Summary

Progestogen-only methods of contraception offer an alternative for women who cannot take oestrogens. Most progestogen-only methods increase the viscosity of cervical mucus to impede sperm penetration and make the endometrium unsuitable for implantation. They have a variable effect on the hypothalamic-pituitary axis with the exception of depot medroxyprogesterone acetate (DMPA) which causes complete suppression of ovulation. Progestogen-only methods have little metabolic activity and no deleterious effect on blood pressure and coagulation factors. The major adverse effect is poor menstrual cycle control. This is unpredictable and may result in erratic or prolonged bleeding or nuisance spotting. Amenorrhoea develops in half the women given DMPA within 12 months of starting use. Women using DMPA usually have a delay in the return of their fertility after treatment. Counselling before starting progestogen-only methods is essential in helping women accept the menstrual irregularity. Progestogen-only methods are contraindicated in suspected pregnancy, breast cancer and undiagnosed vaginal bleeding. Relative contraindications are active viral hepatitis and severe chronic liver disease. In the future, long-acting methods such as implants or levonorgestrel-releasing intrauterine systems and vaginal rings will provide alternative routes of administration.

 

Formulations
Progestogen-only methods of hormonal contraception provide options for women in whom oestrogens are contraindicated or not tolerated. There are oral, subcutaneous, intramuscular, intrauterine and intravaginal routes of administration. At present, only the oral and intramuscular preparations are available in Australia.

Progestogen-only pill (mini-pill)
The mini-pill contains between one third and one fifth of the dose of progestogen used in the combined pill. Two formulations are available in Australia, one containing levonorgestrel 30 micrograms, the other norethisterone 350 micrograms. The mini-pill is slightly less effective than the combined pill as its major effect relies on changes in the cervical mucus. These are maximal 2-3 hours after ingestion and lessen after about 21 hours. This means that the mini-pill should be taken at the same time each day, preferably at least 3 hours before intercourse usually occurs. Failure rates per year are 3-10% compared with 2-6% for the combined pill.

The mini-pill is started on the first day of the menstrual cycle and taken continuously with no break. If started later than day one of the cycle, additional contraception, e.g. condoms, should be used for 48 hours. If a pill is missed, 48 hours of additional contraception or avoidance of intercourse is necessary. A woman wishing to change from the mini-pill to the combined pill or vice versa should start with an active tablet on the first day of menstruation.

Depot preparations of medroxyprogesterone acetate (DMPA)
DMPA is an aqueous suspension of microcrystals of medroxyprogesterone acetate with a similar structure to natural progesterone. Given by intramuscular injection into the gluteal or deltoid muscle in a dose of 150 mg every 12 weeks ± two weeks, it provides highly effective contraception with a failure rate of less than 0.5% annually.

If started during the first 7 days of the menstrual cycle, no additional contraception is required. If pregnancy can be excluded, DMPA can be started at any time of the cycle, but additional contraception should be used for 24 hours. In non-breastfeeding women, it can be started immediately postpartum, in the sixth week postpartum if breastfeeding, or immediately following abortion.

Norplant (not yet available in Australia)
The Norplant subdermal implant system consists of 6 silastic capsules (diameter 2.4 mm, length 3.4 cm) which release levonorgestrel. This provides highly effective contraception for 5 years. At first, the capsules release levonorgestrel at a rate of approximately 85 microgram/day reducing to a constant rate of 30-35 microgram/day over the next 18 months. They are inserted under local anaesthesia through a small incision and placed subdermally in the inner aspect of the upper arm.

Norplant is highly effective with a failure rate 0.09-0.2% during the first year. This remains at approximately 0.2% annually over its 5-year lifespan. The steady release rate of levonorgestrel, producing constant concentrations, and the absence of compliance problems probably account for the much lower pregnancy rate compared with the progestogen-only pill.

A critical factor in the use of Norplant is adequate training of practitioners in insertion and removal techniques. Much of the litigation overseas has been related to difficulties with removal which in turn are related to poor insertion techniques. In order to avoid such problems in Australia, it may be advisable to recommend that insertions are only carried out by practitioners who have undergone a training program.

Mode of action
Most progestogen-only methods act by increasing the viscosity of cervical mucus to impede sperm penetration and changing the endometrium making it unsuitable for implantation. They also have a variable effect on the hypothalamic-pituitary axis. While 40-50% of cycles are ovulatory, there appears to be some follicular development without ovulation in other cycles and complete ovarian suppression in a smaller number of cycles. The exception is DMPA which suppresses the hypothalamic-pituitary-ovarian axis resulting in total suppression of ovulation.

Metabolic effects
Progestogen-only methods have no deleterious effect on blood pressure and coagulation factors, and little or no effect on carbohydrate metabolism. They have no clinically significant effect on liver, kidney, adrenal or thyroid function. Studies have shown a lowering of HDL cholesterol, but conflicting effects on LDL cholesterol. This may reflect differing methodologies or patient profiles.

A controversial area at present is the effect of DMPA on bone mineral density. A New Zealand study1 found decreased bone density in the lumbar spine and hip in long-term DMPA users. This was reversed on discontinuation and may be due to fluctuations in oestrogen levels. There was also a difference in the proportion of DMPA users who smoked compared to the controls, which may have influenced the results of the study. A prospective study is under way in the U.S.A. to clarify the issue. Other progestogen-only methods appear to have no effect on bone mineral density.

Fertility usually returns immediately following discontinuation of progestogen-only methods, except for users of DMPA where it is unpredictable. Although fertility returns in the majority of women within 7 months of the last injection, it can take up to 18 months for other women. There is no permanent effect on fertility.

Indications for use
Progestogen-only methods provide a useful contraceptive option for any woman, irrespective of age or parity, in whom oestrogens are contraindicated, women with a variety of medical conditions (see box) or during lactation. No deleterious effects have been found on long-term follow-up of children whose mother used DMPA during lactation. The long-acting methods are useful for women who require highly effective, long-acting contraception with minimal action required on the part of the user. However, women contemplating their use must be prepared to accept menstrual irregularities and amenorrhoea.

Conditions in which progestogen-only methods are suitable

Hypertension

Superficial thrombophlebitis

History of thromboembolism

Biliary tract disease

Thyroid disease

Epilepsy

Diabetes without vascular disease

Provided that adequate counselling and support are available, particularly in regard to menstrual changes, DMPA is a useful method for some adolescents. With informed consent, the long-acting methods can also be used successfully by women who have problems with compliance using other methods e.g. women with psychotic disorders, intellectual disability or who are intravenous drug users. Previously, the use of DMPA in the intellectually disabled, without informed consent, has been severely criticised.

Contraindications
Progestogen-only methods are contraindicated in suspected pregnancy, breast cancer and undiagnosed vaginal bleeding. Giving DMPA to a woman with a severe bleeding disorder may result in a large haematoma at the injection site. Women who want to become pregnant within 18 months or who are afraid of injections should be discouraged from using DMPA. Progestogen-only methods are unsuitable for women unwilling to accept menstrual changes.

Relative contraindications are active viral hepatitis and severe chronic liver disease. For all progestogen-only methods, with the possible exception of DMPA, drug interactions are likely with many anticonvulsants, rifampicin, spironolactone and griseofulvin. This may result in lowered efficacy.

Adverse effects
The most common adverse effect of progestogen-only methods is disturbance of bleeding patterns. Erratic cycle length, prolonged episodes of bleeding, and nuisance spotting, but not heavy bleeding, are common. There are more problems with injectables and implants than with the mini-pill. Amenorrhoea is common with DMPA. By 12 months, at least 50% of users have developed amenorrhoea and, with increased duration of use, approximately 75% will be amenorrhoeic.

Menstrual disturbances can usually be managed by explanation and counselling. Prolonged irregular bleeding or daily spotting can be managed by giving 1.25 mg conjugated oestrogen daily for 3 weeks to achieve a more normal endometrium and a withdrawal bleed. If the bleeding disturbances recur, a further course can be given. Alternatively, a cycle of a fixed low-dose, combined pill can be used. Oestrogens should not be given to women taking the mini-pill as this will affect the cervical mucus changes reducing its effectiveness. Tranexamic acid or non-steroidal anti-inflammatory drugs (NSAIDs) may also be helpful in managing bleeding disturbances. Further investigations of irregular bleeding are indicated where a woman for example has had amenorrhoea for some time and then has erratic bleeding or suddenly develops intermenstrual bleeding or daily spotting.

Functional but generally asymptomatic ovarian cysts sometimes occur. They usually disappear spontaneously and surgery is not required. Other adverse effects which have been reported are similar to those reported with all steroidal methods: headache, nervousness, nausea, dizziness, weight gain, mastalgia, hirsutism and hair loss. Weight gain is variable and when it does occur is usually moderate, varying from 0.5-2.0 kg.

There is no evidence that progestogens in the doses used in progestogen-only contraceptives have a teratogenic effect. Therefore, women who have become pregnant whilst using them can be reassured and the pregnancy managed depending upon their wishes.

Counselling
It is important to ensure that women using progestogen-only methods are able to accept and cope with the likely bleeding irregularities. As these methods provide no protection against sexually transmitted diseases (STDs), they should also be instructed to use condoms as well in situations where protection against STDs is required. Experience has shown that women who are well informed about the likely menstrual disorders tolerate them better and are less likely to discontinue treatment.

Future
The development of long-acting contraceptive methods will offer women the possibility of effective, safe, reversible contraception requiring little effort on the part of the user.

Implants
With the aim of simplifying insertion and removal techniques, a number of implant systems are under development utilising either a single or, at most, two rods. Implanon is a single rod system, releasing 3 keto-desogestrel, which is inserted subdermally by an injection-like technique. New progestogens, such as nestorone, which is not absorbed from the gastrointestinal tract making it particularly suitable for use during lactation, are also being studied.

Vaginal rings
A silastic vaginal ring releasing levonorgestrel at a rate of approximately 20 microgram/day has been developed by the World Health Organization. This is absorbed through the vaginal mucosa with similar effects to the mini-pill. The ring has many of the benefits of injectables and implants, but, unlike these methods, is still under the control of the woman who can reverse its effects immediately by removing the ring herself.

The progestogen-only releasing rings are left in the vagina continuously for the lifespan of the device, usually 5 months. Since they release only progestogen, the major problem is the erratic bleeding patterns associated with the use of all progestogen-only methods.

Progestogen-releasing intrauterine systems
A levonorgestrel-releasing intrauterine system (Mirena) has been marketed in Europe. This releases 20 microgram levonorgestrel at a steady rate over 24 hours with a lifespan of 5 years. It is a highly effective contraceptive with a pregnancy rate at 5 years of 1.8/100 woman years. As it produces a dramatic decrease in menstrual blood loss, it is extremely useful in the management of menorrhagia.

Other approaches
Trials are about to start on a progestogen-releasing gel. This is rubbed into the skin of the abdomen every day.

New emergency post-coital methods

Levonorgestrel
At present, levonorgestrel in a dose of 0.75 mg given within 72 hours of unprotected intercourse is being studied. It appears to be more effective than the ethinyloestradiol/levonorgestrel regimen*, and should have fewer adverse effects such as nausea. At present, a dose of 0.75 mg levonorgestrel in Australia would require taking 25 tablets of the 0.03 mg mini-pill.

Conclusion
Progestogen-only methods have been neglected in Australia and many women are unaware of the existence of such methods. It is necessary for medical practitioners to inform women about the existence, advantages and disadvantages of progestogen-only methods so that women can make an informed choice of which method of contraception they wish to use.

* The ethinyloestradiol/levonorgestrel regimen consists of 100 micrograms of ethinyloestradiol plus 500 micrograms of levonorgestrel, the initial dose given within 72 hours of unprotected intercourse and a second dose given exactly 12 hours later. An antiemetic should be provided as nausea and vomiting are common.

 

Further Reading

McCann MF, Potter LS. Progestin-only oral contraception: a comprehensive review. Contraception 1994;50:6(1 Suppl):1S-198S.

Hickey M, Fraser I. The contraceptive use of depot medroxyprogesterone acetate. Clin Obstet Gynecol 1995;38:849-58.

Sivin I. International experience with Norplant and Norplant-2 contraceptives. Stud Fam Plann 1988;19:81-94.

Xiao B, Zeng T, Wu S, Sun H, Xiao N. Effect of levonorgestrel-releasing intrauterine device on hormonal profile and menstrual pattern after long-term use. Contraception 1995;51:359-65.

 

Edith Weisberg

Director of Research, Family Planning NSW, Sydney