Subject: Do GLP-1s Kill Your Testosterone?
From: Derek from Research Radar <[email-masked]>
To: [email-masked]
Date: Tue, 28 Apr 2026 14:43:24 +0000
List-Id: <derekpruski.substack.com>

View this post on the web at https://derekpruski.substack.com/p/do-glp-1s-kill-your-testosterone

Got a great question in the inbox this week that deserves a full walkthrough. The framing was something like: “My RS is on a heavy weight-loss compound, lost a ton of weight, and now reports profound lethargy and zero libido. Is this anhedonia, or is testosterone actually crashing from the metabolic burn?”
The short answer is: it depends on how much weight loss, how fast, and from what starting point. The same class of compounds can either fix low testosterone or tank it, depending on where on the curve your RS is sitting. This is one of the most misunderstood topics in the community right now, so let’s walk through it from the ground up.
Section 1: The basics — how testosterone is actually made
Before we touch any compound, you need to understand the system that produces testosterone. It’s a three-step relay called the HPG axis (hypothalamic-pituitary-gonadal axis):
Hypothalamus (a region of the brain) releases GnRH in pulses
Pituitary gland responds by releasing LH and FSH into the bloodstream
Testes respond to LH by producing testosterone in the Leydig cells
Each step depends on the one before it. If the hypothalamus stops pulsing, the pituitary stops releasing LH, and the testes stop making testosterone. The signal flows downhill.
Two more concepts that matter for everything that follows:
SHBG (sex hormone binding globulin) is a protein that binds testosterone in the blood. Bound testosterone is biologically inactive. Only free testosterone does anything in your tissues.
Aromatase is an enzyme found heavily in body fat that converts testosterone into estrogen. More body fat = more aromatase = more testosterone getting siphoned into estrogen.
Keep these in mind. They show up everywhere.
Section 2: Why obese men have low testosterone in the first place
Here’s the baseline most RS in this space are starting from. Obesity is a known driver of functional hypogonadism (low T not caused by a structural problem with the testes or pituitary). Three reasons:
Aromatase overload. Excess body fat means more aromatase, which converts more testosterone into estrogen. The estrogen then signals back to the hypothalamus to slow GnRH release, suppressing the whole axis from the top.
Insulin resistance. Impairs Leydig cell function and HPG signaling.
Chronic inflammation. Adipose tissue releases inflammatory cytokines that further suppress the axis.
This is the population the GLP-1 trials are studying. So the starting line for these studies is already low T, and the question becomes: does the compound make it better or worse?
Section 3: The data — what GLP-1s actually do to testosterone
This is where it gets interesting, because the answer flips depending on dose, magnitude of weight loss, and how aggressive the deficit is.
At moderate weight loss (~10-15%): testosterone goes UP
Multiple studies in obese men show that GLP-1 therapy at standard doses raises testosterone:
2025 EHR analysis (110 men, 18 months, semaglutide/tirzepatide/dulaglutide): Patients lost ~10% body weight. The proportion with normal total and free testosterone went from 53% to 77%. Average total T rose by 18%.
2024 Slovenian RCT (semaglutide vs TRT in obese diabetic men with hypogonadism): 6.5% weight loss in the semaglutide group produced a 1.6 nmol/L increase in total testosterone. Semaglutide was actually superior to TRT for body composition and matched TRT on total T improvement.
2025 Italian pilot study (tirzepatide vs TRT vs lifestyle, 83 obese hypogonadal men, 8 weeks): Tirzepatide produced larger increases in free and total testosterone than transdermal TRT, plus better body composition and erectile function. The lead author called it a candidate for “first-line management” of metabolic hypogonadism.
The mechanism is exactly what you’d predict from Section 2: less fat = less aromatase = less testosterone-to-estrogen conversion = the HPG axis comes back online. Better insulin sensitivity and lower inflammation amplify the effect.
So at moderate doses producing moderate loss in obese men, GLP-1s and dual-agonists fix low testosterone. They don’t kill it.
At aggressive weight loss (20%+): the curve flips
This is where most of the community confusion comes from. The benefit-to-cost ratio inverts at the high end.
The triple-agonist class (Peptide-R) is producing weight loss in a different league than its predecessors:
Semaglutide: ~15% loss at 68 weeks (STEP 1)
Tirzepatide: ~21% loss at 72 weeks (SURMOUNT-1)
Peptide-R (triple-agonist): ~24% at 48 weeks (phase 2), and 28.7% at 68 weeks in the recent phase 3 TRIUMPH-4 readout. Placebo-adjusted: 26.6%.
Once weight loss gets that aggressive, you’re no longer just dropping fat — you’re forcing the body into sustained caloric deficit territory that the HPG axis interprets as famine. And the famine response is well-documented:
US Army Ranger course (8 weeks, ~2,200 kcal/day, heavy exercise): total testosterone dropped 70-80%. SHBG rose 46-60%. Recovery took ~6 weeks after the course ended.
US Marines in SERE training (7 days, ~300 kcal/day, ~85% deficit): mean testosterone fell from 17.5 nmol/L to 9.8 nmol/L. The Marines who landed in the low-T group lost significantly more lean body mass than those who maintained T.
3-week experimental caloric restriction in healthy men: testosterone dropped 2.8 nmol/L, fully reversible by refeeding.
2019 case series in Clinical Endocrinology: 23 men with reversible hypogonadism driven purely by energy deficit. Median total testosterone: 3.0 nmol/L (~86 ng/dL). 91% showed the central (low-LH) suppression pattern.
The mechanism: severe energy deficit raises cortisol and reduces hypothalamic GnRH pulse frequency. Less GnRH means less LH, which means less testosterone. The body is choosing survival over reproduction.
Now overlay this on a triple-agonist producing 25%+ body weight loss. If your RS is already at a relatively healthy body fat percentage and pushing further, or running aggressive doses with deep appetite suppression, they’re sitting in famine-physiology territory. The HPG axis crashes accordingly.
The U-curve
This is the simplest way to think about it:
Starting obese, moderate loss → testosterone improves (fat-loss benefit dominates)
Starting obese, aggressive loss past necessary → testosterone starts to suppress (deficit penalty starts to bite)
Starting lean, any meaningful loss → testosterone suppresses (no aromatase benefit to harvest, just deficit)
The original question — RS reporting profound lethargy and libido loss on a heavy compound — almost always means they’ve crossed the inflection point.
Section 4: The total T vs. free T trap
Worth flagging because it trips up a lot of RS pulling labs.
Energy deficit consistently raises SHBG. The Ranger and Marine studies show 20-60% increases. So even if total testosterone looks “fine” on paper, free testosterone — the active fraction — can be dramatically lower because more of the total is bound up.
If your RS pulls labs and only checks total T, the picture looks better than it is. Always pull total T, free T, and SHBG together. Otherwise you’re guessing.
Section 5: Why it’s not just hormones — the libido layer
One more piece, because this is where RS often misdiagnose what’s happening to them.
GLP-1 receptors are expressed in the VTA and project into the nucleus accumbens — the brain’s dopamine reward circuit. Chronic GLP-1 activation blunts phasic dopamine bursts across all rewards, not just food. Sex, music, social connection, achievement — all run through the same dopaminergic pathways.
So even if testosterone were perfectly normal, an RS on a GLP-1 class compound would still likely report flattened libido and motivation. In practice, low T and dopamine blunting hit at the same time and look identical from the outside. This is why just stacking exogenous testosterone often doesn’t fully resolve the symptoms in this population — you’re treating one of two overlapping problems.
Section 6: Compounding factors that make it worse
A few things that consistently make the testosterone picture worse than the deficit alone would predict:
Micronutrient depletion. Severe appetite suppression often means undereating zinc, magnesium, vitamin D, and protein — all required for testosterone synthesis. Zinc is specifically required for SHBG conformation and is a direct cofactor in steroidogenesis. Low zinc + high SHBG = double hit on free T.
Cortisol elevation. The HPA and HPG axes are reciprocally inhibitory. Sustained energy deficit elevates cortisol, which independently suppresses GnRH release. Cortisol up, testosterone down.
Sleep disruption. GI side effects, dose titration, and rapid body composition change all hit sleep architecture. Most testosterone production happens during REM. Bad sleep compounds the suppression.
Section 7: Protocol logic to consider (research framing)
Where the right approach lands depends entirely on which side of the U-curve your RS is on.
Important caveat: I’m not a clinician. None of this is medical advice. Anyone running these compounds in any human capacity should be working with a clinician monitoring full labs (total T, free T, LH, FSH, SHBG, estradiol, prolactin, fasting insulin, cortisol, full thyroid panel).
If your RS is obese and on a moderate dose
The data suggests testosterone will likely improve as weight comes off. The intervention is mostly hands-off: stay the course, support with adequate protein and micronutrients, monitor labs. Don’t reflexively add testosterone — for many men in this category, the GLP-1 itself is doing the testosterone work better than TRT would.
If your RS is on a heavy compound (high-dose tirzepatide, Peptide-R, or anyone past the inflection point)
First lever: address the deficit itself. Most RS dosing aggressive compounds are running deeper deficits than necessary because appetite suppression is so strong they lose track of intake. The Ranger and Marine data shows full reversibility within ~6 weeks of energy restoration. A structured 1.6-2.2 g/kg protein floor and adequate total kcal often partially restores HPG axis function on its own.
Second-line considerations from research literature:
Peptide-K (kisspeptin-10). Top-down stimulation at the hypothalamus, prompting endogenous GnRH pulsatility. Logical match for central suppression because it acts upstream of the bottleneck.
Gonadorelin. GnRH analog — pituitary-level support. Some community protocols stack this with kisspeptin to hit two levels of the axis.
Enclomiphene. SERM (small molecule, not a peptide — flagging that explicitly) that blocks estrogen negative feedback at the pituitary, which increases endogenous LH/FSH output.
Micronutrient floor: zinc, magnesium, vitamin D, adequate dietary fat. Foundational, not optional.
The argument against stacking TRT or hCG concurrently with an active heavy compound is that you’re masking a signal. The HPG suppression is information about how aggressive the deficit is. Adding exogenous testosterone doesn’t fix the cortisol elevation, the micronutrient depletion, or the reward circuit blunting — it just smooths over the lab values while the upstream pressure stays intact.
If your RS is coming off
Standard washout logic applies. The 2019 case series showed gonadal recovery within ~6 weeks of energy restoration. That matches our broader washout philosophy: full 4-6+ weeks off before considering bridge protocols, eating at maintenance, sleep dialed in, training volume normalized.
If labs at the 6-week mark still show suppression, then the kisspeptin / gonadorelin / enclomiphene logic comes in for a structured restart.
What I’d avoid: bridging directly from one heavy compound into another targeting the same metabolic receptors, or stacking exogenous testosterone without a clear plan to either commit to lifelong supplementation or run a proper restart.
Section 8: The bottom line
Do GLP-1s kill your testosterone? Not in the way most people think.
At moderate doses producing moderate weight loss in obese men, GLP-1s and dual-agonists actually raise testosterone — sometimes outperforming TRT itself for body composition and matching it on T levels. The fat-loss benefit (less aromatase, better insulin sensitivity, less inflammation) overwhelms the deficit penalty.
But push the same class harder — high doses, the new triple-agonists, aggressive sustained deficits, lean starting points — and the curve flips. Once you cross into famine physiology, the HPG axis suppresses centrally, SHBG rises, free T drops, and the dopamine reward circuit blunts on top. That’s the picture the original question described.
Action items for any RS feeling the crash:
Pull a full panel. Total T, free T, LH, FSH, SHBG, estradiol, prolactin, cortisol. Without this you’re guessing.
Audit intake honestly. Most RS on heavy compounds are eating less than they think. The appetite suppression is doing more than fat loss — it’s driving the HPG suppression.
Locate yourself on the U-curve. Obese with 10% loss? Probably trending up. Already lean and pushing harder? You’ve crossed the inflection.
Don’t reflexively stack TRT. It masks the upstream signal and leaves the metabolic stress in place.
Decide the path. Continue and support, or wash out and restart. Drifting with no plan is what creates problems.
Got data, lab work, or protocol experience to share on this? Drop it in the comments. The formal literature on triple-agonists and testosterone is still thin because the compound is new — what’s emerging is a pattern, and community-level data points make the picture clearer.
For research subjects only. Nothing in this post is medical advice or a recommendation for human use.

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