regression of the uterine size, with or without diminution in the fibroids mass (13, 14). This effect was thought to be secondary to inhibition of the endometrial growth factors. Nevertheless, such devices can be used only when the cavity is not significantly affected by any fibroid. The system is licensed for 5 years following its insertion into the uterine cavity. Unlike cupper containing intrauterine contraceptive devices, it is not licensed for postcoital emergency contraception.

The mirena system has no metal component and accordingly different ultrasound characteristic to CuT devices, but still more echogenic than a Vcu200 device. Figures 42 - 44 show sagittal uterine transvaginal ultrasound views with a CuT device, mirena system and Vcu200 device correctly sited inside the cavity respectively. Note the progressively softer echogenic patterns created by the mirena system and Vcu200 device compared to the sharp echo created by the CuT.

When available, 3D ultrasonography can be helpful in showing the exact type of IUCD, especially with the less commonly used and less echogenic Vcu200 device.

Figure 45 is coronal transvaginal ultrasound scan of a uterus with a normal triangular cavity and Vcu200 contraceptive device in situ.

Vaginal rings with combined oestrogen and progestogen, and progestogen only medication are gaining popularity as reversible contraceptive means in certain parts of the world. One example of a combined oestrogen and progestin ring is NuvaRing (Schering), which is available in the United Kingdom market. It is a flexible one size ring (54 mm) made of ethylene vinylacetate copolymers and magnesium stearate. It liberates 15 µg ethinyl oestradiol and 120 µg etonorgestrel daily into the vagina. It should be inserted into the vagina on the first day of menstruation by women who did not use hormonal contraception in the preceding cycle. On the other hand, women who are using any form of combined hormone contraception can switch to use the ring on any day, the latest being the day following the usual hormone free interval. It can be used for 3 weeks, followed by seven ring-free days every month. Personal application is easy by squeezing the ring during its insertion into the vagina, while squatting, lying down, or with one leg lifted up on a chair. It does not need to stay in any specific shape or position within the vagina. Its mode of action is similar to other combined contraceptives. The ring can be removed for cleaning but replaced within 3 hours to maintain proper contraception. Good cycle control was reported by 98% of users (15). Nevertheless, 2-5% reported device-related problems including vaginal discharge, vaginal discomfort and problems during intercourse in the same study. This last problem can easily be overcome by removing the ring during intercourse, but replacing it immediately thereafter. The grace period for changing vaginal rings is longer than for transdermal patches. Accordingly, one ring can be used continuously for 4 weeks, and changed immediately on the same day after that with a new one, to avoid onset of menstruation if desirable. Leaving the same ring in the vagina for more than 4 weeks reduces its contraceptive efficacy, as advised by the manufacturer’s patient information sheet. There is also a small risk that NuvaRing can be accidentally expelled from the vagina during intercourse, with straining during a bowel movement, and while removing a tampon.

Progestogen-only vaginal rings are also available in certain countries, with different durations of action. They act through their progestational effects on the cervical mucous and endometrium, as for other progestogen contraceptives. Progering (Andromaco Laboratories, Chile) is a brand suitable to extend the contraceptive effectiveness of lactation in breastfeeding women. It was initially tested for 3 months (16), but a more recent study showed that it is effective for 4 months without affecting breast-feeding or the rate of infant growth. It also prolonged the period of lacational amenorrhoea (17). The ring can be removed for comfort during sexual intercourse, but additional contraception will be necessary for one week if it has been removed for more than 3 hours. Bleeding disturbances are common, as for other progestogen only contraceptives.

The statistics used to compare the efficacy of different contraceptive methods is usually documented as failure per hundred women years. This estimate of efficacy refers to the first year of use, though the longer a woman uses a contraceptive method, it is less likely for that method to fail. It is important to understand that failure rate depends on many factors which can reduce the efficacy of the contraceptive method. Parts of these factors are related to the method itself, but a major part is related to the way it has been used. This is reflected by failure in relation to the typical use and perfect use of the specific contraceptive. Perfect use is a measure of efficacy when the method has been used perfectly according to the manufacturer’s guidelines, without fail. Failure in such cases reflects the inherent capabilities of the method itself. On the other hand, typical use failure rate reflects the probability of pregnancy during the first year, allowing for non-compliance and incorrect use of the method. This is the statistics usually quoted in the literature, which is obviously affected by many confounders. It is understable why long acting contraceptive methods which rely less on patients’ compliance offer similar typical and perfect use failure rates. The perfect use failure rates of depoprovera and Norplant are 0.03% and 0.05% respectively, with the typical use failure rates being almost identical. This is in contrast to the other methods which depend on the patients’ compliance. The combined oral contraceptive pills perfect use failure rate is approximately 0.1-0.5%, but the typical failure rate is as high as 5% (18).

Family planning remains to be the most common indication for using hormonal contraceptives. Nonetheless, patients who need such protection may have other gynaecological or chronic medical problems, which make proper selection of a specific brand with a specific route of administration more important. These issues will be discussed in the following sections of this chapter.

2. Cycle control in oligomenorrhoea or amenorrhoea is an indication to prevent endometrial hyperplasia and hypo-oestrogenic state. This should be done after making a proper diagnosis of the initial cause of anovulation. This is especially so for thyroid dysfunction and hyperprolactinaemia, as treatment of these conditions is most likely to correct the menstrual problem. Oligomenorrhoeic and amenorrhoeic women with polycystic ovary syndrome are at risk of developing endometrial hyperplasia. This increases the risk of endometrial carcinoma. Using an oral contraceptive pill to induce regular monthly withdrawal bleeding will reduce this risk. Alternatively, a mirena system can be used instead. On the other hand, young women with hypo or hyper gonadotrophic hypogonadism are at risk of developing hypoestrogenic side effects including osteoporosis. One option to deal with this problem is to use a low dose oral contraceptive brand.

3. Treatment of abnormal uterine bleeding especially excessive blood loss is also an indication for using an oral contraceptive pill, or the mirena system. This is especially so in patients with dysfunctional uterine, when no specific treatable endocrine or organic uterine causes can be detected. This subject has been discussed in detail before in this chapter under the subtitle ‘Intrauterine contraceptive devices’.

4. Treatment of hyperandrogenisation is an important indication for using non androgenic oral contraceptive pills. This is affected by inhibiting ovulation, reducing ovarian androgens production, and increasing the level of SHBG which reduces the level of free testosterone. It is also important to exclude other specific treatable conditions which may increase the level of serum androgens, including ovarian and adrenal tumours. Adult onset adrenal hyperplasia should also be excluded, as treatment usually entails suppression of the adrenal androgens as a priority. The highest level of SHBG is reported after using a combined pill with cyproterone acetate as the progestogen fraction (Dianette, Bayer plc). The role of non androgenic progestogens has already been discussed in this chapter. Pills with low progestogen / oestrogen activity are preferable in the treatment of patient with acne, but may not give the best cycle control, and breakthrough bleeding is more likely. The direct antiandrogenic effect of drospirenone in reducing 5a reductase activity is well utilised in the combined pill Yasmin (Bayer plc).

5. Using an oral contraceptive pill to inhibit ovulation has been shown to reduce the risk of developing functional ovarian cysts while under treatment (19). This effect has been well documented for high dose older contraceptives with 50 µg ethinyl oestradiol, but not for the lower dosage group. Once a cyst was formed such treatment achieved similar results to expectant management (20, 21). A significant similar effect has also been found with other benign ovarian tumours including serous and mucinous adenomas, teratomas and endometriomas (22). The reduction in risk was related to the duration of use. Similar to functional cysts, oral contraceptives are not useful for the treatment of these benign ovarian cysts once they already developed.

6. Oral contraceptive pills are also used in cycle preparation during assisted reproduction treatment cycles. This is done usually in cases with irregular menstruation for good planning of the treatment cycles. One protocol involves the use of an oral contraceptive pill after a progestogen withdrawal bleeding episode. This is followed by daily injections of a gonadotrophin releasing hormone (GnRH) agonist, from day 17 of the cycle to affect down regulation of the pituitary gland. Nasal sprays can be used instead. Controlled hyperstimulation is started within a day or two after the withdrawal bleeding has started, usually within a week after stopping the pill. There will be less risk of developing an ovarian cyst following the GnRH agonist during such a protocol. Accordingly, a similar protocol can be prescribed for patients who developed ovarian cysts following GnRH agonist use during previous assisted reproduction treatment cycles.

7. The use of oestrogens and combined oral contraceptive pills in the management of young women with absent or delayed pubertal development has been discussed in Chapter 2. Unopposed oestrogen is usually a priority for some time till normal height has been attained, before converting to an oral contraceptive pill.

8. Low dose combined contraceptive pills can also be used as hormone replacement therapy in cases of premature ovarian failure as discussed in Chapter 10. These patients usually need a higher oestrogen dose than women who went through natural menopause. Furthermore, having regular withdrawal bleeding has a good psychological effect on these patients. Neither the combined contraceptive pills nor any designated hormone replacement therapy are effective as contraceptives in these cases. Pregnancies have been reported in young women with premature ovarian failure while on the pill. This information should be conveyed to all patients in such a situation who are adamantly keen not to get pregnant. Women with anorexia nervosa are at special risk of severe hypoestrogenism. Using a low dose combined contraceptive pill will provide the missing oestrogen, while the patient is having the necessary psychological treatment. This is also valid for professional women athletes, who are at risk of the triad of amenorrhoea, anorexia and osteoporosis.

9. Medical treatment of endometriosis also involves using different types of hormonal contraceptives. Cyclic or continuous use of oral contraceptive pills are two options. Recently, the extended use of an oral contraceptive pill for 84 days has been introduced. Depoprovera and the mirena system are also useful in this respect. The dominant progestational effect of all these drugs is the main factor in controlling endometriosis growth and symptoms. This does not give permanent cure, and symptoms and signs usually recur after medication is suspended. Furthermore, such medication is not suitable for women who are keen to conceive, which is a real limitation for this therapy.

10. The role of hormonal contraceptives in the management of premenstrual dysphoric disorders has been discussed in Chapter 10. Suffice to say that mixed results have been reported about the effect of the oral contraceptive pill, and the risk of worsening symptoms during the pill free period. This resulted in the release of brands with 24 and 26 pills to reduce the pill free period. Using an extended brand for 84 days, like Seasonale (Duramed Pharmaceutical, Inc), has also been shown to improve premenstrual dysphoric disorders. It contains 84 active pills, each containing 30 µg ethinyl oestradiol and 0.15 mg levonorgestrel, with 7 inert tables. A pill which gained notoriety in this respect is Yasmin (Bayer plc), as the progestogen fraction has been replaced with drospirenone which is a spironolactone derivative. Each pill contains 30 µg ethinyl oestradiol and 3 mg drospirenone, and used for 21 days with one pill-free week. Another pill with 20 µg ethinyl oestradiol and 3 mg drospirenone with 24 active pills is marketed in America, and used especially for premenstrual dysphoric disorders. In very severe cases, the mirena system can be used, together with continuous transdermal oestrogen.

11. The mirena system has a wide range of non contraceptive benefits which have been alluded to before in this chapter. One benefit not mentioned before, is its role in protecting the endometrium against the chronic hyperplastic effect of tamoxifen during treatment of breast cancer. Other benefits include control of endometriosis induced pelvic pain, and for endometrial protection in postmenopausal women on continuous oestrogen replacement therapy. An extra important benefit of the mirena system is its effect in reducing the symptoms and size of endometriotic lesions in the rectovaginal septum (23). This will obviate the need for the difficult surgery necessary to deal with this pathology in most cases. Furthermore, suggestions have been put forward to use it immediately after endometriosis surgery to reduce the need for further operations in the future (24). Levonorgestrel has been found in the peritoneal fluid in significant amounts, approximately two thirds of the serum level, in women who showed improvement in their symptoms after six months of using a mirena (25). Similarly, the level of the serum marker CA-125 showed equivalent decline after long term use of the device as for GnRH-a, when used for the treatment of endometriosis (26). All these effects were related to the high levels of peritoneal levonorgestrel causing increased programmed cell death (apoptosis), atrophy of the ectopic endometrial glands, and decidual transformation of the stroma. It has also been reported to have anti-inflammatory and immunomodulatory effects (27). Furthermore, levonorgestrel has been shown to decrease and then block DNA synthesis and mitotic activity (28).

There are many coincidental health benefits related to the use of the oral contraceptive pills including:

• An epidemiological study reported by Schlesselman in 1991 (29) showed a duration-related protective effect of combined oral contraceptive pills against endometrial cancer. The risk before the age of 60 years was reduced by about 38% with two years of use. Longer use for 4, 8, and 12 years, conferred 51%, 64%, and 70% reduction in endometrial cancer risk respectively. Such protective effect lasted for ≥15 years after stopping medication.

• Many reports documented a protective effect of oral contraceptives against ovarian cancer in general. This risk also decreased with increased duration of use. The adjusted odd ratio for ovarian cancer with any past use of oral contraceptives was 0.5 (95 CI 0.3 – 0.8). A 60% risk reduction was noted after 6 years of use or more (30). Such protective effect was noted even in carriers of BRCA1 (odd ratio, 0.5; CI 0.3 – 0.9), and BRCA2 mutations (odd ratio , 0.4; CI 0.2 – 1.1)

• Reduced risk of functional ovarian cysts is another benefit related to suppression of ovulation. Risk reduction was also related to the duration the oral contraceptives use. Such benefit persisted for at least 15 years after stopping using the pill. The protection rate in comparison to non-users has been estimated as 30% for women who used the pill for 4 years or less. This figure increased to 50% and 80% for 5 – 11 years, and >12 years of the pill use respectively (31, 32).

• Reduced risk of colorectal cancer has been documented for patients who used oral contraceptives with 50 µg ethinyl oestradiol, with a relative risk of 0.6 after 96 months of use. The effect of low dose brands has not been verified.

• Decreased incidence of benign breast diseases including fibrocystic changes and fibroadenomas has been attributed to the use of oral combined contraceptives. This effect was seen even after only one or two years of use (33), and lasted for one year after stopping the pill (34). Conversely, the ESHRE Capri Workshop Group in 2005 (35) thought there were significant problems with bias, study design and interpretation of results related to this topic. Furthermore, they thought there was no evidence of biological plausibility. In short, they did not endorse the idea of a beneficial effect on the breasts.

• The subject relating bone mass density to hormonal contraception has generated a lot of contradictory results. The osteoporotic effect of depoprovera has been discussed already. Oral progestogens only pills do not inhibit ovarian function, and do not have similar effect on bone density. The difficulty with studies which addressed bone mass density has been confounded by different factors which affect bone. Examples of such factors included hereditary factors, age, body mass index, smoking, level of physical exercise and diet. On the other hand, there is some evidence of a little favourable effect of the combined oral contraceptives on bone mineral density and fracture risk in women of reproductive age as concluded by the ESHRE Capri Workshop Group (35). This is despite of the fact that oestrogen blood concentrations over the whole month are lower in women using the combined oral contraceptive pill than during natural ovulatory cycles. They did not endorse any benefit on bone mass density in patients with anorexia nervosa.

Young women with different non gynaecological medical problems may need contraceptive advice to prevent unplanned or unwanted pregnancies. This occasionally creates different difficulties, because of the direct effect of the method used on the medical condition, or its interaction with the different drugs necessary to control her basic medical problem. The most likely conditions to be encountered in this age group include obesity, high blood pressure, diabetes mellitus, migraine, hypothyroidism, pituitary adenomas and thrombophilias. Patients with certain risk factors may also request contraceptive advice. This group includes women with previous history of deep vein thrombosis, and those with personal or family history of breast cancer

It is not uncommon for obese patients to seek contraceptive advice. They may even have pre perceived ideas against using barrier methods for different reasons. A more urgent situation can arise when an obese patient presents with irregular or excessive menstrual blood loss, which needs immediate hormonal treatment and cycle control in the long term. Obesity is a known risk factor for venous thrombosis, pulmonary embolism, insulin resistance, and diabetes mellitus. There is increased risk of thromboembolism in women with BMI >35 kg/m². The Royal College of Obstetricians and Gynaecologists considered a BMI of 40 kg/m² or more as a contraindication to use oral contraceptives. In fact the risks of using oral contraceptives generally outweigh their benefits for women with BMI of 35 to 39 kg/m². This is coupled with a negative correlation between BMI and the contraception effectiveness of transdermal patches and the vaginal ring, leading to higher failure rates. This may be due to altered steroid metabolism, and / or dilution of the steroid dose in a larger blood volume. The evidence for an association between oral contraceptives failure and obesity has been conflicting. This subject has been reviewed by Brunner et al in 2006 (36). They confirmed a negative association, but the results were largely attenuated after adjustments for age, ethnicity and parity. Taking all the risks involved into consideration, it seems that the preferred option for obese women is a mirena system. The revised Depoprovera Product Monograph in 2006 (3) reported variable results related to weight gain after using the product. The majority of studies reviewed showed weight gain of 5.4 lbs (2.5 kg) at the end of one year. Other studies reported weight gain of 8 lb (3.5 kg) by the end of the second year, but 20-40% of depoprovera users actually lost weight during treatment.

High blood pressure is another possibility in patients seeking contraceptive advice. It is a risk factor for cardiovascular events and stroke, even in young women, who are normally expected to have a low risk (37). The estimated annual incidence of myocardial infarction and strokes has been reported as 1.7 and 34.1 cases per 1 million respectively, for normotensive women aged 30–34 years. These rates increased to 10.2 for myocardial infarction and 185.3 for stroke among hypertensive women of the same age group (38). Women using combined oral contraceptives are at increased risk of developing high blood pressure. Certain factors are known to increase this risk, including a strong family history of high blood pressure especially in female relatives, and history of high blood pressure during a previous pregnancy. Other risk factors include racial origin, age, obesity, smoking and alcohol abuse. Duration of the oral contraceptives use is also important. There were higher age-adjusted blood pressure levels after 8 years of use than in women who used the pill for shorter periods of time as reported by Lubianca et al in 2003 (39). The same authors concluded that hypertensive women on oral contraceptives had significant elevation of diastolic blood pressure and poor blood pressure control, independent of age, weight and antihypertensive drug treatment. In a subsequent publication Lubianca et al in 2005 (40) reported reductions of 15.1+/-2.6 mm Hg and 10.4+/-1.8 in systolic and diastolic blood pressure respectively after stopping oral contraceptives use. They recommended stopping such medication as an effective antihypertensive intervention in such a clinical setting. This finding was agreeable with another study reported by Atthobari et al in 2007 (41) who showed worsening of high blood pressure with hormonal contraceptives and its improvement after discontinuation of medication. It also showed some deterioration in renal function during usage of hormonal contraceptives. Urine albumin excretion increased by 14.2% in starters (P = 0.074), and fell by 10.6% after stopping medication (P = 0.021). On the other hand, the glomerular filteration rate fell by 6.3% in starters (P < 0.001), and did not recover after stopping the contraceptive. The same authors reviewed previous studies for the correlation between hormonal contraception and renal function, in relation to these findings. Two previous studies proposed that contraceptives use may be associated with an increased risk of microalbuminuria, independent of the blood pressure effect. On one hand, higher levels of albuminuria are considered as an early marker of vascular endothelial damage, but there is no significant evidence relating renal disease to the use of hormonal contraception. Both pathologies are related to an increased risk of progressive renal failure and excess cardiovascular morbidity and mortality (41).

This section can be concluded that the combined oral contraceptive pill is better avoided by hypertensive patients, and by women liable to develop high blood pressure. Progestogen only contraceptives can be used instead. Nonetheless, controlled mild high blood pressure as an isolated problem is not an absolute contraindication against using a low dose oral contraceptive pill. Readjustment of the antihypertensive treatment dose may be necessary, due to stimulation of the renin angiotensin system and aldosterone production by oestrogens. At the same time, regular medical supervision will be needed, if the patient opted to continue with the same medication, rather than using an alternative method. Conversely, uncontrolled or complicated hypertension is an absolute contraindication to use the combined oral contraceptive pill. Other risk factors like obesity and smoking should be taken into consideration when making the decision.

Thrombophilia is a term used to indicate increased tendency to intravascular coagulation. It may follow hereditary or acquired causes. Congenital factors include factor V Leiden mutation, prothrombin, protein C and S, and antithrombin III deficiencies. High homocysteine and sickle cell disease are other factors to consider. Thombophilia can also be acquired due to antiphospholipid antibodies. Factor V Leiden forms the most common inherited thombophilia, and 3 – 8% of Caucasians carry a copy of the mutation in each cell. Furthermore, 1 in 5000 individuals carries 2 copies of the mutation. The risk of thromboembolism for Factor V Leiden is >10 times more (80%) in this group than for the heterozygous state (7%). It is less common in other ethnic groups. It is important to note that not all thrombophilias carry the same risk of venous thromboembolism. The lowest risk is attributed to a single mutation such as Factor V Leiden, and the highest to antithrombin deficiency (42). Using the combined oral contraceptive pills is associated with a small increase in thrombosis and pulmonary embolism risks. In numerical terms, about 20 – 30 women in every 100,000 pill users may develop deep vein thrombosis or pulmonary embolism. Previous history of either problem or a personal history of thrombophilia will increase the risk. Despite the controversy regarding the increased risk with third compared to second generation oral contraceptives, epidemiological data confirmed this increased tendency for venous, but not arterial thrombosis (43). Furthermore, the increased risk of venous thromboembolism is more pronounced during the first year of use. Other contributing factors included obesity, cigarette smoking, immobility, fractures, surgery and cancerous conditions especially of the pancreas. There is an exponential increased risk when genetic factors are combined with these conditions. Accordingly, great care should be taken to identify patients with such genetic risk factors, but screening all women is not indicated before prescribing oral or other hormonal contraceptives. Additionally, oestrogen containing pills should be avoided in these cases when contraception is needed. Though progestogen contraceptives, whether oral or injectable, do not increase the thrombosis tendency in the general female population, their role in individual women with thrombophilia has not been investigated. Accordingly, there is an opinion that a copper IUCD should be the first-line contraceptive method for women with a history of deep venous thrombosis, pulmonary embolism, or coronary events (44).

Classical teaching has always associated combined oral contraceptives, and in some cases even the progestogen only brands, with changes in carbohydrate metabolism. Such changes included decreased glucose tolerance and increased insulin resistance, which are risk factors for type II diabetes mellitus and cardiovascular disease. This issue has been addressed by a meta-analysis published by Lopez et al in 2009 (45). They concluded that the current evidence showed a limited effect for hormonal contraceptives on carbohydrate metabolism in women without diabetes. Furthermore, they criticised many of the published articles because of the small numbers of women involved, lack of comparison between different types of contraceptives, and lack of information regarding the effects among overweight women. In the same year, Cagnacci et al (46) found that vaginal contraceptive rings were less likely to change insulin resistance than combined oral contraceptives. They concluded that a vaginal ring may be a better choice for long-term contraception in women at risk for developing diabetes mellitus or the metabolic syndrome. In a study which addressed the effect of depoprovera injections, Xiang et al found increased risk of diabetes which they explained by three factors (47):

All this information indicates that proper selection of the suitable contraceptive should always take into consideration the inherent characteristics of the drug to be used, and the risk factors shown by each individual woman.

Contraception is an important issue for diabetic women, as unplanned pregnancy can induce major maternal and perinatal complications. There was little evidence that changes in blood sugar control induced by combined oral contraceptives had any clinical consequence as reported by Shawe and Lawrenson 2003 (48). Furthermore, low dose combined contraceptive pills have minimal effect on the lipid profile which may even by beneficial. Conversely, there is some concern regarding the effect of oral and injectable progestogens on HDL and LDL cholesterol levels. Diabetes mellitus is a risk factor for thromboembolism and cardiovascular diseases, but well controlled diabetes is not an absolute contraindication for using the oral contraceptive pill. The same authors (48) stated that short term studies of young women with uncomplicated diabetes who were taking low-dose combined oral contraceptives have been reassuring. On the other hand, patients with complicated diabetes and macrovascular or microvascular changes should be prescribed nonhormonal contraceptive methods. The same is valid for cases with uncontrolled diabetes, or in the presence of other risk factors like obesity, hypertension or smoking. In a different approach Nikolov et al in 2005 (49) made a clear distinction between types I and II diabetics in relation to contraceptive advice. They recommended the use of low dose combined contraceptive pills in women with uncomplicated type I diabetes of less than 15 years duration. A change in the insulin dose and control of body weight will be needed to maintain good glycaemic control. Conversely, they advised against using combined oral contraceptives in women with type II diabetes, because they may provoke clinical changes and worsen the progress of the disease itself. This last point is very much valid for prediabetics and diabetics controlled only by diet. Further deterioration of the glycaemic condition, which may follow using combined contraceptives, adds a further burden on the patient to take hypoglycaemic drugs, which also adds cost and the need for more strict compliance.

This section will be dealt with in bullets form to focus the attention of the reader, as most points have already been addressed before in this chapter. Few of the complications are gynaecological in nature, but systemic and organ specific complications or risks will also be addressed.

· Unfavourable changes in cervical cytology have been seen in women using combined oral contraceptive pills. Furthermore, prolonged use of these pills has been associated with a small increased risk of cervical cancer. Among current users of the pill, the relative risk (RR) after 5 years of use was 1.9 (95% CI, 1.69-2.13) compared to those who never used the pill. There was gradual decline in the risk, which returned to normal 10 years after stopping the pill. This pattern was seen in invasive and in situ cancers and for women who tested positive for the high risk human papilloma virus, as reported by the International Collaboration of Epidemiological Studies of Cervical Cancer in 2007 (50). The same group estimated an increased cumulative incidence of cervical cancer from 3.8 to 4.5 per 1000 women by the age of 50 years in women who used the pill for 10 years between the ages of 20 and 30 years, in developed countries. The corresponding increase was from 7.3 to 8.3 per 1000 for developing countries. The reason for this increased risk of cervical cancer was not well elucidated, but was thought to be an association rather than a cause and effect relationship. Women using the pill are more likely to be sexually active and may not use barrier contraceptive means regularly. This can put them at increased risk of contacting human papilloma virus, which is the likely cause of cervical cancer. Accordingly, it is important that all women on combined oral contraceptive pills should have regular cervical smear screening, especially if human papilloma virus infection was detected (51). A note should be documented here about the effect of depoprovera. An overall non significant relative risk of 1.11 (95% CI, 0.96 – 1.29) has been reported for invasive sqaumous cell cervical carcinoma in women who ever used the drug. This was not affected by the duration of use, or the times since the initial or most recent injection (2).

· The issue relating breast cancer risk to the oral contraceptive pill is more complicated than the pill’s relationship to cervical cancer. It is a subject which had attracted, and still attracts the attention of the media and public. Many scares have hit the public in waves since the 1970s, which lead to thousands if not millions of unplanned or unwanted pregnancies, and equally distressing terminations of pregnancies. The relationship has been confounded by the multifactorial nature of breast cancer, which is affected by many variables. The odd ratio is 200 for those with the BRAC gene mutation. A figure of 3 has been reported for women with familial history of breast cancer (52). Furthermore, many life style and other related variables have been known to increase the risk. The list includes lack of exercise, excessive alcohol intake, cigarette smoking, postmenopausal obesity, early menarche, late menopause, first full-term pregnancy after the age of 35 years, and reduced breast feeding (53). Each of these factors increased the risk of breast cancer more than the risks reported for combined oral contraceptives (53). As an example of such confounders, women who had their menarche before the age of 12 years had 30% higher risk of developing breast cancer than those who started menstruating by the age of 15 years, as reported by ESHRE Working Capri Group (35). A meta-analysis published by Kahlenborn et al in 2006 (54) examined 34 studies that met stringent inclusion criteria since 1980, for an association between using oral contraceptives and premenopausal breast cancer in general. A small increased risk with an odd ratio (OR) of 1.19 was found (95% CI, 1.09-1.29). Both parous (OR, 1.29; 95% CI, 1.20-1.40) and nulliparous (OR, 1.24; 95% CI, 0.92-1.67) women were affected. Prolonged use did not change the OR risk for nulliparous women. The risk was stronger when the pill was used before the first full term pregnancy. Furthermore, the maximum risk was seen when the pill was used 4 years before the first full term pregnancy, with an OR of 1.52 (95% CI; 1.26-1.82). Despite all these figures, the risk of breast cancer remains to be small, and the benefits of using the oral contraceptive pill outweigh their risks in most women. To put this statement into mathematical perspective, there will be 0.5 additional breast cancers per 100,000 women 16-19 years of age, during the time of use and 10 years follow up. The corresponding figures for women in the age groups 20-24 years and 25-30 years are 1.5 and 4.7 additional cancers per 100,000 respectively as reported by Reid in 2007 (53).

Emergency or postcoital contraception should be used to prevent unwanted pregnancy after unprotected intercourse. It is an occasional method and should not be used as a regular means of contraception. Copper intrauterine contraceptive devices are the most efficient means if inserted within 5 days of unprotected intercourse, with a failure rate <1.0% (55). They act mainly by preventing fertilisation through the toxic effect of copper on sperm, but impede implantation at the same time. TT380 Slimline (Durbin PLC, South Harrow, Middlesex, UK) and T-Safe 380A (Williams Medical Supplies Ltd, Rhymney, Gwent, UK) are the most effective, and have the lowest failure rate. They are the preferred method for women using liver enzymes inducing drugs, such as barbiturates, carbamazine, rifampicin and phenytoin. Nulliparous women could be offered the Mini TT380 Slimline, which has a small plastic frame.

The two main hormonal means are Levonorgestrel 1500 µg tablets and ulipristal acetate which is a synthetic second generation selective progesterone receptor modulator. The levonorgestrel contraceptive pill (Levonelle 1500, Bayer Schering) is licensed for use within 72 hours of intercourse. It prevents pregnancies in 95%, 85% and 58% of the cases if used within 24, 24 – 48 and 48 – 72 hours after the first intercourse respectively (56). It interferes with follicular development and impairs ovulation, with little evidence regarding inhibition of implantation. Another tablet should be taken if vomiting occurs within 3 hours after taking the pill. It is also recommended that a woman on liver inducing enzymes should take 2 tablets soon after unprotected intercourse, if she is not agreeable to use a copper IUCD. Ulipristal acetate (30 mg tablet) could be used up to 120 hours after intercourse, and is more effective than levonorgestrel for inhibiting ovulation (57, 58). It also affects implantation, and accordingly could be used for emergency contraception after ovulation but before the expected time of implantation. No teratogenic effects have been attributed to either drug, and termination of pregnancy is not indicated on this context in cases of failed contraception. Both drugs could lead to menstrual irregularities and delay of menstruation, which may cause patients some concern.

An alternative method of emergency hormonal contraception is to take 4 combined oral contraceptive pills immediately after intercourse and repeat the dose 12 hours later. Microgynon 30 (Bayer Schering) has been recommended for this purpose (59). This may lead to nausea and vomiting, and an anti-emetic drug may be needed in these cases. This method is indicated if the single-tablet protocols or copper IUCD are not available or unacceptable.

Previous studies showed lower tendency by women over the age of 40 years to use contraception, with 40% opting for sterilization in the United Kingdom (60). This pattern may change because of the introduction of newer methods of contraception. It is important to emphasise that no method of contraception is contraindicated on the basis of age only, in the absence of risk factors or medical problems. Perimenopausal women are more likely to develop high blood pressure, diabetes mellitus, obesity and dysfunctional uterine bleeding which make selection of an appropriate contraceptive method rather difficult. At the same time, pregnancy at this age carries great risks for the mother and fetus, and appropriate contraception should be guaranteed to prevent unplanned pregnancies. The following points should be taken into consideration when offering contraceptive advice to women in this age group:

· It is most important to take a woman’s preference into consideration and to discuss with her the merits and drawbacks of her chosen method of contraception to improve compliance. Certain taboos may be attached to the use of certain methods which make them less acceptable in different areas and cultures.

· Women above the age of 40 years can use combined hormonal contraceptives up to the age of 50 years, unless there are coexisting risk factors. They should be switched to another form by that age. The last statement is also valid for women using injectable progestogen only contraceptives, but inherent predisposition to osteoporosis should be taken into consideration even in younger women.

· Smoking is a significant cardiovascular risk factor even at the age of 35 years and in younger obese women. This risk falls significantly one year after stopping smoking and almost disappears 3-4 years later.

· There is 50% increased risk of thromboembolic attacks among cigarette smokers independent of oral contraceptives use or age (61).

· Women with migraine, history of stroke or cardiovascular disease should not be prescribed combined hormonal contraceptives.

· The progestogen only pill and mirena system are good options, but there is a higher risk of dysfunctional uterine bleeding with the former method, which made it unsuitable for many perimenopausal women (62). They are not associated with increased risk of thromboembolism (61, 63). Both methods can be used by patients with previous history of ischaemic heart disease and stroke, but the progestogen only pill should not be used during an active thrombotic episode. The risks involved by using injectable progestogen only contraceptives outweigh their benefits in these conditions. The role of copper IUCD in such cases has already been mentioned before (44).

· Monophasic contraceptive pills with £30 µg ethinyl oestradiol and low dose northisterone or levonorgestrel are good first line options for women with no risk factors who opted to use a combined pill. The risk of venous thrombosis decreases with lower oestrogen dose and duration of use.

· The non-contraceptive health benefits of low dose contraceptive pills alluded to before, justify their use in healthy perimenopausal women (63). Kaunitz viewed their use in this age group as a general strategy not only to provide effective contraception, but also to improve perimenopausal symptoms and to enhance quality of life (64).

· Oral contraceptive pills with desogestrel, gestodene or drospirenone have significantly higher risk of venous thrombosis than other brands containing levonorgestrel, as confirmed by Lidegaard et al in 2009 (65).

· In general, the risk of cerebral thromboembolic attacks is reduced by >30% when using low dose pills compared to 50 µg preparations (61). This is equivalent to one additional death per one million low dose pill users per year in comparison to IUCD users (66). On the other hand the General Practice Research Study (67), and the WHO Collaborative Studies of Cardiovascular Disease and Steroid Hormone Contraception (68, 69) showed no increase in mortality rate from stroke or venous thrombosis in low dose pill users.

· A copper IUCD is an alternative non-hormonal method of contraception, but may exacerbate menstrual problems in this age group (70). The T380 device offered contraceptive effectiveness equivalent to surgical sterilization (71). Accordingly, such a device may be offered to women free of any pre-existing menstrual problems, otherwise the mirena system should be used if this mode of contraception is preferred (72).

· Combined HRT does not provide effective contraception and women on such medication should use effective contraception till the age of 55 years. This can be provided by the progestogen only pills or a mirena system. Two FSH blood level estimations will be needed 6 weeks after stopping HRT for confirmation of the menopause, before contraception can be stopped (73).

The subject of hormonal contraception has been a prime issue in the public domain many times over the last 30 years, but mostly for the wrong reasons. Women who seek contraceptive advice are mostly young and healthy, and can use hormonal contraceptives safely in the majority of cases. This is a different scenario to other patients who have known risk factors, or are currently under treatment for one or another chronic illness. An unwanted pregnancy can cause more damage than the small risks of inducing cardiovascular problems or breast cancer, which are not very common in this young age group. Furthermore, the thromboembolic risks of pregnancy exceed those related to the use of the combined oral contraceptive pill. The medical and psychological risks involved with termination of pregnancy should be taken into consideration as well. Many women can not even consider the option of having a termination, because of ethical or religious reasons, and get stuck with an unwanted pregnancy. Accordingly, the most appropriate contraceptive should be selected for each individual woman taking into account her own preferences, any available risk factors, the issues of expenses, compliance, and ease to see a medical or nursing professional when necessary. The other non contraceptive benefits mentioned before in this chapter should be added to the whole package when discussing the issues related to contraception with patients.

1. Sangi-Haghpeykar H, Poindexter AN III, Bateman L, Reid ED. Experiences of injectable contraceptive users in an urban setting. Obstet Gynecol. 1996; 88: 227 - 233.

3. Pettiti DB, Piaggio G, Mehta S, Cavioto MC, Meirik O. Steroid hormone contraception and bone mineral density: a cross-sectional study in an international population: the WHO Study of Hormonal Contraception and Bone Health. Obstet Gynecol. 2000; 95: 736 - 744.

4. Westhoff C, Britton JA, Gammon MD, Wright T and Kelsey JL (2000) Oral contraceptives and benign ovarian tumours. Am J Epidemiol 2000; 152: 242 – 246.

5. Long-acting hormonal contraceptives. In: FIGO Manual of Human Reproduction, Vol 2. Fathalla MF, Rosenfield A and Indriso C (ed). The Parthenon Publishing Group. Casterton Hall, 1989; 67 – 83.

6. Bahamonds L, Lavin P, Ojeda G, Petta C, Diaz J, Maradiegue E, Monteiro I. Return of fertility after discontinuation of the once a month injectable contraceptive, Cyclofem. Contraception 1997; 55: 307 - 310.

7. Gallo MF, Grimes DA, Lopez LM, Schulz KF, d'Arcangues C. Combination injectable contraceptives for contraception. Cochrane Database of Systematic Reviews 2008, Issue 4. Art No: CD004568. DOI: 10.1002/14651858. CD004568.pub3.

8. Rai K, Gupta S, Cotter S. Experience with Implanon in a northeast London family planning clinic. Eur J Contracept Reprod Health Care 2004; 9: 39–46.

9. Creasy GW, Abrams LS, Fisher AC. Transdermal Contraception. Semin Reprod Med 2001; 19(4): 373 - 380.

10. Smallwood GH, Meador ML, Lenihan JP, Shangold GA, Fisher AC, Creasy GW; Ortho Evra/Evra 002 Study Group Efficacy and safety of a transdermal contraceptive system. Obstet Gynecol 2001; 98: 799 - 805.

11.Archer DF, Bigrigg, Smallwood GH. Assessment of compliance with a contraceptive patch (Ortho Evra TM/Evra TM) among North American women. Fertil Steril 2002; 77: S27 - S31

12. Lahteenmaki P, Rauramo I, Backman T. The levonorgestrel intrauterine system in contraception. Steroids 2000; 65: 693 - 697.

13. Fong YF and Singh K. Effect of levonorgestrel-releasing intrauterine system on uterine myomas in a renal transplant patient. Contraception 1999; 60 (1): 51 - 53.

14.Magalhaes J, Aldrighi JM and de Lima GR. Uterine volume and menstrual patterns in users of levonorgestrel-releasing intrauterine system with idiopathic menorrhagia or menorrhagia due to leiomyomas. Contraception 2007; 75 (3): 193 - 198.

15. Roumen FJME, Apter D, Mulders TMT, Dieben TOM. Efficacy, tolerability and acceptability of a novel contraceptive vaginal ring releasing etonogestrel and ethinyl oestradiol. Human Reprod 2001; 16:469 - 475.

16. Massai R, Miranda P, Valdẻs P, Lavin P, Zepeda A, Casado ME, Silva MA, Fetis G, Bravo C, Chandia O, Peralta O, Croxatto HB and Diaz S. Preregistration study on the safety and contraceptive efficacy of a progesterone-releasing vaginal ring in Chilean nursing women. Contraception 1999; 60(1): 9-14.

17. Massai R. Quinteros E, Reyes MV, Caviedes R, Zepeda A, Montero JC, and Croxatto HB. Extended use of a progesterone-releasing vaginal ring in nursing women: a phase II clinical trial. Contraception 2005; 72(5): 352 – 357.

18. Contraceptive Technology. Robert A Hatcher (ed); 17^th Revised Edition, 1998; Ardent Media Incorporated, page 410.

19. Holt VL, Daling JR, McKnight B, Moore D, Stergachis A and Weiss NS. (1992) Functional ovarian cysts in relation to the use of monophasic and triphasic oral contraceptives. Obstet Gynecol 1992; 79: 529 – 533.

20. Turan C, Zorlu CG, Ugur M, Ozcan T, Kaleli B and Gökmen O. Expectant management of functional ovarian cysts: an alternative to hormonal therapy. Int J Gynaecol Obstet 1994; 47 (3): 257 - 260.

21. Nezhat FR, Nezhat CH, Borhan S and Nezhat CR. Is hormonal suppression efficacious in treating functional ovarian cysts? J Am Assoc Gynecol Laparosc 1994; 1 (4, part 2): S26.

22. Westhoff C. Depot medroxyprogesterone acetate contraception. Metabolic parameters and mood changes. J Reprod Med. 1996; 41 (suppl 5): 401 - 406.

23. Spencer JE. Anovulation and monophonic cycles. Ann N Y Acad Sci 1997; 16: 173 - 176.

24. Livingstone M and Fraser IS. Mechanisms of abnormal uterine bleeding. Hum Reprod Update. 2002; 8 (1): 60 - 67.

25. Sharma JB, Roy KK, Pushparaj M, Gupta N, Jain SK, Malhorta N and Mittal S. Genital tuberculosis: and important cause of Asherman’s syndrome in India. Arch Gynecol Obstet 2008; 277 (1): 37 - 41.

26. Grivell RM, Reid KM and Mellor A. Uterine arteriovenous malformation: a review of the current literature. Obstet Gynecol Surv 2005; 60 (11): 761 - 767.

27. Halperin R, Schneider D, Maymon R, Peer A, Pansky M and Herman A. Arteriovenous malformation after uterine curettage: a report of 3 cases. J Reprod Med 2007; 52 (5): 445 - 449.

28.Shapley M, Jordon K and Croft. An epidemiological survey of symptoms of menstrual loss in the community 2004. Br J Gen Pract 2004; 54 (502): 359 – 363.

29. Schlesselman JJ. Oral contraceptives and neoplasia of the uterine corpus. Contraception 1991; 43: 557 - 579.

30. Narod SA, Risch H, Moslehi R, Dørum A, Neuhausen S, Olsson H, Provencher D, Radice P, Evans G, Bishop S, Brunet JS and Ponder BA. Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary ovarian cancer clinical study group. N Engl J Med 1998; 339(7): 424 – 428.

31. The Cancer and Steroid Hormone Study of the Centres for Disease Control and the National Institute of Child Health and Human Development. The reduction in risk of ovarian cancer associated with oral contraceptive use. N Engl J Med 1987; 316: 650 - 655.

32. Ness RB, Grisso JA, Cottreau C, Klapper J, Vergona R, Wheeler JE, Morgan M, Schlesselman JJ. Factors related to inflammation of the ovarian epithelium and risk of ovarian cancer. Epidemiology 2000; 11: 111 - 117.

33. Mishell DR Jr. Noncontraceptive benefits of oral contraceptives. Am J Obstet Gynecol 1982; 142: 809 – 816.

34.Brinton LA, Vessey MP, Flavel R, Yeates D. Risk factors for benign breast disease. Am J Epidemiol 1981; 113: 203 – 214.

35.The ESHRE Capri Working Group. Non contraceptive health benefits of combined oral contraception. Hum Reprod Update 2005; 11(5): 513 – 525.

36. Brunner Huber LR and Toth JL. Obesity and oral contraceptive failure: Findings from the 2002 National Survey of Family Growth. Am J Epidemiol 2007; 1666: 1306 – 1311.

37. Curtis KM, Mohllajeea AP, Martinsa SL, Petersonb HB. Combined oral contraceptive use among women with hypertension: a systematic review. Contraception 2006; 73: 179 – 188.

38. Farley TMM, Collins J, Schlesselman JJ. Hormonal contraception and risk of cardiovascular disease. An international perspective. Contraception 1998; 57: 211 – 230.

39. Lubianca JN, Faccin CS, Fuchs FD. Oral contraceptives: a risk factor for uncontrolled blood pressure among hypertensive women. Contraception 2003; 67(1): 19 - 24.

40. Lubianca JN, Moreira LB, Gus M, Fuchs FD; Stopping oral contraceptives: an effective blood pressure-lowering intervention in women with hypertension. J Hum Hypertens. 2005; 19(6):451 -455

41.Atthobari J, Gansevoort RT, Visser ST, de Jong PE and de Jong-van den Berg LTW.The impact of hormonal contraceptives on blood pressure, urinary albumin excretion and glomerular filtration rate. Br J Clin Pharmacol 2007; 63(2): 224 – 231.

42.Rees DC, Cox M and Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133 – 1134.

43.Blickstein D and Blickstein I. Oral contraception and thrombophilia. Curr Opin Obstet Gynecol 2007; 19: 370 – 376.

44.No authors listed] Intrauterine devices: an effective alternative to oral hormonal contraception. Prescrire Int 2009; 18(101): 125-130.

45. Lopez LM, Grimes DA, Schulz KF. Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus. Cochrane Database Syst Rev. 2009; 7(4): CD006133.

46. Cagnacci A, Ferrari S, Tirelli A, Zanin, Volpe A. Route of administration of contraceptives containing desogestrel/etonorgestrel and insulin sensitivity: a prospective randomized study. Contraception 2009; 80(1): 34 - 39.

47. Xiang AH, Kawoakubo M, Kjos SL, Buchanan TA. Long-acting injectable progestin contraception and risk of type 2 diabetes in Latino women with prior gestational diabetes mellitus. Diabetes Care. 2006; 29(3): 613 - 617.

48. Shawe J, Lawrenson R. Hormonal contraception in women with diabetes mellitus: special considerations. Treat Endocrinol. 2003; 2(5): 321 – 330.

49. Nikolov A, Dimitrov A, Kolarov G, Todarova K, Mekhandzhiev TS. Contraception in women with diabetes. Mellitus Akus Ginekol (Sofia). 2005; 44(5): 47 - 52.

50.International Collaboration of Epidemiological Studies of Cervical Cancer. Appleby P, Beral V, Berrington de Gonzalez A, Colin D, Franceschi S, Goodhill A, Green J, Peto J. Plummer M, Sweetland S. Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet 2007; 370(9599): 1609 – 1621.

52.Singletary AE. Rating risk factors for breast cancer. Ann Surgery 2003; 237(4): 474 – 482.

53.Reid RL. Hormonal Contraception and Breast Cancer: Keeping Perspective. J Obstet Gynaecol Can 2007; 29(3): 207 – 209.

54. Kahlenborn C, Modugno F, Potter DM, Severs WB. Oral contraceptive use as a risk factor for premenopausal breast cancer: a meta-analysis. Mayo Clin Proc 2006; 81(10): 1290 – 1302.

55.Liying Z, Bilian X. Emergency contraception with Multiload CU-375sl IUD: a multicentre clinical trial. Contraception 2001; 64: 107 – 712.

56. Bhathena RK and Guillebaud J. Review Postcoital contraception. The Obstetrician and Gynaecologist 2011; 13: 29 – 34.

57.Cameron S, Glasier A. The need to take a ‘new look’ at emergency contraception. J Fam Plann Reprod Health Care 2010; 36: 3 – 4.

58.Brache V. Cochon L, Jesam C, Maldonado R, Salvatierra AM, Levy D Gainer E, Croxatto HB. Immediate pre-ovulatory adminstration of 30 mg ulipristal acetate significantly delays follicular rupture. Hum Reprod 2010; 25(9): 2256 – 2263.

59.World Health Organisation. Emergency contraceptive pills. In: Family Planning-A Global Handbook for Providers. Geneva: WHO; 2007. P. 45 – 58.

60.Guillebaud J. Contraception for women over 35 years of age. Br J Fam Plann 1992; 17: 115 – 118.

61.Lidegaard O. Oral contraception and the risk of cerebral thromboembolic attack: results of a case-control study. BMJ 1993; 306: 956 – 963.

62.Broome M, Fotherby K. Clinical experience with the progestogen-only pill. Contraception 1990; 42: 489 – 495.

63.Wong MT and Singh K. The combined oral contraceptive pill in women over age forty. Ann Acad Med Singapore 2003; 32(5): 624 – 631.

64. Kaunitz AM. Oral contraceptive use in perimenopause. Am J Obstet Gynecol 2001; 185(2 Suppl): S32 – 37.

65.Lidegaard O, Lokkegaard E, Svendsen AL and Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009; 339: b2890.

66.Hirvonen E, Idanpaan-Heikkila J. Cardiovascular death among women under 40 years using low oestrogen oral contraceptives and intrauterine devices in Finland form 1975 to 1984. Am J Obstet Gynecol 1990; 163: 281 – 284.

67.Jick H, Jick SS, and Gurewich V, Myers MW and Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestogen components. Lancet 1995; 346: 1589 – 1593.

68.WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. Lancet 1995; 346: 1575 – 1582.

69.WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined and combined oral contraceptives: results of international multicentre case-control study. Lancet 1996; 348: 498 – 505.

70.Gebbie A. Contraception in the perimenopause. J Br Menopause Soc 2003; 9(3): 123 -128.

71.Alexander IM. Contraceptive options for perimenopausal women. Contracept Technol Update 1999; 20(10): 122 – 124.

72.Bhathena RK and Guillebaud J. Contraception for the older woman: an update. Climacteric 2006; 9()4): 264 – 267.

73.FHRPHC Guidance: contraception for women aged over 40 years. J Fam Plann Reprod Health Care 2005; 31(1): 51 – 63.