Chapter 15 Exercises: Growth Hormone Secretagogues

These exercises are written to be worked, not skimmed. Several have no clean answer, which is deliberate — the skill this chapter teaches is holding a distinction under pressure, not retrieving a fact.

† marks a harder item. These require you to reason across chapters, sit with genuine uncertainty, or argue a position you may not hold. There are roughly ten of them. Do not skip them all.

No answers are provided here. Worked solutions live in the instructor materials; several items are deliberately open.

Section A — The axis, and what you can measure

15.1 Draw the GH axis from memory. Label the hypothalamic accelerator, the hypothalamic brake, the gland, the downstream messenger, and the feedback arrow. Then mark, with a star, every point at which a compound in this chapter acts.

15.2 A person has a single morning blood draw showing growth hormone near the lower limit of detection. Write three sentences: one stating what this might mean, one stating what else it might equally mean, and one stating what you would measure instead and why.

15.3 Explain in your own words why IGF-1 is a more usable measurement than growth hormone, using the word pulsatile exactly once.

15.4 Name the two receptors through which every compound in this chapter acts, and assign each of the following to one of them: sermorelin, GHRP-6, tesamorelin, MK-677, ipamorelin, CJC-1295.

15.5 † IGF-1 is simultaneously the best readout of whether a secretagogue is working and the signal that tells the axis to stop. Write a short paragraph explaining why that dual role makes interpreting a rising IGF-1 over many months harder than interpreting a rising IGF-1 over four weeks.

15.6 Somatostatin is described in this chapter as a brake. Give one consequence of the brake's existence for someone attempting to raise growth hormone with a secretagogue, and one consequence for someone attempting to interpret a trial of one.

Section B — The compounds, precisely

15.7 State, for each of the following, whether it is a peptide: sermorelin, ipamorelin, MK-677, tesamorelin, GHRP-6. For the one that is not, explain what it is and why the distinction changes what you should expect.

15.8 What does DAC do, chemically and pharmacokinetically? Answer in three sentences without using the phrase "half-life."

15.9 † The name "CJC-1295" is applied in the consumer market to two different molecules. Describe both, state how they differ in duration, and then explain the specific reason this makes informal reports about the compound unusable — not merely weak, but unusable for the purpose of aggregation.

15.10 Ipamorelin is described as more selective than GHRP-6. Selective for what, and against what? Be specific about the three activities selectivity was aiming to reduce.

15.11 Sermorelin has a generic name and a regulatory history; CJC-1295 has neither. Using Chapter 1 §1.8, state exactly what that difference is evidence about. Then state, in one sentence, what it is not evidence about.

15.12 † GHRP-2 has been assigned a generic name and, where it appears in formal medical use at all, has appeared as a diagnostic agent. Construct the strongest argument someone could make that this supports the compound's popular claims. Then dismantle it.

15.13 Explain why a growth hormone secretagogue cannot treat a patient whose pituitary has been surgically removed, and what this tells you about the general class of "stimulate rather than replace" strategies.

Section C — Pulsatile versus tonic

15.14 State the pulsatility argument for secretagogues in four bullet points, as strongly and sympathetically as you can. Do not include any counter-argument.

15.15 Now give the three counter-arguments from §15.6, in one sentence each.

15.16 † "Preserving the feedback loop" is offered as a safety feature. Write a paragraph arguing that it is one, and a paragraph arguing that it is not. Then state which paragraph you find more persuasive and identify the specific fact that decided it for you.

15.17 Explain, in terms a non-scientist would follow, why an extended-duration GHRH analog is a different signal to the pituitary rather than a longer-lasting natural one.

15.18 † Chapter 3 §3.5 established that GnRH given in pulses stimulates the reproductive axis while GnRH given continuously suppresses it, and that the second is the mechanism of an approved cancer drug class. Write the two-sentence version of what this does establish about extended-duration GHRH analogs, and the two-sentence version of what it does not. Be strict with yourself on the second part.

15.19 Give two independent mechanisms by which a secretagogue's effect might diminish over months of continued use. State, for each, whether it has been measured for the compounds in this chapter.

Section D — Surrogate and outcome

15.20 Define surrogate endpoint in one sentence, then give two examples from outside this chapter.

15.21 Reproduce the seven-step diagram from §15.7 from memory, and mark the line separating surrogate from outcome.

15.22 For each of the following statements, say whether it is a mechanism claim or an outcome claim: (a) "It raises IGF-1." (b) "It improves recovery." (c) "It binds GHS-R." (d) "It reduced visceral adipose tissue by roughly 15 percent." (e) "It restores your hormones to youthful levels." (f) "Participants were no stronger at two years."

15.23 † The two-year MK-677 trial described in Figure 15.1 succeeded at Steps 1 through 5 and failed at Step 6. Write a short essay — 300 words is plenty — on why that pattern is more informative than either a clean success or a clean failure would have been.

15.24 Give two distinct explanations for a one-kilogram increase in measured fat-free mass following GH axis stimulation. State which of the two would satisfy someone hoping to be stronger.

15.25 † "The outcome may be limited by something else entirely" is listed as one reason the surrogate-to-outcome arrow fails. Apply this specifically: name three plausible rate-limiting factors for recovery from resistance training, and explain what raising growth hormone does about each.

Section E — Ratings

15.26 Write out the four ratings from this chapter, verbatim, including the population and the endpoint in each.

15.27 For each of the four, state in one sentence what would change it.

15.28 Tesamorelin holds a ✅ and sermorelin holds a ❌, and both are GHRH analogs acting at the same receptor. Explain the difference without using the words "better" or "worse."

15.29 † The CJC-1295 plus ipamorelin rating is written as ⚠️→❌ rather than as a single symbol. Argue that this is the correct treatment. Then argue that it is a cop-out. Then decide.

15.30 MK-677 receives ⚠️ despite being unapproved, non-peptide, and heavily marketed with claims its own trial data contradicts. Which rating rule is doing the work here, and what would it look like if that rule were ignored?

15.31 † Rule 3 says never upgrade with mechanism. Every compound in this chapter has a good mechanism. Write the paragraph a sympathetic advocate would write arguing that mechanism should count for something here — make it as strong as you can — and then identify precisely where it goes wrong.

Section F — In the wild

15.32 A clinic's website states: "Our peptide protocol restores growth hormone to youthful levels, verified by laboratory testing, without the risks of synthetic HGH." Identify every claim in that sentence. For each, state whether it is supported, unsupported, or unfalsifiable as written.

15.33 † Someone you care about has been using a secretagogue for six months and reports feeling better. You have read this chapter. Write what you would actually say to them — not what a debunking article would say. Then note which sentences in your draft would make them stop listening, and revise.

15.34 † Draft the trial you would want to see run on CJC-1295 plus ipamorelin. Specify the population, the duration, the primary endpoint, the comparator, and one pre-specified analysis that would distinguish a real functional benefit from fluid retention. Then estimate what would make such a trial unlikely ever to be funded.

Section G — Dossier

15.35 Complete Field 3 (indirect form) for one secretagogue of your choice, following the worked demonstration in the chapter. Do not skip the opposing forces line.

15.36 For every entry currently in your dossier, mark whether its mechanism is direct or indirect. For the indirect ones, write the evidence stops at line. Then rank all of your entries by how far their evidence runs, and note whether that ranking matches the order of your confidence in them.