Page 20 - Science Focus (Issue 19)

receiving a proper signal for sperm production. In light RAR antagonists as contraceptives, the next step is to อɓ˾Ӳ׌ᒒ̳ᖹ 法和候選藥物可能會在未來湧現，全新的男性避孕方式也可
of this, testosterone and progestins can potentially be assess its efficacy on higher mammals, such as non- 另一方面，荷爾蒙性男性避孕藥有著某些缺點。使用睾 能會在不久的將來投入市場，為男性提供上述兩種傳統避孕
leveraged for contraceptive functions. human primates, before conducting clinical trials on 酮的療法被發現與多種不良副作用有關，例如由情緒變化（例 方法以外的替代方案。但直至現在，避孕套和輸精管切除
Some of such candidates have already entered human. In addition, researchers are trying to screen for 如變得具攻擊性）和性慾降低，到對心臟有毒性和損害肝臟 術仍是男性避孕的主流方法，尤其是可以同時預防性病的
clinical trials. A transdermal gel containing testosterone an RARα-selective antagonist which does not inhibit 等 [4]。對於運動員而言，使用睾酮和某些類固醇更可能會導 避孕套。
and a progestin seems promising at the initial stage of RARβ and RARγ, so as to prevent any possible side 致他們失去比賽資格。那麼我們還有其他選擇嗎？
the clinical trial. Meanwhile, another molecule named effects that might arise due to the interference in the
dimethandrolone undecanoate (DMAU) was found to normal functions of the irrelevant RARs. 維生素 A 的活性代謝產物 ─ 維生素 A 酸（retinoic 1 避孕貼：一種可將雌激素和孕酮經皮膚釋放到血液的黏貼，避孕原理主要是
be a potential “single-agent” contraceptive, because acid，俗稱「A 酸」），被發現對製造精子至關重要。維生 防止排卵。
it can bind to and activate the receptors of both Conclusion 素A 酸 受體（retinoic acid receptor/RAR）共 有三種同 2 陰道環：一個可由使用者放入陰道內的細小軟塑料環，它能將雌激素和孕酮
持續釋放到血液中，避孕原理也主要是防止排卵。
androgens (including testosterone) and progesterone, In the era of gender equality, it is preferable that 功型（isoforms）：RARα，RARβ 和 RARγ，但與正常精子
so the molecule can mimic the contraceptive effects of both men and women can take an active role and 生產有關的就只有 RARα。因此，可以阻礙維生素 A 酸與 3 子宮環：一個由醫生或護士放入子宮內的塑料或銅製裝置。它通過釋放孕酮
（塑料裝置）或銅（銅裝置）以改變子宮頸黏液的特性，使精子不易存活而
the two hormones [2]. share the responsibility in preventing unintended RARα 結合的候選藥物 — 即 RARα 拮抗劑，則有望能被 無法到達卵子，受精卵也將不能植入子宮內膜。
pregnancies by adopting contraception. As our 用作避孕藥。
understanding of the biology of our body develops
How do hormones and some small molecules through intensive research, novel contraceptive 研究數據表明一種可以抑制全部三種 RAR 的泛 RAR
(e.g. retinoic acid) exert their functions in our 拮抗劑 ─ BMS-189453，可以使雄鼠不育但不影響睾酮水
body? methods and drug candidates will probably arise. Novel 平 [4]。在停止長達 16 週的藥物療程後，雄鼠的生育能力得 References 參考資料：
male contraceptives are likely to present themselves in [1] Schwartz, P., & Kempner, M. (2015). 50 Great Myths of
Steroid hormones and retinoic acid bind to a 以完全恢復 [4]。儘管這些研究結果初步證明了使用 RAR 拮 Human Sexuality. Chichester, UK: John Wiley & Sons.
special class of proteins called nuclear receptors, the market in the near future, providing alternatives for 抗劑作為避孕藥的可行性和優勢，但在對人類進行臨床試驗 [2] Amory, J. K. (2016). Male contraception. Fertility
which are in fact transcription factors. Upon hormone men beyond the two traditional methods. But until now, and sterility, 106(6), 1303-1309. doi:10.1016/
binding, nuclear receptors are activated to induce condoms and vasectomy are still the mainstream male 前，下一步先要評估的是它對高等哺乳動物（例如非人類靈 j.fertnstert.2016.08.036.
the expression of certain genes. This can in turn affect 長類動物）的功效。研究人員亦正在嘗試篩選出不會同時抑 [3] Frezieres, R. G., Walsh, T. L., Nelson, A. L., Clark, V. A., &
the individual as a whole (e.g. enhance/inhibit sperm contraceptive methods, especially condoms which 制RARβ 和 RARγ 的 RARα 選擇性拮抗劑，以避免產生因 Coulson, A. H. (1998). Breakage and Acceptability of
production). can also prevent STDs. a Polyurethane Condom: A Randomized, Controlled
Study. Family Planning Perspectives, 30(2), 73-78.
為影響其他不相關 RAR 而帶來的任何潛在副作用。
Therefore, it is possible to manipulate a pathway, doi:10.1363/3007398
for example, by administering an alternative 1 Contraceptive patch: A sticky patch which prevents [4] Noman, M. A. A., Kyzer, J. L., Chung, S. S. W., Wolgemuth,
molecule that can activate the same receptor pregnancy by releasing estrogen and progestogen into the ഐႧ D. J., & Georg, G. I. (2020). Retinoic acid receptor
antagonists for male contraception: current status.
(pharmacologically called an agonist) or blocking bloodstream via skin, mainly to prevent ovulation. Biology of Reproduction, 103(2), 390-399. doi:10.1093/
the receptor with another molecule (antagonist), to 2 Vaginal ring: A small soft plastic ring which can be placed 在兩性平等的時代，最理想的當然是不論男女都能積極 biolre/ioaa122
achieve our purpose (e.g. inhibit sperm production). into the vagina by the user. It works by continuously releasing 地採取避孕措施和分擔避孕的責任。隨著研究不斷有所進
estrogen and progestogen into the bloodstream, mainly to 展，我們對身體運作機制的認識也日益加深，嶄新的避孕方
prevent ovulation.
3 Intrauterine device (IUD): A plastic or copper device placed
Next-Generation Male Contraceptives into the uterus by a doctor or nurse. It prevents pregnancy by
releasing progestogen (plastic device) or copper (copper
On the other hand, there are certain downsides device) to alter the cervical mucus, so that sperm is less like
of hormonal male contraceptives. Treatment with to survive and reach an egg. Implantation of a fertilized egg
testosterone were shown to associate with various can also be halted.
negative side effects, from mood changes (e.g.
aggression) and decreased libido, to cardiac
toxicity and liver damage [4]. For athletes, the use of
testosterone and some steroids may lead to sports
disqualification. Are there any alternatives?
It was discovered that the active metabolite of
vitamin A, retinoic acid, is crucial to sperm production.
There are three types (isoforms) of retinoic acid
receptors (RAR), RARα, RARβ and RARγ, but proper
sperm production is found to be related to only RARα.
Therefore, drug candidates which can impede the
binding of retinoic acid to RARα, i.e. RARα antagonists,
could possibly be used as contraceptives.
Research data showed that a pan-RAR antagonist,
BMS-189453, which can inhibit all three kinds of RAR,
can induce infertility in male mice without affecting
the testosterone level [4]. Fertility was fully restored after
the cessation of drug treatment which lasted for as
long as 16 weeks [4]. While these results preliminarily
demonstrated the practicality and advantages of using