GnRH agonists

GnRH (gonadotropin-releasing hormone) is secreted by the hypothalamus to initiate the release of luteinising and follicle-stimulating hormones from the pituitary gland. Drugs with a similar chemical structure to GnRH are called GnRH analogues. GnRH analogues either mimic the action or stop the secretion of an individual’s GnRH, depending on the chemical structure of the drug and the way it is administered. Given continuously, they stop ovulation and are called gonadotropin-releasing hormone agonists. They are primarily used to treat endometri-osis and fibroids.

The gonadotropin-releasing hormone agonists are used increasingly to reduce fibroid size and the amount of blood vessels surrounding it prior to a myomectomy because of the reduced rate of bleeding and the relative ease in removing a smaller fibroid. There is also the advantage of reducing excess menstruation pre-operatively, which allows time for anaemia to be corrected prior to surgery. They are not used unless surgery is to follow because once these drugs are stopped, the fibroid invariably grows again.

GnRH agonists can be used to treat endometriosis by inducing a temporary menopausal state. Compared to danazol, the gonadotropin-releasing hormone agonists are equally effective in reducing the symptoms and the size of endometrial growths, but obvious side-effects are less severe. (Bone density loss causes no symptoms until late in life, but should be considered in the decision to use GnRH agonists.) On average, endometriomas (endometrial cysts) have returned to their initial size four months after stopping the treatment, making some sort of additional treatment necessary. GnRH agonists have no additional benefits in improving fertility.

Gonadotropin-releasing hormone agonists have also been trialled either alone or in combination with the Pill as ‘add-back therapy’ for premenstrual symptoms. This latter protocol is not commonly used, but require that a woman take the gonadotropin-releasing hormone agonist with low doses of oestrogens and progestogens. Most women are not prepared to exchange premenstrual syndrome for menopausal symptoms and reduced bone density when GnRH agonists are used alone. Results of trials have been mixed. GnRH agonists alone did not help mood symptoms, but add-back therapy showed more promise. Understandably, many women are suspicious of a drug protocol that aims to stop their own hormone production, but then add in the same type of prescribed hormones to stop symptoms. These sorts of treatments are controversial and are reserved for severe and intractable cases of premenstrual syndrome (PMS). This is a realistic option only for those women for whom all else has failed.

Occasionally, gonadotropin-releasing hormone agonists are also suggested for abnormal bleeding which has failed to respond adequately to other methods.

GnRH agonists cannot be used as oral preparations because of their chemical make-up. Instead, they are either given as an injection (Zoladex), usually once per month in a long-acting form; or as a nasal spray (Synarel). They cause a pseudo-menopause and a temporary cessation of the period, but ovulation returns within about four weeks of stopping the drugs. Menopausal symptoms such as hot flushes, dry vagina and headaches are common, and some women have difficulty with sexual intercourse because of vaginal dryness and lowered libido. Sylk, a vaginal lubricant made from kiwi fruit, can be used to improve comfort during sexual activity.

There is an early and significant bone density loss after commencing gonadotropin-releasing hormone agonists. Radial bone density (in the wrist) is not affected, but the bone density of the spine shows significant changes. For some women, this may not be reversible and should be considered as part of their decision to use GnRH agonists. Oestrogen and progestogen given at the same time (add-back therapy) might prevent bone density loss (but aggravate the condition the GnRH agonists were prescribed for) and this regime requires further study.

Occasionally, women will develop ovarian cysts in the first two months of treatment with gonadotropin-releasing hormone agonists, especially if they have a previous history of polycystic ovarian syndrome. These cysts will often resolve as the treatment progresses, but can grow large enough to require surgery or cessation of the drug.

Women who take GnRH agonists should ensure that their calcium and magnesium intake is adequate. Information on calcium is included on site and on magnesium on site.

Bromocriptine

Bromocriptine (Parlodel) is a dopamine agonist and reduces elevated prolactin, stops lactation and re-instates ovulation, cyclic regularity and fertility when women have hyperprolactinaemia. Prolactin-secreting tumours can decrease in size with continued use and because bromocriptine also improves oestrogen levels, it is useful when there is a risk of low bone density.

Bromocriptine has also been used to treat premenstrual syndrome and breast pain, but the validity of this treatment has been questioned. Breast soreness is the only symptom to consistently respond and the drug often causes unacceptable side-effects. These include nausea, vomiting, dizziness, headaches and a blocked nose. These are usually only transitory and can be reduced if the drug is taken at night or given as a suppository.

Women on bromocriptine continue or start to ovulate. If they do not want to become pregnant they will need to use a barrier contraceptive such as a diaphragm or condoms. The inhibitory (dopamine-like) effect on the hypothalamus is only temporary and most women with hyperprolactinaemia who discontinue the drug stop menstruating again.

Cabergoline

Cabergoline is a newer dopamine agonist, a long- acting ergot derivative that is used for the treatment of hyperprolactinaemia. It is effective in improving cyclic regularity and fertility relatively quickly, and has the additional benefit of reducing tumour size in some women. Side-effects such as nausea, vomiting, dizziness and postural hypotension can be minimised by taking the drug at night. Cabergoline is often prescribed once or twice weekly, which tends to reduce adverse effects even further. Safety in pregnancy is still under review and some doctors recommend that women wanting to become pregnant should be given bromocriptine instead because it has a longer history of safety with pregnant women.

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