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Keywords:

  • Contraception;
  • new;
  • technology;
  • sterilisation

Abstract

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

New technologies in both reversible contraception and sterilisation are described. The review includes recent advances in the development of oral contraception, emergency contraception, injectable contraception, vaginal rings, subdermal implants, transdermal contraception, intrauterine devices, spermicides and barrier methods. It also covers methods of transcervical female sterilisation and more easily reversible male sterilisation. The emphasis is on the technology and its safety and effectiveness. Hormonal delivery systems are described in some detail. Mention is also made of research into vaccines and male hormonal methods, where progress has been disappointing.


Context

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

Technology is of limited value unless governments can supply their populations with contraceptive services and supplies. In many developing countries, individuals and couples who cannot afford to purchase contraceptives do not enjoy the human right to decide on the number and spacing of their children. More than 200 million women in the developing world are not using any form of contraception or using traditional methods only.1 Governments and individuals should work towards the Millennium Development Goal target of universal access to reproductive health services by 2015 through the primary care health system.

Uptake of contraception is variable around the world, varying from 3% in Chad to 90% in China in women aged 15–49 years who are married or in a union.2 Uptake is high in the UK, but methods used are still predominantly pill and condom.3 Despite the advent of long-acting reversible contraceptive (LARC) methods,4 these remain to be minority methods: for example, implants were used by only 1% of women of age 16–49 years in Britain in 2006.3 Use of any method of contraception, regardless of its degree of effectiveness, is better than using no method. But there are large differences in effectiveness between the methods: for instance, a 300-fold difference between typical use failure rates of male condom and subdermal implant.5 Simultaneous use of methods where one is a barrier method dramatically lowers the risk of unintended pregnancy as well as giving sexually transmitted infection (STI) protection, known as dual protection. Most women and men still perceive contraceptive choice as a matter of finding the ‘least worst’ option, balancing effectiveness and ease of use against perceptions and expectations of adverse effects and health risks.6

Many men are willing to take on the adverse effects and health risks of contraceptive use.7 A cross-cultural survey found that women believed the contraceptive burden too frequently falls to them and they welcomed the availability of a reversible male contraceptive, which they would trust their partners to take.8

Oral contraception

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

Newer progestogens9,10 have been used in combined pills: dienogest, nomegestrol and drospirenone. All three progestogens have antiandrogenic activity; drospirenone has antimineralocorticoid activity. Newer progestogens are being produced to develop novel positive attributes, to enhance positive attributes of existing progestogens or to reduce or eliminate undesirable attributes.

Dosage of both estrogen and progestogen has been markedly reduced in recent years. Hitherto, ethinylestradiol (EE) has been the main estrogen used in combined pills. Further work is being carried out on the use of estradiol (E2) in the combined pill; previous attempts had been thwarted by poor cycle control. The rationale for this is that a natural steroid would be expected to be less thrombogenic than synthetic estrogens11 and less likely to increase breast cancer risk. An E2/drospirenone combination is being studied in both monophasic and triphasic formulations in Germany with respect to cycle control and safety. E2 has been combined with dienogest in a quadriphasic formulation. This product has been shown to provide efficient ovulation inhibition.12 When compared with a 20 microgram levonorgestrel (LNG) pill in a randomised controlled trial (RCT), cycle control and adverse effect profile was considered to be good.13 E2 has also been combined with nomegestrol; a trial in the Netherlands investigating ovarian function, which compares E2/nomegestrol with EE/drospirenone, has been completed. Estetrol (E4) is a steroid produced by the human fetal liver. E4 is about 18 times less potent than EE, so fewer adverse effects would be predicted. Preliminary work on combinations with progesterone or desogestrel has been undertaken.14 There is a possibility that E4 might be protective against breast cancer; it is classified as a natural selective estrogen receptor modulator.

Other types of work on combined pills have perhaps been less original but nevertheless have the potential for considerable impact on women’s lives. Extended use of the combined pill has become widespread; running several or all packets together reduces bleeding days and menstrual cycle-related symptoms.15 When used continuously for 1 year, 18% of women achieve amenorrhoea by 3 months of use and 88% by 10 months.16 Bleeding is significantly decreased in continuous users compared with cyclical users, with an average of 3 days for cycles 1–3 (versus 10 days, P < 0.001) and 0 days for cycles 10–12 (versus 9 days, P < 0.001).

Formulations of 30 micrograms of EE and 150 micrograms of LNG with 84 pills per packet have become available, giving a 91-day cycle.17 Sixty percent of women using a monophasic formulation containing 20 micrograms of EE and 90 micrograms of LNG with 28 pills in a packet reported amenorrhoea within 1 year.18 It has also been shown that shortening the pill-free interval below 7 days results in more effective ovarian suppression;19 combined pills have become available with 24 pills per packet.20,21

Mifepristone is a selective progesterone receptor modulator (PRM) or antiprogestogen. PRMs block receptors in the ovary, inhibit the luteinizing hormone surge and have a powerful endometrial effect. Mifepristone has been studied in a phase-2 trial at a daily dose of 5 mg compared with an LNG progestogen-only pill.22 It was shown to be an effective pill with a better bleeding pattern than the progestogen-only pill. More women were amenorrhoeic while taking mifepristone than progestogen-only pill (49 versus 0%, P < 0.001), and fewer women bled or spotted for more than 5 days per month (4 versus 39%, P < 0.001). There were no pregnancies in 356 months of exposure in women who used only mifepristone for contraception. In a Chinese pilot study, once weekly mifepristone at a dose of 25 mg showed potential as an oral contraceptive pill.23 Among 76 women, no pregnancies occurred in 456 cycles. During the six study cycles, there was a persistent trend towards fewer bleeding days and more amenorrhoea.

Another PRM, ulipristal (CDB-2914 or VA 2914), has been piloted as a daily pill.24 Forty-six women took this for 84 days, and ovulation was suppressed in 80% of women without inducing hypoestrogenism.

The development of estrogen-free oral contraception has significant advantages in relation to acceptability and safety. Many women prefer to have either predictable bleeding less often than once a month or not to bleed at all.25,26 Amenorrhoea during mifepristone use is not accompanied by hypoestrogenism, and there are theoretical reasons for thinking that breast cancer risk may be reduced.

Emergency contraception

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

The combined estrogen–progestogen regimen was superseded by the progestogen-only method. The latter has now been combined into one dose. Mifepristone has been used in trials for emergency contraception since the early 1990s. Mifepristone has as good efficacy as emergency contraception at a dose of 10 mg as at a dose of 600 mg.27 Mifepristone has effectiveness equivalent to 1500 micrograms of LNG when used as hormonal emergency contraception.28 At present, no pharmaceutical company wants to pursue marketing for this purpose because of the political connotations of its abortifacient effect. In addition, further toxicology testing would be needed to obtain a licence for use as long-term contraception.

Ulipristal, not known to have abortifacient properties has been shown to have similar efficacy to LNG in an RCT.29 Although PRMs have endometrial inhibitory activity, this is probably not a significant mechanism of action at the low doses used for emergency contraception.30 Thus, all methods of emergency contraception investigated so far have as their main mechanism of action either blockade or delay of ovulation. This raises the point that effectiveness of currently available hormonal emergency contraception may be inferior in the luteal phase; there is a suggestion that this is so for LNG.31

It has also been shown that meloxicam, a cox-2 inhibitor, can prevent rupture of the dominant follicle even after the ovulatory process has been triggered by the luteinizing hormone surge, and so, its addition to LNG might improve the efficacy of LNG emergency contraception.32 A similar delay in follicular rupture has been found using rofecoxib.33

Injectable contraception

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

Depot medroxyprogesterone acetate (DMPA) has been licensed for long-term use in the UK since 1982. Stimulated by reports of a possible negative effect on bone health,34 micronised subcutaneous medroxyprogesterone acetate 104 mg/0.65 ml has been produced, which is a 30% dose reduction compared with the standard formulation. This formulation has a slower rate of absorption and lower peak serum levels than intramuscular DMPA and is given at the same interval. Two large phase-3 noncomparative trials of subcutaneous DMPA have shown high effectiveness and a good tolerability profile. Amenorrhoea rates of 55% at 12 months were found with subcutaneous DMPA compared with about 50% with the intramuscular formulation.35 There have been no published studies so far of subjects using self-injection of subcutaneous DMPA.36

Two combined products, both given monthly, have been developed by the World Health Organization (WHO). These injectables are now available in many countries after extensive trials in South America and China from the 1960s onwards. They both add E2 to existing injectable progestogens. The first product is medroxyprogesterone acetate 25 mg with estradiol cypionate 5 mg and the second is norethisterone enanthate 50 mg with estradiol valerate. Compared with progestogen-only injectables, combined injectables disturb bleeding patterns less37 and allow earlier return to ovulation after discontinuation.38 Bleeding patterns are similar to the combined pill, patch or ring. Effectiveness has been shown to be good in studies of everyday use.39 Pilot studies show that self-injection of monthly injectables is feasible.40

Vaginal rings

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

Delivery of sex steroids through the vaginal route offers several advantages: steroid absorption through the vaginal epithelium is rapid, technology allows a constant release rate, the method is under the woman’s control and she can remove the ring for sex for up to 2 hours. Problems associated with first-pass metabolism and with reduced hormone absorption due to gastrointestinal problems are avoided. The use of safe and pliable polydimethylsiloxane carriers and the development of hormone-containing controlled-release polymers have permitted the manufacture of rings that can release hormone for up to 1 year.41 All vaginal rings come within the definition of LARCs, that is, administration once per cycle or less often.4 Acceptability is high among self-selected women taking part in trials, with many women changing their minds about which method of contraception they perceive to be best, from the combined pill to the combined ring, after a few cycles of use.42

The first combined ring to be widely introduced releases 120 micrograms etonogestrel and 15 micrograms EE/day from an ethylene vinyl acetate (EVA) copolymer ring. Women use a ring for 3 weeks followed by a ring-free week during which time they have a withdrawal bleed. A new ring is needed for each 4-week cycle. Steady-state hormone release is achieved within 3 days of insertion. Continuous serum hormone levels are achieved with ring use, avoiding the peaks and troughs seen with the combined pill. Systemic exposure to EE has been shown to be lower for the combined etonogestrel ring than for both the transdermal patch and a 30 microgram pill.43 Two comparative trials showed high efficacy, which was not different from the combined pill, especially when adherence is good.44,45 Evidence from both clinical studies and clinical experience programmes shows better cycle control than with the combined pill.46–49 The ring can, however, cause leucorrhoea, vaginal discomfort, vaginitis and ring-related events comprising foreign body sensation, coital problems and expulsion.44,45

Nestorone rings have undergone preliminary investigation by the Population Council.41 Nestorone (formerly known as ST-1435) is ineffective orally, but due to its high progestogenic potency when given systemically, low doses are sufficient for contraceptive efficacy. Rings releasing a combination of nestorone9,10 at a dose of 150 or 200 micrograms/day with EE 15 or 20 micrograms/day are effective for 12 months and so are more cost-effective. Phase-3 trials are continuing.

Progestogen-only vaginal rings are less effective than combined rings but have a particular application in lactating women as they are estrogen-free. A ring releasing progesterone 10 mg/day can be used for up to 4 months; it is on the market in Chile and Peru.50 Rings using nestorone are particularly apposite due to rapid inactivation when taken orally and so the suckling baby cannot possibly be affected.9 Nestorone-releasing rings are effective for up to 1 year.51

In view of the powerful antiovulatory effect of nestorone, twice that of LNG, a phase-1 study was conducted into the potential of the nestorone combined ring for use as emergency contraception in women not at risk of pregnancy.52 Judging by ultrasound scanning and hormonal profiles, the ring appears to be more effective in disrupting ovulation when given in the follicular phase, and ovulation was absent after the ring had been in situ for 7 days. Like the copper intrauterine device (IUD), this method could be used as continuing contraception too. The Population Council has started investigating the possibility of using the PRM ulipristal in a vaginal ring.53

Subdermal implants

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

Implant technology has been improved considerably. Pharmacokinetics approaching zero-order release is now possible; this means that the release is constant over time and serum levels are steady. The original LNG implant had the disadvantage of comprising six capsules, which made insertion and removal lengthy and sometimes difficult and so local complications more likely. The capsules were hollow polymer tubes filled with free steroid crystals and quite easily torn or divided by forceps or scalpel. Newer systems consist of either one or two implants, and these are now usually solid rods filled with a mixture of steroid crystals and polymer, which are much more robust but still flexible.

Contraceptive implants are highly effective4 and higher even than vasectomy.5 Bleeding disturbances remain the single most problematic adverse effect of implants, and the newer implants are not different in this respect.

LNG implants are now available in the form of two silastic rods releasing around 50 micrograms/day per rod and lasting for 5 years.54 Single-rod etonogestrel (3-keto desogestrel) in EVA polymer implants give an initial release rate of about 60 micrograms/day, which maintains serum levels well above those needed to inhibit ovulation (90 pg/ml) for 3 years.55 They are inserted using a disposable applicator. A trial is in progress to evaluate a modified etonogestrel implant applicator together with a radio-opaque rod; the latter would assist in the event of a difficult removal.

A nestorone implant in the form of a single rod releases steroid from a silicone matrix core and has completed phase-2 trials. This implant provides effective contraception for 2 years and has higher acceptance by lactating women who have a more favourable bleeding pattern than by those who do not breastfeed.56

Nomegestrol acetate9,10 has been developed in Monaco. It is a potent progestogen, exerting a strong effect on the endometrium. Release of about 1000 micrograms/day from a 1-year single silastic rod inhibits ovulation effectively.57 A multicentre trial in more than 1500 women showed a low pregnancy rate and a discontinuation rate of only 16% at 1 year. However, there is no plan to commercialise this product.

Biodegradable implants have the advantage of not needing removal, so that the possibility of difficult removals is eliminated. LNG has been studied in a phase-2 trial as a single capsule composed of the polymer caprolactone over a period of 1 year.58 The release of LNG from caprolactone is ten times faster than that from the silastic in the original implant, allowing a big decrease in size of implant. Norethisterone (85%) with cholesterol (15%) mixed by a heat fusion technique has been studied in the form of four or five pellet systems.59

Transdermal administration

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

With the successful development of matrix technology, it has been possible to deliver both EE and progestogens through the skin. Norgestimate and its active metabolite norelgestromin can be delivered through a transdermal patch, remaining active for 7 days. A combined patch that releases EE 20 micrograms/day and norelgestromin 150 micrograms/day is now widely available. The patch comprises three layers: an outer protective layer of polyester, a medicated adhesive middle layer and a clear polyester release liner, which is removed just before application. Adherence to the regimen of use is better with the patch than with the combined pill, especially in teenagers.60

Systemic exposure to EE is higher with the patch than with a 30 microgram pill, despite the fact that it releases less EE than the pill.43 Effectiveness is as good as the combined pill overall but not in those who weigh more than 90 kg.61 Breakthrough bleeding and mastalgia are more common in cycles 1 and 2 with the patch than with the combined pill, but thereafter, there is no difference.60 Three percent of subjects discontinue the patch due to skin reactions.60

Another patch is being developed: this patch releases 50 micrograms/day of gestodene and 18 micrograms of EE and was shown to suppress ovulation in all 199 women in a study over two cycles.62

Nestorone has also undergone preliminary evaluation in the form of both a gel63 and a spray.64 In trials with the gel, mean serum levels of 150 pmol/l were observed, achieving 83% ovulation suppression. The Metered Dose Transdermal System® (Acrux Ltd, Melbourne, Australia) is a precisely engineered spray that is capable of delivering drugs to the skin surface from where they can be rapidly absorbed into the stratum corneum, which acts as a drug reservoir. Steady-state levels of nestorone were shown to be achievable with a single daily application of this spray. The mean serum level was 391 pmol/l after 5 days. This is above the level of 250 pmol/l needed to suppress ovulation in at least 98% of women.

Intrauterine devices

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

Extensive experience from trials and evidence from systematic reviews have shown the TCu380S IUD and the LNG intrauterine system (IUS) to be the most effective IUDs developed so far.65 As the TCu380S and TCu380A can remain in place for up to 10 years, their cost-effectiveness is particularly high.65 Sivin66 has suggested that such devices can retain their efficacy for up to 20 years. A frameless device, the GyneFix® (Contrel, Ghent, Belgium), has been found to have comparable effectiveness to the TCu380A,67 but the effectiveness of the frameless device may be compromised by a higher rate of expulsion. Effectiveness of copper IUDs is almost as good as female sterilisation, and effectiveness of the IUS is better than female sterilisation.5

The development of frameless IUDs has been pursued because plastic frames increase blood loss and pain. These devices have a very different insertion mechanism, which requires specific training and achievement of a high level of operator skill; performance of frameless devices inserted by those with less experience is not so good. GyneFix consists of six copper sleeves threaded on a length of polypropylene suture material. A knot at the proximal end is placed in the fundal myometrium, anchoring the device. Long-term efficacy has been demonstrated in a randomised comparative WHO trial.68

The LNG-IUS is a well-established method that for some time has been the only device of its type. Other designs have now been developed. Femilis™ (Contrel) has shorter side arms than the original LNG-IUS. Initial studies show good clinical performance.69 Insertion is by a simple push-in technique, as with a Multiload, and the device is well accepted by nulliparous women. There are no comparative effectiveness studies. FibroPlant® (Contrel) is a frameless IUS with a LNG-releasing EVA delivery system.70 Two versions are being developed, releasing 14 and 20 micrograms LNG/day, respectively. These IUSs have a lifespan of 5 years. A metal clip is placed 1 cm from the anchoring knot, which locates the device on ultrasound or X-ray. FibroPlant is suitable for insertion into uteri of any shape or size.71 There are as yet no published data on the contraceptive efficacy of this device. The Population Council has started to investigate the possibility of using the PRM, ulipristal, in an IUS.53

Spermicides

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

In view of the increase in incidence of STIs and HIV, much effort has been put into the development of spermicides that have additional microbicidal properties. The long-used spermicide nonoxinol-9 (N-9) needs to be replaced for two reasons. First, there is no evidence to show that it aids efficacy with condoms.72 Second, we now know that its surfactant effect can damage lower genital tract epithelial surfaces and thereby possibly increase the risk of acquisition of infections, including HIV.73 As well as research into spermicides with microbicidal activity, there has also been intensive activity identifying pure microbicides to protect those wanting to achieve pregnancy. Of the former category, two preparations reached the stage of clinical trials for pregnancy prevention. C31G or Savvy (Biosyn, Philadelphia, PA, USA) is a surfactant, which has a satisfactory safety and adverse effect profile.74 A phase-3 multicentre RCT of C31G compared with N-9 gel is under way in the USA to investigate its efficacy, safety and acceptability. Cellulose sulphate (Ushercell™; Polydex Pharmaceuticals Ltd, Toronto, ON, Canada) is a polyanion that inhibits hyaluronidase, induces acrosomal loss and inhibits cervical mucus penetration. In 2007, two phase-3 HIV prevention trials of cellulose sulphate were halted because in one of the trials, a trend had been found towards increased HIV risk.75 A phase-2 contraceptive efficacy study of cellulose sulphate gel conducted in Los Angeles has yet to be reported on. A phase-1 study of the spermicide ACIDFORM applied once daily showed it to be a safe product.76 A phase-1 study of polystyrene sulphonate gel showed a safety profile comparable with N-9.77

A phase-1 study has been carried out of a gel composed of polyoxyethylene–polyoxypropylene block copolymer with the microbicide 2% sodium lauryl sulphate.78 This is applied inside the vagina and acts as both a physical and a chemical barrier. The product was imperceptible to all male partners in the study, potentially empowering women whose partners will not use condoms. A large phase-3 RCT showed that an acid-buffering gel, BufferGel, used with a diaphragm was as effective as use with N-9 spermicide.79 BufferGel is a nonsurfactant spermicide, which reinforces normal vaginal acidity to inactivate both sperm and acid-sensitive sexually transmitted pathogens. The 6-month pregnancy rate was 10.1% for BufferGel and 12.3% for N-9 users.

Finally, a highly innovative pilot study has examined the vaginal administration of LNG in Carraguard® gel (Population Council, New York, NY, USA) as a potential emergency contraceptive with microbicidal properties.80 A single vaginal administration of 750 micrograms LNG in CARRA gel in the late follicular phase was found to be effective in interfering with ovulation. Therefore, this is a promising method for use as an emergency contraceptive method for occasional use and has the potential for providing dual protection when used before sex, thereby putting women more in control. The microbicidal properties of CARRA gel have yet to be demonstrated, but even if found not to be effective, the principle is established and another microbicide could be substituted.

Male barrier methods

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

Alternative materials to latex rubber have been developed. These include polyurethane and styrene ethylene butylene styrene. Condoms made with these materials have two advantages over latex condoms: a longer shelf-life and the ability to be used in the presence of oil-based lubricants. Synthetic non-latex condoms have a high acceptability, and despite being more liable to split or slip off, most are as effective in preventing pregnancy as latex condoms.81

Female barrier methods

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

Since the introduction of the original polyurethane female condom (FC1) in 1992, there have been a number of other products tested, which incorporate different designs and materials with cost reduction as a major driver. The FC2 female condom is made from synthetic latex, which is softer than polyurethane, and is manufactured by a dipping process, which is cheaper than the welding used in the original type.82 The VA feminine condom (also known as the Reddy condom and V-Amour) contains a soft sponge to hold it in place inside the vagina rather than a ring; it has a higher acceptability than the FC1.83 The Program for Approved Technology in Health (PATH) has developed a woman’s condom, which consists of a dissolvable capsule intended to make the insertion easier, a polyurethane condom pouch and a soft outer ring allowing for a nearly universal fit. Once inserted, sections of urethane foam on the condom pouch allow the condom to cling lightly to the vaginal walls, so that it does not move during use; acceptability studies are promising.84

The SILCS diaphragm is being developed by PATH in an iterative process based on a needs assessment and subsequent feedback from users and clinicians. It is a single-size, non-latex diaphragm with a polymer spring. It fits most women without assessment by a healthcare professional, appears to be more comfortable than existing metal spring devices and can be used with either a spermicide or a lubricant. Magnetic resonance imaging in six subjects showed that the diaphragm covered the cervix in all cases and was not dislodged during simulated sex.85 A phase-1 study of the SILCS diaphragm examined use with either N-9 gel or lubricant only. A reduction in the average number of progressively motile sperm per high-power field in the cervical mucus from a baseline of 12.5 to 0 was seen when the diaphragm was used with N-9.86 It has now entered phase-3 trials with randomisation to SILCS diaphragm used with BufferGel or SILCS used with 2% N-9 gel.

The effectiveness of the FC1 is lower than that of male condoms.5 With all the newer female barrier methods, there is a general dearth of efficacy data.

Male hormonal methods

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

After two decades of research, there is still no hormonal method for men. Work has focused on hormones that will suppress follicle-stimulating hormone and luteinizing hormone. Because lack of luteinizing hormone leads to atrophy of Leydig cells and testosterone deficiency, exogenous testosterone needs to be added to any regimen. Progress has been painfully slow in this area of research partly because of difficulty in finding an appropriate testosterone formulation. To this day, testosterone has to be administered by injection or implants; testosterone in the form of tablets or patches suppresses sperm less effectively.

The most promising regimens are combinations of testosterone with an oral progestogen or progestogen implant.87 No combination so far has resulted in 95% azoospermia. Due to these small proportions of men who are resistant to hormonal suppression, semen analysis would be needed to identify these individuals if a product was to be launched.

In multicentre male hormonal trials, it was noted that Asian men respond to exogenous androgens with or without progestogens with more suppression of spermatogenesis than non-Asians.87 Postulated explanations for this have been a more sensitive hypothalamo-pituitary axis, lower testis volume or higher basal apoptotic rate of germ cells in Asian men. Therefore, it is likely that an ethnic or geographical variation exists in the testicular responsiveness to gonadotrophin suppression by exogenous androgens and/or progestogens. Androgen alone contraceptive regimens may be feasible and effective in Asian men but not in non-Asian men.

Trials in men have been characterised by low numbers of subjects mainly due to low levels of funding. It is disappointing that both pharmaceutical companies that have been funding male hormonal methods have decided to withdraw from this field of research.88 Reasons for this decision would appear to be perceived poor profitability in the context of a shrinking global market and the possibility of legal suit from men for whom the method fails. Nevertheless, there is still support from WHO and Contraceptive Research and Development Program.

Vaccines

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

Despite extensive efforts, the quest for a contraceptive vaccine has been largely unsuccessful so far.89 Only one vaccine has gone through phase-2 trials, an anti-human chorionic gonadotrophin vaccine.90 This vaccine gives contraceptive protection to some women, but it generates above protective threshold titres in only 60–80% of women.

Female sterilisation

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

Mechanical devices such as plugs and thermal occlusion have been investigated with limited success and some adverse effects. Two so-called hybrid methods have been much more successful.

Essure® (Conceptus Inc, San Carlos, CA, USA) is a metallic and fibre microcoil device inserted through the ostia of the fallopian tubes using a 5F gauge hysteroscope. The inner coil is stainless steel and the outer coil nickel titanium alloy. Woven throughout the inner coil are polyethylene terephthalate fibres. The device is delivered into the tube in a tightly wound position. When in situ, the device is released so that the rapidly expanding outer coil fills the tubal lumen, anchoring the device. Fibrosis occurs into and around the microcoil, providing an irreversible method. Specific training in its insertion is necessary. Placement has to be confirmed, usually by X-ray or ultrasound imaging 3 months after the procedure. Placement failure occurs in about 6% of cases.91 In women with correctly placed devices, bilateral tubal occlusion is demonstrated in 99.5% of women at 12 months. A pregnancy rate of 1.2 per 1000 has been reported to the device manufacturer in an analysis of 64 pregnancies out of an estimated 50 000 procedures carried out between 1997 and 2005.92 The procedure can be performed in a treatment room setting, with no need for operating theatre facilities.93 However, UK National Institute for Health and Clinical Excellence guidance is still that this procedure should only be performed with special arrangements for consent and for audit and research.94 In a recent case series report, three tubal perforations were described in 143 consecutive insertions.95

Adiana® (Hologic Inc, Bedford, MA, USA) is a two-step procedure comprising controlled thermal damage of the endosalpinx followed by insertion of a biocompatible matrix plug within the tubal lumen. Results in trials are encouraging.96

Women need a full explanation about hybrid methods regarding their complete irreversibility, but their greater safety as the abdomen, is not entered.

Male sterilisation

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

Reversible inhibition of sperm under guidance (RISUG) is a clear polymer gel made of styrene maleic anhydride mixed with dimethyl sulphoxide, which has been developed in India. RISUG is injected into the vas and then solidifies; it appears to cause partial obstruction of the vas while also causing the membranes of passing sperm to rupture. Phase-2 trials show that users have azoospermia or non-motile sperm for at least 1 year.97 Further toxicology studies are awaited.

The intra vas device (Shepherd Medical, Minneapolis, MN, USA) is implanted into the vas. It consists of two flexible silicone plugs per vas; these are joined by a thread, which remains outside the vas to remove the device. The method is slightly less likely to cause azoospermia than no-scapel vasectomy, but delayed complications are less frequent.98

The VasClip (VasClip, Roseville, MN, USA) is a small polymeric clip applied to the vas. In a phase-2 study, 116 of 119 subjects were azoospermic at 10–14 months after the procedure.99 Sperm granuloma formation incidence was low and acceptability high.

Conclusions

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References

There are more than a dozen existing methods of contraception, all except two designed for women. New methods rely on varying existing technology. The development of male hormonal methods has been set back by withdrawal of pharmaceutical company support. One has to question the philosophy of the pharmaceutical industry in not comprehensively supporting research in contraception, which can do so much to promote reproductive rights and to relieve suffering of millions of women and their families worldwide.

Although some new estrogen and progestogen hormones have been synthesised, greater progress has been made in developing new delivery systems. Hormones can now be delivered by six different routes: oral, injectable, implantable, vaginal, transdermal and intrauterine. The development of hormone-containing controlled-release polymers has allowed steady hormone levels to be maintained for several years.

Mifepristone has great potential as an oral contraceptive and emergency contraceptive agent, but it would appear that industry is unlikely to invest in this as opposition from the public and politicians would be likely to undermine product development. A possible solution to this is the development of PRMs without abortifacient properties.

References

  1. Top of page
  2. Abstract
  3. Context
  4. Oral contraception
  5. Emergency contraception
  6. Injectable contraception
  7. Vaginal rings
  8. Subdermal implants
  9. Transdermal administration
  10. Intrauterine devices
  11. Spermicides
  12. Male barrier methods
  13. Female barrier methods
  14. Male hormonal methods
  15. Vaccines
  16. Female sterilisation
  17. Male sterilisation
  18. Conclusions
  19. Disclosure of interests
  20. Funding
  21. References
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