Advice on next steps - mid-low free T

[Forty2]

It sounds reasonable, and might be helpful in some cases.

I'm going to give it a try in about a weeks time. 250iu/day hCG with 5 drops of 10% DHT.
BTW the experiment I did with 150 iu hCG eod was a failure. It completely suppressed my LH and lowered my testosterone further.

 

[Cataceous]

... However, studies of men on TRT with suppressed GnRH do not show higher rates of dementia, nor do they show higher rates of all cause mortality. If the lack of GnRH is having negative effects then, it's either too subtle to affect health outcomes, or it's being overpowered by the benefits of testosterone.
...

Which studies evaluated the rates of dementia? Healthy controls or just untreated hypogonadal subjects? What's needed to answer this question more definitively is a study with large N that has matched eugonadal men as controls. The study needs to last long enough and/or have old enough subjects such that the prevalence of dementia is high enough to observe any differences.

 

[Cataceous]

What are the additional functions of GnRH?
Do you know if LH does anything more than just stimulate the leydig cells?

As noted, GnRH may play a role in adult neurogenesis. Also in the post I linked to:

”[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]​

It's a similar story with LH. Wikipedia says:

Luteinizing hormone receptors are located in areas of the brain associated with cognitive function. The role of LH role in the central nervous system (CNS) may be of relevance to understanding and treating post-menopausal cognitive decline.​

​

Some research has observed an inverse relationship between circulating LH and CNS LH levels. After ovariectomy (a procedure used to mimic menopause) in female mice, circulating LH levels surge while CNS levels of LH fall. Treatments that lower circulating LH restore LH levels in the CNS.​

This suggests men may want to avoid high levels of hCG for long periods. Also:

LHCGR [luteinizing hormone/choriogonadotropin receptors] have been found in many types of extragonadal tissues, and the physiologic role of some has remained largely unexplored. Thus receptors have been found in the uterus, sperm, seminal vesicles, prostate, skin, breast, adrenals, thyroid, neural retina, neuroendocrine cells, and (rat) brain.​

There are still things to be learned about these hormones, which is why I have misgivings about suppressing them indefinitely.

 

[metflex]

In the kyzatrex trial I mentioned, they started at 7 ng/dL free T and increased by 7 ng/dL to 14 ng/dL with the 200 mg bid dose. I would be looking to create a dramatic difference from your 10 ng/dL baseline with this experiment to ensure the results are noticeable, and targeting something more like 20 ng/dL free T. I'm not sure where your personal comfort zone is with levels, but bear in mind we're measuring this at peak with oral T, while many doing well on injectable TRT are troughing significantly higher than that.

Good stats to know. And my assumption is that you'd keep an eye on TT but more so base decisions on symptoms and free T levels getting them into the upper quartile? It's interesting that we measure T levels on Kyzatrex at it's peak but don't necessarily do that will all T forms.

 

[FunkOdyssey]

Which studies evaluated the rates of dementia? Healthy controls or just untreated hypogonadal subjects? What's needed to answer this question more definitively is a study with large N that has matched eugonadal men as controls. The study needs to last long enough and/or have old enough subjects such that the prevalence of dementia is high enough to observe any differences.

The following review discusses the findings of over 20 studies that investigated the effects of TRT on cognition, in both healthy men, and men with Alzheimer's or other forms of cognitive decline. We might expect worsened cognition if the lack of GnRH is impactful, or an acceleration of cognitive decline in men who begin with dementia. Instead, except for a single outlier, these studies uniformly show TRT has either neutral or positive effects on cognition:

Testosterone, cognitive decline and dementia in ageing men - PMC

As men grow older, circulating testosterone concentrations decline, while prevalence of cognitive impairment and dementia increase. Epidemiological studies of middle-aged and older men have demonstrated associations of lower testosterone ...

pmc.ncbi.nlm.nih.gov

Besides the puberty angle, which suggested longer lifetime exposure to GnRH is not helpful in any measurable way, androgen deprivation therapy is another useful model to tease apart the contributions of GnRH and testosterone to cognitive health. ADT is relevant here because the most common medications used are long-acting GnRH agonists, which have shown neuroprotective, neuroregenerative, and anti-inflammatory effects in animal models, just like natural GnRH.

https://www.nel.edu/userfiles/articlesnew/1726422092_45_3_baca-alonso_188-pdf.pdf

Leuprolide acetate (LA) is a synthetic form of GnRH, acting as an agonist by emulating the natural hormone function and transiently stimulating gonadotropin hormone excretion (Wilson et al. 2006). It differs from natural GnRH in its reduced susceptibility to degradation, granting it a longer-lasting effect. LA has been utilized for treating various nervous system conditions as pituitary apoplexy and spinal and bulbar atrophy, enhancing the perceived neuroregenerative and neuroprotective role of GnRH (Sasagawa et al. 2015; Suzuki et al. 2012).

Numerous studies have explored the neuroregenerative potential of leuprolide acetate. For example further investigations focused on spinal cord injury regeneration in rats, revealing structural and functional recovery through LA treatment as evidenced by gait analysis and spinal cord histology (Díaz-Galindo et al. 2015). Another study targeted spinal cord inflammation using an autoimmune encephalomyelitis model in rats, showing a significant reduction in NF-κB and proinflammatory cytokine markers IL-1β, IL-17A, and TNF-α (Guzmán-Soto et al. 2016). In 2018, a clinical trial administered 6 months of LA treatment to human 194 patients with spinal cord injury, resulting in substantial improvements in sensory function, motor activity, and independence (Quintanar et al. 2018). Additionally, in the same year, LA treatment led to the recovery of urination in a rat model of spinal cord injury, reinforcing its efficacy in functional recovery (MedinaAguiñaga et al. 2018). Furthermore, an article two years later demonstrated the positive effects of LA treatment on anal sphincter recovery in spinal cord injury in rats (Altamira-Camacho et al. 2020).

LA has also been used to treat significant disorders in the peripheral nervous system. In 2020, researchers investigated its effects on the peripheral nervous system using an animal model of complete sciatic nerve transection, confirming its ability to enhance nerve functionality and integrity post-injury (HernándezJasso et al. 2020). Moreover, improvements in electrical conductivity were reported in a glaucoma model in rats, with electroretinograms showing enhanced signals for the LA-treated groups (Esparza-Leal et al. 2023). In a recent study, LA administered to rats with neonatal hypoxic-ischemic injury resulted in a reduction of inflammatory markers and anxious behavior (Pedroza-García et al. 2023).

While LA is the most renowned GnRH analogue, other analogues are also under neuroscientific research. Triptorelin has been used to treat neurofibromatosis and/or optic glioma in case reports, demonstrating efficacy in suppressing gonadotropin and sex steroid levels and reducing neurofibromatosis manifestations (Kocova et al. 2015; Laue et al. 1985). Buserelin has shown potential as a treatment for cyclical sciatica in women and has been associated with adverse effects on enteric neuropathy (Sand et al. 2014; Takata & Takahashi, 1994). Goserelin has been explored in treating optic glioma and enhancing cognitive ability in a sheep model (Nuruddin et al. 2013).

What happens when you have robust neuroprotective GnRH signaling, and no testosterone? Increased risk of all-cause dementia:

Unraveling the bidirectional link between cancer and dementia and the impact of cancer therapies on dementia risk: A systematic review and meta‐analysis - PMC

Observational studies on the cancer–dementia relationship have yielded controversial results. This study systematically reviews the evidence to clarify this association. We searched Embase, Global Health, Ovid Medline, and APA PsycInfo. Colorectal ...

pmc.ncbi.nlm.nih.gov

Notably, the pooled RR showed that cancer patients who received androgen deprivation therapy (ADT) had a significantly 1.26‐fold higher risk of ACD compared to those who did not (RR 1.26 [1.07–1.47], P = 0.005). No significant risk change was noted for tamoxifen or other endocrine therapy methods. In addition, Figures S5 and S6 in supporting information show a significant increase in the risk of AD among cancer patients who received ADT (RR 1.09 [1.02–1.16], P = 0.015) and a significant decrease in the risk of AD among cancer patients receiving tamoxifen or chemotherapy (Tamoxifen: RR 0.79 [0.70–0.89], P < 0.001; Chemotherapy: RR 0.82 [0.68–0.98], P = 0.031). However, no significant association was observed with other endocrine therapies or radiotherapy.

While it seems likely that both GnRH and testosterone play some role in brain health, if you have to pick healthy levels of just one, testosterone is clearly far more important.

 

[FunkOdyssey]

Good stats to know. And my assumption is that you'd keep an eye on TT but more so base decisions on symptoms and free T levels getting them into the upper quartile? It's interesting that we measure T levels on Kyzatrex at it's peak but don't necessarily do that will all T forms.

In my opinion, it's more helpful to think about specific target levels, independent of reference ranges, which vary widely from lab to lab. You'll test total testosterone, and you'll need it (together with SHBG) to calculate free testosterone, but free testosterone is where the rubber meets the road with regard to biological effects of testosterone. Total testosterone is less meaningful, and correlates with symptoms only to the extent that it serves as a surrogate marker for free testosterone.

We need to test peak levels on oral testosterone to quantify its impact, because at other times of day, your levels will likely be around baseline, or below, depending on which form of oral testosterone you choose and how many times per day you take it.