Negative Feedback Mechanism of steroids on Gonadotropin Releasing Hormone
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The standard picture of the HPTA in males is: Hypothalamus releases GnRH, which induces the pituitary to release LH and FSH, which induces the leydig cells in the tests to produce testosterone.
Now, I want to get clear on what the negative feedback mechanism is between the hypothalamus and sex hormones.
I am well aware that there are other signals the triggering of which will induce a negative feedback mechanism on the hypothalamus, such as decreased dopamine levels, increased CRH levels, increased leptin levels, and so on. I am for my present purpose not interested in those processes.
From some surface level research, it seems as though the primary negative feedback mechanism is with estrogen, as regards the negative feedback mechanism the hypothalamus has with sex hormones. So, in men this would presumably be with estradiol (E2).
Although, there is some discussion of how very high androgen levels can also have a negative feedback mechanism with the hypothalamus.
So, how exactly does the hypothalamus detect this estradiol? Are there estrogen receptors in the specialized neurons in the hypothalamus the binding of which constitutes the negative feedback mechanism?
And (assuming there is a negative feedback mechanism with androgens, which I think is probably true at a sufficiently high level of androgens), how exactly does that work? Are there androgen receptors in some of the neurons in the hypothalamus that when activated decrease the output of GnRH?
I ask because depending on what the mechanism is, it might be interesting to design a drug that influences the binding of androgens or estrogens to these receptors in the hypothalamus, which could potentially increase the "natural" testosterone levels (i.e the testosterone produced by the testicles)
Drugs that limit estrogen synthesis like exemestane are known to work on this mechanism, but I want to know what the full story is.
