Admittedly the last thing we need is some other nebulous danger to worry about that may not even exist. Read on at your peril.
TL;DR: Testosterone replacement therapy suppresses the production of GnRH. Receptors for GnRH are found in places besides the pituitary. One animal model suggests GnRH may have health benefits independent of its stimulation of LH and FSH production.
The background: Gonadotropin-releasing hormone, or GnRH, is the signal the hypothalamus uses to tell the pituitary gland to secrete luteinizing hormone and follicle stimulating hormone. Luteinizing hormone (LH) signals the gonads to make testosterone. In turn, testosterone and its metabolite estradiol tell the hypothalamus to reduce GnRH production. This is how testosterone is regulated in normal males, via the so-called HPT axis.
The problem: With testosterone replacement therapy we disrupt the normal regulation of the HPTA, suppressing GnRH, LH and FSH. Lack of FSH seems to affect mainly sperm production, and when needed FSH can be taken directly or in the form of HMG. When testosterone is delivered exogenously, the necessity of LH is debatable. There are numerous LH receptors in the body whose function and importance are not well understood. We simply don’t know if shutting down this signaling is a problem. Enter hCG. HCG is an LH analog, meaning it functions very similarly in the body, at least with regard to activating LH receptors. Many men use hCG along with TRT to reduce testicular atrophy. Some report subjective benefits, including better libido and mood. Others are unable to tolerate hCG at all.
The preceding is quite familiar to most TRT veterans. But GnRH is usually ignored in all this, perhaps due to an underlying assumption that it’s not used for anything beyond signaling the pituitary. But is this the case? Maybe not. “The detection of GnRH and its receptor in other tissues, including the breast, ovary, endometrium, placenta and prostate suggested that GnRH agonists and antagonists may also have direct actions at peripheral targets.”[1] Furthermore: “Multiple lines of evidence indicate that the expression of extrapituitary GnRH receptor is not limited to reproductive tissues. For instance, it has been demonstrated by RT-PCR and Southern blot hybridization that the receptor is also expressed in the liver, heart, skeletal muscle, kidney, and peripheral blood mononuclear cells.”[2]
What we see with GnRH is analogous to the situation with LH: receptors in many places and uncertainty as to their importance to our health.
If we look at some research on mice there are tantalizing links between GnRH and aging [3]:
TL;DR: Testosterone replacement therapy suppresses the production of GnRH. Receptors for GnRH are found in places besides the pituitary. One animal model suggests GnRH may have health benefits independent of its stimulation of LH and FSH production.
The background: Gonadotropin-releasing hormone, or GnRH, is the signal the hypothalamus uses to tell the pituitary gland to secrete luteinizing hormone and follicle stimulating hormone. Luteinizing hormone (LH) signals the gonads to make testosterone. In turn, testosterone and its metabolite estradiol tell the hypothalamus to reduce GnRH production. This is how testosterone is regulated in normal males, via the so-called HPT axis.
The problem: With testosterone replacement therapy we disrupt the normal regulation of the HPTA, suppressing GnRH, LH and FSH. Lack of FSH seems to affect mainly sperm production, and when needed FSH can be taken directly or in the form of HMG. When testosterone is delivered exogenously, the necessity of LH is debatable. There are numerous LH receptors in the body whose function and importance are not well understood. We simply don’t know if shutting down this signaling is a problem. Enter hCG. HCG is an LH analog, meaning it functions very similarly in the body, at least with regard to activating LH receptors. Many men use hCG along with TRT to reduce testicular atrophy. Some report subjective benefits, including better libido and mood. Others are unable to tolerate hCG at all.
The preceding is quite familiar to most TRT veterans. But GnRH is usually ignored in all this, perhaps due to an underlying assumption that it’s not used for anything beyond signaling the pituitary. But is this the case? Maybe not. “The detection of GnRH and its receptor in other tissues, including the breast, ovary, endometrium, placenta and prostate suggested that GnRH agonists and antagonists may also have direct actions at peripheral targets.”[1] Furthermore: “Multiple lines of evidence indicate that the expression of extrapituitary GnRH receptor is not limited to reproductive tissues. For instance, it has been demonstrated by RT-PCR and Southern blot hybridization that the receptor is also expressed in the liver, heart, skeletal muscle, kidney, and peripheral blood mononuclear cells.”[2]
What we see with GnRH is analogous to the situation with LH: receptors in many places and uncertainty as to their importance to our health.
If we look at some research on mice there are tantalizing links between GnRH and aging [3]:
GnRH treatment prevents aging-impaired neurogenesis
Based on the known role of GnRH in regulating sex hormones, GnRH changes in our mouse models might correlate with changes in sex hormones, and this prediction was proved ... However, a sex hormone may not be a primary mediator for aging phenotypes in our models, since hypothalamic IKKβ/NF-κB is important for aging in both sexes. This context provoked us to hypothesize that GnRH works as a primary mediator independently of a specific sex hormone. To explore if GnRH exerts intra-brain actions to affect aging, we delivered GnRH into hypothalamic third-ventricle of old mice, and examined aging-related changes in brain cell biology. A striking observation was that GnRH promoted adult neurogenesis despite aging. Using 7-day BrdU tracking to report neurogenesis12, we found that aging is characterized by diminished neurogenesis particularly in the hypothalamus and the hippocampus; however, this defect was substantially reversed by GnRH treatment. …
Then they see if they can get similar results with normal injections.GnRH therapy decelerates aging development
Finally, to study if GnRH could affect aging, we subjected old MBH-IKKβ mice and MBH- Con described in Fig. 2 to daily GnRH therapy for a prolonged period, and then examined their aging physiology and histology. As we were also interested in testing if GnRH could act peripherally to affect aging, we treated mice with GnRH via peripheral injections. Excitingly, GnRH treatment reduced the magnitude of aging histology in control mice and abrogated the pro-aging phenotype in MBH-IKKβ mice (Fig. 6f–h). Interestingly, despite the peripheral administration, GnRH led to an amelioration of aging-related cognitive decline (Fig. 6i, suppl. Fig. 11). Thus, prolonged elevation of systemic GnRH can cumulatively yield actions on the brain; despite the mechanism remains to be studied, some GnRH-responsive brain regions outside of the blood-brain barrier, such as the median eminence, subfornical organ and area postrema, can have access to peripheral delivered GnRH. These effects of GnRH were not specific to a sex, as similar outcomes were shown in male (Fig. 6f–i, suppl. Fig. 11) and females (suppl. Fig. 12)
What does it mean? Well if you’re an old mouse then it looks like GnRH therapy could be worthwhile. What about humans? Particularly the ones who have artificially suppressed their GnRH production? I don’t have an answer to that. What might we do? If you don’t mind experimenting on yourself, then—under a doctor’s supervision—you might obtain some GnRH, readily available as gonadorelin, and inject yourself with 5-10 mcg one or more times a day. Is this advisable? I have no idea. This post is meant to stimulate discussion and further reviews of the literature, not to encourage self-treatment.
Last edited:
