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									                             On The Pill
news                                                                                                              f e at u r e

                                                                          Illustrations by JT Morrow

This month marks the fiftieth anniversary of the approval of oral contraception in the US, and the Pill’s age is
starting to show. Problems abound with its delivery, dosage and side effects. Ellen Friedrichs investigates how
researchers have conceived of new ways to deliver birth control.

Had she been a little older, Susan Magill would     ‘the Pill’ upon request. And for the next 13        How does the Pill really work?
have faced a quandary familiar to many prior        years, Magill relied on this oral method of         The primary goal of hormonal contraception is
generations of women: how to effectively            hormone-based contraception to keep herself         to prevent pregnancy by controlling a woman’s
control her fertility while staying sexually        pregnancy free.                                     ovulation. As early as 1945, Harvard endocri-
active. Fortunately, by the time she needed            Today, the number of women on the Pill has       nologist Fuller Albright suggested that oral reg-
birth control the most—at 26 years of age,          skyrocketed; the UN estimates that more than        imens of synthetic estrogen could do the trick.
after the birth of her second child—Magill          100 million women worldwide now take some           Although the Pill ultimately came to depend
was in luck.                                        form of hormonal contraception. Nevertheless,       on synthetic progesterones (called progestins)
   It was 1964, and four years earlier the US       compliance issues and side effects remain           often combined with estrogens, Albright’s basic
Food and Drug Administration (FDA) had              problematic. Researchers have tinkered for          premise was accurate, and today most birth
approved Enovid, a combination hormonal             decades with delivery systems and dosages           control methods upset a woman’s natural cycle
pill, for contraceptive use. “I didn’t know too     to address these issues, yet the promise of         by flooding her body with hormones.
many people taking it, but I trusted that it was    nonsteroidal methods, male options and                 The hormone surge causes a negative feedback
safe,” recalls Magill, a retired drug and alcohol   contraceptive microbicides continues to             loop that decreases the brain’s production of
policy planner now living in Hamilton, New          dangle just out of reach.                           gonadotropin-releasing hormone, which, in
Jersey. “It made my periods regular, and it was        Now, fifty years after the Pill first appeared   turn, prevents the anterior pituitary gland from
very convenient because you didn’t have to          on the scene, the trusty oral daily dose            releasing other reproductive hormones, namely
use any other contraceptives.”                      remains the mainstay of women’s handbags            luteinizing and follicle-stimulating hormones.
   The social stigma surrounding premarital         and bathroom cabinets. Even so, many                The primary effect is suppression of ovulation.
sex meant that birth control was often              unanswered questions remain about a drug            Secondary outcomes, such as thicker cervical
unavailable to women who were not                   that, more than any other, changed the              mucus and thinning of the uterine lining, also
married. But as a married woman with kids,          reproductive landscape. Here are some of the        help prevent any eggs that are released from
Magill’s gynecologist promptly prescribed           most intriguing.                                    implanting.

506                                                                                         volume 16 | number 5 | may 2010 nature medicine
                                                                                                                       n e w s f e at u r e

   This much we know. What we don’t                                                                          FDA’s regulatory gauntlet. That might soon
know, for example, is whether certain                                                                        change. Ormeloxifene became available in
side effects are pharmacological or                                                                          Peru in 2008, and its Indian manufacturer,
psychological, or why an immature                                                                            HLL Lifecare Limited, is expanding into at
egg’s surrounding follicle doesn’t                                                                           least six other countries in South America,
develop properly after estrogens and                                                                         according to the company’s manager of
progestins bind the surface receptors.                                                                       regional exports Vipin Raj. “We are also
These questions deserve further                                                                              beginning the procedures to enter into the
exploration, but researchers are much                                                                        US market,” Raj adds.
more interested in finding a product                                                                            Another potential nonsteroidal
that works better.                                                                                           option is the anti-inflammatory
   “Fifty years after the Pill, all we                                                                       medication meloxicam, an inhibitor
have are incremental improvements,”                                                                          of the cyclooxygenase-2 enzyme,
says Michael Harper, director of                                                                             which prevents ovulation by stopping
the Consortium for Industrial                                                                                the release of the maturing egg from
Collaboration in Contraceptive                                                                               the surrounding follicle. A team led
Research at CONRAD, a reproductive                                                                           by Jill Schwartz, medical director for
health research organization based                                                                           CONRAD, reported earlier this year that
near Washington, DC. Vanessa Cullins,                                                                        a 30-milligram dose administered for five
vice president for medical affairs at                                                                        straight days in the lead-up to ovulation
Planned Parenthood Federation of                                                                             was a safe and effective form of emergency
America, adds, “We always welcome                                                                            contraception2.
methods that work differently and may                                                                           Now, Schwartz and her colleagues are
be associated with different forms of                                                                        exploring whether meloxicam, a drug
convenience.”                                                                                                already on the market for arthritis, could
                                                   in collaboration with the World Health              be used more broadly as a daily method of
How can drug delivery be improved?                 Organization and CONRAD, is developing a            pregnancy prevention. “The good thing about
Although they remain the most popular form         new shot involving levonorgestrel, a progestin      using something that is already out there
of birth control, oral contraceptive pills face    that is thought to have less of an effect on bone   and manufactured is that it will speed up the
increasing competition. Over the past 20 years,    mass density than does the existing injectable,     timeline” to regulatory approval, Schwartz
shots, implants, patches and vaginal rings have    Depo-Provera. However, this product won’t           says.
all entered the market. Commercial motivation      be available anytime soon. Toxicology and
has driven this development, of course. But so,    pharmacokinetic studies in animals have been        Don’t we have a ‘male Pill’ yet?
too, has the fact that no single method offers     completed, but similar studies in humans have       The concept of manipulating male hormones
a perfect delivery system. Pills are forgotten,    not yet begun.                                      to prevent contraception predates the approval
patches cause irritation and implants or                                                               of the female Pill by more than 20 years; in
injections must be administered by a medical       What about nonhormonal birth control?               1939, two independent research teams in the
professional.                                      Women in the US who are not candidates for          Midwest investigated testosterone’s ability to
   To move away from pill popping and address      hormonal contraceptives—either because              block or severely reduce the production of
many of the compliance issues of the other         of underlying health conditions, or because         sperm3,4. But, since female birth control pills
approaches, Régine Sitruk-Ware, a reproductive     they experience severe side effects—have only       took over the contraceptive market, nothing
endocrinologist and executive director of          two sets of reversible choices of birth control:    has been developed for men that is affordable,
research and development at the Population         barriers, such as condoms and diaphragms, and       reversible, safe and more effective than a
Council’s Center for Biomedical Research           intrauterine devices (IUDs), small, T-shaped        vasectomy—which has a failure rate of only 1
in New York, is working on an easy-to-apply        objects that are placed in the uterus to prevent    in 2,000.
transdermal gel that, like hormone-based           pregnancy.                                             Hopes were raised last year after a Chinese
lotions developed to treat menopause, can be          For women in India and Peru, however,            study showed that monthly injections of a long-
absorbed through the skin.                         there is a third option: a small molecule called    acting form of testosterone could temporarily
   Last October, Sitruk-Ware and her colleagues    ormeloxifene that prevents implantation by          and reversibly prevent spermatogenesis5. That
completed a phase 2 trial testing three hormone    binding estrogen receptors to enhance the           excitement faded, however, when it became
doses of such a contraceptive cream. Their         effects of the hormone in some parts of the body    clear that this formulation was less effective in
unpublished data show that a midlevel dose         (such as bone) and block estrogen-induced           non-Asian men, possibly because non-Asian
of the ointment sufficiently blocked ovulation     gene expression in other parts (including the       men tend to have a higher body fat mass,
with few serious side effects. Most importantly,   uterus). Marketed in India under the name           which has been found to inhibit the response
perhaps, “women who participated in the            Saheli, this weekly oral medication sells 25        to androgens6.
studies liked the gel,” Sitruk-Ware says. “This    million doses a year in that country and has           Researchers are also considering options
was not a visible method and not detectable,       been used as birth control for almost twenty        besides direct hormone injections, which can be
even by their partners.”                           years.                                              inconvenient and produce mild, but unpleasant,
   A gel isn’t the only new delivery method           In all that time, however, ormeloxifene has      side effects, such as changes in mood and blood
on the horizon. The US National Institute          never been available in the US because no           cholesterol concentrations. Christina Wang, a
of Child Health and Human Development,             company has risked taking the drug through the      reproductive endocrinologist who has been

nature medicine volume 16 | number 5 | may 2010                                                                                                    507
n e w s f e at u r e

heading up clinical trials of male hormonal             Over the years, researchers have investigated a Philip Hannaford, an epidemiologist at the
contraceptives at Harbor-University of              number of microbicidal agents to prevent HIV University of Aberdeen, UK.
California–Los Angeles Medical Center, thinks       and other pathogens, but few of these candidate        Some pharmaceutical companies have
that molecules that selectively modulate the        drugs have been designed to offer protection claimed that the Pill also decreases fatigue,
hormones’ receptors only in particular tissues      from pregnancy. One promising contender for anxiety, headaches, bloating and other
could address some of these issues. Such            a dual-acting, contraceptive microbicide is a symptoms of premenstrual syndrome. But
selective androgen receptor modulators “will        naturally occurring antimicrobial peptide called many of these purported benefits are more
suppress sperm production and will have a           nisin, a byproduct                                                    speculative than proven. The
good effect on muscles and bones and sexual         of culturing the                                                      pharmaceutical giant Bayer
function, and less of an effect on the prostate,”   bacterium Lactococcus                                                 discovered the complexity of
                                                                                 “A contraceptive
says Wang.                                          lactis. K.V.R. Reddy of                                               making such claims in 2008 after
   Evidence that this idea could work came          the National Institute       microbicide would                        the FDA slapped the company
last year when a team led by James Dalton, a        for Research in              really be best.”                         with a warning letter for a series
pharmacologist at Ohio State University in          Reproductive Health                                                   of television ads that overstated
Columbus, showed that a small molecule called       in Mumbai, India                         —Jill Schwartz the approved use of its Yaz birth
S-23 suppressed spermatogenesis in male rats;       showed last year that                                                 control pills. To date, more than
adding another steroid also kept the rats’ sexual   nisin disrupts the                                                    1,000 complaints have been
behavior intact7. According to Dalton, however,     membranes of both sperm and bacteria8. Since filed against the company as part of a class-
S-23 has not yet entered clinical trials.           then, however, Reddy has also found that the action suit alleging that these birth control
                                                    compound kills many of the symbiotic microbes pills also caused potentially fatal blood clots
What new contraceptives prevent disease?            living in the vaginal tract. “Therefore, this may in otherwise healthy women.
Condoms can reliably prevent sexually               not be a good candidate microbicide,” he says.
transmitted disease. But condoms aren’t                 Microbiologist Adriano Brandelli and his Where do we go from here?
a universal solution, because they can be           colleagues at the Federal University of Rio On 10 May 1960, the day after the Pill gained
difficult to apply and may interfere with sex.      Grande do Sul in Brazil discovered another FDA approval for contraceptive use, the
Additionally, whereas many people accept male       antimicrobial peptide produced by a newly New York Times ran a brief article about the
condom use, the female condom has yet to be         discovered Bacillus species that can also kill event, quoting the agency’s then associate
embraced. In light of these issues, CONRAD’s        sperm without damaging surrounding tissue. commissioner, John Harvey. “Approval was
Schwartz knows exactly what she wants: “A           “This peptide could be spermicidal if used in based on the question of safety,” Harvey
contraceptive microbicide would really be best,”    increased concentrations,” says Brandelli, who explained. “We had no choice as to the morality
she says. Such a form of birth control would        reported the molecule’s in vitro cytotoxicity in that might be involved.” It wasn’t exactly an
prevent both pregnancy and certain sexually         February9.                                          enthusiastic endorsement, but it wasn’t a
transmitted infections, thereby achieving                                                               surprising statement either, given the climate
the same benefit as a prophylactic without          Does the Pill offer other benefits?                 of the times.
the physical barriers and                           Birth control is not without its risks.                To be sure, questions of safety and morality
psychological resistance that                       Some forms of the Pill have been linked to still circulate today, as do those asking what
can arise with condoms.                                 blood clots, and this medication can be it will take to deliver a better, more effective
                                                           particularly unsafe for smokers over product. And although it’s unlikely that the
                                                             35. Advocates of the Pill, however, perfect contraceptive will ever be developed,
                                                             are far more likely to tout the benefits it isn’t such a stretch to assume that the
                                                          rather than the drawbacks of hormonal next 50 years, like the 50 that came before,
                                                          contraceptives. For example, last year’s will continue to be a time of birth control
                                                          survey of 45 observational studies from innovation.
                                                          21 countries found evidence that the Pill
                                                        offers some protection against colorectal                  Ellen Friedrichs is a writer and health
                                                      cancer, benign breast disease and ovarian                   educator living in Brooklyn, New York.
                                                      cysts, among other ailments10.
                                                         Last month, Scottish researchers also 1. Lal, J. Contraception 81, 275–280 (2010).
                                                                                                        2. Jesam, C., Salvatierra, A.M., Schwartz, J. L. &
                                                       reported the results of a 39-year study              Croxatto, H.B. Hum. Reprod. 25, 368–373 (2010).
                                                         that followed more than 46,000 women 3. Heckel, N. J. Proc. Soc. Exp. Biol. Med. 40, 658–659
                                                          across the UK. They found that women
                                                                                                        4. McCullagh E.P. & McGurl, F.J. J. Urol. 42, 1265–1267
                                                           on the Pill were less likely to die from         (1939).
                                                           any medical cause, including heart 5. Gu, Y. et al. J. Clin. Endocrinol. Metab. 94, 1910–
                                                                                                            1915 (2009).
                                                           disease and all cancers, compared 6. Kornmann, B. et al. J. Andrology 30, 602–613
                                                           to those who had never taken oral                (2009).
                                                          contraception11. Although the study 7. Jones, A. et al. Endocrinology 150, 385–395
                                                         only considered early forms of the Pill, 8. Gupta, S.M., Aranha, C.C., Bellare, J.R. & Reddy,
                                                        “it is not unreasonable to suppose that             K.V.R. Contraception 80, 299–307 (2009).
                                                       a similar overall lack of risk in the long 9. Vaucher, R.A., da Motta Ade, S. & Brandelli A. Cell
                                                                                                            Biol. Int. 34, 317–323 (2010).
                                                     term would also be found among today’s 10. Amy, J.-J. & Tripathi, V. BMJ 339, b2895 (2009).
                                                    oral contraceptive users,” says lead author 11. Hannaford, P.C. et al. BMJ 340, c927 (2010).

508                                           volume 16 | number 5 | may 2010 nature medicine

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