Nafarelin
Also known as Synarel, nafarelin acetate, Synarela
GnRH agonist given as a nasal spray for endometriosis and central precocious puberty; flare first, then suppression.
At a glance
- Category
- Hormonal & sexual
- Status
- approved drug
- Route
- intranasal spray, 200 micrograms per actuation
- Half-life
- approximately 3 hours in serum; intranasal bioavailability averaged 2.8% from a 400 mcg dose (range 1.2-5.6%); plasma protein binding around 80% 1
- Onset
- peak serum concentration reached between 10 and 40 minutes after a dose 1; gonadal suppression established by roughly 4 weeks
- Molecular weight
- approximately 1322 g/mol for nafarelin free base; supplied as the acetate
- Sequence
- pGlu-His-Trp-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-Gly-NH2 (native GnRH with 3-(2-naphthyl)-D-alanine at position 6)
Approved in the US and EU as Synarel nasal solution, indicated for the treatment of endometriosis in women aged 18 and over and for central precocious puberty in children of both sexes 1. Unusual among GnRH analogues in being delivered intranasally rather than by injection or depot. Availability has become limited in some markets.
Doping status: Prohibited in males (WADA S2.2.1, GnRH agonist analogues)
Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.
Mechanism of action
Nafarelin is a decapeptide GnRH agonist in which glycine at position 6 is replaced by the bulky, lipophilic 3-(2-naphthyl)-D-alanine. That substitution blocks enzymatic cleavage and increases receptor affinity roughly 200-fold over native GnRH — enough potency to make intranasal delivery viable despite a bioavailability of only about 2.8% 1.
Its pharmacology follows the agonist pattern exactly. Repeated dosing first stimulates the pituitary, transiently raising LH, FSH and gonadal steroids, and only then causes downregulation: GnRH receptors are lost from the gonadotroph surface and the cell stops responding. The label puts the timeline at roughly four weeks to suppression of gonadal steroid production 1. Clinically this means women starting treatment for endometriosis may experience a worsening of symptoms and often a menstrual bleed in the first weeks, and children treated for precocious puberty may show transient breast enlargement or vaginal bleeding before suppression takes hold.
This is the same flare-then-suppress behaviour seen with triptorelin and leuprolide, and it is the opposite of the GnRH antagonists cetrorelix and ganirelix, which competitively block the receptor and suppress from the first dose with no flare at all. Gonadorelin, native GnRH, is a third case: given in physiological pulses it sustains the axis rather than suppressing it. The determining factor across all of them is the pattern of receptor exposure — pulsatile stimulation maintains gonadotropin secretion, continuous exposure to an activating ligand suppresses it, and competitive blockade suppresses it immediately.
The sustained hypo-oestrogenic state is what treats endometriosis: ectopic endometrial tissue is oestrogen-dependent and regresses when oestradiol falls to postmenopausal levels. The same state produces the entire adverse-effect profile, of which bone mineral density loss is the most consequential.
The nasal route has one practical implication that injections do not: absorption depends on an intact nasal mucosa. Rhinitis, sneezing immediately after dosing or a nasal decongestant used too soon after a dose can reduce delivered drug enough to allow breakthrough ovulation.
What the research shows
Nafarelin is a licensed medicine with controlled trial evidence in both of its indications, including direct comparison against danazol in endometriosis. The efficacy evidence is solid; equally solid, and quantified in the same trials, is the bone mineral density loss that limits how long it can be given.
Research in humans
In endometriosis, six-month courses of 400 micrograms daily produced symptom relief and lesion reduction comparable to danazol, with a different side-effect profile 1. Bone densitometry in those trials showed vertebral trabecular bone decreasing by an average of 8.7% and total vertebral bone mass by 4.3% over six months 1, with incomplete recovery afterwards — trabecular bone remained 4.9% below pretreatment levels. In central precocious puberty, treatment suppressed gonadotropins and sex steroids to prepubertal levels and slowed the progression of secondary sexual characteristics and bone age advance.
Animal and lab research
Preclinical work established the potency gain from the naphthylalanine substitution and confirmed the downregulation mechanism and reversibility. It does not add to the human evidence base.
Caveats. The endometriosis trials are 6-month studies; long-term outcomes such as fracture risk are not directly measured. Retreatment is not recommended precisely because the bone data beyond one course are inadequate. The intranasal route introduces variability in delivered dose that injectable analogues do not have, and adherence to a twice-daily nasal regimen is harder to verify than a depot injection. Post-marketing psychiatric signals, including depression and suicidal ideation, come from spontaneous reports rather than controlled data.
What it is used for
- Endometriosis: relief of pain and reduction of endometriotic lesions in women aged 18 and over 1
- Central (gonadotropin-dependent) precocious puberty in children of both sexes 1
- Off-label: uterine fibroids, pituitary downregulation in assisted reproduction, and suppression of endogenous sex steroids in gender-affirming care
Dosing
- Treatment for endometriosis should begin between days 2 and 4 of the menstrual cycle, and pregnancy should be excluded before starting 1.
- The dose may be raised to 800 micrograms daily (one spray in each nostril, twice daily) if amenorrhoea is not achieved after two months of treatment 1.
- Avoid sneezing during or immediately after dosing, as it impairs absorption. If a nasal decongestant is needed for rhinitis, wait at least two hours after the nafarelin dose before using it 1.
- Missed doses risk breakthrough ovulation and menstruation. Non-hormonal contraception should be used throughout treatment.
- The 6-month limit for endometriosis is stated on the label on the grounds that safety data beyond six months are not available, and retreatment is not recommended because of the bone loss measured over the first course 1. It is not a soft recommendation.
- This is a metered nasal spray, not a reconstitutable powder; there is no scope for dose improvisation.
These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.
Protocols
Synarel nasal spray (endometriosis)
approved product informationSource: SYNAREL (nafarelin acetate) nasal solution prescribing information, DailyMed
| Start, between day 2 and day 4 of the menstrual cycle | 200 mcg (one spray) into one nostril in the morning and 200 mcg into the other nostril in the evening - 400 mcg per day |
|---|---|
| If menstruation persists after 2 months | 800 mcg per day - one spray into each nostril, morning and evening |
| Course length | 6 months; retreatment is not recommended |
Pregnancy must be excluded before starting and non-hormonal contraception used throughout, because breakthrough ovulation follows missed doses. Sneezing during or just after a spray impairs absorption, and a nasal decongestant should be delayed at least two hours after the dose.
Synarel nasal spray (central precocious puberty)
approved product informationSource: SYNAREL (nafarelin acetate) nasal solution prescribing information, DailyMed
| Usual dose | 1600 mcg per day - two sprays into each nostril in the morning and two into each nostril in the evening |
|---|---|
| If suppression is inadequate | 1800 mcg per day - three sprays into alternating nostrils, three times daily |
| Duration | continued until puberty is to resume |
The paediatric dose is four times the endometriosis dose, which is why the two schedules must not be read across. Adequate suppression is confirmed by hormone testing rather than assumed from the dose.
Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.
Reconstitution
- Vial sizes
- 8 mL bottle containing nafarelin 2 mg/mL as the base, with a metered spray pump delivering 200 micrograms per actuation
- Solvent
- Not applicable — supplied as a ready-to-use nasal solution
- Storage
- Store upright at 25 °C, with excursions permitted to 15-30 °C. Protect from light.
Worked example
No reconstitution. One bottle provides approximately 60 sprays, which is about 30 days at the endometriosis dose of two sprays daily, or about 7 days at the precocious puberty dose of eight sprays daily.
Prime the pump before the first use as directed. Keep the bottle upright; storing it on its side interferes with the metering pump and results in an unreliable delivered dose.
Safety
Side effects
- Hot flushes, the most common effect, reported in the large majority of women treated for endometriosis 1
- Loss of bone mineral density: on average 8.7% of vertebral trabecular bone density and 4.3% of total vertebral bone mass over six months, with only partial recovery afterwards 1
- Nasal irritation and rhinitis, reported in around 5%, a consequence of the delivery route 1
- Headache
- Emotional lability, reported in around 6% 1
- Depression, which may occur or worsen during treatment; post-marketing reports include suicidal ideation
- Decreased libido and vaginal dryness
- Acne, reported in around 10% 1
- Transient breast enlargement and vaginal bleeding early in treatment in children, reflecting the initial flare
- Hirsutism, seborrhoea and myalgia
- Weight change and fluid retention
- Convulsions, reported post-marketing including in patients without a seizure history 1
- Pituitary apoplexy, rare, reported post-marketing, usually shortly after the first dose in patients with an undiagnosed adenoma 1
- Severe cutaneous adverse reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS and AGEP, reported post-marketing 1
Do not use if
- Hypersensitivity to nafarelin, other GnRH analogues or any excipient 1
- Pregnancy — may cause fetal harm; pregnancy should be excluded before treatment and non-hormonal contraception used throughout 1
- Breastfeeding 1
- Undiagnosed abnormal vaginal bleeding 1
- Retreatment for endometriosis is not recommended, particularly in women with risk factors for osteoporosis: chronic alcohol or tobacco use, a family history of osteoporosis, or chronic use of corticosteroids or anticonvulsants 1
- Caution in patients with a history of depression or other psychiatric illness
- Caution in patients with a history of seizures or CNS lesions
Interactions
No formal drug interaction studies of significance have been reported and nafarelin is a peptide not cleared by cytochrome P450. The most practically important interaction is with the delivery route: topical nasal decongestants reduce absorption if used within two hours of a dose 1. Corticosteroids, anticonvulsants, chronic alcohol and tobacco add to the bone loss caused by hypo-oestrogenism. Concurrent GnRH antagonists negate the effect, and exogenous hormonal contraception or sex steroids confound both the intended effect and any hormonal monitoring.
Sources
- SYNAREL (nafarelin acetate) nasal solution — full prescribing informationDailyMed, US National Library of Medicine
- World Anti-Doping Code International Standard — Prohibited ListWorld Anti-Doping Agency