The More You Know: Past and Current Research on Male Hormonal Contraception

BACKGROUND:

Since 1960, when the FDA approved the first form of oral contraception, people with uteruses have
been utilizing hormonal birth control.1 However, at this time, research on male hormonal birth control
also began. But, due to the complicated intersecting pathways of the production of sex steroids,
researchers became stuck and put this research on the backburner. Now, there are only two forms of
male contraception: condoms and vasectomies. Condoms offer the benefit of preventing the
transmission of sexual diseases, but are also known to have a fairly high failure rate. Vasectomies are
incredibly effective, but are invasive and not always reversible. Therefore, for couples interested in
family planning, there are limited male contraception options. This leaves couples, with whom the
females are medically unable to take hormonal birth control, with very limited contraception options.
Additionally, studies have found that a majority of men wish to be a part of the family planning
process, and would take a male contraceptive if made widely accessible and was surely reversible.2
Therefore, with population growth on the rise and the increasing need for family planning options,
research into male forms of contraception is absolutely necessary.

MALE HPG AXIS

Depending on how much is already in the OER, can cut/add to

this section…

Male hormonal birth control can target a number of hormones

along the hypothalamic-pituitary-gonad (HPG) axis. Since the
production of testosterone begins with the hypothalamic signal of
gonadotropin-releasing hormone (GnRH), many proposed
hormonal contraceptives have begun at that starting point. GnRH
then stimulates the production of luteinizing hormone (LH) and
follicle-stimulating hormone (FSH). LH then stimulates leydig
cells within the testes, which are able to produce testosterone. The
secretion of testosterone activates the sertoli cells in the
seminiferous tubule, leading to the secretion of inhibin, and a
negative feedback loop that inhibits the further secretion of FSH
and GnRH. FSH, and sertoli cells, are what regulate sperm
maturation and spermatogenesis. Therefore, in order to design a
contraceptive, it must have an inhibitory effect on these cells to
lower viable sperm counts. Since this step is close to the end of
the pathway, there are a number of proposed hormonal treatments
that can lead to reversible male infertility.

1
Kao A. History of oral contraception. AMA Journal of Ethics. 2000;2(6):55-56. doi:10.1001/virtualmentor.2000.2.6.dykn1-0006
2
Thirumalai A, Page ST. Male hormonal contraception. Annual Review of Medicine. 2020;71(1):17-31.
doi:10.1146/annurev-med-042418-010947
 MALE HORMONAL CONTRACEPTION METHODS
Throughout history, there have been three major forms of male hormonal contraception:
injection-based, transdermal and oral. Each method aims to reduce sperm count to below 1 million/ml,
as normal range varies between 15-200 million/ml of ejaculate. Some methods have even achieved
azoospermia, when there are no viable sperm in ejaculate.2 However, each method also offers different
pros and cons, ranging from effectiveness, to safety, to cost. Listed below are some of the past and
current research into these different contraception methods:

1. Testosterone Only - Injection: One of the first proposed methods of male hormonal birth
control was testosterone injections. Increasing the concentration of testosterone would increase
the activity of the negative feedback loops in the male HPG axis, leading to inhibition of the
anterior pituitary, less FSH, and therefore a decrease in spermatogenesis. The first study
investigating testosterone as a male hormonal contraception method began in the 1970s. The
NIH found that intramuscular injections of testosterone enanthate (TE) led to drastically
decreased sperm counts, with 65% of participants becoming azoospermic after 6 months of
weekly injections. Additionally, all participants were able to make a full recovery, with the
average recovery time being 3.7 months.3 While this birth control method was highly effective
and reversible, it did lead to some side effects, including reported psychological changes,
which made the researchers want to explore other forms of contraception.
2. Testosterone Plus Progestin Trials - Injection and Implant: The next area of research
tackled the idea of adding a progestin to the testosterone-based methods. Progesterone is a
naturally synthesized hormone in the body and a precursor to testosterone. By adding a
progestin, a lab-created hormone that mimics the actions of progesterone, more testosterone is
naturally produced, inhibiting the secretion of FSH, and leading to less spermatogenesis.
Adding progestin to the testosterone-based method also leads to less side effects, as the
concentration of testosterone is not drastically increased and therefore does not cause other
downstream effects. One study combined an etonogestrel implant with testosterone
undecanoate (TU) injections every 10-14 weeks. TU was already widely used to treat
hypogonadism in men, and was therefore deemed safe. In this study, 89% of men reached a
viable sperm count of less than 1 million/ml of ejaculate within 16 weeks, and saw full
recovery within the span of a few months. During recovery, LH and FSH levels recovered
rapidly and did not lead to any long term complications.4 This study had more promising
results than the previous testosterone-only studies, and led to further research combining
testosterone with other hormones that impact the HPG axis.
3. Testosterone Plus GnRH Antagonists - Injection: GnRH antagonists compete with
endogenous GnRH to bind to their receptors on the pituitary. This competition leads to less
activity of the male HPG axis, and therefore less production of FSH. In combination with
testosterone injections, this contraception method activates testosterone’s negative feedback
loops while also decreasing the overall rate of the entire pathway. This form of male
contraception has proven very effective, with one study showing decreases in sperm count in
only 4 weeks and azoospermia after only 6-12 weeks in 75% of the participants.5 However, the
issue with this effective and reversible form of birth control is that GnRH antagonists are very
expensive and not widely accessible. This method would require frequent injections, which

3
Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for the
regulation of male fertility. Lancet. 1990;336(8721):955-959.
4
Mommers E, Kersemaekers WM, Elliesen J, et al. Male hormonal contraception: a double-blind, placebo-controlled study. J Clin Endocrinol
Metab. 2008;93(7):2572-2580. doi:10.1210/jc.2008-0265
5
Pavlou SN, Brewer K, Farley MG, et al. Combined administration of a gonadotropin-releasing hormone antagonist and testosterone in men
induces reversible azoospermia without loss of libido. J Clin Endocrinol Metab. 1991;73(6):1360-1369. doi:10.1210/jcem-73-6-1360
 would be so expensive that this method of contraception is currently impossible.6 However, an
area of current research is attempting to find longer-lasting GnRH antagonists and increase
their accessibility to the wider population.7

All of these injection-based forms of male hormonal birth control have proven to be very effective.
However, they are invasive and inaccessible, as they require frequent injections. Surveys asking men
about male hormonal birth control have indicated that men are more likely to use contraception
methods that do not require injections. Therefore, further research has been conducted on other forms
of male-hormonal birth control.

4. Testosterone Plus Nestorone - Transdermal: One accessible form of male birth control is a
gel that combines testosterone and nestorone, a progestin. As mentioned before, a testosterone
and progestin combination is effective as it impacts the concentration of gonadotropins and
testosterone, leading to less production of FSH, and therefore less spermatogenesis. Nestorone
is also already licensed by the FDA, as it is used in female contraceptive methods, such as
vaginal rings. The study researching this gel recently entered phase IIb clinical trials, and has
seen effective results as 88.5% of the men enrolled reached a sperm count of less than 1
million/ml after daily application of the gel for 20-24 weeks. Only minor side effects were
reported, indicating that this is an effective, long-term form of contraception.
5. “The Male Pill” - Oral: However, the most desired form of male hormonal contraception
would be “the male pill.” Oral administration of birth control is the most accessible and easy
form of contraception. However, this has been a difficult task to complete, as many compounds
need to be ingested multiple times per day. For example, researchers proposed the use of oral
TU as TU was a proven safe drug. However, those pills would need to be ingested 2-3 times
per day, which is inaccessible to the general population. Now, research is attempting to identify
novel androgens that can work as contraceptive methods. Current research is studying
dimethandrolone undecanoate (DMAU) as it is biologically converted to the active drug DMA,
which can then bind to androgen and progesterone receptors, influencing the HPG axis.
However, DMA is still under review, as the observation of hypogonadism in some study
participants indicate that DMA may have androgenic effects outside the testes. Therefore, even
though DMA is a convenient option, there is still more research to be done before “The Male
Pill” becomes available.2

CONCLUSION
Even though research on both male and female forms of contraception began at a similar time, male
hormonal birth control research was put on the backburner. Whether that was because the male HPG
axis has less room for influence or due to gender-related biases, may not be known. However, as the
world has begun to practice more gender equality, the research on male hormonal birth control has
continued. It is important to remember that even though these male forms of contraception have side
effects, so do female birth control methods. These are not new, and have been experienced by women
for decades. Therefore, it is important to view this area of research from a gendered lens, and ensure
that all individuals can be involved in family planning. Research into male hormonal birth control will
benefit both women who are medically unable to use contraception and women who don’t want to, and
will hopefully reduce biases and stereotypes of femininity in our society.

6
Reynolds-Wright JJ, Anderson RAMale contraception: where are we going and where have we been?BMJ Sexual & Reproductive Health
2019;45:236-242.
7
Gava G, Meriggiola MC. Update on male hormonal contraception. Ther Adv Endocrinol Metab. 2019;10:2042018819834846. Published 2019
Mar 14. doi:10.1177/2042018819834846
 WORKS CITED

1. Kao A. History of oral contraception. AMA Journal of Ethics. 2000;2(6):55-56.

doi:10.1001/virtualmentor.2000.2.6.dykn1-0006
2. Thirumalai A, Page ST. Male hormonal contraception. Annual Review of Medicine.
2020;71(1):17-31. doi:10.1146/annurev-med-042418-010947
3. Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health
Organization Task Force on methods for the regulation of male fertility. Lancet.
1990;336(8721):955-959.
4. Mommers E, Kersemaekers WM, Elliesen J, et al. Male hormonal contraception: a
double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2008;93(7):2572-2580.
doi:10.1210/jc.2008-0265
5. Pavlou SN, Brewer K, Farley MG, et al. Combined administration of a
gonadotropin-releasing hormone antagonist and testosterone in men induces reversible
azoospermia without loss of libido. J Clin Endocrinol Metab. 1991;73(6):1360-1369.
doi:10.1210/jcem-73-6-1360
6. Reynolds-Wright JJ, Anderson RAMale contraception: where are we going and where
have we been?BMJ Sexual & Reproductive Health 2019;45:236-242.
7. Gava G, Meriggiola MC. Update on male hormonal contraception. Ther Adv Endocrinol
Metab. 2019;10:2042018819834846. Published 2019 Mar 14.
doi:10.1177/2042018819834846