The work of two doctors at King’s College London made a big splash in November 2006. Drs. Nnaemeka Amobi and Christopher Smith have been working since 1995 to discover how two drugs – phenoxybenzamine, a high blood pressure medication, and thioridazine, a discontinued schizophrenia medication – each act as a male contraceptive. As early as the 1950s, doctors with patients taking these drugs to regulate their blood pressure and mental health noticed that their patients became infertile. It turns out that the two drugs have a similar contraceptive effect.
How does it work?
During sexual arousal, some of the sperm in the epididymis are propelled by smooth muscle contractions along the vas deferens (plural: vasa deferentia). When the vasa deferentia meet the urethra, the sperm mix with fluids made by the seminal vesicle and prostate, forming semen. Finally, during orgasm the semen is propelled through the urethra by more smooth muscle contractions and ejaculated. The smooth muscles in the male reproductive system are not under conscious control; they contract and relax according to signals from the autonomic nervous system.
Drs. Amobi and Smith found that the two medications they studied disrupted the transport of sperm by changing the way the smooth muscles of the vasa deferentia behaved during an orgasm. The vasa deferentia have two different types of smooth muscle: longitudinal muscle fibers and circular muscle fibers. Normally, the two types of muscle work together to move sperm toward the urethra. But when segments of vasa deferentia were exposed to phenoxybenzamine or thioridazine in the lab, the longitudinal smooth muscle fibers did not contract. The circular smooth muscles did, however, clamping the vas shut (Amobi et al 2003).
The researchers hypothesize that this clamping action caused infertility in the men taking these medications, because sperm are prevented from mixing with the semen. (The drugs may have other effects which also contribute to infertility; see below.) Drs. Amobi and Smith have also observed the effects of similar drugs on the vasa deferentia (Amobi et al 2002, 2006). They’ve successfully identified other drugs which will have a similar contraceptive effect, but a reduced side-effect profile. Thioridizine’s side effects were so extreme that the manufacturer discontinued it in 2005 (WHO 2005); the common side effects of phenoxybenzamine range from dizziness to a fast heartbeat to a stuffy nose (Mayo Clinic 1998).
Although there is no actual product yet, the researchers have described their hopes in interviews with journalists. They intend to tailor a drug which will take effect within 2-3 hours of ingestion, and wear off within 24 hours. A man could take this pill only as needed before having sex. The researchers are now seeking partnership with a pharmaceutical company, which should speed the process of bringing a product to market.
What do we already know about these drugs?
Phenoxybenzamine belongs to a class of drugs known as alpha-blockers. It blocks the actions of chemical messengers released from nerve cells, known as adrenergic neurons. The smooth muscles of the vasa deferentia are controlled by this type of nerve cell (Kedia 1981). The blocked chemical messengers include epinephrine / adrenaline, norepinephrine / noradrenaline and dopamine. Cells responding to these signaling molecules are common throughout the body’s smooth muscle. That’s why phenoxybenzamine is an effective high blood pressure medication: it relaxes some of the smooth muscle fibers along the blood vessels, lowering blood pressure.
Doctors Amobi and Smith have studied the effects of alpha-blockers on segments of vasa deferentia removed from men undergoing vasectomy. Thanks to other medical uses of alpha-blocker drugs, we have additional information about how they affect other parts of the male reproductive system. Several alpha-blocker medications are used to treat a condition known as benign prostatic hyperplasia (BPH). BPH is an enlargement of the prostate which becomes increasingly common as men age. The condition makes urination difficult, and it can lead to urinary tract infections. Treatment with alpha-blockers helps relax the smooth muscles in the bladder neck, allowing complete emptying of the bladder (Michel 2004). Other studies have shown that alpha-blocker drugs decrease the contractions of the seminal vesicle, too (Hisasue 2006).
Based on this information, we can speculate that the product eventually emerging from the work of Drs. Amobi and Smith will have certain characteristics. It is likely that men taking such a pill will experience an orgasm which feels normal. However, they will likely produce a decreased a volume of semen which contains little to no sperm. If the pill does create truly dry orgasms in which no ejaculate is produced, it may have several added benefits in addition to contraception. It could reduce the transmission of HIV from HIV-positive men. Female partners of men using the hypothetical drug may also benefit from fewer semen-induced fluctuations in the vaginal pH, which can lead to yeast or other bacterial infections. However, such optimism should be tempered by the likelihood of systemic side effects and the need for many more clinical tests.
- Amobi, NI, J Guillebaud, AV Kaisary, E Turner and IC Smith (2002) “Discrimination by SZL49 between contractions evoked by noradrenaline in longitudinal and circular muscle of human vas deferens.” British Journal of Pharmacology 136(1):127-35.
- Amobi, N, J Guillebaud, A Kaisary, RW Lloyd-Davies, E Turner and IC Smith (2003) “Contractile actions of imidazoline alpha-adrenoceptor agonists and effects of noncompetitive alpha1-adrenoceptor antagonists in human vas deferens.” European Journal of Pharmacology 462(1-3):169-77. Erratum in: 464(2-3):241.
- Amobi, NI, IP Chung and IC Smith (2006) “Attenuation of contractility in rat epididymal vas deferens by Rho kinase inhibitors.” Autononmic & Autacoid Pharmacology 26(2):169-81.
- Hisasue, S, R Furuya, N Itoh, K Kobayashi, S Furuya and T Tsukamoto (2006) “Ejaculatory disorder caused by alpha-1 adrenoceptor antagonists is not retrograde ejaculation but a loss of seminal emission.”International Journal of Urology 13(10):1311-6.
- Kedia, KR, and L Persky (1981) “Effect of phenoxybenzamine (dibenzyline) on sexual function in man.” Urology 18(6):620-1.
- Mayo Clinic (1998) “Drugs & Supplements: Phenoxybenzamine (Systemic).” Accessed online at http://www.mayoclinic.com/health/drug-information/DR202458.
- Michel, MC (2004) “Ejaculatory dysfunction and alpha-adrenoceptor antagonists.” BJU International 94(3):443-4; author reply 444-5.
- World Health Organization (2005) “Thioridazine – Withdrawn due to poor benefit/risk profile.” WHO Pharmaceuticals Newsletter 1:2.