Nafarelin

Synarel, Synarela, nafarelin acetate, RS-94991; [D-Nal(2)6]-GnRH

Sexual health, hormones & signalling

Awaiting medical reviewEN ES DE FR PT ZH+ Follow for updates

Note on this profile. Nafarelin is an approved prescription medicine (a nasal spray) in most countries, not a research-only compound. This page explains the published science. Use outside a prescription carries the risks of prolonged hormone suppression discussed below.

Summary

Class: Synthetic GnRH (LHRH) agonist decapeptide with D-naphthylalanine at position 6
Mechanism: After a brief stimulation, desensitises pituitary GnRH receptors and suppresses LH/FSH, taking oestrogen (or testosterone) to post-menopausal/prepubertal levels
Routes studied: Intranasal spray (approved); subcutaneous in early pharmacology
Dose range reported: Approved: endometriosis — 400 µg/day (one 200 µg spray in one nostril in the morning, one in the other nostril in the evening), may be increased to 800 µg/day, maximum 6 months; central precocious puberty — 1,600 µg/day (two sprays in each nostril morning and evening), may be increased to 1,800 µg/day; IVF pituitary down-regulation (UK/EU licence) — 400 µg twice daily. Community use: rare
Half-life: ~3 h; intranasal bioavailability ~3% (range ~1–6%)
Storage: Room temperature, upright, protect from light; each 8 mL bottle delivers about 60 sprays (one month at 400 µg/day)
Regulatory status: Approved medicine (US 1990, EU, UK, AU and others)

Doses are as reported in studies or by the community — never recommendations.

1What it is

Nafarelin is a GnRH like leuprolide and triptorelin, but given as a nasal spray rather than an injection. The unusual amino acid at position 6 (a naphthylalanine) makes it about 200 times more potent than natural GnRH, which is what allows a nasal route with only ~3% absorption to work. It was developed by Syntex and approved in 1990 for endometriosis, then for central precocious puberty, and in several countries for suppressing the pituitary before IVF. Twice-daily dosing is needed because of the short , and the "flare" and suppression pattern is the same as for injectable agonists.

2How it's thought to work

Days 1–14: LH, FSH and oestradiol rise (flare), which can transiently worsen endometriosis symptoms or cause a withdrawal bleed.

From roughly week 3–4: receptors are desensitised, gonadotrophins fall and oestradiol drops to post-menopausal levels (typically <30 pg/mL), creating a reversible "medical menopause" that starves oestrogen-dependent endometriosis tissue.

In children with CPP the same mechanism halts pubertal progression and slows bone-age advancement.

Everything reverses within 4–8 weeks of stopping, with ovulation usually returning within two months.

A GnRH agonist delivered nasally. Continuous receptor stimulation first provokes a flare of LH and sex hormones, then downregulates the pituitary and suppresses the ovary or testis.Schematic — not to scale

3What the research shows

Endometriosis

In a randomised double-blind trial of 213 women, nafarelin 400 or 800 µg/day for six months matched oral danazol for reducing laparoscopic disease scores and pain, with fewer androgenic side effects (weight gain, acne, oily skin) but more hot flushes (Henzl 1988, NEJM). Three months of treatment relieved pain as well as six in a randomised comparison, with less bone loss (Hornstein 1995, Fertil Steril). Pain recurrence after stopping is common (roughly half within 5 years, class data). [1][2]

Central precocious puberty

Open-label studies underpinning approval showed suppression of LH, FSH and sex steroids to prepubertal levels and slowing of bone-age advancement; most children required the 1,600 µg/day dose and some 1,800 µg/day. Compliance with eight daily sprays is a recognised limitation versus depot injections.

Graded A (class)

IVF pituitary down-regulation

Nafarelin 400 µg twice daily is a licensed long-protocol option in the UK and Europe. Comparative trials against buserelin and leuprolide show similar pregnancy rates (class evidence; see Al-Inany 2016, Cochrane, for agonist-versus-antagonist comparisons). [4]

Uterine fibroids, hirsutism/PCOS, premenstrual syndrome

Small studies in the late 1980s and 1990s; not licensed for these uses.

Pharmacology

Chrisp & Goa (1990, Drugs) review the dose–response, nasal absorption and tolerability data. [3]

4Reported side effects and interactions

Literature-reported

Common (literature; endometriosis dosing). hot flushes (~90%), decreased libido (~22%), vaginal dryness (~19%), headache (~19%), emotional lability (~15%), acne (~13%, mostly early), myalgia (~10%), reduced breast size (~10%), nasal irritation (~10%), insomnia, oedema, weight change. In CPP: acne, transient vaginal bleeding or breast enlargement during the flare, hot flushes, body odour, seborrhoea.

Serious / warnings. ovarian cyst enlargement during the first two months (rarely requiring intervention); pituitary apoplexy (rare, class); hypersensitivity (chest pain, dyspnoea, rash, pruritus — rare); pseudotumour cerebri/idiopathic intracranial hypertension reported with the GnRH class in children (label update 2022); depression and mood change. Contraindicated in pregnancy, breastfeeding, undiagnosed abnormal vaginal bleeding.

Community-reported

minimal; occasional patient reports of persistent nasal irritation and that rhinitis makes dosing awkward.

Bone. label reports average losses of about 8.7% in vertebral trabecular bone density and 4.3% in total vertebral bone mass after six months (quantitative CT), with partial recovery by six months after stopping; retreatment is not recommended for this reason.

Interactions. nasal decongestant sprays should be used at least two hours after nafarelin, since they can reduce absorption; rhinitis itself does not meaningfully change absorption. Hormonal contraception interferes with efficacy assessment and should not be relied on concurrently (a barrier method is advised). No CYP interactions expected.

Markers researchers commonly monitor

Per label and gynaecological/paediatric practice:

Marker	Why it's watched
Oestradiol	confirms suppression (<30–40 pg/mL) after the first month; a persistently higher level suggests poor nasal absorption or compliance.
LH and FSH	fall after the flare; in CPP, a GnRH-stimulated LH test confirms suppression.
Bone mineral density (DEXA)	before treatment if risk factors exist and after six months; the main cost of therapy.
Pregnancy test	before starting; nafarelin is contraindicated in pregnancy.
Pelvic ultrasound	baseline and if pain increases in the first two months (ovarian cysts).
Height velocity, bone age, Tanner staging (children)	the CPP outcomes.
Mood screening	emotional lability and depression are common enough to track.

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Supplied as a metered nasal spray (2 mg/mL, 200 µg per actuation) that requires priming before first use. Doses are counted in sprays, not volumes, and alternating nostrils is part of the label instruction. The calculator is not applicable.

Open in calculator, pre-loaded →

6Commonly studied alongside

Leuprolide and triptorelin (injectable agonists, this batch), danazol (historical comparator, not a peptide), norethisterone or tibolone "add-back" (bone protection), cetrorelix and ganirelix (antagonist alternatives in IVF).

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	FDA-approved (Synarel) for endometriosis and central precocious puberty; IVF use off-label
European Union	Authorised nationally (Synarel, Synarela) for endometriosis and in several countries for pituitary desensitisation before IVF; CPP in some markets
United Kingdom	MHRA-licensed (Synarel) for endometriosis and controlled ovarian stimulation programmes; prescription-only
Australia	TGA-approved (Synarel); S4
South Africa	Registration status †
Sport	WADA S2: GnRH and its analogues, including nafarelin, are prohibited in males

8Open questions

Whether add-back therapy allows safe courses beyond six months with nasal as it does with depot leuprolide.
Long-term bone outcomes after repeated courses.
Adherence-adjusted efficacy in CPP versus depot injections.

9References

1Henzl MR et al. (1988). Administration of nasal nafarelin as compared with oral danazol for endometriosis: a multicenter double-blind comparative clinical trial. N Engl J Med. PubMed · DOI
2Hornstein MD et al. (1995). Prospective randomized double-blind trial of 3 versus 6 months of nafarelin therapy for endometriosis associated pelvic pain. Fertil Steril. PubMed
3Chrisp P, Goa KL (1990). Nafarelin: a review of its pharmacodynamic and pharmacokinetic properties, and clinical potential in sex hormone-related conditions. Drugs. PubMed · DOI
4Al-Inany HG et al. (2016). Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev. PubMed · DOI
5Synarel prescribing information (US label) and SmPC (UK), current versions. PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

10Community

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Self-reported side effects Phase 2

Not enough data yet. 0 of the 50 members needed have logged this compound for 4+ weeks. We don't show anything below 50, so no one can be identified.

11Page history

26 Oct 2026Profile published — awaiting medical review

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