Leydig Cells & Suppression
TL:DR A simplistic and theoretical look at how SARMs suppress testosterone.
How SARMs decrease testosterone without significantly lowering luteinizing hormone (LH) leads many to draw parallels to AAS cycles, and the low testosterone levels post-cycle. But the two actions are only slightly related, despite the similar outcome.
LH is a glycoprotein produced in pituitary, and stimulates the leydig cells to secrete testosterone, androstenedione and DHEA. LH also increases the conversion of cholesterol to pregnenolone. The leydig cells are found in the testicles in men. Oddly, prolactin increases response of leydig cells to LH which in natty individuals I imagine is pretty important.
Endogenous testosterone (i.e. injected) inhibits LH release via feedback inhibition. Simplistically, this fall in LH reduces natural testosterone production and is why PCT for AAS cycles works and is necessary - SERMs increase LH.
SARMs Impact On Luteinizing Hormone
SARMs have a small impact to LH: an Ostarine trial showed LH decreased between 0.01 to 1 nmol/L while on cycle. Our Meta Analysis Survey (MAS) also backs up this finding, with reductions in LH on SARM only cycles (n=8, thanks to all that posted their bloods!). Yet, in looking at the MAS data, the LH is still within range and should not be lowering testosterone as much as it does. This is perhaps most clearly illustrated by LGD4033 study results in a graph: significant reductions in test at the 1mg dose with only minor reductions in LH.
To explain how SARMs might lower testosterone in addition to the slightly lower LH we’re paradoxically drawing upon a similar action found in an AAS, fluoxymesterone aka halo. Halo, like SARMs, lowers test without significantly impacting LH.
Reduced plasma testosterone levels were seen within 24 h after beginning fluoxymesterone, and further reductions were noted throughout the treatment period. Changes in plasma estrogen levels did not correlate with fluoxymesterone administration. Neither plasma LH nor plasma FSH levels were significantly altered by fluoxymesterone. A short term study utilizing a single dose of fluoxymesterone yielded similar findings. It is proposed that fluoxymesterone has a local effect on the Leydig cell which is not mediated by gonadotropins.
There’s a lot to break down in this paragraph. Firstly, note the lower test levels within 24 hours of starting halo. In fact, it drops off the end of a cliff within a week, declining from an average of ~650ng/dl to ~225ng/dl. This speaks to how rapidly test levels can change when running a PED - when folks complain about being suppressed within a week or two of starting a compound, I’m inclined to believe them. The test levels continued to decline more gradually to <50ng/dl in weeks 10-12.
Second, no changes in estrogen. Third, no significant changes in LH or FSH which ties in to the last and most important conclusion that there is a hypothetical local effect on the leydig cell that is causing the testosterone suppression. The same researcher goes on to explain that circulating levels of androgens would act within the testes to modulate the effective stimulation of the Leydig cell by LH. Despite this work being published in 1977, I’m unable to find anything more recent that offers an alternative explanation or update on this action.
Assuming This Is True, What Can I Do About It?
Given that we know so little about the action, there’s not much we know will work. I’ve speculated before on the role that a SERM may play alongside a SARM, and viagra seems to have an action that impacts leydig cells, but there’s no evidence to suggest the best way to increase testosterone while on a SARM only cycle, short of actually injecting test.
Slight reductions in LH that otherwise remains in normal range does not explain large reductions in testosterone, so it’s likely there’s a second action at work as well, such as the local effect on leydig cells which I put forward here. We don’t understand why most SARMs suppress testosterone in this manner in those commonly used for performance enhancement (LGD4033, Ostarine, RAD140). Understanding the action is not essential (think of anaesthesia - we don’t really know how that works either), but it could help us better prevent or mitigate the effects of low testosterone.