Schally, GnRH and a Nobel Prize from 250,000 pig brains
In 1971 Andrew Schally in New Orleans isolated a single decapeptide from the hypothalami of hundreds of thousands of pig brains: gonadotropin-releasing hormone. Six years later he received the Nobel Prize for it. The substance and its agonists/antagonists became the basis of an entire class of oncological and endocrinological therapies.
A 15-year race for tiny amounts
By the mid-1950s it was clear: the hypothalamus controls the pituitary through chemical messengers — Geoffrey Harris and others had postulated this. But nobody had isolated a single one of these messengers in pure form. Andrew Schally, an endocrinologist born in Wilno who came to the VA Hospital in New Orleans in 1962 after stations in Scotland and Canada, and Roger Guillemin in Houston (later La Jolla) started a fierce competition for this isolation. Both groups collected pig and sheep brains in industrial quantities over years — by his own account, Schally acquired about 250,000 pig hypothalami over the 1960s from pig slaughterhouses in Iowa and the Midwest.
The problem was concentration: a single hypothalamic hormone exists in brain tissue in nanogram amounts per animal. To reach milligram amounts for structural analysis, hundreds of thousands of animals had to be processed. The parallel development of the radioimmunoassay by Rosalyn Yalow and Solomon Berson delivered the decisive tool to make trace concentrations measurable. Without RIA, neither Schally nor Guillemin would have made it through.
TRH first, then GnRH
In 1969 Guillemin and, in parallel, Schally isolated the first hypothalamic hormone: thyrotropin-releasing hormone (TRH), a tiny tripeptide. 1971 followed the second: gonadotropin-releasing hormone (GnRH), a decapeptide with the sequence pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂, controlling the release of luteinising hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary. Both groups published nearly simultaneously; the competition is legendary to this day for the harshness with which academic credit for the respective first publication was contested.
In 1977 the Nobel Prize for Physiology or Medicine was shared: Schally and Guillemin for the hypothalamic hormones, Yalow for the radioimmunoassay. Schally was 51 years old at the time.
From decapeptide to cancer therapy
GnRH was pharmacologically unusual: with pulsatile administration it stimulates LH/FSH release, whereas with continuous administration it leads after initial stimulation to a down-regulation of pituitary GnRH receptors — LH/FSH secretion drops dramatically, and with it testosterone or oestrogen production in the gonads. This 'medical castration' became the basis for treating hormone-sensitive tumours — especially prostate cancer and some breast cancers.
In the 1970s and early 1980s, Schally and his team developed synthetic GnRH agonists with extended duration of action. In 1985 leuprolide (Lupron) was approved in the US — the first clinical GnRH agonist, originally for advanced prostate cancer. Goserelin (Zoladex, 1989), triptorelin (1986 EU approval), buserelin and others followed. These substances revolutionised treatment of hormone-sensitive prostate cancer — instead of surgical castration, hormonal blockade could now be done reversibly and pharmacologically.
„We needed 15 years to isolate what turned out to be a ten-amino-acid peptide. The substance had practically hidden itself — and the clinic was already waiting for a reversible castration."
The iteration: from agonist to antagonist
GnRH agonists have a pharmacological peculiarity: before down-regulation they cause a short initial testosterone surge ('flare effect'), which in advanced prostate cancer can cause bone pain or neurological complications. The second generation — GnRH antagonists — blocks the receptor directly, without initial stimulation. Cetrorelix (1999) and ganirelix (1999) were approved for in-vitro fertilisation; degarelix (Firmagon, 2008) for prostate cancer. In 2020, relugolix became the first oral GnRH antagonist approved for prostate cancer — almost 50 years after Schally's original isolation.
The GnRH family is today among the most prescribed oncological hormonal therapies worldwide. In gynaecology, GnRH analogues are additionally used for endometriosis, uterine fibroids, prepubertal precocious puberty and in reproductive medicine. The annual revenue of the class has been in the high single-digit billions since the 2000s.
What this line scientifically shows
The GnRH story is a teaching case for several phenomena at once. First: a single hypothalamic hormone could found an entire therapy class because its pharmacological peculiarity (down-regulation under continuous administration) offered a clinically usable lever. Second: the competition between two top research groups over 15 years did not slow progress but accelerated it — both Schally and Guillemin isolated hormones that might have been identified only years later without their rivalry. Third: the substance class has continuously evolved since the first approval in 1985 — from injectable agonist via depot implant to oral antagonist — showing a reproducible iteration logic found in many peptide families.
Open questions
- What role did Yalow's radioimmunoassay methodology and the parallel technological development of solid-phase peptide synthesis (Merrifield, Nobel Prize 1984) play in the speed of GnRH development?
- Would a joint Schally-Guillemin project have produced more or less output than the competition configuration?
- Which further hypothalamic peptides are still not in clinical use today, although their structure is known?
- How do economic incentives change when the substance class becomes generic-eligible — and which next generation is already in phase 2/3?