Experimental MHC formulations

Researchers have experimented with dozens of possible formulations for MHCs. We\'ve broken these into 3 major categories: androgen only, progestin with androgen replacement therapy, and GnRH antagonist with androgen replacement therapy. The graphs below summarize the results of a dozen clinical trials using distinct formulations.

The MHC drug formulations shown in these graphs are just a few of the formulations under investigation. The effectiveness of each formulation varies with the dosage of each component; the convenience varies with the delivery method. Below the graphs is a table describing the delivery methods and properties of the androgens, progestins and GnRH antagonists used in the featured trials.

Note that the researchers in these studies did not all use the same definition of oligospermia. Some researchers described anything less than 5 million sperm/ml as oligospermic, while others adhered to the severe oligospermia definition of 1 million sperm/ml. The former level of oligospermia would not provide safe contraception, but the latter would. Check with the source papers for precise information. N represents the number of men receiving treatment. Note that the sample sizes are typically quite small.

The drugs in MHCs

Androgens

Currently the androgens represent the biggest delivery challenge. Researchers recognize that intramuscular injections are an inconvenient and sometimes painful way to administer an MHC. Unfortunately, such injections are the only way to deliver several of the more effective androgens. Testosterone enanthate (TE), 19-nortestosterone hexoxyphenylpropionate (19NT), and testosterone buciclate (TB) must be injected. TE is potent for about 10 days, with higher than normal levels of T 1-4 days after injection and lower than normal levels of T after a week. These characteristics make TE an unlikely candidate for a marketable MHC. TE has, however, been invaluable in proving that MHCs can be safe and effective. 19NT and TB are potent for longer periods of time: 19NT is administered every 3 weeks, and TB is administered every 3 months.

The research community widely recognizes the need for new androgen formulations with improved pharmacokinetics. Various groups are pursuing long-acting androgens that could be delivered by some method other than injection. Implants are one such option. Implants have the advantage of a very steady release of androgen. Unfortunately, they also have a 3 - 7% risk of breaking the skin above them. Pure testosterone implants can deliver steady rates of T for 4 - 6 months. The Population Council has developed the potent 7-alpha-methyl-nortestosterone (MENT), which could deliver steady rates of androgen for up to 1 year. In a recent trial in Germany , 9 of 11 men with MENT implants were azoospermic or severely oligospermic.

There is only one type of synthetic T which is active orally; all other forms of T are degraded by the liver when ingested. Testosterone undecanoate (TU), which can be administered as an injection every 2 months, can also be taken as a pill 3 times daily. Levels of T in the blood fluctuate constantly under an oral TU regimen.

Researchers are also experimenting with the delivery of T across the skin using patches and creams. So far patches have been unable to deliver large enough quantities of T to consistently suppress spermatogenesis. Creams could be applied to a large enough area of the body to deliver an effective T dose, but they can rub off the man and onto his partner, dosing her as well.

An androgen-only MHC regime is not effective for all men. Fewer than half the men on an androgen-only regime attain azoospermia. Adding another drug to block the production of gonadotropins boosts the effectiveness of MHCs; GnRH antagonists and progestins are two such drugs.

GnRH antagonists

GnRH antagonists are relatively new compounds. They are chains of peptides (basic units of proteins) which are very complicated and time-consuming to synthesize. They must be injected subcutaneously and are only active for 1 day. In some men these compounds cause a histamine reaction (allergic response like a mild skin rash) at the injection site. GnRH antagonists used in small scale trials have been extremely effective; unfortunately their expense and inconvenience makes them poor candidates for wide use. Researchers experimenting with inducing azoospermia using a GnRH antagonist, and then maintaining it with only an androgen, have had mixed success.

Progestins

Progestin-based MHCs are currently the main focus of the research community. In contrast to GnRH antagonists, progestins are available worldwide, reasonably priced, and can be administered via injection, orally or as implants. Progestins have such favorable characteristics because they have been developed for use in female hormonal contraceptives since the 1960s. Progestins used in trials have had varied results because the therapeutic dose range is extremely narrow.

Progestin-based MHCs are by far the closest to the market. Several of the key researchers have the financial and technical support of N.V. Organon, a multinational pharmaceutical company based in the Netherlands. Due to the more favorable social and political climate in Europe, MHCs are likely to be available there well before they are approved for sale in the US.