Nefa Inhibit Steroidogenesis

[Koveras]

Points to supplements such as aspirin, niacinamide, and vitamin E to support hormone production

"The effects of nonesterified fatty acids (NEFA) in modulating testosterone synthesis stimulated by luteinizing hormone (LH, 10 ng/sample) were investigated in isolated adult mouse Leydig cells. LH-stimulated testosterone production was inhibited by triglycerides (0-500 mg/dl, 50 mg/dl, 94% of the control and 500 mg/dl, 40%) and by a mixture of NEFA (100 microM, 70% of control, 200 microM, 54%, and greater than 200 microM, less than 50%). Oleic acid was a more potent inhibitor than linoleic, stearic, or palmitic acids. 8-Bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP, 5 mM) stimulated testosterone production comparable to LH but failed to reverse the inhibition of steroidogenesis produced by the NEFA. The inhibition produced by NEFA was dependent on extracellular Ca2+; and a Ca2+ channel antagonist, verapamil (10 microM), enhanced the inhibition of chylomicrons and fatty acids. 22(R)-hydroxycholesterol (10 microM) reversed the inhibition produced by NEFA. The inhibitory effects of NEFA were reversible by removal of the fatty acids. The results indicate that NEFA are potent modulators of testosterone synthesis in Leydig cells stimulated with either LH, cAMP, or intracellular Ca2+. NEFA inhibit steroidogenesis at one of the steps preceding conversion of cholesterol to pregnenolone."

Nonesterified fatty acids modulate steroidogenesis in mouse Leydig cells | Endocrinology and Metabolism

 

[ecstatichamster]

great find...it's in vitro but still looks like it does provide further evidence for PUFAs inhibiting important metabolic functions, this time testosterone production.

 

[NathanK]

Interesting. It is essentially says that NEFA and triglycerides, promoted largely by PUFA, can promote non structurally damaged primary hypogonadism. Will read full text when i get home.

Ironically, its been said smoking increases testosterone and in "Similar Articles" on side bar:
Nicotine and cotinine inhibit steroidogenesis in mouse Leydig cells
Nicotine and cotinine inhibit steroidogenesis in mouse Leydig cells. - PubMed - NCBI
"...These results suggest that nicotine and cotinine either affect intracellular calcium content or block the effects of calcium on steroidogenesis in mouse Leydig cells."

 

[tara]

It is essentially says that NEFA and triglycerides, promoted largely by PUFA

"Oleic acid was a more potent inhibitor than linoleic, stearic, or palmitic acids."

Isn't this saying that oleic MUFA inhibited steroidogenesis more than linoleic PUFA (or stearic and plamitic SFAs)?

 

[NathanK]

Isn't this saying that oleic MUFA inhibited steroidogenesis more than linoleic PUFA (or stearic and plamitic SFAs)?

It does! I think I read hamster's post and was more focused on the FA part. Thanks for catching that. It'll be an interesting read to see what they did here

 

[NathanK]

Interesting study from 1989 and unfortunately in vitro as Hamster pointed out. They didn't discern much the difference between NEFA and TG as I had hoped, but this study makes a case for not fasting or eating a high fat diet for male steroidogenesis. This is contrary to the intermittent fasting ketogenic crowd that praise high fat for hormone production. Regardless of what fat you are eating, excessive FFA is detrimental as Ray makes clear.

The one exception to fats. All fats lowered testosterone (even SFA stearic acid modestly) with the exception of palmitic acid which increased T production up to 40%! That's remarkable. Palmitic acid, commonly found in coconut oil, is what our body converts extra carbohydrates into endogenously. So there's the case for high carb over high fat.

"...Diet is one environmental factor associated with alterations of sex hormone levels in men. In male identical twins, the twin with the highest fat intake has the lowest testosterone levels (3). Dietary fat (3, 29), obesity (7, 20, 30), diabetes mellitus (8, 24), fasting (14), and aging (2) are all associated with a reduction in plasma testosterone concentrations and result in elevation of either nonesterified fatty acids (NEFA) or triglycerides or both. Fasting decreases plasma testosterone without a reduction in LH, suggesting possible resistance of the Leydig cells to the effects of LH (14). This indicates that blood triglycerides and NEFA may contribute to alterations of sex hormones observed in these clinical situations or disorders. In support of an effect of dietary lipids on testosterone production by Leydig cells, Sebokova et al. (31) observed terone production in the linoleic acid. a reduction in in vitro testostestes of rats..."

"...A high ratio of carbohydrate to protein elevates testosterone and sex hormone-binding globulin (SHBG), whereas reversing the ratio lowers both testosterone and SHBG..."

"Steroidogenesis in Leydig cells is regulated by luteinizing hormone (LH) (6, 28), but many factors, including Ca2+ (32), metabolites of arachidonic acid (4), and adenosine 3’5’-cyclic monophosphate (CAMP) (6, 28) affect the response to LH."

After a meal with fat, triglycerides derived from the diet could result in elevated NEFA in tissues in preparation for storage as tissue triglycerides, whereas in the fasting state the NEFA would be released from tissue stores as a reflection of the NEFA derived from previous meals and endogenous synthesis. These changes in NEFA associated with diet could affect control of steroidogenesis regulated by LH...."

"Reversibility of NEFA effects on Leydig cells. When Leydig cells were incubated for 2 h in the presence of NEFA and LH, washed, and then incubated in basal media with LH and without NEFA, there was reversal of inhibition during the next 2 h of incubation"

"NEFA might either modify activity of enzymes involved in steroidogenesis or alter the binding of LH to its specific receptor...."

"Our results suggest that fatty acids either affect intracellular Ca2+ concentrations or action and thereby modulate steroidogenesis in response to LH. Verapamil is a Ca2+ channel blocker that inhibits testosterone production... Verapamil enhanced the inhibition of testosterone production produced by the mixture of fatty acids. This suggests that the mixture of fatty acids might reduce extracellular Ca2+ entry in response to LH."

"In addition to effects on Ca2+ metabolism or action, NEFA could influence enzyme activity. Activities of some key enzymes are affected by fatty acids (22,23,26). The fatty acids could alter testosterone production by Leydig cells by modifying the activity of a key enzyme involved in steroidogenesis...."

"Hydroxylase and lyase enzymes of the testosterone synthesis pathway require cytochrome P450 (9). The conversion of cholesterol to pregnenolone is catalyzed by cytochrome P 450 in three steps, 22. and 20-hydroxylases and a C-20-22 lyase. 17-Hydroxylase and 17,20-lyase also utilize this cytochrome system in the microsomes. Our observation that the inhibitory effect of NEFA is partially reversed by 22( R)-hydroxycholesterol suggests that their major effect on steroidogenesis is before utilization of the P 450 cytochrome systems (except for 22- hydroxylation)."