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Engineering the Pill: It’s the Male’s turn
The pharmaceutical industry is one of the most difficult biomedical industries to
enter. This is because of all the patents already in place and because of the high volumes of
drugs being developed. An example of this is the contraceptive industry. Not only is there
already a pill out there, but also there are many other forms of contraception that are well
established. Currently, there is an effort to develop a new form of oral contraception for
males. During the development of the pill they have tried to mimic how the female pill
works on the female body by manipulating male hormones. Unfortunately, that failed and
now there has been a break through discovery that could lead to the development of a male
oral contraceptive within the next ten years.
When scientists were first attempting to create a male oral contraceptive they aimed
to copy how the female oral contraceptive worked. In order to understand why they tried
to mimic the female pill we must first understand how the female pill works. The two
reproductive cycles in females are the ovarian cycle and the menstrual cycle. Since the pill
tries to eliminate chances of pregnancy, it only affects the Ovarian Cycle because that is the
cycle that produces the egg for the sperm to fertilize. The Ovarian Cycle begins when there
is a large amount of estradiol. Estradiol is a hormone that is released from a maturing
follicle within the ovaries. This maturing follicle is a “sack” that holds the egg which can be
potentially fertilized. As the follicle travels to the edge of the ovary near the fallopian tube,
the follicle is growing and maturing so that it can be properly fertilized by a sperm. Once
the brain recognizes that there is a large secretion of estradiol within the body, another
hormone, Gonadotropin-Releasing Hormone (GnRH), is released by the brain. GnRH then
stimulates the anterior pituitary, another part of the brain, and releases two more
hormones, Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH). These two
hormones are the hormones that help the follicle grow and mature while the follicle is in
the uterus. Once the follicle has fully
developed, it releases the original hormone,
estradiol [Reece]. This creates a positive
feedback loop between these three hormones
which causes a large spike in all three
hormones. A positive feedback loop is a
snowball effect created from hormones
(Figure 1). One hormone activates the other
hormone which reactivates the old hormone,
creating an avalanche of hormones. This
spike in FSH and LH promotes the excretion
Figure 1: This figure expresses how each hormone
will cause another hormone to be expressed and
cause the female ovarian and menstrual cycles
[Reece]
of the egg from the follicle into the fallopian
tube. The leftover follicle, or corpus luteum,
then secretes progesterone. Finally, the corpus luteum then degenerates and estradiol
begins the ovarian cycle again.
The main reason the pill successfully works is because it imitates a pregnant
female’s body. In order to better understand how the pill works at that level, we need to
understand the hormones involved and secreted during pregnancy. If the egg is fertilized
then the corpus luteum remains and continues to secrete progesterone which promotes the
growth of the lining of the uterus for implantation of the egg. The progesterone is secreted
and then creates a feedback loop with the brain. This means that when the brain sees the
high levels of progesterone, the brain inhibits the release of GnRH. This occurrence inhibits
the release of FSH and LH and prevents the growth of another follicle or possible egg. This
process ensures that there will not be a second fertilization as long as the pregnancy is
occurring.
With a greater understanding of the hormones involved in the female reproductive
system we can already see how there is a possibility to play with some of these hormones
in order to trick the female body into thinking it is pregnant. When engineering this pill,
developers looked at the female reproductive system from many angles to find the simplest
and easiest way to trick the female body. Therefore, developers concluded that creating a
fake influx of hormones and mimicking pregnancy was the best solution. By taking the pill,
a female is essentially overdosing on a combination of a synthetic estrogen and a synthetic
progestin (a progesterone-like hormone). By taking these hormones which resemble the
hormones secreted from the corpus luteum after fertilization, the brain tricks itself into
thinking that the egg has been fertilized. Thus, the brain shuts off the GnRH, FSH, and LH
and prevents a follicle from maturing, therefore preventing ovulation and stopping the
egg’s release.
Because scientists were so successful in mimicking female hormones and succeeded
in creating a successful drug that could prevent pregnancy, they began to think they could
manipulate male hormones to create the same effect. One method that has been
experimented with is immunocontraception. This method involves using the male’s
immune system to prevent fertilization of offspring. Engineers have targeted the same
hormone in females that cause the secretion of FSH and LH in females, GnRH. Scientist have
tried to make the male’s immune system attack GnRH. By attacking GnRH and preventing
its release from the brain an individual will not produce FSH and LH. This affects males
because it prevents gamete production and secondary sexual characteristics, such as their
libido. Unfortunately, the reason this was unviable was because this process was
irreversible after destroying the hormone balance in males. When GnRH is targeted by the
immune system it demolishes the gonads and there is a failure to produce gametes that are
fertile. Engineers have tried targeting multiple other hormones but to the same effect- they
all cause permanent infertility in males. Additionally, engineers have tried targeting the
gonads directly. By targeting the gonads, scientist’s goals are to infiltrate the gonads and
find a way to prevent sperm from maturing in the testis. This method has been a failure
because scientists cannot find a drug that can’t infiltrate the blood-testis barrier in the
gonads. Because drugs cannot penetrate that barrier there is no way to directly target
maturing sperm and prevent the male’s fertility, until now.
Engineers have finally made the breakthrough to discover how to create a male pill
that will prevent pregnancy but won’t cause infertility after taking the drug. Scientists at
University of Kansas, Male Contraceptive Research and drug Development have discovered
a small molecule that can rapidly reduce the amount of sperm count in mice. They have
discovered a compound named JQ1 that can penetrate the blood-testis barrier that so many
drugs have struggled to break through. This drug penetrates the blood-testis barrier and
stops the maturation of the sperm. This means that when the male is ejaculating, he is
ejaculating immature sperm that will not be able to make the journey through the fallopian
tubes to the
female egg. Even
if the sperm
would happen to
make it to the egg,
the sperm would
not be fertile and
unable implant
and cause
conception
Figure 2: This is a screenshot taken from a video that displays the sperm’s
immobility and inability to impregnate a female egg when exposed to JQ1 [Pearson]
(Figure 2). JQ1 is
able to do this because it is a selective inhibitor of the bromodomain testis-specific protein,
BRDT. BRDT is essential for chromatin remodeling during sperm maturation. By blocking
BRDT, JQ1 prevents the production of sperm in the testis and is therefore an effective
contraceptive [Matzuk]. The major benefit to using JQ1 versus a drug that interacts with
the male’s hormones is that JQ1’s effects are totally and completely reversible. During mice
testing there was also no adverse symptoms while taking the drug. The only effects of JQ1
were the effects that were desired for infertility such as testicular size, sperm number,
sperm motility and fertility.
The engineers and scientists at Univeristy of Kansas are now looking further into
JQ1 and trying to develop a non-hormonal contraceptive agent known as a “gamendazole”
which will also interrupt sperm maturation. This drug has been tested on rodents, rabbits
and primates with success and they are trying to take the research to the next step by
attempting clinical trials within the near future.
With every pharmaceutical drug there are many hurdles that need to be overcome
to make the drug worthy of producing it on the market and making the drug a successful
product. With the possibility of gamendazole entering human testing phases soon there is
still a large chance this drug doesn’t make it. Human bodies are much different than
rodents and the other animals this drug has been tested on. There is the possibility that it
doesn’t have the same ability to break the blood-testis barrier in humans that it did in
rodents. This would prevent the drug from interrupting the maturation of the sperm. The
drug would then not be a viable contraceptive. There is also the possibility that there are
mental health issues, such as depression, within humans that were not seen in rodents. Not
to mention, if this drug passes the health standards and is capable of being sold then it still
has to compete with current contraception. Between the female pill and condoms, which
are 99% effective, it will be hard to enter the market and be a top seller against these
products that already have established a strong presence in the market. But because it is in
its own niche of oral contraceptive for males it could easily succeed but only time will tell.
With every engineering innovation and achievement, there are always harmful side
effects that could develop in the future. In this case, there are diseases that could possibly
accompany the pill. However, there is always a huge upside as well, like pregnancy
prevention without the risk of permanent side effects. The ultimate question engineers face
is if the invention is socially acceptable and reasonable. In this case, the pill is not only
socially accepted but encouraged especially with young adults. Pharmaceuticals will always
land on slippery slopes when deciding if the benefits are worth the risks especially when
the market is so competitive and difficult to enter because of patents. With this product it
appears there are no adverse side effects so hopefully there will be a new contraceptive in
the market in the near future. But with the possibility of failure like so many
pharmaceuticals have encountered we can only hope that this male contraceptive can pass
the tests and provide our society with another form of birth control.
Works Cited
Amy JJ, Tripathi V. Contraception for women: an evidence based overview. BMJ.
2009;339:b2895.doi:10.1136/bmj.b2895.
Matzuk, M. M.; McKeown, M. R.; Filippakopoulos, P.; Li, Q.; Ma, L.; Agno, J. E.; Lemieux, M. E.;
Picaud, S.; Yu, R. N.; Qi, J.; Knapp, S.; Bradner, J. E. (2012). "Small-Molecule Inhibition
of BRDT for Male Contraception".Cell 150 (4): 673–684.
Pearson, Catherine. New Male Birth Control Option Shows Promise, Preliminary Study
Finds. http://www.huffingtonpost.com/2012/08/16/male-birthcontrol_n_1791953.html
Reece, Jane B., and Neil A. Campbell. "Chapter 46." Campbell Biology / Jane B. Reece ... [et
Al.]. San Francisco, CA: Benjamin Cummings, 2011. N. pag. Print.