Gonadotropin-Releasing Hormone Agonists
Name) Strength Dosage Form Dosage Regimen
Nafarelin (Synarel) 2 mg/mL delivers 200
Leuprolide (Lupron) 3.75 mg, 11.25 mg IM depot 3.75 mg/month or 11.25
Goserelin (Zoladex) 3.6 mg, 10.8 mg SC implant 3.6 mg implant every
BID, 2 times daily; GnRH, gonadotropin-releasing hormone; IM, intramuscular; SC, subcutaneous.
The most recently studied therapy for endometriosis, aromatase inhibitors (AIs), was
originally developed for use in patients with breast cancer. Aromatase, the enzyme
responsible for the synthesis of estrogens, is required for the conversion of
androstenedione and testosterone to estrone and estradiol.
progestins, and GnRH agonists all decrease serum levels of estrogen, only AIs
decrease secretion and production of estrogen by endometrial tissue itself.
Anastrozole and letrozole are type II AIs, binding reversibly to the enzyme to
produce a beneficial effect on endometriosis symptoms.
decrease estrogen conversion in the periphery, addition of an agent to reduce ovarian
estrogen levels is also necessary in premenopausal women; hence, most of the
studies in this population have included double therapy with AIs and oral
contraceptives or GnRH analog. AIs may be used alone in postmenopausal women.
Although the end result of GnRH agonists and AIs is similar, the adverse effects of
the AIs are decreased, with fewer hot flashes, and primarily mild headache, nausea,
and diarrhea. Although few long-term trials have been conducted, decreased bone
density is suspected with the use of AIs and estrogen add-back therapy is appropriate
(described later in this section and Case 50-4, Question 1). All AI studies, although
small, have demonstrated reduction in pain and reduced lesion size. The largest study
to date used a combination of anastrozole with GnRH agonists compared with GnRH
agonists alone in patients after surgery.
131 Although effective at controlling pain, the
combination resulted in significantly more bone loss than either regimen alone at 6
months, but no difference was seen at the 2-year follow-up.
needed to determine the role of AIs in the treatment of endometriosis, because
currently they do not have an FDA indication for the treatment of endometriosis.
Their use should be reserved at this time for those patients with severe endometriosis
who have failed other therapies.
Danazol, an androgenic drug derived from 17-ethinyl testosterone, also induces a
pseudomenopausal state by increasing androgen levels and decreasing estrogen
levels. It inhibits the enzymes involved in ovarian steroidogenesis and increases the
metabolic clearance of estradiol. By creating a hypoestrogenic, hypoprogestogenic
state, danazol causes anovulation, amenorrhea, and atrophy of endometrial implants.
Although effective at decreasing pelvic pain, danazol is poorly tolerated because of
its significant side effects, which include weight gain, voice changes, edema, acne,
hot flashes, vaginal dryness, hirsutism, liver disease, and increased cholesterol; these
occur in up to 85% of treated patients.
106 Because of safety concerns, use should be
limited to 6 months at a time and should only be initiated in women after all other
Two new medication classes hold promise for the treatment of endometriosis, with
the hope of decreased side effects when compared with current therapy. HMG-CoA
reductase inhibitors (Statins) have been studied in one small clinical trial in
comparison with a GnRH analog and were found to have similar efficacy in
132 Further investigation needs to be done with these agents
particularly in women who wish to retain the option of fertility.
An additional emerging group of therapeutic agents is the GnRH antagonists,
thought to maintain the beneficial effects on pain control in endometriosis, but with
decreased side effects. When compared to depot medroxyprogesterone, the first agent
in this class studied for endometriosis, elagolix, (a once-daily oral medication)
demonstrated noninferiority in its effects on pain control, with little effect on bone
PAIN MANAGEMENT: NONPHARMACOLOGIC THERAPY
eliminate the risk of recurrence of the disease. These procedures are not an option for
many women with endometriosis who desire pregnancy in the future. It is invasive
surgery, reserved for those patients whose pain is unresponsive to other therapies or
to conservative surgery. Furthermore, removal of all endometriosis is difficult, and
recurring pain is not uncommon. Sinaii et al. surveyed patients with endometriosis
regarding treatments and benefits, and found that, of the 1,160 women surveyed, 12%
had had definitive surgery, with 40% reporting the surgery was successful, 33%
reporting partial benefit, 5.6% reporting no benefit, and 6% of patients actually
reported increased pain and symptoms after surgery.
In contrast to definitive surgery, conservative surgery (involving ablation and
removal of implants, and lysis of adhesions) preserves fertility and is commonly
conducted during the initial diagnostic laparoscopy. In the Sinaii et al. survey, 70%
of patients had undergone laparoscopy with removal of lesions, with 30%
considering the procedure a success, 50% reporting partial benefit, 15% with no
difference in symptoms, and 10% reporting increased symptoms.
women reported having three surgical procedures.
134 Drug treatment is used after
conservative surgery, because it is not possible to remove all lesions, many of which
Clinical trials in endometriosis have not singled out one treatment as the treatment
of choice for all women, with most investigations demonstrating equivalence of the
studied therapies. An NSAID and combined hormonal contraception (e.g., N.H.’s
contraceptive vaginal ring) are the drugs of choice for initial management, owing to
their safety profile and, in this case, the contraceptive agent’s dual utility in
preventing conception. As a next step, progestins, GnRH agonists, and AIs are
options. Because of adverse effects and poor tolerability, danazol should be reserved
as an agent of last choice. If N.H. were uninterested in having children in the future,
surgical sterilization would be an option. Conservative surgery, including removal of
endometriomas and adhesions and ablation of visible lesions, is not curative, but may
provide pain relief in 50% to 95% of patients at 1 year.
conservative surgery, followed by postoperative progestin, combined hormonal
contraceptive, GnRH agonists, or danazol, has been shown to prolong the duration of
pain relief and decrease recurrence after surgery.
CASE 50-3, QUESTION 3: N.H. has not had a problem in the past tolerating a variety of contraceptive
N.H. is a smoker, with poor calcium intake and some cardiovascular risk factors
(family history, high cholesterol), who would rather avoid injectable medication and
has trouble with daily medication taking. Danazol, with its ability to increase
cardiovascular risk factors and extensive side effects, is not a good option. Although
some GnRH analogs are available as nasal sprays or injectable implants, the
significant risk of decreased bone density and menopause-like adverse effects place
them as a second-line option. Progestins, particularly the long-acting progestins,
either in the form of the medroxyprogesterone acetate 3-month depot or subcutaneous
injection, or the levonorgestrel IUS, make these appropriate first-line options for
N.H., although the risk of diminished bone density with depot formulations remains
Depot medroxyprogesterone acetate (DMPA) is available in two dosage forms:
150 mg to be given intramuscularly (IM) every 3 months and a 104-mg formulation
given subcutaneously (SC) every 3 months. Product choice may be based on
insurance coverage or potential for the patient to self-administer (the SC product may
be more patient-friendly). Because N.H. does not want to self-inject, either choice,
administered by her provider’s office, or a pharmacist if law allows, would be an
appropriate option. Although the DMPA does provide the contraception N.H.
desires, she should be informed that it may take longer than usual (up to 1 year) to
become pregnant after its use. More than 80% of patients treated with progestins will
experience partial or complete pain relief.
123 Although devoid of the menopause-like
adverse effects of other medications used to treat endometriosis, DMPA is
associated with weight gain (which may be significant in some patients), bloating,
and irregular periods or bleeding for several months, with most users eventually
experiencing amenorrhea. To reduce bone density loss, which is significant but less
than with GnRH agonists, N.H. should be advised to ensure her daily intake by diet
or supplementation of calcium is at least 1,000 mg/day and at least 400 to 600 IU of
vitamin D/day, receive smoking cessation counseling and pharmacotherapy as
appropriate, and start a regular weight-bearing exercise regimen.
monitored for pain relief, weight gain, amenorrhea or bleeding changes, and
adherence to the quarterly injections. When N.H. desires conception, significant
planning is required and she may require a different therapy for her endometriosis
because she regains fertility.
GONADOTROPIN-RELEASING HORMONE AGONISTS AND ADD-BACK
QUESTION 1: M.F., a 24-year-old single woman with a history of moderate-to-severe endometriosis, has
had trouble with adherence in the past. What options are available for the treatment of M.F.’s pain?
M.F. has tried numerous pharmacologic and surgical treatments (NSAIDs,
combined oral contraception, and progestin-only contraception) for endometriosis
with limited benefit. Given that she does not desire pregnancy at this time, GnRH
analogs, aromatase inhibitors, and danazol are other options. Leuprolide, nafarelin,
and goserelin are GnRH analogs (agonists) typically used for the treatment of
endometriosis (Table 50-4). Although GnRH analogs have not been shown to
produce better results than the therapies M.F. has already used, they may provide her
with pain relief. Choice of GnRH agonist is driven by patient choice of
administration method (nasal twice daily [BID] with nafarelin, monthly SC implant
with goserelin, or IM injection either once monthly or once every 3 months with
leuprolide). In M.F.’s case, the once every 3 months dosing with leuprolide would be
most desirable for her, eliminating the need for daily administration. Efficacy is
similar for all the GnRH agonists. Before use of these agents, pregnancy,
undiagnosed vaginal bleeding, and breastfeeding should be ruled out. Because M.F.
does not desire conception, and use of the GnRH agonists is contraindicated in
pregnancy, she should be counseled regarding choices of nonhormonal contraceptive
Onset of response to GnRH therapy depends on the phase in the menstrual cycle
during which the agent is initiated. Administration beginning in the luteal phase
causes decreased estrogen levels within 2 to 3 weeks, and amenorrhea within 4 to 5
weeks versus the 6 to 8 weeks if started in the follicular phase.
adverse effects, with continued efficacy.
136 Add-back therapy is based on the concept
of an estrogen threshold hypothesis, formulated by Barbieri,
is a critical amount of estrogen that exacerbates endometriosis, and below that level
the presence of estrogen serves to decrease adverse effects but does not have an
adverse effect on the disease itself. Add-back therapy should be initiated at the
beginning of GnRH agonist therapy to try to reduce the occurrence of all
hypoestrogenic adverse effects.
Estrogen-containing OCs contain a dose of estrogen that is above the threshold,
and they should not be used for add-back therapy. Doses
of estrogen equivalent to 0.625 mg of conjugated equine estrogen have been
studied in combination with either medroxyprogesterone 2.5 mg daily, or
norethindrone 5 mg daily. This dose of norethindrone alone, or a dose of 20 mg of
medroxyprogesterone alone, has also demonstrated benefit.
regimen of a progestin plus a bisphosphonate has been studied with positive results.
No studies have demonstrated superior efficacy or safety of one regimen over
another. Women using add-back therapy should consume in diet or supplement a total
of 1,000 mg of calcium daily, and have vitamin D levels in the normal range.
Therapy beyond 3 to 6 months requires the use of add-back therapy to reduce the
risk of hypoestrogenic complications. Monitoring for efficacy includes monitoring for
amenorrhea, decreases in pain and dyspareunia, and quality of life. After
discontinuation of GnRH agonists, menses and ovarian function return to normal in 6
to 12 weeks, although benefits may be maintained for another 6 to 12 months.
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