Chapter 3 — Quiz

Twenty-two questions. Write your answers before opening the key.

Multiple choice

1. Hypothalamic releasing hormones reach the pituitary via: a) the general circulation b) a dedicated portal circulation c) direct neural connection d) cerebrospinal fluid

2. Which of these is NOT a peptide? a) GnRH b) ACTH c) cortisol d) growth hormone

3. The GH axis differs from the other three in that it has: a) no hypothalamic control b) an explicit inhibitory hormone as well as a stimulatory one c) no feedback d) a non-peptide final hormone

4. Negative feedback means: a) the hormone has harmful effects b) the system's output inhibits its own production c) the response is delayed d) two hormones oppose each other

5. Supplying a hormone from outside typically causes endogenous production to: a) increase b) stay the same c) decrease d) become pulsatile

6. Growth hormone release is: a) steady throughout the day b) highest at midday c) strongly pulsatile, mostly nocturnal d) triggered only by exercise

7. GnRH delivered continuously to the reproductive axis: a) stimulates it more strongly than pulses b) has no effect c) suppresses it after an initial surge d) converts it to a thyroid axis

8. The pancreatic hormone that opposes insulin is: a) somatostatin b) glucagon c) amylin d) GIP

9. The incretin effect refers to: a) insulin resistance in diabetes b) greater insulin release after oral than intravenous glucose c) the rise in glucose after eating d) glucagon suppression by insulin

10. The two principal human incretins are: a) insulin and glucagon b) GLP-1 and GIP c) ghrelin and leptin d) ANP and BNP

11. Natriuretic peptides are released by cardiac muscle in response to: a) low oxygen b) stretch c) adrenaline d) high potassium

12. GLP-1 receptor agonists rarely cause hypoglycemia when used alone because GLP-1's effect on insulin secretion is: a) weak b) delayed c) glucose-dependent d) confined to the liver

13. Which best explains why GLP-1 drugs do not suppress endogenous GLP-1? a) they are too short-acting b) GLP-1 release is triggered by nutrients, not by circulating GLP-1 levels c) the gut has no receptors d) they are broken down before feedback occurs

14. Somatostatin's role in the GH axis is to: a) stimulate GH release b) inhibit GH release c) convert GH to IGF-1 d) transport GH in blood

15. Which hormone was the first substance ever identified as a hormone, in 1902? a) insulin b) secretin c) adrenaline d) thyroxine

16. Counter-regulation describes: a) a hormone inhibiting its own release b) two opposing signals correcting excursions in either direction c) a drug blocking a receptor d) an axis suppressed by an external hormone

Short answer

17. Explain why measuring a hypothalamic releasing hormone in a blood sample from the arm is nearly meaningless.

18. State the general rule for predicting whether a peptide drug will suppress its endogenous counterpart, and apply it to two examples that come out differently.

19. Explain how continuous delivery of a pulsatile hormone can produce less net signaling than pulses do.

20. Insulin therapy causes hypoglycemia; GLP-1 receptor agonists used alone rarely do. Explain both, in terms of counter-regulation and glucose-dependence.

Applying the rating discipline

21. The natriuretic peptide system supports a strong rating as a biomarker, a failed one as an infused therapy, and a strong one for a drug that blocks its breakdown. Explain what this demonstrates about the difference between rating a molecule and rating a claim.

22. A source states: "Peptide therapy is safer than hormone replacement because it works upstream and preserves your natural feedback loops." Identify what is mechanistically true in this and what is being assumed without evidence. Name which of §2.9's steps the assumption skips.

Answer key **1.** b — a dedicated portal circulation, which delivers high local concentration without systemic exposure. **2.** c — cortisol is a steroid. Note the pattern: the *control layer* of the axes is peptidergic almost throughout, while several final hormones are not. **3.** b — somatostatin inhibits GH release, so the axis has both an accelerator (GHRH) and a brake. **4.** b. **5.** c — decrease. The system measures total hormone and cannot distinguish sources. **6.** c — strongly pulsatile, with the largest bursts during deep sleep. **7.** c — an initial surge followed by profound suppression. This is the basis of the GnRH agonist cancer drugs. **8.** b — glucagon. (Somatostatin inhibits both insulin and glucagon, from delta cells, and amylin is co-secreted with insulin — but the opposing partner is glucagon.) **9.** b — the same blood glucose curve produces substantially more insulin when glucose arrives orally, because gut hormones amplify the pancreatic response. **10.** b — GLP-1 and GIP. **11.** b — stretch, from excess volume or pressure. **12.** c — glucose-dependent. GLP-1 amplifies insulin release when glucose is elevated and does not force insulin out at normal glucose. **13.** b — GLP-1 release is triggered by nutrients arriving in the gut, not by a sensor measuring circulating GLP-1 against a set point. There is no upstream tier detecting the total. **14.** b — inhibit. **15.** b — secretin, in 1902. **16.** b. **17.** Because hypothalamic releasing hormones are released into a short private portal circulation that runs directly to the pituitary. They reach the pituitary at high concentration and are diluted to essentially undetectable levels by the time anything reaches the general circulation. This is a real obstacle to studying these systems, and it is also why a drug mimicking a releasing hormone faces a delivery problem the natural molecule does not. **18.** **Rule:** expect suppression where there is an upstream sensor comparing total circulating hormone against a set point — that is, in a hierarchical axis. Do not assume one exists. **Testosterone:** the HPG axis measures circulating sex steroid and reduces GnRH, LH, and FSH accordingly. Exogenous testosterone suppresses endogenous production, reliably. **GLP-1:** there is no such sensor. GLP-1 release is stimulus-triggered by nutrients in the gut. A GLP-1 agonist therefore does not produce classical axis suppression. **19.** Between pulses, desensitized receptors resensitize and internalized receptors are recycled — the system resets. Continuous stimulation removes that recovery window, so desensitization and downregulation accumulate. The receptor population becomes progressively less responsive, and net signaling can fall well below what an intermittent stimulus produces despite the higher total exposure. **20.** **Insulin:** injected insulin does not go away when glucose falls. The natural system lowers insulin *and* raises glucagon in response to falling glucose; a fixed injected dose only permits the second half of that correction, so glucose can fall past the set point. **GLP-1 agonists:** GLP-1's enhancement of insulin secretion is glucose-dependent — it amplifies a response that is already happening rather than forcing one. At normal glucose there is little to amplify, so hypoglycemia is uncommon when the drug is used alone. **21.** It demonstrates that the evidence attaches to the **claim**, not to the molecule or the system. "Does NT-proBNP indicate cardiac stress?" is answered by diagnostic accuracy studies. "Does infusing synthetic BNP improve outcomes in acute heart failure?" is answered by an outcome trial, and it answered no. "Does blocking natriuretic peptide breakdown improve outcomes in chronic heart failure?" is answered by a different outcome trial, and it answered yes. Three claims, three study designs, three verdicts, one biological system. Any rating that named only the molecule would have to be wrong about at least two of them. **22.** **Mechanistically true:** acting upstream at the hypothalamic tier does leave the axis structurally intact in a way that supplying the final hormone does not, and the suppression dynamics genuinely differ. **Assumed without evidence:** that this translates into being "safer," that feedback does not oppose the intended effect (it does — a rise in GH and IGF-1 raises somatostatin), that the signal pattern produced resembles the physiological one, and that any of it improves an outcome anyone cares about. **The steps skipped are 6 and 7** — whether an outcome a person notices improves, and whether benefit exceeds harm. The claim argues steps 1 through 3 convincingly and asserts 6 and 7 without data.