Over the years, countless drugs have been developed, but only one has had enough of an impact to be referred to as The Pill. Today, approximately 100 million women worldwide use oral contraceptives. This is a remarkable statistic, especially considering it was illegal to even talk about contraception in public a little under 60 years ago.


The birth of The Pill

Humans have attempted to control reproduction for thousands of years, an activity of limited success which was often shrouded in secrecy. Access to safe and efficient methods of birth control did not become legitimate until the beginning of the 20th century, in 1916, when Margaret Sanger, an activist for women’s reproductive rights, opened the first birth control clinic in the United States (and later founded Planned Parenthood). During this time, contraception was considered to be taboo—socially and politically—and research studies often had to be disguised as “fertility studies”. In the late 1930s, it was observed in animals that high doses of progesterone could arrest ovulation and by the 1940s, these findings had been brought into humans. Dr. John Rock alongside Dr. Gregory Pincus, under the support of Sanger, organized the first large-scale trial of a hormone oral contraceptive which took place in Puerto Rico, where there were no prohibitive laws on contraception. Finally, in 1960, the US Food and Drug Administration (FDA) approved Enovid, the first oral contraceptive. However, as a high amount of stigma was still associated with birth control, it was first advertised as a method of “cycle control” and was only administered to married women. In Canada, Dr. Elizabeth Bagshaw, a graduate of Women’s College Hospital here in Toronto, served as the medical director of the first Canadian birth control clinic in 1932. It took some time for birth control to be legalized as public discussion of the subject was also illegal under the 1892 Criminal Code and contraception itself was not decriminalized until 1969.

How it works

Oral contraceptives can generally be divided into 2 types: combined (progestin + estrogen) or progestin-alone. Combined oral contraceptives (COCs) are the more common of the two and prevent ovulation by disrupting the natural hormonal regulation of the menstruation cycle. Normally, at the beginning of a cycle, low levels of estrogen and progesterone signal to the hypothalamus to produce gonadotropin-releasing hormone (GnRH). This leads to increased production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary, promoting the development of a follicle that in turn secretes estrogen. As estrogen accumulates, LH levels are driven upwards (known as the LH surge) resulting in follicle rupture and the release of an egg. The ruptured follicle forms the corpus luteum, a structure that secretes progesterone, which negatively regulates GnRH, FSH, and LH. Estrogen and progesterone levels decline and the endometrial lining is sloughed off (menstrual phase), triggering the start of another cycle. With COCs, the presence of high levels of estrogen and progestin throughout the cycle disrupts the induction of GnRH. Without GnRH, secretion of FSH and LH is decreased and follicular development and the subsequent release of the egg are inhibited—in other words, ovulation does not occur.

Evolution throughout the years

Formulations of The Pill have changed drastically since it was introduced in 1960. Today there are a multitude of brands, each differing from the next in dosage, administration schedules, hormone content, and intended uses. Common side effects include weight gain, nausea, headaches, breast changes, as well as mood disturbances, and so improvements are still very much needed. Below are some of the changes that have been implemented through the decades:

Hormone Dosage: The most noticeable change can be seen in the much lower doses of hormones present in today’s Pill. In early generations, doses of mestranol (a form of estrogen present in the first COC) as high as 150 µg could be found. Today, there is generally 35 µg or less. This reduction aimed to improve safety as well as tolerability. Levels of progestin have also been considerably reduced from 10 mg of norethindrone to 0.5-1.5 mg.

Modified Hormones: New hormones have been developed that vary in potency and affinity. New synthetic forms are meant to bind more specifically to the desired receptors, preventing interaction with other steroid receptors, which minimizes unwanted androgenic, estrogenic and glucocorticoid responses.

Continuous versus Multiphasic Regimens: Early regimens were generally monophasic meaning that each pill had a fixed dose of hormone that was taken during the first three weeks of the cycle. Biphasic and triphasic plans emerged during the 1980s, where hormone doses varied with progression of the cycle. These regimens were designed to mimic hormone levels seen at particular phases of the cycle and normal physiologic conditions. Presently, a 28-day regimen—with 21 active and 7 inactive pills (to mimic the menstrual phase)—is commonly used. During the 7-day inactive period, the absence of hormones allows for release of the endometrial lining, similar to that of a normal menstruation.

Social, Economic, and Medical Impact

One of the reasons why The Pill was so revolutionary is because it gave women an unprecedented method of birth control that was non-invasive, reversible, and highly effective. In addition, the decision of whether to use it was completely private and autonomous—it was a choice that a woman was able to make solely on her own. The Pill also gave women a say in family planning, as they could decide on when or whether they even wanted children. Being able to control their reproduction enabled women to delay childbearing, allowing them opportunities previously limited to them like pursuing a higher education or advanced professional careers. But the impact of The Pill goes further than just family planning. According to the World Health Organization, each year there are approximately 19-20 million abortions conducted either by individuals who are not adequately trained/licensed or in environments that do not meet minimal medical standards. A large proportion of these occur in developing countries and almost 70,000 women die from these procedures while many more experience lasting consequences to their health (e.g. haemorrhage, infection). Access to contraception and awareness on proper use aids in decreasing maternal mortality.

A pill for men?

In just a couple of years, we may be witnessing the arrival of a pill—for men. Trials for hormonal contraception in males began in the 1970s and were aimed at suppressing endogenous production of testosterone and spermatogenesis. Present research is also looking into the development of novel molecules that may be able to elicit more potent responses than testosterone and also limit some of the side effects observed in trials (acne, weight gain, mood changes). Long-term effects are not yet known and dosage/administration regimens still remain to be determined.

More to come . . .

Continued research into improved methods of contraception is surely to continue but it is indisputable that The Pill has already made great strides in establishing itself as one of the most revolutionary drugs of the 21st century.


References: 

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  2. Liao PV, Dollin J. “Half a century of the oral contraceptive pill”. Dec 2012. Can Fam Physician. Available Online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520685/pdf/058e757.pdf  
  3. Cooper DB, Adigun R. “Oral Contraceptive Pills”. 20 April 2017. StatPearls. Available Online: https://www.ncbi.nlm.nih.gov/books/NBK430882/  
  4. Reed BG, Carr BR. “The Normal Menstrual Cycle and the Control of Ovulation “. 22 May 2015. Endotext. Available Online: https://www.ncbi.nlm.nih.gov/books/NBK279054/  
  5. Frye, CA. “An overview of oral contraceptives: Mechanism of action and clinical use” . 28 March 2006. Neurology.  
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  8. Stewart M. “Choosing a combined oral contraceptive pill”. Feb 2015. Aust Prescr 38(1): 6—11  
  9. Seligson H. “Beyond the Bedroom: What the Birth Control Pill Really Did For Women”. 12 May 2010. Forbes. Available Online: https://www.forbes.com/2010/05/12/sexual-revolution-planned-parenthood-unplanned-pregnancy-forbes-woman-health-birth-control-pill.html#736cac322133
  10. Chadwick KD, Burkman RT, Tornesi BM, Mahadevan B. “Fifty Years of ‘the Pill’: Risk Reduction and Discovery of Benefits Beyond Contraception, Reflections, and Forecast”. 22 Sept 2011. Toxicological Sciences 125(1): 2—9   
  11. Urist J. “Social and Economic Benefits of Reliable Contraception”. 2 Jul 2014. The Atlantic. Available Online: https://www.theatlantic.com/health/archive/2014/07/the-broader-benefits-of-contraception/373856/   
  12. Ahmed S. “Maternal deaths averted by contraceptive use: an analysis of 172 countries”. 10 July 2012. The Lancet. Available Online: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2960478-4/abstract?code=lancet-site   
  13. Chola L, McGee S, Tugendhaft A, Buchmann E, Hofman K. “Scaling Up Family Planning to Reduce Maternal and Child Mortality: The Potential Costs and Benefits of Modern Contraceptive Use in South Africa”. 15 June 2015. PLoS One 10(6): e0130077 
  14. Grimes DA, Benson J, Singh S, Romero M, Ganatra B, Okonofua FE, Shah IH. “Unsafe abortion: the preventable pandemic”. Oct 2006. The Lancet.  
  15. Wang C, Festin MPR, Swerdloff RS. “Male Hormonal Contraception: Where Are We Now? “. 29 Jan 2016. Curr Obstet Gynecol Rep. doi: 10.1007/s13669-016-0140-8  
  16. University of North Carolina Health Care. “Male contraceptive compound stops sperm without affecting hormones: Study in monkeys: In preclinical tests, researchers have shown how a new compound can immobilize sperm temporarily without side effects.” ScienceDaily. ScienceDaily, 19 April 2018. <www.sciencedaily.com/releases/2018/04/180419172654.htm>. 
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Sharon Ling

Sharon is an MSc candidate within the lab of Dr. Rae Yeung in the Department of Immunology at the University of Toronto. Outside of the lab, Sharon enjoys watercolour painting, working out, and grabbing weekly dim-sum with her grandma.

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