Gonadorelin

Overview

Gonadorelin is synthetic gonadotropin-releasing hormone — GnRH, also called LHRH — the decapeptide released by the hypothalamus to control pituitary secretion of luteinising hormone and follicle-stimulating hormone.

Almost everything else in this library is an analogue: a natural sequence truncated, substituted, capped or conjugated. This is the unmodified hormone, and it is the clearest available demonstration of a principle that recurs throughout these pages — that timing can matter as much as molecule.

We do not stock it. It is documented for that principle.

Chemical identity

• Also known as: GnRH, LHRH, luteinising hormone-releasing hormone
• Sequence: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂
• CAS number: 33515-09-2
• Molecular formula: C₅₅H₇₅N₁₇O₁₃
• Molecular weight: 1182.3 g/mol
• Classification: Hypothalamic releasing hormone, decapeptide

Both termini are protected in the natural molecule rather than by design. The N-terminus is pyroglutamate — a glutamine whose side chain has cyclised onto its own backbone nitrogen, closing off the amino terminus. The C-terminus is amidated. Between them they make the hormone considerably more resistant to exopeptidases than a peptide with free ends, which is a natural solution to the problem that most compounds in this library address with engineering.

At 1,182 g/mol it sits just above the point where a structure diagram stays comfortably readable, so the sequence above serves instead.

The hormone, not an analogue

GnRH was isolated and sequenced in 1971 by Andrew Schally’s group, working with enormous quantities of hypothalamic tissue to obtain milligram amounts of hormone. Schally shared the 1977 Nobel Prize in Physiology or Medicine for that work, alongside Roger Guillemin, whose group characterised the hypothalamic hormones covered on the GHRH pages in this library.

The two lines of work are companion pieces from the same era, establishing that the hypothalamus governs the pituitary through specific, isolatable peptide hormones. Gonadorelin and sermorelin are both those hormones made synthetically — the raw material from which the modified compounds elsewhere in this library were subsequently built.

Pulsatile versus continuous

This is the section that matters, and the finding it describes is one of the more consequential in endocrine pharmacology.

GnRH is normally released in pulses — roughly hourly bursts, with the frequency varying across the reproductive cycle. Those pulses drive LH and FSH secretion, and through them the gonadal hormones.

In 1978 Belchetz and colleagues asked what happens if the same total amount of GnRH is delivered continuously rather than in pulses. The answer was not “the same, but smoother”. Continuous delivery suppressed gonadotropin release. The receptors desensitised and downregulated, and the axis shut down.

The direction of the effect reverses depending on the delivery pattern. The same molecule at the same dose either stimulates the reproductive axis or switches it off, according to timing alone.

That finding is the entire basis of the GnRH agonist drug class. Compounds such as leuprolide are agonists — they activate the receptor — yet are used to suppress sex hormone production in prostate cancer, endometriosis and precocious puberty. They work by being long-acting enough to provide the continuous stimulation that desensitises the system. A drug that shuts down a pathway by activating it constantly is counterintuitive until you know this result.

It also generalises. The GHRH analogues in this library differ mainly in duration, and the question of whether pulsatile and continuous stimulation of the growth hormone axis are equivalent is a live one there too. GnRH is the case where the answer is unambiguous and dramatic.

Mechanism of action

Gonadorelin binds the GnRH receptor on pituitary gonadotroph cells, a G-protein coupled receptor signalling through phospholipase C and calcium. Activation triggers synthesis and release of LH and FSH, which act on the gonads.

Its plasma half-life is short — minutes — which is appropriate for a hormone whose function depends on delivering discrete pulses. Persistence would defeat the signalling pattern, as the desensitisation result shows.

Clinical and diagnostic use

Gonadorelin has been used clinically as a diagnostic agent, administered to test whether the pituitary can mount a gonadotropin response — distinguishing hypothalamic from pituitary causes of reproductive dysfunction. It has also been used in pulsatile-delivery devices to reproduce natural secretion patterns in specific conditions.

The synthetic analogues built on it have largely displaced the hormone itself in therapeutic use, precisely because their longer duration produces the suppression that most indications call for.

Handling and storage

• Tryptophan and tyrosine both present, so protect from light — this sequence is more photosensitive than most of its size.
• No methionine or cysteine, so oxidation of those residues and disulphide integrity are not concerns.
• Lyophilised storage: sealed, refrigerated, protected from light; freeze for long-term storage.
• Reconstitution: add diluent slowly down the vial wall and allow to dissolve undisturbed.

Purity and analytical verification

A ten-residue synthesis is routine, so deletion sequences are a modest concern. Two checks are specific to this molecule.

Pyroglutamate formation. The N-terminal residue must cyclise, and cyclisation releases ammonia — so a peptide whose first residue remained an uncyclised glutamine is 17 Da heavier than the correct molecule. On 1,182 g/mol that is comfortably resolvable, and it matters: an open N-terminus is exposed to aminopeptidases that the cyclised form is protected from, so incompletely cyclised material would be markedly less stable.

Tryptophan oxidation adds 16 Da per event and appears as a distinct species, reporting on storage conditions as well as identity.

Both are mass-detectable, which puts gonadorelin among the more straightforward compounds here to verify — a mass figure consistent with 1,182 addresses both questions at once.

References

• Schally AV, Arimura A, Baba Y, et al. Isolation and properties of the FSH and LH-releasing hormone. Biochemical and Biophysical Research Communications, 1971. PMID 4930860
• Matsuo H, Baba Y, Nair RM, et al. Structure of the porcine LH- and FSH-releasing hormone: the proposed amino acid sequence. Biochemical and Biophysical Research Communications, 1971. PMID 4936338
• Belchetz PE, Plant TM, Nakai Y, et al. Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin-releasing hormone. Science, 1978. PMID 100883

Summary

Gonadorelin is synthetic gonadotropin-releasing hormone, pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂, CAS 33515-09-2, molecular formula C₅₅H₇₅N₁₇O₁₃, molecular weight 1,182.3 g/mol — the natural decapeptide rather than an analogue of it, with both termini naturally protected by pyroglutamate and amidation. It stimulates pituitary LH and FSH release when delivered in pulses and suppresses it when delivered continuously, a reversal demonstrated in 1978 that underpins the entire GnRH agonist drug class. It is the clearest illustration in this library that a compound’s effect can depend on the pattern of its delivery as much as on its structure. We do not stock it.

This page is provided for research reference. Compounds described in this library are for laboratory research use only, are not drugs, foods or cosmetics, and may not be used for any purpose other than in vitro or non-human laboratory research.