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GnRH-agonists
as a treatment for endometriosis
by Ros Wood
The 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 and 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.
| Generic name |
Brand name |
Form |
Dosage |
| Buserelin |
Suprecur |
Nasal spray |
Buserelin comes in a nasal spray pump. The recommended
dosage is two sprays into each nostril every 8 hours
(3 times a day). |
| Suprefact injectable |
Daily injection |
Daily injections of buserelin start with a dosage
of 200 micrograms, and increase up to a maximum
of 500 micrograms. The final dose is the minimum
needed to alleviate pain symptoms. |
| Goserelin |
Zoladex |
Monthly or three-monthly injection |
Goserelin is embedded in a small biodegradable
implant about the size of a grain of rice. The implant
is injected under the skin in the lower half of
the abdomen once a month. |
Leuprorelin
Leuprolide |
Lupron Depot |
Monthly injection |
Leuprorelin comes as a monthly or,
three-monthly, injection that is injected under
the skin of the abdomen or arm, or sometimes into
the buttock or thigh muscles. |
| Prostap SR |
| Enantone |
| Lucrin Depot |
| Trenantone-Gyn |
Three-monthly injection |
| Naferelin |
Synarel
|
Nasal spray |
Nafarelin comes in a nasal spray pump.
The recommended dosage is one spray of the pump
into one nostril in the morning, and one spray into
the other nostril in the evening every day. In a
few women, the recommended dosage does not stop
menstruation. If symptoms persist in these women,
the dosage may be increased to one spray in both
nostrils morning and night. |
| Synarella |
| Triptorelin |
Decapeptyl SR |
Monthly and three monthly injection |
Triptorelin comes as an injection
that is injected under the skin or into the buttock
muscle once a month or once every three months. |
| Gonapeptyl |
Monthly injection |
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 and depression. The menopausal-type
symptoms usually disappear soon after treatment ceases.
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.
|
| EFECTIVENESS
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 BREAST FEEDING |
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 con¬servative surgery
for symptomatic endo¬metriosis 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.
|
| ACKNOWLEDGMENTS |
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
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