The Department of Health promotes the use of long-acting, reversible contraceptives as a method of family planning and their use is a Quality and Outcomes Framework (QOF) target.¹ This target has been retained in the QOF 2011-12 update.

A progestogen-only injectable contraceptive (POIC) is a long-acting, reversible contraceptive. A synthetic progesterone or progestogen is slowly released into the systemic circulation following intramuscular injection.

There are two forms of depot injection currently available on the UK market:

• Depo-Provera® is depot medroxyprogesterone acetate (DMPA) aqueous suspension 150 mg in 1 ml.² This is most commonly used.
• Noristerat® is norethisterone enantate (oenanthate) 200 mg in 1 ml in an oily liquid.³ This is only licensed for short-term use, e.g. for women whose partners have undergone vasectomy, until the vasectomy is effective.

Mechanism of action

• Its main mechanism of action is to suppress ovulation.
• It also makes the endometrium unsuitable for implantation if fertilisation occurs.
• It also increases the viscosity of cervical mucus, making the mucus less easily penetrable to sperm.

Epidemiology

3% of women aged 16-49 years use the injection as their method of contraception.⁴ This percentage has been stable for some time. The majority of these women are young - 18-19 years old.

Depot contraceptives are available only for women in the UK, but trials of monthly testosterone injections for men have been undertaken in China.⁵

Failure rate

• Provided that the Depo-Provera® is given on a regular basis every 12 weeks (8 weeks for Noristerat®), there is a very low failure rate - fewer than 4 per 1,000 women over two years.⁶
• As a long-acting contraceptive, Depo-Provera® has a greater efficacy than the oral contraceptives.⁷
• Neither obesity, nor the use of liver enzyme-inducing medication affects the failure rate of Depo-Provera®. The efficacy of Noristerat® is lowered by enzyme-inducing drugs. Broad-spectrum antibiotics do not affect the efficacy of either injectable.

Patient selection

NB: migraine (with or without aura), diabetes, obesity and breast-feeding are NOT contra-indications to use of Depo-Provera®:⁸

• Depo-Provera® is suitable for those who want a reliable but reversible form of contraception that does not require daily vigilance like oral contraceptives, or action at the time of intercourse like barrier contraceptives. It should only be used in adolescents (aged 12-18) after other methods have been considered unsuitable or unacceptable.^6,9
• It is a useful alternative for women who need a reliable form of contraception but who have contra-indications to oestrogen therapy in the combined oral contraceptive pill (COCP). Long-acting reversible contraceptives are recommended by the National Institute for Health and Clinical Excellence (NICE) on the grounds of their low failure rates and better cost-effectiveness than short-acting methods (e.g. oral contraceptive pill, barrier methods).⁸
• Noristerat® is for short-term use (maximum of two injections), as mentioned above.

Contra-indications

See individual drug monographs for complete list.⁶

• Current breast cancer (within the previous five years).
• Gestational trophoblastic neoplasia with abnormal human chorionic gonadotrophin (hCG) level.
• Current severe impairment of liver function or history of liver adenoma or steroid-induced cholestatic jaundice.
• History of severe arterial disease or very high risk factors - risk of thrombosis and arterial disease may be increased.
• Acute porphyria, even if there is no history of active disease.
• Pregnancy - this should be excluded before injection (a history of recent normal menstruation is adequate).
• Noristerat® may not be used during breast-feeding of neonates with severe or persistent jaundice.
• Unexplained vaginal bleeding.

Contraceptive injections are not appropriate for those who may wish a return to fertility in the near future:⁶

• Median delay to conception has been reported as 5.5 months plus the estimated duration of the effect of the last injection of Depo-Provera®. This is compared to 3 months for oral contraceptives and 4.5 months after discontinuing the intrauterine contraceptive device (IUCD).⁸
• Long-term, there is no difference in failure to conceive.

Risks and side-effects

Progestogen-only contraception, whether in the form of progestogen-only contraceptive pills (POCPs), depot injections or slow-release implants, seems to have an extremely good safety profile.⁸

Irregular bleeding

This is found in 80% of women using this method:⁶

• 70% women become amenorrhoeic after 12 months of use. The likelihood of amenorrhoea increases with duration of use. Spotting and heavy bleeding are also found. Counselling before administration greatly improves tolerance for this.
• If menstrual problems are difficult, it is possible to overcome intermenstrual bleeding and to establish a cycle by giving oral ethinylestradiol, usually at 10 to 20 micrograms daily, but this negates the advantage of an oestrogen-free product.

Bone mineral density

There is conflicting evidence that Depo-Provera® causes a reduction in bone mineral density:⁶

• Any loss is small and recovered as soon as the injections are stopped.¹⁰
• There is no available evidence for long-term fracture risk.
• Women aged under 18 years may use progestogen-only injectable contraception (POIC) as first-line, only after considering the suitability of other methods.
• Women with significant risk factors for osteoporosis (family history, smoking, corticosteroids, excessive alcohol, anorexia nervosa, coeliac disease) should consider other methods of contraception.
• Depo-Provera® is licensed for long-term use, but it is recommended that the benefit/risk profile for an individual be re-evaluated if she wishes to continue using it for more than two years.

Cardiovascular disease (CVD)

Changes in serum cholesterol (particularly low-density lipoprotein (LDL) cholesterol) levels have been demonstrated, but a direct increased risk in CVD has not been shown.^11,12

In the current World Health Organization (WHO) medical eligibility criteria recommendations, depot medroxyprogesterone acetate (DMPA) and norethisterone are category '3' for women with multiple risk factors for arterial CVD, current venous thromboembolism (VTE), ischaemic heart disease or history of stroke. This means that the risks of using POICs may outweigh the benefits.

Breast cancer

Breast cancer incidence is slightly raised during and for up to 10 years after use of injectable contraceptives:

• For those stopping by age 30 after five years of POIC use, there would be an estimated 2-3 extra cases (additional to the 44 cases of breast cancer per 10,000 women in this age group never exposed to oral contraceptives).
• For those stopping by age 40 after five years of use, there would be an estimated 10 extra cases diagnosed up to 10 years afterwards (additional to the 160 cases of breast cancer per 10,000 never-exposed women in this age group).

However, this may be because of patient selection, as risk factors for breast cancer are a contra-indication to oestrogen-containing methods of contraception.

Mastalgia (breast tenderness) is common.

Weight gain

Weight gain of up to 3 kg in one year may occur.⁶

Congenital malformation

The NICE guidelines state that women should be advised that there is no evidence of harm to the pregnancy or the fetus.⁸
The Summary of Product Characteristics is naturally more cautious.² Thankfully, pregnancy whilst using POIC is rare.

Advantages⁸

• Depo-Provera® DOES NOT increase the risk of cervical carcinoma, ovarian carcinoma or liver tumours. Risk of endometrial carcinoma is reduced.
• Contraceptive injections give protection against ectopic pregnancy and functional ovarian cysts, because ovulation is inhibited.
• Neither Depo-Provera® nor Noristerat® affects blood pressure.
• In women with epilepsy, frequency of seizures may be reduced while using Depo-Provera®.
• Acne vulgaris, depression and headaches are not associated with the injection.

Administration

Pre-injection counselling⁸

• Always take a full medical history - family, menstrual, contraceptive and sexual.
• Always give full counselling about the injection's prolonged action, delayed return to full fertility and possible side-effects, e.g. menstrual irregularities, loss of bone mineral density, etc; backed up with a patient information leaflet. Once an injection is given, clearly it cannot be removed and its effects will last for three months.
• Promotion of safer sex and assessment of risk of sexually-transmitted infections should form part of the consultation. Screening for sexually transmitted infections should be advised if appropriate.

Route of injection

• Depot injections are given by deep intramuscular injection. Depo-Provera® is given every 12 weeks into the gluteal muscles (preferred), deltoid muscles or the lateral thigh. Noristerat® is given every 8 weeks - always into the gluteus maximus.

Timing⁸

• Injections should be started on or before the 5th day of the menstrual cycle. If it is given later than day 5, barrier contraceptives should be used for the next seven days.
• It can be given at any time postpartum if the patient is not breast-feeding. If the patient is breast-feeding it should be delayed until six weeks postpartum. After first- or second-trimester abortion it can be given immediately, or later if necessary.
• Repeat injections can be given up to five days late without the need for additional contraception. If it is given after this time, pregnancy should be excluded and additional contraception used for fourteen days.

Document references

1. QOF Changes and New Indicators for 2009/10
2. Summary of Product Characteristics (SPC) - Depo-Provera® 150 mg/ml injection (medroxyprogesterone acetate), Pharmacia Limited, electronic Medicines Compendium. Updated August 2010
3. Summary of Product Characteristics (SPC) - Noristerat® (norethisterone enantate), Bayer Schering, electronic Medicines Compendium. Updated June 2009
4. Contraception and Sexual Health 2008/09, Office for National Statistics (2009)
5. Gu YQ, Wang XH, Xu D, et al; A multicenter contraceptive efficacy study of injectable testosterone undecanoate in healthy Chinese men. J Clin Endocrinol Metab. 2003 Feb;88(2):562-8. [abstract]
6. Progestogen-only Injectable Contraception, Faculty of Sexual and Reproductive Healthcare (2009)
7. Freeman S; Nondaily hormonal contraception: considerations in contraceptive choice and patient counseling. J Am Acad Nurse Pract. 2004 Jun;16(6):226-38. [abstract]
8. Long-acting reversible contraception, NICE Clinical guideline (October 2005); (the effective and appropriate use of long-acting reversible contraception)
9. Statement on MHRA Guidance on Depo-Provera, Faculty of Family Planning and Reproductive Healthcare (2004)
10. Kaunitz AM, Miller PD, Rice VM, et al; Bone mineral density in women aged 25-35 years receiving depot medroxyprogesterone acetate: recovery following discontinuation. Contraception. 2006 Aug;74(2):90-9. Epub 2006 May 19. [abstract]
11. Berenson AB, Rahman M, Wilkinson G; Effect of injectable and oral contraceptives on serum lipids. Obstet Gynecol. 2009 Oct;114(4):786-94. [abstract]
12. Yadav BK, Gupta RK, Gyawali P, et al; Effects of long-term use of depo-medroxyprogesterone acetate on lipid metabolism Korean J Lab Med. 2011 Apr;31(2):95-7. [abstract]

Internet and further reading

• Contraception - progestogen-only methods, Prodigy (Sept 2007)
• John Guillebaud. Your Questions Answered: Contraception, 4th Edition