Medical Treatment of Endometriosis

Treatment of endometriosis with drugs can result in great improvement of symptoms such as painful periods, pain on intercourse and pelvic pain. Three important facts must be understood before choosing a medical treatment:

- Medical treatment does not improve the chances for pregnancy and, as it is a hormonally contraceptive treatment, just delays it further.
- Medical treatment suppresses endometriosis, rather than removing it and is effective only for short term management of symptoms, the active endometriosis returning gradually over 12-24 months after stopping.
- The various medical treatment options are of equal effectiveness in treating endometriosis, but the cost and side effects vary.

The aim of medical treatment is to break the cycle of stimulation and bleeding. By stopping the ovary's usual hormonal cycle and reducing oestrogen levels, the endometriosis deposits shrink down and become inactive. The endometriosis is still there, and will gradually become reactivated when the normal menstrual cycle starts again. Ovarian endometriomas of greater than 3cm diameter are unlikely to respond to medical treatment, and similarly if there is a significant amount of adhesions - these will respond best to laparoscopic breakdown (also called adhesiolysis).

It was initially thought that use of the more 'powerful' treatments, such as GnRH agonists, was more likely to cure the endometriosis or result in a greater improvement in symptoms. Studies have compared the various options and it is now clear that they are all pretty much the same in terms of improvement of symptoms.

Each drug will be discussed in turn, but continuous use of the combined contraceptive pill or progestogens are usually the best options with the lowest chance of side effects. Medical treatments are typically used for 6-12 months, except for the contraceptive pill, which can be used as long as needed. For those wishing for more permanent treatment of their endometriosis, it is likely that surgical treatment will be necessary.

Birth Control Pill

The Pill is one of the most commonly used treatments for endometriosis, and is a good choice for young women with mild disease who also require effective contraception. Despite its long-established use, there has been only one study on the use of the Pill for endometriosis. It compared the Pill with GnRH agonists and found an equal improvement with both drugs with regards to pelvic pain, painful periods and painful sex. There was a trend towards the Pill being better at controlling painful periods and GnRH agonists being best for improving painful intercourse.

In the above study the Pill was used cyclically, but many gynaecologists suggest that it is better taken continuously, with no withdrawal bleed in between each packet. This doesn't do your body any harm and there is no 'build-up' of blood as might be expected, since one of the hormones it contains keeps the lining of the womb quite thin.

If used continuously, it should be for 6-12 months, but breakthrough spotting is not uncommon after a few months and you can either have a seven day break at the end of the next packet or your doctor might prescribe some additional oestrogen for a week, which helps to refresh the lining of the womb.

Progestogens

Progestogens are the most commonly used medical treatment and are effective in about 80% of cases. Examples include the drugs medroxyprogesterone acetate (Provera), dydrogesterone and norethisterone. They work by thinning out and shrinking down the endometriosis and also by suppressing the normal cycle of the ovary. They can be used either continuously or in a cyclical way (eg. taken for 3 weeks, with one week off). Depot Provera, the injection form of the drug commonly used 3-monthly for contraception also works, but its use is limited in women wishing pregnancy as it can delay ovulation some time after the last injection (up to 12 months).

Side effects of progestogens can include: irregular bleeding or breakthrough spotting - which affects around one third of users, weight gain, breast tenderness, water retention and rarely depression. This list of side effects is just what is possible, many people don't have any ill-effects at all and it would be unlikely that all would be experienced at once! Once again, breakthrough bleeding can be managed with a short course of oestrogen tablets.

It has long been known that progestogens can alter the blood lipids (fats) in an unfavourable way, which might theoretically lead to an increased risk of blood clots (thrombosis). Two recent studies have provided more evidence that this could be the case. Although they looked at progestogens used for period problems, the doses used are similar as would be for endometriosis, and the risk of thrombosis was around 5-fold higher than expected. Whilst this is an acceptable risk for women not already at risk for thrombosis, if you have other risk factors (eg. a previous clot or a strong family history) then an alternative treatment might be preferable.

GnRH agonists

GnRH stands for Gonadotrophin Releasing Hormone and an agonist is a drug that acts the same way as the body's own hormone. The body normally makes GnRH in a small gland in the brain (the pituitary) and it is this hormone that stimulates the ovary to develop eggs and produce oestrogen, leading to the normal menstrual cycle. If you give GnRH agonists, this floods the system and confuses the delicately controlled balance, leading to a complete block of egg development, oestrogen production and menstrual cycle. It effectively makes you 'menopausal' for the short time that you use the treatment and without the oestrogen stimulation, endometriosis shrinks down and becomes inactive.

Examples of GnRH agonists include: goserelin (Zoladex), nafarelin (Synarel), Buserelin (Suprecur) and leuprorelin (Prostap). They are all either given by injection or nasal spray - tablet forms are unfortunately not available.

GnRH agonists are effective in relieving symptoms in 80-90% of patients and the best affect is in small areas of endometriosis. Although ovarian endometriomas will shrink down by around 20%, surgery remains the optimum treatment for the more severe disease. Studies looking at the effectiveness of GnRH agonists have found that the benefit is comparable with the other forms of medical treatment.

GnRH agonists work by lowering oestrogen levels and the main side effects of the treatment are due to this: hot flushes, reduced sex drive, vaginal dryness, emotional symptoms, depression and headaches. It really is like going through the menopause for a short time. The other main problem limiting longer courses than 6 months is that bone thinning is a side effect with around 5-6% reduction in bone density in the spine. This is completely reversed by 9 months after stopping treatment.

There is now good evidence that the use of add-back hormone replacement therapy (HRT) is effective in preventing the bone thinning and the unpleasant side effects of GnRH treatment. The HRT used can be a normal cyclical oestrogen/progestogen one, a continuous 'no bleed' preparation or a newer type such as tibolone (Livial). It can be started at the same time as the GnRH agonist and does not diminish the effect of the treatment. It might seem surprising that using oestrogen replacement doesn't undo the effect of the GnRH, but there appears to be a threshold level of oestrogen where endometriosis will be stimulated, and HRT doesn't reach that level, but is enough to prevent the side effects.

Danazol

Danazol is a drug that was once used as first-line medical treatment for endometriosis and it is effective in 80-90% of cases. Fortunately, there is now good evidence demonstrating other drugs as equally effective, as Danazol can have some quite unpleasant side effects. It works by preventing ovulation and reducing oestrogen levels as well as having a directly suppressive effect on the endometriosis itself.

It has some properties that are similar to the male hormone testosterone and possible side effects include: weight gain, water retention, tiredness, decreased breast size, hot flushes, acne, oily skin, growth of facial hair and emotional symptoms. Although some side effects are experienced by about 80% of users, they are only troublesome enough to make women stop treatment in 10% of cases. It can irreversibly deepen the voice. It is also important to use an effective contraceptive, as accidental use in early pregnancy can masculinise a female fetus.

Gestrinone

Gestrinone is a treatment used more commonly in Europe. It works in much the same way as danazol with similar, but milder, side effects. It is taken twice weekly and around 85% of women do not have any periods at all when on treatment.

Reference list

Moore J, Kennedy S, Prentice A. Modern combined oral contraceptives for the treatment of painful symptoms associated with endometriosis (Cochrane Review). In The Cochrane Library 1999, Issue 3. Oxford:Update Software.

Vercellini P, Trespidi L, Colombo A, Vendola N, Marchini M, Crosignani PG. A gonadotropin-releasing hormone agonist versus a low-dose oral contraceptive for pelvic pain associated with endometriosis. Fertil.Steril. 1993; 60:75-79.

Vercellini P, Cortesi I, Crosignani PG. Progestins for symptomatic endometriosis: a critical analysis of the evidence. Fertil.Steril. 1997; 68:393-401.

Prentice A, Deary AJ, Goldbeck-Wood S, Farquhar C, Smith SK. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis (Cochrane Review). In The Cochrane Library 1999 Issue 3. Oxford:Update Software.

Vercellini P, De Giorgi O, Pesole A et al. (1998) 'Endometriosis drugs and adjuvant therapy' in: A Templeton, ID Cooke, PMS O'Brian (Eds) Evidence based fertility treatment, p225-245. London: RCOG press

Poulter NR, Chang CL, Farley TMM et al. Risk of cardiovascular diseases associated with oral progestagen preparations with therapeutic indications. Lancet 1999; 354: 6 November. (link requires Lancet website registration, which is free)

Vasilakis C, Jick H & del Mar Melero-Montes M. Risk of idiopathic venous thromboembolism in users of progestagens alone. Lancet 1999; 354: 6 November. (link requires Lancet website registration, which is free)

British Medical Association & Royal Pharmaceutical Society of Great Britain. (1999) British National Formulary. Oxon: The Pharmaceutical Press

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