Negative feedback of hormones

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If negative feedback is a regulatory mechanism in the dihydrotestosterone biosynthetic pathway, elevated levels of androstenedione could diminish the formation of which of the following?

A. Cholesterol
B. 17-α-OH-pregnenolone
Correct Answer

Why wouldn't an increase in androstenedione inhibit the formation of cholesterol instead of pregnenolone? Wouldn't it be more efficient to inhibit the loop from the beginning precursor rather than an intermediary?

6ce8a62df041fa8bdd5caee9320deefd.png

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I think in this case only the end product (DHT) inhibits cholesterol otherwise the pathway would be shut down before reaching the end product if every intermediate limited cholesterol production. Androstenedione may feedback locally because if there is a build up of this compound it would mean that the enzyme that converts it to testosterone is saturated at the moment.
 
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You also have to keep in mind that cholesterol is the precursor to a LOT of other compounds, not only dihydrotestosterone. That would cause problems. The more local the feedback, the more precision is possible
 
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If negative feedback is a regulatory mechanism in the dihydrotestosterone biosynthetic pathway, elevated levels of androstenedione could diminish the formation of which of the following?

A. Cholesterol
B. 17-α-OH-pregnenolone
Correct Answer

Why wouldn't an increase in androstenedione inhibit the formation of cholesterol instead of pregnenolone? Wouldn't it be more efficient to inhibit the loop from the beginning precursor rather than an intermediary?

6ce8a62df041fa8bdd5caee9320deefd.png

The pathway shown here is misleading because cholesterol participates in many pathways for steroid synthesis. After all, cholesterol serves as a precursor for all steroids. Feedback inhibition from dihydrotestosterone may initially decrease levels of cholesterol, but cholesterol levels can increase when levels of other products are decreased, essentially nullifying the negative feedback. For example, if dihydrotestosterone levels are high, cholesterol levels may be a bit lower but if another product like aldosterone or corisol is low, cholesterol levels may increase needed to synthesize these products.

The strength of negative feedback is thus inversely related to number of metabolic steps involved between substrate and product. You want to minimize as many branch points and extra steps as possible. So this means dihydrotestosterone levels will most strongly affect testosterone levels but branch points due to testosterone's other roles can mitigate negative feedback effects. Working backwards, 17-a-OH-pregnenolone will be more strongly affected by dihydrotestosterone negative feedback than cholesterol since there are fewer metabolic steps involved and less room for compensating factors.

Here is a more detailed metabolic pathway for better visualization.

1920px-Steroidogenesis.svg.png
 
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