Review

Oral contraceptives - journey so far: A review Kanaka Bhushanam GVVS1 and Sakuntala Devi Gampa2,*

1 2 Gitam Medical Collage, Gandhi Nagar, Rushikonda, Visakhapatnam, Andhra Pradesh, India Krishna Institute of Medical Sciences, Minister Road, Secunderabad-500003, Telangana, India

Abstract since 1970s. As per WHO (1998), over 100 million women are using oral contraceptive pills (OCPs) worldwide, mostlyOral contraceptive in developed is acountries. widely accepted In India and only most 2% effectiveof married method women of offertility reproductive control. ageIts wereuse has using been OCPs growing for fertility control during the period from 1990 to 2001. The history, evolution and development of oral pills till

Keywords:date is discussed oral contraception; along with the fertility benefits, control; risks and contraceptive side effects pills of oral contraceptive pills.

*Corresponding author: Dr. Sakuntala Devi Gampa, Gitam Introduction Medical Collage, Gandhi Nagar, Rushikonda, Visakhapatnam, [email protected] Once upon a time contraception was a taboo in many countries and practicing or even promoting AndhraReceived Pradesh, 28 October India. 2015; Email: Revised 11 December 2015; Accepted 19 December 2015; Published 29 December 2015 contraception was punishable. From that situation oral pills have now reached a stage where they are Citation: most widely accepted method of and Kanakabhushanam GVVS, Gampa SD. Oral1 contraceptives- also became a useful therapeutic modality for many journey so far: A review. J Med Sci Res. 2016; 4(1):35-40. DOI: gynaecological conditions avoiding unnecessary Chttp://dx.doi.org/10.17727/JMSR.2016/4-01opyright: © 2016 Kanakabhushanam GVVS, et al. Published by hysterectomies. Many breakthroughs in the article distributed under the terms of the Creative Commons evolution of birth pills are responsible for today’s AttributionKIMS Foundation License, and which Research permits Center. unrestricted This is use, an distribution, open-access high acceptance of oral pills in fertility control and and reproduction in any medium, provided the original author and source are credited.

Htheiristory other and clinical evolution uses and benefits. Since ages human beings have attempted to invent and use contraception. In the past oral contraception was practiced with herbs, roots, minerals and oils.

contraception. Oral pill is a major breakthrough in the field of

money of Katherine McCormi, the pharmacological geniusEven though of Gregory the passion Pincus of Margaret and the Sanger, clinical the

Vol. 4 | Issue 1 | January - March 2016 35 of oral contraceptive pill, Gregory Pincus (Figure1) containing 10mg of norethinodrel and 150mg of nameresponsibility is associated of John withRock oralresulted pill. in First the invention pill was meThusstranol in 1957was developed first contraceptive by Searle Company. pill “enovid” First developed in 1961. Since then several stepwise it was approved by FDA only for the treatment of changes in dosage and composition of pill have taken menstrual disorders and later it got approved as contraceptive in 1961. However Searle did not market enovid 10mg as contraceptive pill as they developed place in order to get a safe and effective pill. low dose enovid with 5/2.5mg of norethinodrel

and got approval in 1961 for oral contraception. In earlyand 75mg 60s Scheringof , developed which isoralpill equally containing effective 4mg of and 50mg of ethynylestradiol (anovlar).

Organon developed “lyndiol” (2.5 mg of Hohlweg& 75mg in of 1938 mestranol). and later it Ethinyl replaced mestranol was in synthesized by Hans Herloff Inhoffen and Walter sequential pill in which oestrogen will be given forall OC 2 pills. weeks Joseph followed Goldzieher by oestrogen was first alongto develop with , for one week. Pills with natural oestrogens have been developed very recently.

Knowledge of the fact that high doses of sex Figure 1: (standing behind him). Katherine McCormi. particularly ethnylestradiol are responsible for the Gregory Pincus (at the microscope) and John Rock of newer pills with low dose oestrogen, newer Milestones serious side effects of pills, led to the development In 1921, Ludwig Haberlandt, grandfather of administrative routes and schemes . This resulted pill found that rabbits and guinea pigs became inprogestins the development with more specific of combined action and pills alternative & phasic temporarily sterile after transplantation of ovaries pills. Due to dose reduction, extension of pill intake

suppression of follicular development. Only in the from pregnant animals. This finding led to the study recentto 24 days past, became the extended necessary regimens to ensure are promoted. sufficient of the effect of progesterone on ovulation. In 1937, Besides, ‘progesterone only’ pills have also been A. W. Makepeace and co- workers demonstrated Marker, organic chemistry professor found that developed for use in women in whom oestrogen progesteronethe anti-ovulatory can be effect synthesized of progesterone. from a substance Russell

Dioscorea mexicana. Gregory Pincus along with nausea,use is breastcontraindicated. tenderness, Even vomiting, though and the bloating, dose Min“” Chueh Chang extracted found from that the repeated root injections of plant reduction resulted in reduction of side effects like of progesterone stopped ovulation in animals. Carl of progestin on endometrium even in low dose is dominant.the pro thrombotic effect is not nullified. The effect orally active progestin ‘norethindrone’. Djerassi (syntex company) synthesized the first The newer progestins are 2nd generation Frank Colton (Searle) developed close isomer of (); 3rd generation ( norethindrone namely norethinodrel. First oral and ); 4th generation (drospirinone, contraceptive trials were started with norethinodrel. Subsequently it was found that addition of a attempts to replace ethynylestradiol with natural synthetic esrogen mestranol stops the breakthrough oestrogendienogest (estradiol) & normogestrol); resulted in Natural the development estradiol of - bleeding. a four phasic pill, a combination of estradiolvalerate

36 Journal of Medical and Scientific Research which is cleaved into estriol and in an and extended cycle of 26/28 days. once in a month. pills that can be used less frequently - may be A second OC containing 17 alpha estradiol and Classification of steroidal contraceptives normogestrol acetate 24/4 regimen is about to be launched. In 1980 low dose pills containing 0.015 has been tried through various routes in order to and/or progesterone administration are frequently used now. Research is currently going provide a reliable contraceptive cover. Various types -0.025 mg of ethinyl estradiol are developed, which of available steroidal contraceptives are shown in used only in post ovulatory phase or following coitus on to develop non-steroidal pills, pills that can be Steroidal Contraceptivesfigure 2.

Oral Injectable Implants IUD (Progestasert) (Norplant), Mirena Combined Injectable Combined contr. (DMPA,Contraceptive) NET-EN, patch/ring

Combined Single preparations (Containing only )

Monophasic Triphasic Mini pill contraceptive pill Post-coital

Standard dose Very low dose (Mala D/Mala N) Low dose (EE 0.3 mg) (EE 0.5 mg) (EE 0.2 mg)

Figure 2: Steroidal contraceptives. Classification Depending upon the amount of oestrogen and type of ethinyl estradiol and progestin drosperenone/ dienorgest/desogestrel/ normegestrol. gestodine 4th generation with 20-30µg

1stof progesterone, generation pills with are 50µg classified of ethinyl below: estradiol Oral pills and progestin , 2nd generation combined pill, and 2) progesterone only pill or mini levonorgestrel/ 3rd generation pillOral pills are broadly divided in to two groups: 1) with 20-35µg of ethinyl estradiol and progestin multiphasic. . Combined pills are of two types - monophasic or withVol. 4 20-30µg | Issue 1 of | ethinylJanuary - estradiol March 2016 and progestin 37 Monophasic pills Newer oral contraceptives Monophasic pills contain oestrogen and progestin in Nupil (noperalate): Chewable pill. Ovacon 35; the same amount in each pill. They are again divided contains progesterone (norethindrone) and into a) low dose pills containing ethinyl estradiol less oestrogen ethinyl estradiol. It is available as 28 day than 0.05mg and b) very low dose pills with ethinyl regimen. After chewing the pill they have to take estradiol less than 0.015-0.025 mg in each pill along 8-oz of water. with progestins. Alternative routes and administration Multiphasic pills These include hormone releasing intrauterine With a view to reduce total monthly dose of steroids, contraceptive device (IUCD), injectable phasic pills have been introduced. They contain contraceptives, implants, vaginal rings and dermal low doses and variable amount of oestrogen and patches. Vaginal rings and dermal patches came progestogen in 2 (biphasic) or 3 (triphasic) periods in to market in 2001. Parenteral route has got with in a menstrual cycle. The dose of progestin is low at the beginning and high at the end, while There is no evidence that these new modalities of the advantage of bypassing the 1st pass effect. oestrogen dose is constant or slightly rises in mid administration are superior to OC pills. cycle. Biphasic pill contains 0.035mg of ethinyl estradiol and low dose progestogen for 10 days Mechanism of action and higher dose of progestogen for the following Inhibition of ovulation by suppressing the 11 days, not popular because of higher failure rates. hypothalamo-pituitary axis, thickens the cervical They are not available in India. Triphasic pills in mucus thereby preventing sperm migration through India contain 0.05mg of l- and 0.03 mg of cervix, makes endometrium less receptive for ethinyl estradiol per day for the 1st 6 days, 0.075mg implantation. of l-norgestrel and 0.03 mg of ethinyl estradiol per day next 5 days and 0.125mg of l-norgesrel and 0.03 Benefits mg of ethinyl estradiol per day during last 10 days (triquilar). Triphasic pills with newer with a pregnancy rate of 1/1000 women in 1st One of the most effective method of contraception are available in other countries. year better than any other reversible contraceptive method except injections and implants; In addition Mini pill or ‘progesterone only’ pill to cycle stabilization, withdrawal bleeding is predictable, which can be postponed safely by means The ‘progesterone only’ pill contains only of extended regimens; Menstrual disorders such progestrogen in the form of norethisterone (0.0350 as cycle abnormalities, dysmenorrhoea, ovulation mg). This quantity is 50% of that of combined pills. pain can be controlled by using low dose pills (IPPF, They are available in India by name zerogen. It is 2003). Protection against cancer is one of the most suitable for lactating mother and in women in whom oestrogen is contraindicated. they prevent endometrial cancer by 50% (IMAP) important benefits of OCPs. It has been proved that Extended regimens with one year of usage and both high and low dose Monophasic pills prescribed continuously during 42 and effect lasts for about 15 years (Cash,1987a) (bi) or 63 (three cycling) days. FDA approved a pre- for 10 years (Cash, 1987b). They indirectly prevent packaged extended cycle regimen 84/7 containing choriocarcinomapills prevent ovarian by preventing cancers by pregnancy; 40%, effect Protection persist 30mg ethinyl estradiol along with 0.15mg of l-norgestrel. Other brands like Seasonique and inagainst pill users. benign Protection breast diseases- increases fibroadenoma with duration and of hormones. Both of these pills use oestrogen in the usagefibrocystic and dose diseases of progesterone; of breast are The reduced risk of follicular by 50% LoSeasonique use a different configuration of cyst is reduced to 50% and that of corpus luteum by option. In 2007 an annual regimen of extended cycle wasfinal approved week with by LoSeasonique FDA. It contains providing 20 µg of low ethinyl dose planning association has shown in their long term estradiol along with 90 µg of l-norgestrel to be taken 80% (WHO, 1996); Uterine fibroidsd - isoxford reduced family by throughout the year. about 30% with 10 year usage of OCPs. Protection study that the risk of uterine fibroi 38 Journal of Medical and Scientific Research is proportional to duration of use. Low dose pills users may be mainly due to alteration in coagulation system brought about by oestrogen component. 1996; IMAP, 2002, 2003); Protection against ectopic Progestogens are associated with the increase of pralso reduce fibroids and menstrual bleeding (WHO, (50%). Combined pills can be used continuously to controlegnancy endometriosis; (50%) and pelvic Low dose inflammatory pills with disease newer atherosclerosis,low- density lipoprotein coronary cholesterol heart disease and aand decrease cerebral of high – density cholesterol, which enhance the risk of hirsutism by reducing sex hormone binding globulin progestogens are effective in controlling acni and dosethrombosis: pills. Todate, but oestrogens there are have no data the oppositeto suggest effect, that and these actions seem relatively balanced in low- inand the significantly development increasing of rheumatoid free testosterone arthritis levels; and low- dose OCP have clinically significant adverse mayRheumatoid reduce progressionarthritis - pills from have mild a protective to severe effectstage Ceffectardiovascular on lipid profile. effects reports show that low dose pills reduce the chance of the disease (Speroff and Darney 1996); Some women without hypertension (HTN) and diabetes mellitusThere is (DM) no increased with the risk usage of MI of in low non-smoking dose pills, monthsand degree after of stopping osteoporosis the pill (IPPF, (Tindall, 2003); 1987) No effect irrespective of their age and duration of the use of on future fertility - ovulation usually returns in 3 pill (WHO, 1998). The suggestion that there is less Side effects risk of myocardial infarction with low dose pills containing Desogestrel or Gestodene than LNG is not yet proved. appetite, breakthrough bleeding. Low dose pills may causeMinor side oligomenorrhoea/menorrhagia effects include nausea, vomiting, or irregular loss of bleeding due to either low oestrogen or progestogen, Stroke resulting in lack of proliferation or regression of The increased relative risk of ischemic stroke is endometrium. Amenorrhoea is usually temporary about 1.5 times with low dose pills and the risk is and can be treated with changing to triphasic pills more in smokers and 3 times more in women with or by supplementing with ethinyl estradiol 0.02 hypertension (WHO, 1998; IMAP 2002). mg in last 7 days for few cycles (Wentz, 1998). If not responding OCP should be stopped. Post pill Venous thromboembolism amenorrhoea may occur in long term users and The risk of venous thromboembolism is 3 to 6 times can be treated with cyclical treatment with ethinyl more in pill users and rises with increasing age, recent estradiol 0.05mg for 10 days every 4 weeks for few cycles. However 1% of long term users of containing desogestrel and gestodone may carry a surgery, and some forms off thrombophilia. OC pills pills, who have menstrual problems before the slightly greater risk of venous thromboembolism use of pill (Tindall, 1987), may have persistent amenorrhoea and they may require investigations (1.6 fold) than OCP containing l-norgestrel. for micro adenoma of pituitary. They may respond Hypertension to treatment with clomiphene and rarely treatment In women above 35 years OCP use may cause mild with bromocryptine is needed. More often this side component. Hypertension usually disappears on discontinuationhypertension. This of pills.may be the effect of progestogen effect is cured by cyclical oestrogen. heaviness, vaginal discharge, headache, migraine, Breast cancer chloasma,Other minor weight effects gain, acni, include psycho breast sexual troubles,tenderness, The WHO researchers state that in young women corneal edema and hyperlipidaemia. The last two there is a small risk of breast cancer(1.24) which may require withdrawal of pills. reduces gradually and disappears completely 10 years after discontinuing the pill (WHO,1996). Major side effects and risks The risks of low dose pills are much less than high Cervical cancer dos There is a modest increase in the risk of cervical of low dose pills is not yet available. Coagulation e pills. The information on the long term effects OCP for more than 5 years. However it is not clear cancer (1.3 – 1.8 f old) among women who have used andVol. 4 lipids | Issue - cardiovascular1 | January - M complicationsarch 2016 in OCP 39 ect of the pill or Nutritional status (WHO 1980), There is no need of due to other factors such as age at 1st intercourse, vitamin supplementation in pill users (IPPF, 1987). whethermultiple partners,the risk is parity due to smoking direct eff etc. long term use Conclusion cancer risk in women with persistent hypertension. Theof OCP highest may (fourbe a fold)co-factor cancer in riskincreasing was seen the in cervical women who used OCP for 10 years or more. At present it The benefits of oral pills far outweigh the risks, more is acceptable to continue OCP while monitoring or malnutrition and unwanted pregnancies. The risks so in Indian women, who often suffer with anaemia, treating CIN (Guillebaud, 1999; WHO 2002). of voluntary pregnancy termination are much higher than risks from pill. In cases where there are Liver cancer no contraindications, OCPs are practically harmless. The risk of liver cancer is very small in OCP users, the They are less hazardous than common activities risk may be slightly higher in developed countries like games, motoring, sailing, and certainly less where hepatitis infection is more common. WHO hazardous than smoking. Still the quest for achieving ideal OCPs, which is convenient for the present day cancer with short term use of OCP, even in areas wherestudy (1992) Hepatitis did B notinfection find an is increasedmore prevalent. risk of liver going on. Research should be focussed on sustained releaseworking oral women pill, which to accept, can withoutbe administered any side onceeffects in ais Diabetes month so that patients compliance can be improved There is no evidence of increased incidence of diabetes in OC users. (IPPF, 1998). Low dose OCPs can be used in Diabetic patients under Conflictswith desired of effect. interest medical supervision. The insulin dose may have to be increased slightly. BP to be monitored as hypertension in these cases substantially increases Authors declare no conflict of interest the risk of arterial disease (1998). References 1. A

Effect on liver and gallbladder di ED, Tank PD. The Oral Contraceptive Pill: The early days 2. Andersonof a 50 year-old FD, Hait legend. H. AJ Obstet multicenter, Gynaecol randomized India. 2010; study 60(3): of occasionally. There is an increased risk of gallstones an207–209. extended cycle oral contraceptive. Contraception. 2003; andOCPs gallbladdermay cause cholestasis disease inand pill cholestatic users, howeverJaundice 68(2):89–96. women who are susceptible to them in any case, and 3. Chaudhuri SK. Editorial column. J Indian Med Ass. 1986; acceleration of these effects occurs only in those 84:169. 4. Fortney JR, Harper JM, Potts M. Stud Fam Plan. 1986; 2002). 17(3):117. no long-term increased risk has been found (IMAP, 5. Atkinson LE, Lincoln R, Forrest JD. Int fam plan perspect. 1985; 1(4):100. primary hepatocellular adenoma (1.2 per 100,000 7.6. BirtchBack DJ, RL, Brickenridge Olatunbosun AM, OA, Orme Pierson MLE. RA. IPPF Ovarian Med Bull. follicular 1983; 17(1):1. womenOCPs increase Wentz, incidence 1988), but of rareno risk benign of liver liver neoplasia tumour- dynamics during conventional vs. continuous oral in short term users (WHO, 1992). contraceptive use. Contraception. 2006; 73(3):235–243. Effect on lactation: OCP use will reduce milk 8. Dhont M. History of oral contraception. Eur J Contracept Reprod Health Care. 2010;15 Suppl 2:S12–8. production (WHO, 1983). 9. Guillebaud J. In: London N, ed. Handbook of family planning. Manual,Edinburg: 7th Charchill edition Livingstone,2013. 1991. Teratogenicity and future pregnancies 10. Chaudhury SK. Practice of fertility control: A Comprehensive

OCP use in early pregnancy is not associated with 11. Eyong E. IPPF Med Bull Apr. 1987; 21:4. the increased incidence of major fetal malformations 12. CASH: Cancer and hormone study. J Am Med Ass. or spontaneous abortions (IPPF, 1987; population 1987a; 257:786. 13. CASH: Cancer and steroid hormone study. N Engl J Med. reports, 1990). 15. Coney1987b; P, 316: Washenik 650. K, Langley RG, et al. Weight changes and 14. Cohen J. IPPF Med Bull Aug 1985; 18(4)1. Nutritional disorders adverse event incidence with a low-dose oral contraceptive. Studies of women with borderline malnutrition Contraception 2001; 63:297–302. have shown little or no a 16. PopulationConly SR, Camp crisis SL,committee, eds. India’s 1992. family planning challenge: From rhetoric to action, countryside series 2. Washington: 40 dverse effects of OCs on Journal of Medical and Scientific Research