Endometriosis is the presence of hormonally responsive endometrial tissue outside the uterine cavity. In terms of efficacy there is little to choose between the drugs licensed for this indication and product selection depends mainly on patient tolerability.
The side-effects of GnRH analogues mimic symptoms more normally associated with the menopause. Most patients will suffer from hot flushes and up to a quarter will experience a loss of libido, reduction in breast size and/or emotional lability. Although the GnRH analogues can cause a significant reduction in bone mass, this has not been correlated with an increased risk of bone fracture. Care should nevertheless be exercised in patients at risk of osteoporosis.
There is a lower incidence of hot flushes with the gonadotrophin release inhibitor danazol but patients will still frequently experience vaginal dryness, vaginitis and reduction in breast size, though in the latter case this may well stem directly from its androgenic activity. Other androgenic adverse events commonly associated with therapy include acne, hirsutism, oily skin, increased libido, oedema and weight gain. Danazol may cause water retention and should therefore be used with caution in patients who suffer from cardiac or renal dysfunction, epilepsy or migraine. Rarely, signs of virilisation may occur. Therapy should be withdrawn immediately if there is any deepening of the voice, as this may not be reversible. With the risk of masculisation of a female foetus, patients should also be advised to start therapy on day one of their cycle to exclude the possibility of pregnancy, and to use a barrier method of contraception throughout treatment. Danazol can adversely affect the ratio of HDL to LDL and should be used with caution in patients with hyperlipidaemia. It may also cause deterioration in glucose tolerance in diabetics. Transient and symptomatic changes of liver enzymes are not uncommon and there have also been reports of reversible cholestatic jaundice. Care should be exercised in hepatic impairment, and danazol should not be given to those with severe liver disease. It should also be avoided in patients suffering from porphyria as it may enhance porphyrin production.
The progestogens norethisterone and medroxyprogesterone are associated with breakthrough bleeding and breast discomfort. Ovulation is suppressed in the majority of patients, but normal ovulatory cycles are usually resumed within two months of withdrawing oral therapy. With the depot preparation of medroxyprogesterone, anovulatory cycles can persist for 18 months post-therapy and this formulation is best avoided in women who wish to conceive. Progestogens can trigger water retention, changes in libido, blood lipid levels and liver function.
Some GnRH analogues are also licensed for the management of uterine fibroids (leiomyoma), benign tumours of uterine smooth muscle—either to reduce their size before surgery or when surgery is inappropriate. Alternatively, the progesterone receptor modulator ulipristal acetate can be given to reduce fibroid volume and control uterine bleeding for up to 3 months before surgery, or as intermittent treatment courses of 3 months. It is taken orally and seems to have less severe hypoestrogenic effects than GnRH analogues.