Korva is a scroll of the internet’s best ideas.
Lower cholesterol, more heart attacks
The Clomid finding
That obscure episode resurfaced decades later at a longevity clinic that measures the sterols in patients' blood. Patients given the fertility drug Clomid showed an almost universal rise in desmosterol, the molecule just before cholesterol in one of the body's two cholesterol-making pathways.
The likeliest explanation, though the trial literature doesn't seem to describe it, is that Clomid inhibits the enzyme, thought to be delta-24 desaturase, that turns desmosterol into cholesterol. A lipids expert pointed out that the 1960s drug attacked the same enzyme.
The earlier drug
That drug was approved because it lowered cholesterol, which was enough at the time. Today a drug has to show it prevents heart attacks and death. By the late 1960s the cholesterol was coming down while events were going up.
The open question
Nobody knows why. The working suspicion is that desmosterol, which is still a sterol, damaged the lining of the arteries more than cholesterol does and created more oxidative stress beneath it. A very high desmosterol level may therefore be a bad thing.
How does the body make cholesterol?
Cells build cholesterol from acetyl-CoA through a long chain of enzymatic steps that passes through a molecule called lanosterol. After lanosterol, the route splits into two branches: the Bloch pathway, which runs through desmosterol, and the Kandutsch-Russell pathway, which runs through 7-dehydrocholesterol. Konrad Bloch shared the 1964 Nobel Prize in Physiology or Medicine for work on how cholesterol is made. Different tissues lean on different branches.
Why do cholesterol drugs need outcome trials?
A lowered lab number does not guarantee a lower risk of disease. The ILLUMINATE trial, published in the New England Journal of Medicine in 2007, tested torcetrapib, which raised HDL cholesterol substantially, and was stopped early because of an excess of deaths and cardiovascular events. The CAST trial, published in the same journal in 1989, found that drugs that suppressed abnormal heart rhythms after heart attacks increased mortality.
How does a fertility drug affect sterols?
Clomiphene is a selective estrogen receptor modulator, a molecule that blocks estrogen receptors in the brain and so raises the signals that trigger ovulation. It belongs to a chemical family called triphenylethylenes, which also includes tamoxifen. Research by Bénédicte Kedjouar and colleagues in 2004 found that the tamoxifen binding site on cells is a complex of two enzymes from the late steps of cholesterol synthesis.
More from Andrew Huberman
