Gonadorelin

Origin and structure

GnRH was identified in 1971 by Andrew Schally's group, who isolated it from pig hypothalami, showed that a single small peptide releases both LH and FSH from the pituitary, and made it synthetically. Roger Guillemin's group found the same sequence in sheep, and the two later shared a Nobel Prize for their work on the peptide hormones of the brain. The hormone is also called LHRH or LH-RH, for luteinising hormone-releasing hormone.

Gonadorelin is the name of the synthetic hormone. It is a decapeptide, pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2, with a molar mass of about 1,182 g/mol, and its sequence is the same as that of human GnRH. The same decapeptide occurs in pigs and cattle, which is why one molecule serves both human and veterinary medicine. Medicines contain it as a salt: Lutrelef and Lutrepulse as gonadorelin acetate, Factrel as the hydrochloride.

Gonadorelin is not a GnRH analogue. Triptorelin, leuprorelin and buserelin are modified versions of the molecule that resist breakdown and act for far longer; given continuously, they switch the reproductive axis off, which is how they are used in prostate cancer and early puberty. Gonadorelin itself is cleared within minutes.

How it works

GnRH is made by a small group of nerve cells in the hypothalamus and released in bursts into the blood vessels that run to the pituitary. There it binds the GnRH receptor on the gonadotrope cells, which respond mainly with LH and, to a lesser degree, FSH. In women these two hormones drive the maturation of follicles and ovulation; in men they drive testosterone production and the making of sperm. Because gonadorelin works one level above the ovaries and testes, the body's own feedback from those glands stays in play.

The rhythm is the message. In a 1978 study in rhesus monkeys with hypothalamic lesions that had stopped their pituitary releasing LH and FSH, Ernst Knobil's group found that a steady infusion of GnRH failed to restore sustained secretion, while one pulse an hour, the monkeys' natural frequency, restored it; in animals whose secretion had been restored by pulses, starting a steady infusion could shut it down again. The licensed products therefore use a small pump that delivers one pulse every 90 to 120 minutes, and the long-acting agonists suppress the axis precisely because they act continuously.

Gonadorelin disappears from the blood within minutes. The Lutrepulse monograph gives an initial half-life of 2 to 10 minutes and a terminal half-life of 10 to 40 minutes; the Dutch product information gives 3 and 20 minutes. It is broken down in the blood, the lungs and above all the kidneys into inactive fragments, and about 74% of a dose leaves in the urine within 24 hours, mostly as pyroglutamylhistidine. Kidney failure prolongs the half-life.

Is gonadorelin approved?

Yes, in the Netherlands, as a prescription medicine for a small group of patients who make too little GnRH. There is no EU-wide authorisation through the EMA; gonadorelin products are approved country by country. In the US the human products have been discontinued.

The Dutch product, Lutrelef 3.2 mg from Ferring in Hoofddorp, is registered for women whose infertility comes from hypothalamic amenorrhoea and absent ovulation that did not respond to anti-oestrogens, and for men with infertility or delayed puberty from hypogonadotrophic hypogonadism of hypothalamic origin. It is given under the skin by the LutrePulse pump system: a small pod is filled with the solution and replaced every three days. The label does not cover use alongside testosterone therapy; for men it advises a testosterone product once the pump treatment has done its job, to keep the virilisation.

As a diagnostic, a single dose into a vein shows how the pituitary responds, for instance to tell central precocious puberty, driven by the brain, from pseudo-precocious puberty; the Dutch children's formulary lists it for that purpose, which is not among the indications on the Lutrelef label. Research-grade gonadorelin, sold in vials for laboratory use, has no marketing authorisation and may not be used in people.

• Netherlands, human: Lutrelef 3.2 mg (gonadorelin diacetate), RVG 10919, registered on 21 May 1986, prescription only.
• Netherlands, veterinary: Fertagyl 0.1 mg/ml (REG NL 1253, first authorised on 8 September 1992), on veterinary prescription, for cows with cystic ovaries and to raise the number of litters a year in rabbits.
• US, human: Factrel (gonadorelin hydrochloride), a test of pituitary function, was approved on 30 September 1982, and Lutrepulse (gonadorelin acetate for pump use, designated an orphan drug) on 10 October 1989. Drugs@FDA lists both as discontinued, so no FDA-approved gonadorelin product for people is on the market.
• US, compounding: FDA's list of bulk substances nominated for outsourcing facilities (section 503B, updated March 2025) keeps gonadorelin acetate in category 1, under evaluation, and marks it as a component of an FDA-approved drug. Compounded gonadorelin is itself not an approved product, and no approved product was ever labelled for use alongside testosterone therapy.
• US, veterinary: Factrel, Cystorelin, Fertagyl, OvaCyst and Gonabreed are approved injections for cattle, to treat ovarian follicular cysts and, with a prostaglandin, to synchronise cycles for fixed-time insemination. Their labels state that they are not for human use.
• Sport: the WADA Prohibited List names gonadotrophin-releasing hormone (GnRH, gonadorelin) and its agonist analogues in class S2.2.1, testosterone-stimulating peptides prohibited in males at all times; WADA's summary of changes for the 2027 list, in force from 1 January 2027, names no change to this class. In the Netherlands the Dopingautoriteit applies the same list.

What the research shows

Gonadorelin has been studied for half a century, but mostly in small open studies of people with a specific hormone deficiency. There are few randomised trials, and none of gonadorelin as an add-on to testosterone therapy. The main findings:

• Women with hypothalamic amenorrhoea (the US pivotal studies, reported in the Lutrepulse monograph): four open, non-randomised studies of 268 women, most treated through a vein by pump. 94% of women with primary hypothalamic amenorrhoea (45 of 48) and 96% of women with secondary hypothalamic amenorrhoea (94 of 98) ovulated, and 58% of the women with primary amenorrhoea who wanted a pregnancy (25 of 43) became pregnant.
• Placebo-controlled trial (NCT01976728, Ferring, 2014 to 2018): 39 women with primary amenorrhoea from hypogonadotrophic hypogonadism were randomised to 10, 15 or 20 micrograms per pulse under the skin from a pump, or placebo. On 15 or 20 micrograms, 9 of 18 women ovulated against 0 of 10 on placebo (p = 0.012), and 7 of 19 had a clinical pregnancy against none on placebo (p = 0.038); on 10 micrograms, 1 of 9 ovulated. No serious adverse events were reported in any group.
• Men with congenital GnRH deficiency (Wei et al. 2021): a meta-analysis of seven comparative studies with 420 men found that pump-delivered GnRH started sperm production 5.3 months earlier than gonadotrophin injections and gave larger testes, but made no significant difference to the share of men with sperm, sperm concentration or the pregnancy rate. Allergic reactions occurred mostly with GnRH, breast enlargement and acne more often with gonadotrophins. The authors called for good randomised trials.
• Alongside testosterone therapy: no randomised or otherwise controlled trial of gonadorelin given with testosterone appears in the literature or on ClinicalTrials.gov (searched October 2026). The fertility trials above used pump pulses every 90 to 120 minutes in people not on testosterone; the one to three injections a day used by clinics have not been tested.

Gonadorelin, hCG and the long-acting agonists

Three kinds of medicine act on the same hormone axis at different levels, and they are easily confused. hCG works one level down: it binds the LH receptor in the testes or ovaries directly, so it works even when the pituitary is damaged, and it lasts much longer in the body. Gonadorelin works on the pituitary, so it only helps if the pituitary still responds, and it releases both LH and FSH under the body's own feedback. The Lutrepulse monograph credits that preserved feedback for the low rate of ovarian hyperstimulation in its studies: one moderate case among 268 women, in a cycle that also included clomiphene. Multiple pregnancies were not rare, though: 11 of 89 pregnancies with a known outcome (12%).

The long-acting agonists, such as triptorelin and leuprorelin, sit at the same receptor as gonadorelin but do the opposite in practice. After a brief surge they keep the receptor occupied, the pituitary stops responding, and LH, FSH and the sex hormones fall. That is the use they are licensed for. Gonadorelin does the same only if it is given continuously instead of in pulses, which is why the Dutch label warns that continuous, non-pulsatile exposure can temporarily reduce the pituitary's response.

Kisspeptin works one level higher still, on the nerve cells that make GnRH; it has its own article on this wiki.

Frequently asked questions

Is gonadorelin the same as GnRH?

Yes. Gonadorelin is the name for synthetic GnRH, also called LHRH, and its ten amino acids are the same as those of the natural human hormone. It is not an analogue: triptorelin, leuprorelin and the other GnRH agonists are modified molecules that last much longer and are used to switch the axis off, whereas gonadorelin is cleared within minutes and stimulates the axis when given in pulses.

Is gonadorelin legal in the Netherlands?

As a medicine, yes, but only on prescription: Lutrelef 3.2 mg (RVG 10919) has been registered since 1986 for infertility and delayed puberty caused by too little GnRH, given with a pump. For cattle and rabbits, Fertagyl is registered as a veterinary medicine on prescription. Research-grade gonadorelin is not a medicine and may not be used in people.

Is gonadorelin banned in sport?

For men, yes, at all times. The WADA Prohibited List names gonadotrophin-releasing hormone (GnRH, gonadorelin) and its agonist analogues in class S2.2.1, testosterone-stimulating peptides prohibited in males, and WADA announced no change to this class for the 2027 list, which takes effect on 1 January 2027. The class does not cover women. In the Netherlands the Dopingautoriteit applies the same list.

Can gonadorelin replace hCG during testosterone therapy?

That has not been tested. No controlled trial of gonadorelin alongside testosterone has been published. The studies in which it restored testosterone and sperm production were in people with congenital or hypothalamic GnRH deficiency being treated for fertility, not on testosterone, and they used a pump giving a pulse every 90 to 120 minutes rather than one to three injections a day. hCG acts directly on the testes; gonadorelin acts on the pituitary and only works if the pituitary still responds.

Why does gonadorelin have to be given in pulses?

Because the pituitary reads the rhythm, not just the amount. In the 1978 monkey experiments that showed this, one pulse an hour restored LH and FSH release while a steady infusion of the same hormone did not, and switching from pulses to a steady infusion could shut release down. The licensed products therefore use a pump that gives a small pulse every 90 to 120 minutes. Continuous exposure is exactly how the long-acting agonists suppress the axis.

What is gonadorelin used for in animals?

Mostly in cattle. In the US, Factrel, Cystorelin, Fertagyl, OvaCyst and Gonabreed are approved to treat ovarian follicular cysts in cows and, together with a prostaglandin, to time ovulation so that cows can be inseminated on a fixed schedule. In the Netherlands Fertagyl is registered for cows with cystic ovaries and for rabbits. These are veterinary medicines, and their labels say they are not for human use.

Storage and handling

Store according to product-label instructions and batch handling notes. Lyophilized research peptides are commonly kept dry, protected from light, and handled with clean laboratory technique.

References

Checked against these sources on 28 October 2026.

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