Chapter 24 — Exercises

How to use these. Work them with the chapter closed. Items marked † are the harder ones — they require you to combine Chapter 24 with material from earlier chapters, to argue a position you may not hold, or to reason about what evidence would be needed rather than what evidence exists. No answers are provided here; several items have more than one defensible response, and the instructor guide is where the discussion notes live.

A standing rule for this chapter's exercises. Several items concern sexual function. Write about it the way the chapter does — clinically, specifically, and without commentary on the people who have these complaints. If an answer you have drafted would embarrass a patient reading over your shoulder, rewrite it.

Part A — The receptor map and the molecule (§24.1–24.2)

a. In one sentence each, state what activation of MC1R and MC4R does, and name the tissue where each receptor principally sits.

b. Proopiomelanocortin gives rise to α-MSH, ACTH, and β-endorphin. Explain what this fact illustrates about the relationship between a gene, a precursor protein, and a hormone.

c. Bremelanotide is a cyclic heptapeptide containing a D-amino acid and a non-standard residue. For each of those three structural features — cyclization, the D-residue, the non-standard residue — state the pharmacological problem it is solving.

d. Bremelanotide and melanotan II differ essentially at one terminus of a seven-residue ring. Explain, using §24.2, why that small difference produces different clinical profiles, and state what this implies for anyone who argues from structural similarity to expected effect.

e. † A colleague says: "α-MSH is a pigmentation hormone that also happens to affect appetite." Rewrite that sentence so that it is correct, and explain in two sentences what the original sentence gets wrong about how peptide signaling works.

f. Setmelanotide (Chapter 13) is an MC4R agonist for rare genetic obesity, and it causes skin hyperpigmentation. Using only the receptor map, explain why. Then argue for or against calling this a "side effect."

g. † Design a hypothetical melanocortin drug that would have appetite effects with minimal pigmentation effects. You do not need chemistry — state what receptor selectivity profile you would need and one reason why achieving it is hard.

h. Bremelanotide weighs roughly 1,025 Da. Using Chapter 1's size spectrum, name two other molecules in a comparable weight range and state what that weight predicts about the available routes of administration.

i. † The chapter says the origin anecdote about a self-administered dose "cannot possibly settle" anything. Restate the general principle behind that judgment in one sentence that does not mention this chapter's subject matter at all.

Part B — Desire and blood flow (§24.3)

j. Draw the two-column table from §24.3 from memory: site of action, molecular target, and what each drug class does. Then check it.

k. Explain in plain language, to someone with no biology background, why a PDE5 inhibitor requires that sexual stimulation already be occurring.

l. A person reports that a PDE5 inhibitor "did nothing." Give three distinct explanations, at most one of which is that the drug is ineffective in general.

m. † The chapter argues that the phrase "the female Viagra" is wrong in three separate ways. Reconstruct all three without looking, then rank them by how much practical harm each error causes and defend your ranking.

n. Inadequate genital blood flow is described in §24.3 as sometimes the first visible sign of vascular disease elsewhere. Explain why this makes a "just prescribe the PDE5 inhibitor" approach potentially harmful in a way that has nothing to do with the drug itself.

o. † Sexual function is described in §24.3 as having at least four partly independent components. For each of the four, propose what kind of intervention would plausibly address it — you are not naming drugs, you are naming categories (vascular, central, hormonal, psychological, mechanical). Then say which component the chapter's peptides address.

p. The chapter says the most common pharmacological contributor to low desire is a medication the person is already taking. Explain why this fact is relevant to evaluating any new desire drug's apparent effect in an uncontrolled setting.

Part C — The approval and the effect size (§24.4)

q. State the bremelanotide indication in full, including every exclusion the chapter lists. Then underline the parts that a headline would omit.

r. The trials used validated instruments for desire and for distress. Give two reasons investigators did not simply count sexual events.

s. The trials did not show an increase in the number of satisfying sexual events. State two different interpretations of that finding — one favorable to the drug, one unfavorable — and say what additional information would help you choose between them.

t. † Explain the concept of a minimal clinically important difference to someone who understands statistical significance but has never encountered the term. Then explain why a drug can clear one bar and not the other.

u. Nausea occurred in a large minority of trial participants. Explain why the practical importance of that rate is different for an as-needed drug than it would be for a daily one.

v. † The chapter writes: "An adverse effect's importance is not captured by its frequency alone; it depends on what the drug is for." Give two examples from outside this chapter — any drug, any condition — where the same principle applies.

w. Write the four-line 📊 Evidence Rating block for the claim "bremelanotide improves desire in premenopausal women with HSDD" from memory. Then compare with §24.4 and note anything you left out of the "what would change it" line.

x. † Construct the strongest possible argument that bremelanotide's rating should be ⚠️ rather than ✅. Then explain which of the six rating rules your argument would be violating, if any — and if it violates none, say what that implies about the rating.

Part D — HSDD and the medicalization argument (§24.4)

y. State the distress criterion and explain, in one sentence, what would be different about the diagnosis if the criterion were removed.

z. † Write the critics' case against HSDD as a diagnostic category in 150 words, as persuasively as you can, whether or not you agree with it.

aa. † Now write the proponents' case in 150 words, equally persuasively. Then state which one you find more convincing and identify the single fact that, if established, would most move you.

ab. The chapter uses insomnia as a parallel condition. Explain the parallel in two sentences, then name one way the parallel breaks down.

ac. † Chapter 12 established that a phenomenon can be framed as disease, as behavior, or as environment. Apply all three frames to distressing low desire, and for each frame state who becomes responsible for the problem and what kind of help follows.

ad. Rule 4 of the rating system says never downgrade with distaste. Explain how that rule applies specifically to a reader who believes HSDD should not be a diagnosis, and what such a reader is still entitled to say.

Part E — Afamelanotide, melanotan II, and kisspeptin (§24.5–24.7)

ae. Describe erythropoietic protoporphyria in three sentences, and then explain in one sentence why conventional ultraviolet-blocking sunscreen is of limited help.

af. Afamelanotide's approved claim is described in the chapter as narrow, and the narrowness is called a strength. Explain why.

ag. † §24.5's 💊 In the Clinic callout gives four reasons the same pharmacology is acceptable in afamelanotide's setting and concerning in melanotan II's. Reconstruct all four and then identify which one would be hardest to fix if someone wanted to make unsupervised cosmetic use safer.

ah. State precisely what the published case reports on melanotan II establish, and precisely what they do not. Use the chapter's own two phrases.

ai. † Chapter 5 §5.2 established that case reports are near-useless for efficacy and genuinely valuable for rare distinctive harms. Explain why — the asymmetry follows from what the two inference problems require, so your answer should be about inference, not about melanotan II.

aj. The melanotan II ❌ is described as "unusual in that it is reinforced by a safety signal rather than resting only on absent efficacy evidence." Explain how this differs in structure from a standard ❌, and state whether it violates rule 2.

ak. † Kisspeptin's receptor loss-of-function mutations cause failure of puberty — as clean a demonstration of physiological necessity as human biology offers. Explain why this supports a 🔬 rating and not a higher one, and connect your answer to rule 3.

al. GnRH must be pulsatile; continuous stimulation suppresses the axis. Name the drug-class consequence of that fact (Chapter 1 §1.8 will help) and state what it implies about the difficulty of developing a kisspeptin-based therapy.

am. † The chapter calls kisspeptin "the honest version of what melanotan II's sellers pretend to have." Unpack that sentence: what do the two have in common, and what is the single feature that separates them?

Part F — Synthesis

an. † Build the §24.8 ratings table from memory — five claims, five ratings — then write one sentence per row explaining why the rating could not have been assigned to the molecule instead of to the claim.

ao. Explain to a friend, in under 100 words, why a ✅ rating does not mean a drug is dramatic. Use bremelanotide as your example and do not use the words "statistically significant."

ap. † Fill Field 7 for a peptide of your own choosing that is not discussed in this chapter. Then write the gap line — the distance between what is approved and how the compound is discussed — and say what you learned from the exercise that you did not expect.