Nafarelin
The GnRH agonist taken as a nasal spray, for endometriosis and early puberty
Nafarelin is a ten-amino-acid analogue of GnRH with a naphthylalanine at position 6. Sprayed into the nose twice a day, it first stimulates the pituitary and then switches it off, lowering sex hormones within about four weeks. The US approved it as Synarel in 1990; the label covers endometriosis and central precocious puberty.
What is it?
Like leuprolide and triptorelin, nafarelin overstimulates the GnRH receptor until the pituitary stops responding, so there is a brief hormone rise before suppression. Its distinction is the route: under 3% of a nasal dose reaches the blood, but the peptide is potent enough for that to work, with no injection or depot. The label describes the sequence: gonadotropins and sex steroids rise briefly, then twice-daily dosing lowers gonadal steroid secretion within about four weeks.
For endometriosis it was measured against danazol, the standard oral drug of the time. In a US trial of 213 women, more than 80% in every group had less disease at repeat laparoscopy after six months. A large European trial with a year of follow-up found nafarelin and danazol equally effective at shrinking endometriosis and relieving symptoms, with symptoms returning after treatment but less severely than at the start; danazol raised body weight and liver enzymes more, and nafarelin caused more hot flushes. Against leuprolide, a quality-of-life analysis found women with severe symptoms improved more on nafarelin, with fewer days of moderate or severe hot flashes.
The price is the same low-estrogen state every GnRH agonist causes. In the label's data, six months cut vertebral trabecular bone density by 8.7%, and six months after stopping it was still 4.9% below where it started. The label limits a course to six months and asks for a bone density check before any retreatment. Adding a progestogen does not fully prevent it: in a placebo-controlled trial, spine density fell 6.1% over six months on nafarelin with placebo and 3.9% to 5.5% with three doses of norethisterone. A second course after symptoms returned improved pain and tenderness in 36 women, with spine density ending about 2% below its level before the first course.
In children with central precocious puberty, the label dose is much higher: 1,600 µg a day, two sprays in each nostril morning and evening, rising to 1,800 µg as three sprays three times a day if suppression is inadequate, and continued until puberty is wanted. The first report, in 15 girls in 1986, found 800 to 1,200 µg a day reduced oestrogen, gonadotropins and growth velocity over six months. The label asks for close monitoring in the first six to eight weeks to make sure suppression is rapid.
In children the spray peaks within 10 to 45 minutes and has a serum half-life of about 2.5 hours after a 400 µg dose; in adult women under 3% of a nasal dose reaches the blood. Its labelled interactions section says no pharmacokinetic interaction studies were done, and that interactions would not be expected because the peptide is broken down by peptidases rather than liver enzymes.
Outside the label, nafarelin was used to switch off the pituitary in IVF. A meta-analysis of nine trials in 1,014 women found pregnancy rates equal to other agonists with fewer days of stimulation, and a randomised trial against buserelin found clinical pregnancy rates of 31% per recruit with nafarelin 400 µg and with buserelin, with a shorter stimulation on nafarelin.
Mechanism of Action
Nafarelin is a GnRH agonist given as a nasal spray: a brief rise in gonadotropins, then pituitary desensitisation and low sex steroids within about four weeks (label).
Nasal delivery
Under 3% of a dose is absorbed, but the peptide is potent enough to suppress the pituitary without an injection.
Low sex steroids
The intended effect, and the cause of hot flushes and bone loss (8.7% at the spine after six months, label).
Short half-life
About 2.5 hours in children after 400 µg, which is why it is sprayed two or three times a day (label).
Published Research
The studies behind nafarelin, read from their PubMed abstracts: endometriosis trials against danazol and leuprolide, bone effects, precocious puberty and IVF.
Against danazol
In 213 women with endometriosis given nafarelin 400 or 800 mcg a day or danazol for six months, over 80% in each group had less disease at repeat laparoscopy, and severe pain fell from about 40% of women to 5-10%.
European trial against danazol, with a year of follow-up
Nafarelin and danazol were equally effective in reducing endometriosis and symptoms; danazol raised weight and liver enzymes more, nafarelin caused more hot flushes.
Quality of life against leuprolide
Women with severe baseline symptoms improved more on nafarelin, with fewer days of moderate or severe hot flashes and fewer hypoestrogenic symptoms at three months.
With norethisterone add-back: bone
Over six months, spine density fell 6.14% with nafarelin plus placebo and 3.93% to 5.46% with three norethisterone doses.
How much a spray delivers
In 15 healthy women, a 400 mcg nasal dose peaked in about 18 minutes and delivered 2.8% of the dose on average (range 1.2-5.6%), compared against an intravenous dose.
Bone after stopping
In 28 women given 400 mcg a day for six months, spine bone density kept falling for three months after treatment ended and had not returned to baseline six months later.
A second course
In 36 women whose symptoms returned, three months of 200 mcg twice daily improved pain, tenderness and dyspareunia; spine bone density ended 1.94% below its level before the first course.
In IVF: a meta-analysis
Across nine trials in 1,014 women, nafarelin used to suppress the pituitary in IVF gave pregnancy rates equal to other GnRH agonists, with fewer days and ampoules of stimulation; this use is not on the US label.
Precocious puberty in 15 girls
Intranasal nafarelin 800 to 1,200 µg a day reduced oestrogen, gonadotropins, vaginal cytology changes and growth velocity over six months.
In IVF: against buserelin
Nafarelin 400 µg and buserelin both gave clinical pregnancy rates of 31% per recruit; stimulation was shorter on nafarelin and oestradiol higher on the day of hCG.
Dosing Data
Synarel is sprayed into the nose; children with precocious puberty use a much higher daily dose than adults.
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Side Effects & Contraindications
Reported Side Effects
From the Synarel prescribing information (DailyMed set d0aa57cb, version 23, effective March 5, 2026) and the trials.
Contraindications & Cautions
From the label.
Legal Status
Approved in the US since 1990.
Frequently Asked Questions
?Why a nasal spray?
Nafarelin is a peptide, so it cannot survive the gut. Under 3% of a nasal dose is absorbed, but the molecule is potent enough for that to suppress the pituitary.
?Can a course be repeated?
The label does not recommend retreatment, because safety data beyond six months are lacking, and asks for a bone density check first if it is considered.
?How does it compare with leuprolide?
Both are GnRH agonists with the same flare and low-estrogen effects; leuprolide is an injected depot, nafarelin a twice-daily spray.
?What dose is used in children?
1,600 µg a day as two sprays in each nostril morning and evening, increased to 1,800 µg if needed (label).
?How does it compare with danazol?
Equally effective for endometriosis in head-to-head trials, with more hot flushes but less weight gain and smaller liver-enzyme rises.
?Does it interact with other drugs?
No pharmacokinetic interaction studies were done; the label says interactions are not expected because peptidases, not liver enzymes, break it down.
References
- [fda-pi] Synarel (nafarelin acetate) nasal solution US prescribing information (DailyMed version 23, effective March 5, 2026); read October 1, 2026.
- [pubmed] Henzl MR, et al. "Administration of nasal nafarelin as compared with oral danazol for endometriosis. A multicenter double-blind comparative clinical trial." N Engl J Med, 1988;318(8):485-9. PMID: 2963213.
- [pubmed] "Nafarelin for endometriosis: a large-scale, danazol-controlled trial of efficacy and safety, with 1-year follow-up. The Nafarelin European Endometriosis Trial Group (NEET)." Fertil Steril, 1992;57(3):514-22. PMID: 1531464.
- [pubmed] Zhao SZ, et al. "Impact of nafarelin and leuprolide for endometriosis on quality of life and subjective clinical measures." J Reprod Med, 1999;44(12):1000-6. PMID: 10649809.
- [pubmed] Eldred JM, et al. "A randomized double blind placebo controlled trial of the effects on bone metabolism of the combination of nafarelin acetate and norethisterone." Clin Endocrinol (Oxf), 1992;37(4):354-9. PMID: 1483292.
- [pubmed] Chaplin MD. "Bioavailability of nafarelin in healthy volunteers." Am J Obstet Gynecol, 1992;166(2):762-5. PMID: 1531580.
- [pubmed] Taga M, et al. "Reduction of bone mineral density by gonadotropin-releasing hormone agonist, nafarelin, is not completely reversible at 6 months after the cessation of administration." Acta Obstet Gynecol Scand, 1996;75(2):162-5. PMID: 8604604.
- [pubmed] Hornstein MD, et al. "Retreatment with nafarelin for recurrent endometriosis symptoms: efficacy, safety, and bone mineral density." Fertil Steril, 1997;67(6):1013-8. PMID: 9176437.
- [pubmed] Wong JM, et al. "Efficacy of nafarelin in assisted reproductive technology: a meta-analysis." Hum Reprod Update, 2001;7(1):92-101. PMID: 11212082.
- [pubmed] Lin TH, et al. "Intranasal nafarelin: an LH-RH analogue treatment of gonadotropin-dependent precocious puberty." J Pediatr, 1986;109(6):954-8. PMID: 2946840.
- [pubmed] Lockwood GM, et al. "A prospective randomized single-blind comparative trial of nafarelin acetate with buserelin in long-protocol gonadotrophin-releasing hormone analogue controlled in-vitro fertilization cycles." Hum Reprod, 1995;10(2):293-8. PMID: 7769051.
Sources & Citations
Studies were read from their PubMed records (October 6, 2026); the label and Drugs@FDA are listed below with their read dates.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.