GnRH

by Ros Wood

GnRH agonists are a group of drugs that have been used to treat women with endometriosis for over 20 years [1]. They are modified versions of a naturally occurring hormone known as gonadotropin releasing hormone, which helps to control the menstrual cycle.

All the GnRH agonists are very similar chemically, but they come in different forms:

• three-monthly injection
• monthly injection
• daily injection
• nasal spray

The names, forms and recommended dosages of the GnRH agonists used for endometriosis are shown in the table below.

When used in combination with add-back medication (see below), the GnRH agonists are safe, effective and generally well tolerated by most women [2].

How they work

All the GnRH agonists work in exactly the same way. When used continuously for periods of longer than 2 weeks, they stop the production of oestrogen by a series of mechanisms. This deprives the endometrial implants of oestrogen, causing them to become inactive and degenerate.

Most women will stop bleeding within 2 months of starting treatment. However, some will experience 3–5 days of vaginal bleeding or spotting about 10–14 days after beginning treatment.

You should notice an improvement in your symptoms within 4–8 weeks of beginning treatment, but some women will experience a temporary worsening of symptoms in the first 2 weeks. This is because it takes a little while for the body to clear out its hormone production, and during this phase oestrogen levels will actually increase and may therefore stimulate the disease until the stabilising effect of the GnRH agonist kicks in.

The return of ovulation and menstruation is very variable. Most women will menstruate within 4–6 weeks of their last spray of buserelin or nafarelin, or within 6–10 weeks of their last injection of goserelin, leuprorelin or triptorelin.

Dosage

GnRH agonist
At present, the usual length of treatment with a GnRH agonist is 3–6 months. However, in Germany, 12 months treatment with add-back therapy (5 mg of norethisterone per day) has been approved, and other countries may do the same in the future.

A 3 month course of treatment may relieve pain symptoms as effectively as a 6 month course [3], but treatment for 6 months appears to lead to a longer delay before the return of symptoms [4, 5].

The mode of administration and dosage varies according to the drug being used, as shown in the table below.

You should begin your treatment on the first 2–4 days of your period to minimise the likelihood of taking the drug while pregnant. If there is any possibility that you may be pregnant, you should not begin treatment.

Under most circumstances, you are not likely to become pregnant while using a GnRH agonist. However, because of the possibility that it may cause miscarriage or abnormalities in the developing foetus, it is recommended that you use non-hormonal forms of contraception during treatment (condom or diaphragm or both).

Add-back medication
Many gynaecologists recommend that you also take add-back medication to reduce or even prevent the side effects of the GnRH agonists (see below). Add-back therapy involves taking one of the following medications at the same time as a GnRH agonist: a low-dose oestrogen, a low-dose progestin, or tibolone alone. The dosages used are small, so they do not reduce the effectiveness of the GnRH agonist.

If your gynaecologist does not prescribe add-back therapy, you might like to request it.

Side effects

Menopausal-type symptoms
The side effects of the GnRH agonists are largely the result of the low levels of oestrogen in the body, so they are usually confined to the symptoms associated with the menopause.

Side effects are common, and most women will experience at least one or two. The severity of the side effects varies from mild to severe, and some women will find them intolerable.

Most women will experience hot flushes or night sweats or both. The other common side effects are:

• insomnia
• decreased libido
• headaches
• mood swings
• vaginal dryness
• decreased breast size
• increased breast size
• acne
• muscle pains
• dizziness
• depression.

The menopausal-type symptoms usually disappear soon after treatment ceases.

» Tips for coping with side effects of drug treatments

Bone thinning
The most serious side effect of treatment with a GnRH agonist is thinning of the bones, particularly the bones of the spine.

The matrix that makes up our bones is constantly breaking down and regenerating. When the levels of oestrogen in the body are low, the rate of breakdown becomes greater than the rate of regeneration, so the bone matrix becomes less dense or thinner. The decrease in bone density is typically about 4–6% at the end of a 6 month course of treatment.

It is thought that most of the bone lost during treatment regenerates within 6 months of completing treatment, and that 18–24 months after completing treatment probably most, if not all, the lost bone has been replaced. Therefore, a single 6 month course of treatment will not usually be detrimental for women with normal bone density. However, in women at risk of developing the condition, treatment with a GnRH agonist could predispose them to developing osteoporosis.

Osteoporosis (fragile bones) is a serious condition that can severely affect quality of life. In its more severe form, the bones, especially the bones of the spine and hips, break spontaneously. In its less severe form, the bones may just be more prone to breaking. Most of us develop some degree of osteoporosis after menopause, so it is important that we lose as little bone density as possible before menopause.

The most important risk factor for osteoporosis is a history of the disease in a close relative, such as a grandmother or mother. If you may be at risk of developing osteoporosis, you should consider having a bone density scan before embarking on treatment.

Benefits of add-back therapy
Add-back therapy can reduce the menopausal-type side effects of GnRH agonist therapy, which can make life more tolerable while on treatment. More importantly, it may have long-term benefits by preventing or minimising the thinning of the bones associated with treatment with a GnRH agonist alone.

Others
A few women will experience irritation of the nose if using a buserelin or nafarelin spray pump, or bruising and irritation of the skin around the injection site if using goserelin, leuprorelin or triptorelin injections.

Effectiveness for pain symptoms

All the GnRH agonists work in the same way, so they are equally effective in regressing endometrial implants and reducing pelvic pain symptoms [1]. They appear to be at least as effective as progestins in relieving pain [6].

Use before surgery
GnRH agonists should not be used before surgery to reduce the extent of peritoneal (superficial implants) disease. Reducing the number and size of implants can make surgery more difficult by making it harder for the surgeon to see where the disease is present [1].

Treatment with a GnRH agonist before surgery may reduce the likelihood of ovarian endometriomas recurring [7], but the evidence is controversial [8].

Use after surgery
Six months of GnRH agonist therapy immediately following surgery reduces the rate of symptom recurrence [9], and increases the length of time before symptoms recur [1]. It is also more effective in managing endometriosis-related pain after surgery than using oral contraceptives in the same way [10]. The benefits may be particularly relevant for women with active peritoneal disease [1].

Use in recurrent endometriosis
If you have recurrent disease, you may be able to have further courses of GnRH agonist treatment, but the dosage and length of time between courses needs to be carefully considered to minimise the likelihood of losing bone density in the long term [11].

Thinning of the bones may be less marked during a second course of treatment compared with the first [11]. In addition, add-back therapy may reduce the risk of bone thinning, and make repeated, intermittent or even continuous treatment possible for up to 2 years [1].

Effectiveness for infertility

The GnRH agonists — like all the hormonal treatments for endometriosis — do not improve your chances of conceiving, without any reproductive techniques, so they should not be used as a treatment for infertility.

Keeping track

You should see your gynaecologist about 6–8 weeks after beginning your course of a GnRH agonist to discuss how the treatment is progressing. Don’t hesitate to contact your gynaecologist if you have any problems between planned visits.

Pregnancy and breastfeeding

GnRH agonists should not be used during pregnancy.
GnRH agonists are found in small amounts in breast milk, so they should not be used while breastfeeding.

Interactions

GnRH agonists may interact with other medicines. Let your doctor know about any medication you are taking, including non-prescribed drugs such as complimentary therapies or herbal medicine.

References

1. Schweppe K-W, Hummelshoj L. Recommendations on the use of GnRH in the management of endometriosis. In: Lunenfeld B (ed). GnRH Analogs in Human Reproduction. United Kingdom: Francis & Taylor, 2005:53-66.
2. Ihara M, Uemura H, Yasui T, et al. Efficacy of every-other-day administration of conugated equine estrogen and medroxyprogesterone acetate on gonadotropin-releasing hormone agonists treatment in women with endometriosis. Gynaecol Obstet Invest 2001;52:217-22.
3. Hornstein MD, Yuzpe AA, Burry KA, et al. Prospective randomised double-blind trial of 3 versus 6 months of nafarelin therapy for endometriosis associated pelvic pain. Fertil Steril 1995;63:955-62.
4. Kampe D, Sahl AC, Schweppe K-W. Prä- und postoperative Endometriosetherapie mit GnRH-Agonisten in Depotform: drei- versus sechsmonatige Behandlungsdauer. Zentralbl Gynäkol 2003;125:304.
5. Busacca M, Somigliana E, Bianchi S, et al. Post-operative GnRH analogue treatment after conservative surgery for symptomatic endometriosis stage III-IV: a randomized controlled trial. Hum Reprod 2001;16(11):2399-2402.
6. Prentice A., Deary AJ, Bland E. Progestagens and anti-progestagens for pain associated with endometriosis. In: The Cochrane Library, Issue 3. Chichester: John Wiley & Sons Ltd, 2003.
7. Donnez J, Nisolle M, Gillerot S, et al. Ovarian endometrial cysts: the role of gonadotropin-releasing hormone agonist and/or drainage. Fertil Steril 1994;62:63-66.
8. Muzii L, Marana R, Caruana P, et al. The impact of preoperative gonadotropin-releasing hormone agonist treatment on laparoscopic excision of ovarian endometriotic cysts. Fertil Steril 1996;65:1235-1237.
9. Hemmings R. Combined treatment of endometriosis. GnRH agonists and laparoscopic surgery. J Reprod Med 1998;43(3):316-320.
10. Muzii L, Marana R, Caruana P, et al. Postoperative administration of monophasic combined oral contraceptives after laparoscopic treatment of ovarian endometriomas: a prospective, randomised trial. Am J Obstet Gynecol 2000;183:588-592.
11. Uemura T, Yoshikata H, Ishikawa M, et al. Effects of pre-treatment with GnRH-Agonists on bone mineral density in patients with endometriosis. 5th International Symposium on GnRH-Analogues in Cancer and Humann Reproduction, Geneva, Switzerland, 1999: abstract 45.
12. Sallam HN, Garcia-Velasco JA, Dias S, Arici A. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database of Systematic Reviews 2006; Issue 1.

Thank you to the following for reviewing this article prior to its publication

Karl-Werner Schweppe, Professor and Head of Department, Ammerland Clinic, Germany
Andrew Prentice, University Senior Lecturer and Consultant Gynaecologist, Cambridge University, UK
Bruno Lunenfeld, Professor Emeritus, Bar Ilan University, Israel