Editor's Note: Ben has just completed an assignment as part of the "wrap-up" for his BPharm course.
The subject selected was male hormonal contraceptive measures and it covers the latest research.
It is also a topic that most of us may need an update on, so for that reason we are publishing this report.
Ben would be delighted to have your input and comment so please don't hesitate to contact him.
Male Hormonal Contraceptive Measures
Contraception is the “intentional prevention of conception or impregnation through the use of various devices, agents, drugs, sexual practices, or surgical procedures.” 1
Physical and surgical methods of contraception have been available for both males and females for many years. Unfortunately only women have had access to acceptable forms of hormonal contraception. This may soon change, with the continual research into effective and acceptable hormonal contraceptive measures for males.Effective contraception in males requires either the sperm count to be sufficiently low (oligospermia), non existent (azopermia) or for the sperm to fail to reach the ovum. The definition of oligospermia varies from study to study ranging from 1 to 3 to 20 million sperm per ml of semen.2 Reducing sperm levels to below 1 million sperm/ml appears to have the same or better efficacy as current female hormonal contraceptives with a rate of pregnancy at 0.7 to 1 per 100 person years.3 “The ‘pre-testicular’ suppression of gonadotrophins is the most likely approach for reversible therapeutic male fertility control to reach imminent clinical application.”4
The main target for effective MHC is the negative feedback mechanism controlling GnRH release. There are currently many products available that exert this effect making the research and trials of products somewhat different to the discovery of new products. The products currently used in trials have already been through clinical trials to ensure their safety. This will help to expedite the development of MHC as many early stages of drug development are not required. Early trials focused on single agent methods using exogenous testosterone. These trials found that most Chinese men that took part reached azoospermia while Caucasian men had a lower response to testosterone only therapy. The varied results lead to dual therapy treatments using testosterone and a progestin to increase effectiveness.6 Recent trials including levonorgestrel and testosterone undecanoate, norethisterone ethanate plus testosterone undecanoate and testosterone pellets and etonogestrel implants have shown promise as an effective form of contraception.
Levonorgestrel and Testosterone Undecanoate
There have been several studies using oral and injectable forms of levonorgestrel (LNG) and testosterone undecanoate (TU). These studies in general population studies resulted in azospermia in 57% to 67%. Chinese subjects appeared to have a higher rate of azospermia using this combination. Further studies have been conducted using this combination with only Chinese males taking part.4
Chinese subjects had 4 levonorgestrel 75mg implants inserted initially as well as an IM injection of testosterone undecanoate 500 (group 1) or 1000mg (group 2) every 8 weeks. Of the 21 subjects from group 1 (500mg TU every 8 weeks) 13 reached azospermia with 8 subjects reaching varying degrees of oligospermia. The mean time to azospermia was 17.8 weeks. Group 2 (1000mg TU every 8 weeks) had 20 subjects 18 of which reached azospermia and 2 subjects with <1million/ml sperm count. The average time to azospermia was 15 weeks. Throughout the trial serum testosterone levels ranged from 10 to 35 nmol/ml with normal values ranging from 10.5 to 45 nmol/l9. LH and FSH levels were reduced 67% and 79% for group 1 and 85% and 91% respectively for group 2. Group 1 had a wide variation in LH and FSH throughout the trial. Throughout the trail there were slight decreases in total cholesterol and HDL levels with no other significant changes in serum chemistry or heamatocrit levels.6
LNG and TU has shown significant promise for use as a contraceptive method for Chinese males with pregnancy rates similar to or better then female hormonal contraceptives (FHC) or other methods.
Norethisterone Ethanate plus Testosterone Undecanoate
Early studies using this combination injected every 6 weeks have shown profound spermatogenic suppression. Further studies have been conducted to determine if a longer injection interval would produce similar effects. A study was conducted using 50 Caucasian men to determine the optimal dosing regime and interval. The men were randomised into 1 of 5 groups. Group 1 received norethisterone ethanate (NETE) 200mg plus TU 1000mg every 8 weeks. Group 2 received NETE 200mg plus TU 1000mg every 12 weeks. Group 3 received NETE 200mg plus TU 1000mg every 6 weeks for 12 weeks then every 12 weeks for the remainder of the study. Group 4 received NETE 200mg plus TU 1000mg every 6 weeks for 12 weeks then TU 1000mg plus placebo every 12 weeks for the remainder of the study. Group 5 received placebo plus placebo following the dosing intervals of group 3.10
All subjects in group1 reached sperm levels below 1 million /ml with 9 out of 10 reaching azopermia. In group 2 azospermia was reached by only 3 of the 8 subjects that completed the trial reached azospermia with 1 reaching oligospermia. Of the men in group 3, 8 of the 9 subjects reached azospermia with the remaining subject failing to reach oligospermia.
Group 4 reached similar levels to group 3 in the earlier phases of the trial but failed to maintain spermatogenic suppression throughout the trial with only 3 of the 8 subjects reaching azospermia and 1 subject reaching oligospermia. Group 1 showed severe oligospermia after 8 weeks +/- 2 weeks and azospermia at 16 weeks +/- 3 weeks.10
During this study testosterone levels remained within normal parameters. There was no examination of blood chemistry in the subjects. One subject dropped out because of a loss of libido but no other side effects were reported. This study shows that NETE and TU given at 8 weekly intervals provides higher contraceptive efficacy then FHC and other contraceptive methods.
Testosterone pellets and etonogestrel implants
Etonogestrel implants have been available for several years as an effective female contraceptive. The benefit of these implants is their long action (3 years) and their quick reversal of contraceptive effect. A recent study investigated the use of etonogestrel and testosterone. 15 healthy men were given 3 etonogestrel 68mg implants and 2 testosterone 200mg pellets. The testosterone was readministered every 12 weeks. 9 of the subjects remained in the study and all reached oligospermia (<1million/ml) by week 16 with 10 of the 14 subjects at azospermia. By week 28 all subjects reached azospermia. At week 40 one man had a partial recovery reaching 7million/ml by week 48.11
Throughout the study testosterone remained at normal levels. Total cholesterol triglycerides showed significant decreases with LDL showing a less then significant decrease. There were no changes to haemoglobin or haematocrit levels. There was a slight decrease in sexual activity, 3 subjects reported low mood and 2 subjects had testosterone pellets extrude. There are potential health benefits with the alteration to cholesterol levels. This contraceptive method demonstrated contraceptive efficacy comparable or better then FHC or other methods.11
While trials for MHC are still in early stages there are several different androgen and progestin combinations that show great promise. With the results of some trials proving more effective than FHC and vastly more effective than barrier and other methods further investigation is justifiable.
1. The free dictionary by Farlex. Contraception - definition of contraception in the medical dictionary - by the Free Online Medical Dictionary, Thesaurus and Encyclopedia [document on the internet]. Farlex, Inc; 2008 [cited 2008 Apr 1st]. Available from: http://medical-dictionary.thefreedictionary.com/contraception.
2. Grimes DA, Lopez LM, Gallo MF, Halpern V, Nanda K, Schulz KF. Steroid hormones for contraception in men (review). Cochrane Database of Systematic Reviews 2007 [serial online]. 2007 [Cited 2008 Apr 9th]. Available from: http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD004316/pdf_fs.html.
3. Matthiesson1 KL, McLachlan RI. Male hormonal contraception: concept proven, product in sight? Human Reproduction Update [serial online]. 2006 [cited 2008 Apr 9th]; 2(4):463-482. Available from: http://humupd.oxfordjournals.org/cgi/reprint/12/4/463.
4. Wu FCW. Hormonal approaches to male contraception: approaching reality. Molecular and Cellular Endocrinology [serial online]. 2006 [cited 2008 Apr 09]. Available from: http://www.sciencedirect.com.
5. Jones RE. Human reproductive biology. 2nd ed. USA: Elsevier; 1997. p. 97-101.
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8. eMIMIS April 2008 [CD-ROM]. St Leonard NSW: MIMS CMP Media Australia; 2008.
9. Beers MH, Porter RS, Jones TV, Kaplan JL, Berkwits M, Albert RK, et al.The merck manual. 18th ed. New Jersey USA: Merch Research Labratories; 2006. p. 1946.
10. Meriggiola MC, Costantino A, Sadd F, D’Emidio L, Morselli Labate AM, Bertaccini A, et al. Norethisterone enanthate plus testosterone undecanoate for male contraception: effects of various injection intervals on spermatogenesis, reproductive hormones, testis, and prostate. The Journal of Clinical Endocrinology & Metabolism [serial online]. 2005 [cited 2008 Apr 28]; 90(4):2005-2014. Available from : http://jcem.endojournals.org/cgi/reprint/90/4/2005.
11. Brady BM, Walton M, Hollow N, Kicman AT, Baird DT, Anderson RA. Depot testosterone with etonogestrel implants result in induction of azoospermia in all men for long-term contraception. Human Reproduction [serial online]. 2004 [cited 2008 Apr 28];19(11):2658-2667. Available from: http://humrep.oxfordjournals.org/cgi/reprint/19/11/2658.
12. Harat ZN, Sadeghi MR, Sadeghipour HR, Kamalinejad M, Eshraghian MR. Immobilization effect of Ruta graveolens L. on human sperm: A new hope for male contraception. Journal of Ethnopharmacology [serial online]. 2008 [cited 2008 Apr 9]; 115:36-41. Available from: http://www.sciencedirect.com.
13. Solomon H, Yount KM, Mbizvo MT. Culture, Health & Sexuality An International Journal for Research, Intervention and Care. Culture, Health & Sexuality [serial online] 2009 [cited 2008 Apr 9];9(1):1–14. Available from: http://www.informaworld.com/smpp/content?content=10.1080/13691050600902573.